69566 Federal Register / Vol. 79, No. 225 / Friday, November 21, 2014 / Proposed Rules 

DEPARTMENT OF HEALTH AND 

HUMAN SERVICES 

42 CFR Part 11 

[Docket Number NIH–2011–0003] 

RIN 0925–AA52 

Clinical Trials Registration and Results 

Submission 

AGENCY: National Institutes of Health, 

Department of Health and Human 

Services. 

ACTION: Notice of Proposed Rulemaking. 

SUMMARY: This Notice of Proposed 

Rulemaking proposes requirements for 

submitting registration and summary 

results information, including adverse 

event information, for specified clinical 

trials of drugs (including biological 

products) and devices and for pediatric 

postmarket surveillances of a device to 

ClinicalTrials.gov, the clinical trial 

registry and results data bank operated 

by the National Library of Medicine 

(NLM). This proposed rule provides for 

the expanded registry and results data 

bank specified in Title VIII of the Food 

and Drug Administration Amendments 

Act of 2007 (FDAAA) to enhance patient 

enrollment, provide a mechanism to 

track subsequent progress of clinical 

trials, provide more complete results 

information, and enhance patient access 

to and understanding of the results of 

clinical trials. The proposed 

requirements would apply to the 

responsible party (meaning the sponsor 

or designated principal investigator) for 

certain clinical trials of drugs (including 

biological products) and devices that are 

regulated by the Food and Drug 

Administration (FDA) and for pediatric 

postmarket surveillances of a device 

that are ordered by FDA. 

DATES: Comments are due on or before 

February 19, 2015. 

ADDRESSES: Individuals and 

organizations interested in submitting 

comments, identified by RIN 0925– 

AA52 and Docket Number NIH–2011– 

0003, may do so by any of the following 

methods: 

• Electronic Submissions: Use 

Federal eRulemaking Portal: http://

www.regulations.gov. Follow the 

instructions for submitting comments. 

To ensure timelier processing of 

comments, NIH is no longer accepting 

comments submitted directly to it by 

email. The NIH encourages you to 

continue to submit electronic comments 

by using the Federal eRulemaking 

Portal: http://www.regulations.gov. 

• Written Submissions: You may 

submit written submissions by Fax at 

301–402–0169, or by Mail/Hand 

Delivery/Courier (For paper, disk, or 

CD–ROM submissions) to: Jerry Moore, 

NIH Regulations Officer, Office of 

Management Assessment, 6011 

Executive Boulevard, Suite 601, MSC 

7669, Rockville, MD 20852–7669. 

Instructions: We welcome comments 

from the public on all issues set forth in 

this proposed rule, and on specific 

issues identified in the document. All 

submissions received must include the 

agency name, the Docket No., and 

Regulatory Information Number (RIN) 

for this rulemaking. All comments 

received at http://www.regulations.gov 

may be posted without change, 

including any personal information 

provided. The http://

www.regulations.gov Web site is an 

‘‘anonymous access’’ system, which 

means NIH will not know your identity 

or contact information unless you 

provide it in the body of your comment. 

You can assist us in considering your 

comment by referencing the number 

assigned to each key issue discussed in 

section III.C of this preamble or the 

number of the section of this proposed 

rule to which your comment relates. 

For access to background documents 

or comments received, go to http://

www.regulations.gov and insert the 

docket number found in the brackets in 

the heading of this document into the 

‘‘Search’’ box and follow the prompts. 

FOR FURTHER INFORMATION CONTACT: 

Regulatory Process: Jerry Moore, NIH 

Regulations Officer, Office of 

Management Assessment, telephone 

(301–496–4607) (not a toll-free number), 

Fax (301–402–0169), or by email at 

jm40z@nih.gov 

Technical Information: Jerry Sheehan, 

Assistant Director for Policy 

Development, National Library of 

Medicine, National Institutes of Health, 

Department of Health and Human 

Services, telephone (301–496–6221) (not 

a toll-free number), Fax (301–402–2586), 

or by email at sheehanjr@nlm.nih.gov. 

SUPPLEMENTARY INFORMATION: 

Executive Summary 

Purpose of This Regulatory Action 

This proposed rule clarifies and 

expands requirements for the 

submission of clinical trial registration 

and results information to the 

ClinicalTrials.gov database, which is 

operated by the NLM. It implements the 

provisions of section 402(j) of the Public 

Health Service Act (PHS Act) (42 U.S.C. 

282(j)), which were added by FDAAA to 

improve public access to information 

about certain clinical trials of FDAregulated drugs, biological products, 

and devices and certain pediatric 

postmarket surveillances of a device. 

Under section 402(j) of the PHS Act, 

those responsible for specified clinical 

trials of FDA-regulated products have 

been required to submit registration 

information to ClinicalTrials.gov since 

December 26, 2007, summary results 

information for clinical trials of 

approved products since September 27, 

2008, and adverse events information 

since September 27, 2009. Section 402(j) 

of the PHS Act requires the Secretary of 

Health and Human Services (HHS) to 

use rulemaking to expand the 

requirements for submission of 

summary results information, and 

authorizes the Secretary to use 

rulemaking to make other changes in the 

requirements for submission of 

registration and results information. 

This proposed rule does not impose 

requirements on the design or conduct 

of clinical trials or on the data that must 

be collected during clinical trials. 

Instead it specifies how data that were 

collected and analyzed in accordance 

with a clinical trial’s protocol are to be 

submitted to ClinicalTrials.gov. No 

patient-specific data are required to be 

submitted by this proposed rule or by 

the law this proposed rule is intended 

to implement. 

Summary of the Major Provisions of the 

Regulatory Action 

Applicable Clinical Trial 

This proposed rule specifies which 

clinical trials of FDA-regulated drugs, 

biological products, and devices and 

which pediatric postmarket 

surveillances of a device, are applicable 

clinical trials for which information 

must be submitted to ClinicalTrials.gov. 

This proposal specifies an approach for 

determining whether a particular 

clinical trial or study is an applicable 

clinical trial, based on descriptive 

information that would be submitted at 

the time of registration. 

Responsible Party 

This proposed rule specifies that there 

must be one (and only one) responsible 

party for submitting information about 

an applicable clinical trial. The sponsor 

of an applicable clinical trial would be 

considered the responsible party, unless 

and until the sponsor designates a 

qualified principal investigator as the 

responsible party. This proposed rule 

specifies the approach for determining 

who would be considered the sponsor of 

an applicable clinical trial under 

various conditions, what qualifies a 

principal investigator to be designated a 

responsible party by a sponsor, and how 

responsibility reverts to the sponsor if a 

designated principal investigator is 

unable to fulfill the requirement to 

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Federal Register / Vol. 79, No. 225 / Friday, November 21, 2014 / Proposed Rules 69567 

submit information to 

ClinicalTrials.gov. 

Registration 

This proposed rule specifies 

requirements for registering applicable 

clinical trials at ClinicalTrials.gov. It 

would require that the responsible party 

register an applicable clinical trial not 

later than 21 days after enrolling the 

first participant, and it specifies the data 

elements of clinical trial information 

that must be submitted at the time of 

registration. The proposed data 

elements include the descriptive 

information, recruitment information, 

location and contact information, and 

administrative data elements listed in 

section 402(j) of the PHS Act, as well as 

additional data elements that are 

proposed under the Secretary’s 

authority to modify the requirements for 

clinical trial information due at 

registration as long as such 

modifications improve, and do not 

reduce, the clinical trial information 

available to the public in 

ClinicalTrials.gov. We consider the 

proposed additional data elements 

necessary to enable the Agency to 

implement other statutory provisions, 

indicate the status of human subjects 

protection review of the trial, facilitate 

the public’s ability to search and 

retrieve information from 

ClinicalTrials.gov, and help ensure that 

entries are unambiguous. Some of these 

additional data elements were included 

in ClinicalTrials.gov before FDAAA was 

enacted. 

Expanded Access Information 

Section 402(j) of the PHS Act requires 

the submission of information on how 

to obtain expanded access to 

investigational drugs used in applicable 

clinical trials, if the drugs are available 

through expanded access programs to 

patients who are not participating in 

relevant clinical trials. For an applicable 

clinical trial of a drug that is available 

under expanded access, this proposed 

rule would require the submission of a 

separate expanded access record 

containing details about how to obtain 

access to the investigational drug. If an 

expanded access record has already 

been submitted in conjunction with a 

different clinical trial of that same drug, 

the responsible party for the new 

clinical trial could link to the existing 

expanded access record rather than 

create a new one. 

Results Submission 

This proposed rule implements the 

statutory requirement for the 

submission of summary results 

information for applicable clinical trials 

of drugs, biological products, and 

devices that are approved, licensed, or 

cleared by FDA. It also proposes to 

extend the requirement for results 

submission to applicable clinical trials 

of drugs, biological products, and 

devices that are not approved, licensed, 

or cleared by FDA. This proposed rule 

would require the submission of tables 

of data summarizing demographics and 

baseline characteristics of the enrolled 

participants and primary and secondary 

outcomes, including results of any 

scientifically appropriate statistical 

tests. 

In general, this proposed rule would 

require the submission of results not 

later than 1 year after the completion 

date of the clinical trial, which is 

defined as the date of final data 

collection for the primary outcome 

measure studied. Results submission 

could be delayed for up to 2 additional 

years with certification that either an 

unapproved, unlicensed, or uncleared 

product studied in the trial is still under 

development by the manufacturer or 

that approval will be sought for a new 

use of an approved, licensed, or cleared 

product that is being studied in the trial. 

This proposed rule also permits 

responsible parties to request extensions 

to the results submission deadlines for 

‘‘good cause’’. 

Adverse Events 

This proposed rule would require the 

responsible party to submit information 

summarizing the number and frequency 

of adverse events experienced by 

participants enrolled in a clinical trial, 

by arm and organ system. It would 

require submission of two tables of 

information: one summarizing all 

serious adverse events; and another 

summarizing other adverse events that 

occurred with a frequency of 5 percent 

or more in any arm of the clinical trial, 

regardless of whether such adverse 

events were anticipated or 

unanticipated. 

Updates and Other Required 

Information 

This proposed rule would require that 

all submitted information must be 

updated at least annually if there are 

changes to report. More rapid updating 

would be required for several data 

elements to help ensure that users of 

ClinicalTrials.gov have access to 

accurate, up-to-date information about 

important aspects of a clinical trial. This 

proposed rule also requires timely 

corrections to any errors discovered by 

the responsible party or the Agency 

during review of submissions. 

Costs and Benefits 

Based on our cost estimates, this 

regulatory action is not expected to have 

a significant impact on the economy. 

The costs consist primarily of the time 

needed to organize, format, and submit 

to ClinicalTrials.gov information that 

was prepared for or collected during the 

clinical trial (e.g., protocol information 

and clinical trial results). The benefits 

include greater public access to 

information about and evidence from 

applicable clinical trials (and other 

clinical trials) of FDA-regulated drugs, 

biological products, and devices, and 

greater clarity about what is required for 

those who are subject to the legal 

mandate to submit information to 

ClinicalTrials.gov. 

Acronyms 

AHRQ Agency for Healthcare Research and 

Quality 

BLA Biologics License Application 

CBER Center for Biologics Evaluation and 

Research, FDA 

CDC Centers for Disease Control and 

Prevention 

CDER Center for Drug Evaluation and 

Research, FDA 

CDISC Clinical Data Interchange Standards 

Consortium 

CDRH Center for Devices and Radiological 

Health, FDA 

CFR Code of Federal Regulations 

CONSORT Consolidated Standards of 

Reporting Trials 

EMA European Medicines Agency 

EU European Union 

FAQ Frequently Asked Questions 

FDA Food and Drug Administration 

FDAAA Food and Drug Administration 

Amendments Act of 2007 

FDAMA Food and Drug Administration 

Modernization Act of 1997 

FD&C Act Federal Food, Drug, and 

Cosmetic Act 

FOIA Freedom of Information Act 

GCP Good Clinical Practices 

HHS Department of Health and Human 

Services 

ICH International Conference on 

Harmonisation of Technical Requirements 

of Pharmaceuticals for Human Use 

ICMJE International Committee of Medical 

Journal Editors 

ICTRP International Clinical Trials Registry 

Platform, WHO 

IDE Investigational Device Exemption 

IFPMA International Federation of 

Pharmaceutical Manufacturers and 

Associations 

IND Investigational New Drug Application 

IRB Institutional Review Board 

IVD In Vitro Diagnostic 

LPLV Last Patient Last Visit 

MEDLINE® Medical Literature Analysis and 

Retrieval System Online 

MedDRA Medical Dictionary for Regulatory 

Affairs 

MeSH® Medical Subject Headings 

MSSO Maintenance and Support Services 

Organization 

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69568 Federal Register / Vol. 79, No. 225 / Friday, November 21, 2014 / Proposed Rules 

NCT National Clinical Trial 

NDA New Drug Application 

NIH National Institutes of Health, HHS 

NLM National Library of Medicine, NIH 

NPRM Notice of Proposed Rulemaking 

OHRP Office for Human Research 

Protections, HHS 

OMB Office of Management and Budget 

OTC Over-the-Counter 

PDF Portable Document Format 

PhRMA Pharmaceutical Research and 

Manufacturers of America 

PHS Public Health Service 

PI Principal Investigator 

PRS Protocol Registration System 

R&D Research and Development 

RFA Request for Applications 

RIA Regulatory Impact Analysis 

RIN Regulatory Information Number 

SAP Statistical Analysis Plan 

SNOMED CT® Systematized Nomenclature 

of Medicine—Clinical Terms®

SPIRIT Standard Protocol Items for 

Randomized Trials 

U.S.C. United States Code 

WHO World Health Organization 

XML Extensible Markup Language 

Table of Contents 

I. Overview of Statutory Provisions 

II. Background 

A. Clinical Trials Reporting Prior to 

Passage of FDAAA 

B. Implementation of Statutory Provisions 

Prior to Rulemaking 

III. Overview of Proposed Rule 

A. Structure of Proposed Rule 

B. General Considerations in the 

Rulemaking 

C. Key Issues Considered in This Proposed 

Rule 

1. Elaboration of Statutory Definitions 

2. Modifications and Additions to the 

Elements of Clinical Trial Registration 

Information 

3. Posting of Registration Information for 

Applicable Device Clinical Trials 

4. Application of Rule to a Pediatric 

Postmarket Surveillance of a Device That 

Is Not a Clinical Trial 

5. Submission of Results Information for 

Applicable Clinical Trials of 

Unapproved, Unlicensed, or Uncleared 

Products 

6. Submission of Non-Technical and 

Technical Summaries of Trial Results 

7. Submission of the Full Protocol 

8. Increasing the Time Period for 

Submitting Results Information 

9. Retroactive Submission of Additional 

Results Information 

10. Standard Data Formats 

11. Additional Information to Improve 

Patient Understanding of Submitted 

Information 

12. Quality Control Procedures 

13. Updating Submitted Clinical Trial 

Information 

14. Statement To Accompany Certain 

Trials and Other Issues Related to 

Voluntary Submissions 

15. Adverse Event Information 

16. Privacy Considerations 

D. Effective Date/Compliance Date 

1. Effective Date 

2. Compliance Date 

3. Registration Information 

4. Results Information 

5. Voluntary Submissions 

6. Updates and Corrections to Clinical Trial 

Information 

IV. Detailed Description of This Proposed 

Rule 

A. General Provisions—Subpart A 

1. What is the purpose of this part?—§ 11.2 

2. To whom does this part apply?—§ 11.4 

3. What are the requirements for the 

submission of truthful information?— 

§ 11.6 

4. In what form and manner must clinical 

trial information be submitted?—§ 11.8 

5. What definitions apply to this part?— 

§ 11.10 

B. Registration—Subpart B 

1. Who must submit clinical trial 

registration information?—§ 11.20 

2. Which applicable clinical trials must be 

registered?—§ 11.22 

3. When must clinical trial registration 

information be submitted?—§ 11.24 

4. What constitutes clinical trial 

registration information?—§ 11.28 

5. By when will NIH post clinical trial 

registration information submitted under 

§ 11.28?—§ 11.35 

C. Results Submission—Subpart C 

1. Who must submit clinical trials results 

information?—§ 11.40 

2. For which applicable clinical trials must 

clinical trial results information be 

submitted?—§ 11.42 

3. When must results information be 

submitted for applicable clinical trials 

subject to § 11.42?—§ 11.44 

4. What constitutes clinical trial results 

information?—§ 11.48 

5. When will NIH post submitted clinical 

trials results information?—§ 11.52 

6. Under what circumstances will the 

Secretary grant a waiver of the 

requirements of this subpart?—§ 11.54 

D. Additional Submissions of Clinical Trial 

Information—Subpart D 

1. What requirements apply to voluntary 

submission clinical trial information for 

clinical trials of FDA-regulated drugs 

and devices?—§ 11.60 

2. What requirements apply to applicable 

clinical trials for which submission of 

clinical trial information has been 

determined by the Director to be 

necessary to protect the public health?— 

§ 11.62 

3. When must information submitted to 

ClinicalTrials.gov be updated?—§ 11.64 

4. What are the requirements for 

corrections of clinical trial 

information?—§ 11.66 

V. Response to Comments 

VI. Regulatory Impact Statement 

A. The Proposed Rule 

B. Need for the Proposed Rule 

C. Benefits of the Proposed Rule 

D. Costs Associated With the Proposed 

Rule 

1. Registration of Applicable Clinical Trials 

2. Results Submission 

3. Delayed Submission of Results via 

Certification or Extension Request 

4. Triggered Submission of Clinical Trial 

Information Following a Voluntary 

Submission 

5. Expanded Access Records 

6. Non-Recurring Costs of Bringing 

Previously Submitted Registration 

Information Into Compliance With This 

Proposed Rule 

E. Alternatives to the Proposed Rule 

F. Regulatory Flexibility Act 

G. Unfunded Mandates Reform Act of 1995 

H. Federalism 

VII. Paperwork Reduction Act of 1995 

VIII. Congressional Review Act 

IX. Legal Authority 

X. References 

XI. Codified 

I. Overview of Statutory Provisions 

This proposed rule would establish 

procedures and requirements for 

registering and submitting results 

information, including adverse event 

information, for certain clinical trials of 

drugs (including biological products) 

and devices and pediatric postmarket 

surveillances of a device necessary to 

implement section 402(j) of the PHS Act 

(42 U.S.C. 282(j)), as amended by Title 

VIII of FDAAA and including technical 

corrections made to FDAAA under 

Public Law 110–316 (referred to 

hereinafter as ‘‘section 402(j) of the PHS 

Act’’). 

Title VIII of FDAAA, enacted on 

September 27, 2007, amends the PHS 

Act by directing the Secretary of HHS, 

acting through the Director of the 

National Institutes of Health (NIH or the 

Agency) to expand the existing clinical 

trial registry data bank known as 

ClinicalTrials.gov and to ensure that the 

data bank is publicly available through 

the Internet. Among other duties, NIH is 

directed to expand the data bank to 

include registration information for a 

broader set of clinical trials than were 

required to register under a previous 

law, the Food and Drug Administration 

Modernization Act of 1997 (FDAMA). 

Section 402(j) of the PHS Act specifies 

that identified entities or individuals, 

called responsible parties, are to submit 

registration information for certain 

applicable clinical trials of drugs 

(defined by section 402(j)(1)(A)(vii) of 

the PHS Act to include biological 

products) and devices, including any 

pediatric postmarket surveillance of a 

device required by FDA under section 

522 of the FD&C Act. Section 

402(j)(2)(A)(iii) of the PHS Act 

authorizes the Secretary of HHS to 

modify by regulation the data elements 

required for registration, provided that 

the Secretary provides a rationale for 

why such modification ‘‘improves and 

does not reduce’’ the information 

included in the data bank. The statute 

specifies certain deadlines by which 

registration information is to be 

submitted to the data bank. 

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Section 402(j)(3) of the PHS Act 

further directs the Agency to augment 

the registry data bank to include 

summary results information through a 

multistep process, as follows: 

First, for those clinical trials that form 

the primary basis of an efficacy claim or 

are conducted after a product is 

approved, licensed, or cleared, the 

registry data bank is to be linked to 

selected existing results information 

available from the NIH and FDA 

(section 402(j)(3)(A) of the PHS Act). 

Such information includes citations to 

published journal articles focused on 

the results of applicable clinical trials, 

posted FDA summaries of FDA advisory 

committee meetings at which applicable 

clinical trials were considered, and 

posted FDA assessments of the results of 

any applicable drug clinical trials that 

were conducted under section 505A or 

505B of the FD&C Act. Note that we use 

the term ‘‘product’’ hereinafter in this 

preamble to refer to either a drug 

(including a biological product), a 

device, or both, as each is defined in 

proposed § 11.10. 

Second, for each applicable clinical 

trial subject to FDAAA, the responsible 

party must submit to the data bank 

results information required under 

section 402(j)(3)(C) of the PHS Act. Such 

information is to include tables of 

demographic and baseline 

characteristics of the ‘‘patients who 

participated in the clinical trial’’ 

(section 402(j)(3)(C)(i) of the PHS Act), 

i.e., the enrolled human subjects, and 

the primary and secondary outcome 

measures for each arm of the clinical 

trial, as well as a point of contact for 

scientific information about the clinical 

trial results and information on whether 

certain agreements exist between the 

sponsor and the principal investigator 

(PI) that limits the ability of the PI to 

discuss or publish the results of an 

applicable clinical trial after it is 

completed. 

Third, section 402(j)(3)(D) of the PHS 

Act requires the Secretary to further 

expand the data bank by regulation ‘‘to 

provide more complete results 

information and to enhance patient 

access to and understanding of the 

results of clinical trials.’’ It requires 

consideration of specific issues in 

developing the regulations, in 

particular: 

(1) Whether to require submission of 

results information for applicable 

clinical trials of products that are not 

approved, licensed, or cleared (whether 

approval, licensure, or clearance was 

sought) (See section 402(j)(3)(D)(ii)(II) of 

the PHS Act.); and if submission of 

clinical trial results information is 

required for such applicable clinical 

trials, the date by which that 

information is required to be submitted. 

(See section 402(j)(3)(D)(iv)(III) of the 

PHS Act.); 

(2) Whether non-technical written 

summaries of the clinical trial and its 

results can be included in the data bank 

without being misleading or 

promotional. (See section 

402(j)(3)(D)(iii)(I) of the PHS Act.); 

(3) Whether technical written 

summaries of the clinical trial and its 

results can be included in the data bank 

without being misleading or 

promotional. (See section 

402(j)(3)(D)(iii)(II) of the PHS Act.); 

(4) Whether to require submission of 

the full clinical trial protocol or only 

such information on the protocol as may 

be necessary to help evaluate the results 

of the trial. (See section 

402(j)(3)(D)(iii)(III) of the PHS Act.); 

(5) Whether the 1-year period for 

submission of results information 

should be increased to a period not to 

exceed 18 months. (See section 

402(j)(3)(D)(iv)(I) of the PHS Act.); and 

(6) Whether requirements for results 

submission as proposed in this rule 

should apply to applicable clinical trials 

for which results information required 

under section 402(j)(3)(C) of the PHS 

Act is submitted before the effective 

date of the regulation imposing those 

requirements. (See section 

402(j)(3)(D)(iv)(II) of the PHS Act.). 

Section 402(j)(3)(D)(v) of the PHS Act 

further requires that the regulations 

shall establish: 

(1) A standard format for the 

submission of clinical trial information. 

(See section 402(j)(3)(D)(v)(I) of the PHS 

Act.); 

(2) Additional information on clinical 

trials and results written in 

nontechnical, understandable language 

for patients. (See section 

402(j)(3)(D)(v)(II) of the PHS Act.); 

(3) Procedures for quality control, 

with respect to completeness and 

content of clinical trial information, to 

help ensure that data elements are not 

false or misleading and are nonpromotional. (See section 

402(j)(3)(D)(v)(III) of the PHS Act.); 

(4) Appropriate timing and 

requirements for updates of clinical trial 

information and whether and how such 

updates should be tracked. (See section 

402(j)(3)(D)(v)(IV) of the PHS Act.); 

(5) A statement to accompany the 

entry for an applicable clinical trial 

when primary and secondary outcome 

measures for such applicable clinical 

trial are submitted as a voluntary 

submissions after the date specified in 

section 402(j)(2)(C) of the PHS Act. (See 

section 402(j)(3)(D)(v)(V) of the PHS 

Act.); and 

(6) Additions or modifications to the 

manner of reporting the data elements 

established under the results 

submission provisions of section 

402(j)(3)(C) of the PHS Act. (See section 

402(j)(3)(D)(v)(VI) of the PHS Act.). 

Section 402(j)(3)(D)(vii) of the PHS 

Act requires the Secretary to convene a 

public meeting to solicit input from 

interested parties on those issues. The 

public meeting was convened on April 

20, 2009, on the NIH campus. The 

public meeting attracted more than 200 

registered participants and 60 written 

comments. All of the comments 

received prior to, during, and after the 

public meeting are available in the 

Clinical Trials Public Meeting Docket, 

ID: NIH–2009–0002, at Regulations.Gov: 

http://www.regulations.gov/search/

Regs/home.html#docketDetail?R=NIH2009-0002. We carefully reviewed the 

comments received in developing the 

proposed provisions that address the 

considerations enumerated in section 

402(j)(3)(D) of the PHS Act. Many of the 

comments helped inform development 

of this proposed rule. For purposes of 

this rulemaking, we prepared a 

memorandum summarizing these 

comments and the issues commented 

upon [Ref. 1]. 

In addition, section 402(j)(3)(I)(i) of 

the PHS Act directs the Secretary to 

issue regulations to ‘‘determine the best 

method for including in the registry and 

results data bank appropriate results 

information on serious adverse and 

frequent adverse events for applicable 

clinical trials (required to submit results 

under section 402(j)(3)(C) of the PHS 

Act) in a manner and form that is useful 

and not misleading to patients, 

physicians, and scientists.’’ If 

regulations are not issued by September 

27, 2009, then section 402(j)(3)(I)(ii) of 

the PHS Act specifies that the default 

provisions specified in section 

402(j)(3)(I)(iii) of the PHS Act shall take 

effect, requiring the submission of 

certain information summarizing 

serious and frequent adverse events 

observed during an applicable clinical 

trial. Regulations were not issued by the 

deadline, so the default provisions 

required by sections 402(j)(3)(I)(ii) and 

(iii) of the PHS Act took effect on 

September 27, 2009. Section 

402(j)(3)(I)(v) of the PHS Act indicates 

that adverse event information is 

‘‘deemed to be’’ clinical trial 

information that is included in the data 

bank pursuant to the requirements for 

results submission under section 

402(j)(3)(C) of the PHS Act. 

Furthermore, section 402(j)(4)(A) of 

the PHS Act directs that the data bank 

accept ‘‘voluntary submissions’’ of 

complete registration or complete 

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69570 Federal Register / Vol. 79, No. 225 / Friday, November 21, 2014 / Proposed Rules 

results information for certain clinical 

trials for which such information would 

not otherwise required to be submitted, 

provided that the responsible party 

complies with requirements that could 

involve submission of information on 

additional clinical trials. 

Section 801(c) of FDAAA requires the 

Secretary to issue guidance on how the 

requirements of section 402(j) of the 

PHS Act apply to a pediatric postmarket 

surveillance of a device, where that 

pediatric postmarket surveillance is not 

a clinical trial. This preamble and 

proposed rule address this topic and 

serve as the required guidance. 

Section 402(j)(5) of the PHS Act 

specifies certain procedures and 

penalties related to non-compliance. 

Among other things, it directs NIH to 

post public notices of noncompliance in 

the data bank; requires report forms 

under certain HHS grants to include a 

certification that required registration 

and results submission under section 

402(j) of the PHS Act are complete; 

prohibits HHS from funding responsible 

parties who do not fulfill their 

obligations under section 402(j) of the 

PHS Act; and grants FDA the authority 

to sanction responsible parties who fail 

to comply with section 402(j) of the PHS 

Act. Section 801(b) of FDAAA includes 

conforming amendments to the FD&C 

Act, which make failure to comply with 

specified requirements of section 402(j) 

of the PHS Act a prohibited act under 

the FD&C Act (See 21 U.S.C. 331(jj)(1)– 

(3).) Committing any such prohibited act 

could subject the violator to criminal 

and/or civil penalties, including civil 

money penalties. 

Section 801(d) of FDAAA includes a 

preemption provision, which states that 

‘‘[u]pon the expansion of the registry 

and results data bank under section 

402(j)(3)(D) of the Public Health Service 

Act, as added by this section, no State 

or political subdivision of a State may 

establish or continue in effect any 

requirement for the registration of 

clinical trials or for the inclusion of 

information relating to the results of 

clinical trials in a database.’’ 

II. Background 

There is ongoing public interest in the 

transparency of information concerning 

clinical trials. The collection and public 

availability of information about clinical 

trials and their results is seen by many 

as an important public health issue. 

Advocates have argued that a central 

resource of clinical trial information is 

a potentially valuable tool to track the 

existence and progress of clinical trials 

and communicate their results, both 

positive and negative, as well as to 

provide potential participants with 

broad access to information about 

clinical trials seeking participants. 

A. Clinical Trials Registration Prior to 

Passage of FDAAA 

Registration of a limited set of clinical 

trials has been required by U.S. law 

since the U.S. Congress mandated the 

establishment of a clinical trial registry 

in 1997. Section 113 of FDAMA 

amended the PHS Act to require HHS, 

acting through NIH and in coordination 

with FDA and the Centers for Disease 

Control and Prevention (CDC), to 

establish, maintain, and operate a data 

bank of information on clinical trials 

testing the effectiveness of drugs for 

serious or life-threatening diseases and 

conditions, whether federally or 

privately funded, that are conducted 

under an Investigational New Drug 

application (IND). The statute required 

the data bank to include a description 

of the purpose of each drug, participant 

eligibility criteria, the location of the 

clinical trial sites, and a point of contact 

for those seeking to enroll in the clinical 

trial. The FDAMA requirements, which 

were modified slightly in 2002 by the 

Best Pharmaceuticals for Children Act 

(Pub. L. 107–109, 115 STAT 1408, 

1420–21), are currently codified at 42 

U.S.C. 282(i). 

NLM, a part of NIH, developed the 

registry, known as ClinicalTrials.gov, in 

response to this mandate and in support 

of NLM’s statutory mission to improve 

access to information to facilitate 

biomedical research and the public 

health. (See 42 U.S.C. 286(a).) The 

registry became publicly available in 

February 2000. ClinicalTrials.gov is an 

Internet-based data bank that informs 

the public about the conditions and 

interventions being investigated in 

clinical trials, eligibility criteria, the 

location of trial sites, and contact 

information. It also provides links to 

additional public information about 

disorders and interventions relevant to 

the research described. 

While FDAMA required the 

registration of only certain clinical trials 

conducted under an IND, 

ClinicalTrials.gov accepts submissions 

of information about a broader range of 

clinical studies, in keeping with the 

long-standing authorities and 

responsibilities of HHS, the NIH, and 

the NLM. The PHS Act expressly directs 

the Secretary of HHS to ‘‘collect and 

make available through publications 

and other appropriate means, 

information as to, and the practical 

application of,’’ research concerning the 

treatment ‘‘of physical and mental 

diseases and impairments of man.’’ (See 

42 U.S.C. 241(a).) The NLM is expressly 

required to support ‘‘the dissemination 

and exchange of scientific and other 

information important to the progress of 

medicine and to the public health’’ (See 

42 U.S.C. 286(a).) Consequently, since 

its creation, ClinicalTrials.gov has 

accepted registration information on 

different types of clinical trials, 

including trials of drugs for other than 

serious or life-threatening diseases or 

conditions, trials of medical devices, 

surgical procedures, and behavioral 

interventions, and has also accepted 

registration of information on other 

types of clinical studies, such as 

observational studies. Prior to passage of 

FDAAA, ClinicalTrials.gov contained 

information on more than 45,000 

clinical studies. 

The clinical trial data elements and 

descriptions used in ClinicalTrials.gov 

prior to FDAAA [Ref. 2] were developed 

following public notice and comment 

on two guidance documents: (1) A final 

guidance issued by FDA in 2002 

describing the information to be 

submitted to the ClinicalTrials.gov 

registry pursuant to the registration 

requirement set forth in section 113 of 

FDAMA [Ref. 3] (See 67 FR 12022, 

Mar.18, 2002.); and (2) a draft guidance 

issued by FDA in January 2004 [Ref. 4] 

(See 69 FR 3923, Jan. 27, 2004.), 

proposing revisions to the final 

guidance issued in 2002 to include 

information on additional submissions 

required pursuant to the Best 

Pharmaceuticals for Children Act (Pub. 

L. 107–109, 115 STAT 1408, 1420–21). 

This draft guidance was not finalized. 

Following establishment of 

ClinicalTrials.gov, the scientific 

community, general public, industry, 

and others engaged in high-profile, 

public discussions about the need for 

increased access to information about 

clinical trials [Ref. 5]. For example, 

studies revealed that selective 

publication of clinical trial results could 

give a misleading picture about serious 

adverse effects of widely marketed 

drugs and about increased risks of such 

effects in certain segments of the 

population [Ref. 6]. 

The scientific and lay communities 

called for a range of new measures to 

improve access to and transparency of 

information about clinical trials, 

including broader mandatory 

registration and results submission. 

Incomplete access to information about 

clinical trials was seen by some to 

adversely affect investigators, journal 

editors, research funders, clinicians and 

participants. Proponents of more 

comprehensive registration of clinical 

trials in a publicly available data bank 

came from many quarters [Ref. 7, 8, 9]. 

For example, in 2004, the International 

Committee of Medical Journal Editors 

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(ICMJE) adopted a comprehensive trial 

registration policy aimed at increasing 

public access to trial information and 

preventing the selective publication of 

certain results. The updated 2007 ICMJE 

policy requires, as a condition for 

publication, registration of ‘‘any 

research study that prospectively 

assigns human participants or groups of 

humans to one or more health-related 

interventions to evaluate the effects on 

health outcomes’’ prior to the 

enrollment of the first participant [Ref. 

10]. Industry groups also adopted 

registration policies. For example, in 

2005, the International Federation of 

Pharmaceutical Manufacturers and 

Associations (IFPMA) stated that ‘‘all 

clinical trials [sponsored by member 

companies], other than exploratory 

trials, should be submitted for listing in 

a free, publicly accessible clinical trial 

registry within 21 days of the initiation 

of patient enrollment . . .’’[Ref. 11]. In 

a follow-up statement, IFPMA allowed 

for the delayed release of information in 

any of five fields that ‘‘may be regarded 

as sensitive for competitive reasons by 

the sponsor’’ [Ref. 12]. Also in 2005, the 

World Health Organization (WHO) 

International Clinical Trial Registry 

Platform (ICTRP) Secretariat defined a 

20-item minimum clinical trial 

registration dataset [Ref. 13]. The WHO 

minimum trial registration standard has 

been adopted broadly, including by the 

ICMJE, and does not allow withholding 

of the five fields considered ‘‘sensitive’’ 

by IFPMA. The European Union has 

passed legislation requiring the public 

disclosure of registration and results 

information for certain clinical trials of 

drugs that are conducted in European 

Union countries, including trials of 

drugs for pediatric indications. The 

European Medicines Agency (EMA) is 

engaged in a public consultation to 

develop detailed technical 

specifications for the information to be 

submitted [Ref. 14, 15]. 

Because ClinicalTrials.gov is 

compatible with and receptive to a 

variety of registration requirements, it 

may facilitate compliance with many 

laws and policies and attracts an 

extremely large and diverse group of 

data providers. Many trials are 

registered in ClinicalTrials.gov to satisfy 

the ICMJE policy, and the number of 

trials registered in ClinicalTrials.gov 

increased significantly after the 

announcement of the ICMJE policy [Ref. 

16]. Clinical trial records in 

ClinicalTrials.gov account for more than 

85 percent of trials in the registries 

searched by the WHO ICTRP Portal [Ref. 

17]. We believe that the more 

comprehensive the data bank, the better 

suited it will be to serve public health 

goals, including those articulated in 

section 402(j) of the PHS Act. As a 

result, we continue to encourage 

sponsors and other entities associated 

with studies not subject to section 402(j) 

of the PHS Act to voluntarily register 

and submit the results of trials of all 

types of interventions and other types of 

clinical studies in ClinicalTrials.gov, 

bearing in mind that section 402(j)(4)(A) 

of PHS Act may apply to such 

submissions. 

B. Implementation of Statutory 

Provisions Prior to Rulemaking 

Due to the short statutory timelines 

for responsible parties to begin 

submitting registration and results 

information for applicable clinical trials 

under Title VIII of FDAAA, NIH 

proceeded to expand the 

ClinicalTrials.gov registry data bank 

immediately after enactment of FDAAA. 

The intent was to develop a data bank 

that would permit responsible parties to 

meet the statutory requirements to 

submit clinical trial information, even 

though regulations to clarify and expand 

those obligations had yet to be 

developed. In December 2007, NIH 

launched an expanded registry that 

could accommodate the submission of 

clinical trial registration information 

specified in section 402(j) of the PHS 

Act. It included all the registration data 

elements explicitly enumerated in 

section 402(j)(2)(A)(ii) of the PHS Act, 

as well as additional data elements that 

the Agency interpreted as necessary to 

meet other statutory requirements, 

maintain consistency with 

ClinicalTrials.gov data elements that 

were in place prior to FDAAA, and 

allow efficient operation of the data 

bank. Over time, the Agency posted 

information on the ClinicalTrials.gov 

Web site outlining its current thinking 

about the meaning of key terms defined 

in the statute, including ‘‘applicable 

clinical trial’’ and ‘‘responsible party’’ 

[Ref. 18]. 

In further expanding the data bank to 

accommodate the submission of results 

information specified in section 

402(j)(3)(C) of the PHS Act, we 

commissioned a review of practices and 

standards used in existing results data 

banks [Ref. 19]; engaged in active 

dialogue with the clinical trial 

community, public and private sectors, 

including the patient community; and 

consulted with the NLM Board of 

Regents, which established a Working 

Group on Clinical Trials [Ref. 20] in late 

2007 and held meetings open to the 

public in 2008 [Ref. 21] and 2009 [Ref. 

22] that were announced in the Federal 

Register (73 FR 3473, Jan. 18, 2008; 74 

FR 3627, Jan 21, 2009). We held 

discussions with other standards 

development bodies that are active in 

areas related to trial information, such 

as the Clinical Data Interchange 

Standards Consortium (CDISC) and 

Health Level Seven (HL7). We also 

reviewed and considered various 

approaches to preparing summary 

reports on the results of clinical trials, 

including the ICH–E3 Clinical Study 

Report format [Ref. 23], which is used 

to guide the submission of drug trial 

results to regulatory agencies in the 

U.S., Europe, and Japan, and the 

CONSORT statements [Ref. 24], which 

are used to guide the publication of trial 

results in the peer-reviewed literature. 

We found that the ICH–E3 format and 

CONSORT were designed to delineate 

the topics that should be included when 

preparing summary reports of trial 

results for their intended expert 

audiences (regulatory professionals and 

medical professionals, respectively). 

Both the ICH–E3 format and CONSORT 

recommend review and inclusion of 

information beyond that collected 

during an individual clinical trial. 

Neither addresses the communication of 

trial results to the general public, which 

is one of the intended audiences for data 

submitted to comply with section 402(j) 

of the PHS Act. We found no existing 

standards directly addressing the 

submission of summary results tables as 

required by Title VIII of FDAAA. 

As a result of these consultations and 

the review of existing approaches to 

results reporting, we decided to develop 

a results data entry system that would 

enable responsible parties to submit 

information in a structured manner. 

Structured data entry is necessary to 

enable the clinical trials data bank to 

accommodate the full range of study 

design and data types common or 

emerging in the clinical trials 

community, while simultaneously 

ensuring that all required data elements 

are provided; optimize the presentation 

of submitted data, including adverse 

event information, for various types of 

users, including those with less 

experience in interpreting information 

about the relative risks and benefits 

associated with particular interventions; 

and allow for efficient search 

capabilities, including searching by the 

data fields specified by the statute. 

Structured data entry requires a 

responsible party to submit data in prespecified fields. As a result, a data bank 

can be created to manage all of the 

information from different trials at the 

level of the individual fields. This 

approach contrasts with the collection 

of heterogeneous, free-text documents 

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(e.g., PDF documents). In the latter 

situation, NLM would be unable to 

make the displays consistent or create 

and populate a data bank that would 

support the search capabilities specified 

by section 402(j) of the PHS Act and 

needed to use the data bank. The 

development of a structured results data 

bank was consistent with the design of 

the existing ClinicalTrials.gov registry 

data bank, which launched more than 

seven years before the passage of 

FDAAA. 

In the spring of 2008, we announced 

in the Federal Register the beginning of 

an iterative process to advance 

development of a data bank to support 

the submission of the results 

information specified by section 

402(j)(3)(C) of the PHS Act (73 FR 

29525, May 21, 2008). Any user with a 

ClinicalTrials.gov account (i.e., an 

account for submitting registration 

information via the ClinicalTrials.gov 

Protocol Registration System, or PRS) 

was subsequently able to enter real or 

test data into the test system and view 

the resulting clinical trial records. 

Mechanisms for data entry and display 

and descriptions of individual data 

items were refined in response to 

comments from users of the test system, 

leading to the launch of an operational 

results submission system in September 

2008. Further improvements to the 

system were made based on the 

experience of responsible parties 

submitting comments and from the 

Agency in reviewing results information 

submitted under section 402(j)(3)(C) of 

the PHS Act. 

The operational system for results 

information enables responsible parties 

to submit required information. Because 

section 402(j)(3)(C)(i) of the PHS Act 

calls for the information on 

demographic and baseline 

characteristics of the study sample to 

include information on ‘‘the number of 

patients who dropped out of the clinical 

trial and the number of patients 

excluded from the analysis, if any,’’ the 

operational system separates the 

collection of information about 

participant flow (i.e., the number of 

subjects who started the clinical trial, 

completed the clinical trial, and were 

excluded from the analysis or dropped 

out of the trial) from demographic and 

baseline data. Our review of a large 

number of clinical trials determined that 

the only demographic data consistently 

collected across all of these clinical 

trials were age and gender. The 

operational system therefore collects 

information about age and gender, 

facilitates submission of other 

commonly collected demographic data 

such as race or ethnicity, and allows 

definition and submission of other 

demographic data from the clinical trial. 

Responsible parties may define and 

submit information on baseline 

characteristics that are most relevant to 

the particular clinical trial. 

The operational results submission 

system that became available in 

September 2008 also supported the 

voluntary submission of information 

about serious adverse events and other 

frequent adverse events. Responsible 

parties were able to voluntarily submit 

information on serious and other 

adverse events in a manner largely 

consistent with the statutory default 

provisions in section 402(j)(3)(I)(iii)(I) 

and (II) of the PHS Act. Prior to 

implementing the capability to submit 

adverse event information, we found 

through our consultations and 

discussions that, although regulatory 

requirements and standards exist for the 

reporting of adverse events experienced 

by participants during a clinical trial, 

there is no standard approach for 

summarizing adverse event data from an 

entire clinical trial for purposes of 

inclusion in a public data bank. We 

viewed the process of enabling 

voluntary submission of summary 

adverse event information in the initial 

results submission system, prior to the 

statutory default provisions taking 

effect, as a means of determining 

whether the statutory default provisions 

would represent a feasible and ‘‘best 

method’’ of including adverse event 

information, consistent with section 

402(j)(3)(I)(i) of the PHS Act. To help 

the Agency determine whether the 5 

percent threshold specified in section 

402(j)(3)(I)(iii)(II) of the PHS Act was an 

appropriate cap for information about 

frequent adverse events, we permitted 

data submitters to submit summary data 

on non-serious adverse events using a 

threshold other than 5 percent . They 

could choose any higher or a lower 

threshold. 

The Agency did not promulgate 

regulations implementing the best 

method for including adverse events 

within 18 months of the date of 

enactment of FDAAA due to the time 

needed to evaluate different strategies 

for submitting adverse event 

information. As a result, the statutory 

default provisions in section 

402(j)(3)(I)(iii) of the PHS Act for 

submitting adverse events information 

were implemented in the data bank on 

September 27, 2009. Responsible parties 

submitting results information were 

required to submit ‘‘a table of serious 

anticipated and unanticipated adverse 

events, grouped by organ system, with 

number and frequency of such event in 

each arm of the clinical trial’’ and ‘‘a 

table of anticipated and unanticipated 

adverse events that are not included in 

the [serious adverse event table] that 

exceed a frequency of 5 percent within 

any arm of the clinical trial, grouped by 

organ system, with number and 

frequency of such event in each arm of 

the clinical trial’’ (See sections 

402(j)(3)(I)(iii)(I) and (II) of the PHS 

Act.) While there is a requirement to 

submit non-serious adverse events with 

a frequency of 5 percent or more in any 

arm, responsible parties may submit 

data voluntarily on non-serious adverse 

events with a threshold of less than 5 

percent. The system also accommodates 

the voluntary submission of information 

indicating the methodology used for 

assessing adverse events (systematic 

versus non-systematic) and the time 

period during which adverse event 

information was collected. 

We and the community of responsible 

parties have gained considerable 

experience with results submission, 

including adverse event information, 

since September 27, 2008, when results 

submission was required by section 

402(j)(3)(C) of the PHS Act for certain 

applicable clinical trials. As of April 24, 

2013, summary results for about 8,700 

clinical trials had been submitted by 

responsible parties, processed by the 

Agency and made publicly available in 

the data bank. Based on this experience, 

we have refined the design of the data 

entry system, developed instructional 

materials to assist responsible parties in 

preparing data for submission, and 

refined procedures for processing 

submitted information. Responsible 

parties have improved their procedures 

for collecting and preparing data for 

submission to the data bank. We have 

drawn upon this considerable 

experience and the lessons learned in 

formulating this proposed rule. 

III. Overview of Proposed Rule 

A. Structure of proposed rule 

We propose to add a new Part 11 to 

Title 42 of the Code of Federal 

Regulations (CFR) to implement the 

statutory requirements set forth in 

section 402(j) of the PHS Act. This 

proposed rule is divided into four major 

subsections: 

• Subpart A outlines the general 

provisions of this proposed rule. It 

specifies the purpose of the rulemaking, 

to whom this proposed rule applies, 

requirements for submission of truthful 

information, the form and manner of 

submitting information to the data bank 

at ClinicalTrials.gov, and definitions 

specific to this part. 

• Subpart B specifies requirements 

for registering an applicable clinical 

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trial. It specifies who must register 

trials, which trials must be registered, 

when registration information must be 

submitted, where registration 

information must be submitted, what 

registration information must be 

submitted, and when submitted 

registration information will be posted. 

• Subpart C specifies requirements 

for submission of results information, 

including adverse event information, for 

applicable clinical trials of drugs 

(including biological products) and 

devices that have been approved, 

licensed, or cleared by FDA and for 

applicable clinical trials of drugs 

(including biological products) and 

devices that have not been approved, 

licensed, or cleared by FDA. It specifies 

who must submit clinical trial results 

information; for which trials such 

information must be submitted; when 

such information is due, including 

provisions for delayed results 

submission and requesting extensions; 

where such information must be 

submitted; what clinical trial results 

information must be submitted; when 

such information will be posted; and the 

circumstances under which the NIH 

will grant a waiver of the results 

submission requirements. 

• Subpart D specifies additional 

required submissions of information to 

the data bank, including the timing of 

updates and corrections to submitted 

information and mandatory submission 

of clinical trial information in the 

interest of public health for certain 

applicable clinical trials that otherwise 

would not be subject to the registration 

and results submission requirements of 

this part. It also specifies requirements 

affecting the voluntary submission of 

information about clinical trials for 

which the submission of registration 

and results information is not otherwise 

required under this part. 

Elements that are required to be 

considered in the rulemaking under 

section 402(j)(3)(D) of the PHS Act are 

addressed in the relevant subpart. For 

example, proposals related to results 

submission for applicable clinical trials 

of unapproved, unlicensed, or uncleared 

products are contained in subpart C 

(Results Submission), while those 

related to the updating of submitted 

clinical trial information are contained 

in subpart D (Additional submissions of 

clinical trial information). 

B. General considerations in the 

rulemaking 

As stated in section 402(j)(2)(A)(i) of 

the PHS Act, the data bank is intended 

‘‘to enhance patient enrollment and 

provide a mechanism to track 

subsequent progress of clinical trials.’’ 

In addition to satisfying this obligation, 

we believe it is essential to continue to 

provide a comprehensive and robust 

data bank to encourage broad and 

widespread registration and submission 

of results of clinical trials and other 

types of clinical studies. Comprehensive 

registration and results submission for 

such studies is consistent with NLM’s 

statutory obligations to disseminate 

information concerning research and to 

promote public health. It can provide 

information to potential research 

participants, reduce inadvertent and 

unnecessary duplication of clinical 

studies, help journal editors detect 

incomplete descriptions of the results of 

specific clinical trials, and allow 

analysis of the results of multiple 

clinical trials of the same or similar 

interventions, thus providing regulators, 

scientists, health professionals, and the 

public with more information regarding 

the potential benefits and harms of 

different interventions. 

We also believe it is essential for the 

data bank to serve a wide variety of 

users. While the public is the ultimate 

beneficiary of the data bank and the 

information contained in it, the overall 

public benefit will derive from access to 

and use of the data by different 

constituencies within the general 

public. We believe that clinical 

researchers, systematic reviewers, 

experts in evidence-based medicine, 

regulators, drug and device 

manufacturers, human subjects 

protection review boards (including 

institutional review boards (IRBs)), 

healthcare providers, disease and 

patient advocacy groups, students and 

educators, and patients and their family 

members may be able to use the 

available information to learn more 

about FDA-regulated products, to 

increase the efficiency of drug and 

device development processes, and to 

improve the design and conduct of 

clinical research studies, among other 

uses. 

Building a data bank that serves 

multiple users with varying degrees of 

expertise in analyzing and interpreting 

clinical trial data means that not all of 

the collected information will 

necessarily be easy for all users to 

interpret. Some members of the general 

public, for example, may have difficulty 

interpreting certain results information, 

including adverse event information, or 

putting it into context. To address such 

concerns, we currently provide and, 

consistent with sections 

402(j)(3)(A)(ii)(I) and (II) of the PHS Act, 

intend to expand links to additional 

explanatory material, including general 

information about clinical trials; 

publicly available FDA, NIH, and 

systematic review information about the 

products being studied; NIH 

information about the conditions that 

are the focus of the clinical trial; peerreviewed journal articles summarizing 

the results of clinical trials; and 

specified FDA information about the 

clinical trial. We intend to develop 

improved ways of displaying submitted 

clinical trial information and enabling 

users to search for it, as we continue to 

gain experience with the operational 

system and to consult with experts in 

risk communications and clinical trial 

research. We also expect to solicit 

public input on this topic using a 

variety of mechanisms. 

It is important to note that this 

proposed rule does not impose any 

requirements for the design or 

implementation of a clinical trial or for 

the collection of information during a 

clinical trial. This proposed rule 

specifies requirements for submitting 

information that describes a clinical 

trial as it was designed, conducted, and 

analyzed. The proposed data 

submission requirements are intended 

to accommodate current and emerging 

practices in design and implementation 

of clinical trials. We expect that the 

information required to be submitted to 

ClinicalTrials.gov will have been 

developed and collected prior to the 

time it must be submitted to the data 

bank and for reasons distinct from 

compliance with section 402(j) of the 

PHS Act and this proposed rule. In 

general, required information would 

have been included in standard clinical 

trial documentation (e.g., the protocol), 

collected during the course of the 

clinical trial (e.g., the types of adverse 

events specified in the protocol), or 

produced by the analysis that was 

specified in the protocol (e.g., outcome 

measures and statistical tests). 

C. Key issues considered in this 

proposed rule 

In developing this proposed rule, we 

considered a number of issues 

associated with the implementation of 

the statutory requirements for 

registration under section 402(j)(2) of 

the PHS Act and results submission 

under section 402(j)(3)(C) of the PHS 

Act and with the expansion of the data 

bank via rulemaking, as specified in 

section 402(j)(3)(D) of the PHS Act. We 

discuss these issues in this section of 

the preamble and reflect their 

implementation in the specific 

proposals described in section IV. We 

welcome comments on the Agency’s 

proposals for addressing each of these 

topics in this proposed rule and 

additional information that might 

inform their implementation. 

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1. Elaboration of statutory definitions 

Section 402(j)(1)(A) of the PHS Act 

defines a number of terms that are 

essential to implementation of the 

statute and the development of this 

proposed rule. Among the most 

important are the terms applicable 

clinical trial and responsible party, 

which are key elements in defining the 

set of trials that are subject to the 

registration and results submission 

requirements of section 402(j) of the 

PHS Act and the individuals or entities 

that are responsible for submitting the 

required information, respectively. 

(a) Applicable clinical trial. Section 

402(j)(1)(A)(i) of the PHS Act defines the 

term applicable clinical trial as either an 

applicable device clinical trial or an 

applicable drug clinical trial, both of 

which are defined in section 402(j)(1)(A) 

of the PHS Act. Section 402(j)(1)(A)(ii) 

defines applicable device clinical trial 

as ‘‘(I) a prospective clinical study of 

health outcomes comparing an 

intervention with a device subject to 

section 510(k), 515, or 520(m) of the 

[FD&C Act] against a control in human 

subjects (other than a small clinical trial 

to determine the feasibility of a device, 

or a clinical trial to test prototype 

devices where the primary outcome 

measure relates to feasibility and not to 

health outcomes); and (II) a pediatric 

postmarket surveillance as required 

under section 522 of the [FD&C Act].’’ 

Section 402(j)(1)(A)(iii) defines an 

applicable drug clinical trial as a 

‘‘controlled clinical investigation, other 

than a phase I clinical investigation, of 

a drug subject to section 505 of the 

[FD&C Act] or to section 351 of [the PHS 

Act,]’’ where ‘‘clinical investigation’’ 

has the meaning given in 21 CFR 312.3 

or any successor regulation and phase I 

has the meaning given in 21 CFR 312.21 

or any successor regulation. 

This proposed rule, in § 11.10, adopts 

the statutory definitions of all three of 

these terms, replacing the phrase ‘‘phase 

I’’ in the definition of applicable drug 

clinical trial with the phrase ‘‘phase 1’’ 

to be consistent with the numbering 

scheme used in FDA regulations at 21 

CFR 312.21. Because of the significance 

of these terms in determining which 

clinical trials are subject to the 

provisions of this proposed part, we 

include in section IV.A.5 of this 

preamble an extensive elaboration of 

their meanings, interpreting each 

component part of the definitions in a 

way that is consistent with existing use 

of the stated terms in relevant FDA 

regulations, which may differ from 

current usage in some segments of the 

clinical research community. We also 

propose in § 11.22(b) an approach for 

using a limited set of registration data 

elements to determine whether a 

particular study meets the definition of 

an applicable clinical trial. We believe 

there is significant advantage in having 

a simple mechanism for a responsible 

party to determine, based on a standard 

set of factors, whether a study meets the 

definition of an applicable clinical trial. 

Such a mechanism would reduce 

uncertainty among responsible parties 

about their data submission obligations 

under section 402(j) of the PHS Act and 

reduce their burden in making such a 

determination. 

A key consideration in the 

elaborations and the mechanism for 

determining whether a study meets the 

definition of an applicable clinical trial 

is defining what it means for an 

applicable drug clinical trial to be 

‘‘controlled’’ or for an applicable device 

clinical trial to compare an intervention 

against a control. We explain our 

interpretation of these phrases in the 

preamble, and we include in § 11.10 of 

this proposed rule a definition of the 

term ‘‘control or controlled.’’ Our 

proposed definition is consistent with 

the types of controls recognized by FDA 

in its regulations for clinical trials of 

drugs and devices (21 CFR 

314.126(b)(2)(i)–(v) and 21 CFR 

860.7(f)(1)(iv)(a)–(d)) in that it includes 

both concurrent controls, as would be 

used in trials with multiple arms, and 

non-concurrent controls, as may be used 

in single-arm trials that are expressly 

designed to compare the effect of an 

intervention to an historical control or 

to baseline data, e.g., with participants 

serving as controls. It is broader than the 

FDA definitions of ‘‘adequate and well 

controlled’’ in 21 CFR 314.126(b) and 

‘‘well controlled’’ in 21 CFR 860.7(f) in 

that it does not imply a judgment about 

the adequacy or appropriateness of the 

control and the study design. 

Based on this definition, we would 

consider any clinical trial with multiple 

concurrent arms to be controlled for 

purposes of determining whether it is an 

applicable clinical trial subject to this 

proposed Part. We would also consider 

some single-arm clinical trials to be 

controlled. Such trials include singlearm trials of FDA-regulated products 

that, as specified in their protocols, 

intend to evaluate an effect by 

comparing measures taken after an 

intervention to baseline measures taken 

from the participants prior to the 

intervention. Many of these studies have 

explicitly defined ‘‘change from 

baseline’’ measures identified in their 

protocols, i.e., they are designed to 

compare a measure taken after an 

intervention to the participant’s state 

prior to the intervention. Other singlearm trials that we would consider 

controlled include, for example, studies 

with an identified measure of ‘‘response 

rate’’ or measures in which the state 

prior to or without the intervention can 

be assumed (e.g., studies in conditions 

that do not resolve without intervention, 

such as cancer). 

We propose in § 11.28 that a 

responsible party who registers a singlearm trial indicate whether the trial 

protocol or statistical analysis plan 

specifies a control as defined in this 

part. While plans for analyzing collected 

data may change during the course of a 

study, we believe that the requirement 

that the control be specified in the 

protocol or statistical analysis plan will 

improve consistency in the 

interpretation of this requirement across 

trials. We considered requiring greater 

specification about the type of control, 

if any, used in the single-arm study, e.g., 

historical control (including subjects as 

their own control), but believe our 

proposed approach provides the 

information necessary for identifying 

applicable clinical trials while 

minimizing the burden on responsible 

parties. We propose in § 11.22(b) to use 

the information submitted by the 

responsible party to determine whether 

a trial meets the definition of an 

applicable clinical trial. 

We invite comments on our proposed 

approach for identifying single-arm 

trials that would be considered 

controlled and on alternative ways to 

identify such trials. In particular, we 

invite comments on whether there are 

other specific, objective features of 

clinical trials that could serve as the 

basis for differentiating between singlearm studies that are and are not 

controlled. We also invite comments on 

and information about, the types of 

single-arm trials that meet the other 

criteria for an applicable clinical trial 

and do or do not meet our proposed 

definition of controlled. 

(b) Responsible party. Section 

402(j)(1)(A)(ix) defines the responsible 

party with respect to a clinical trial of 

a drug or device as: ‘‘(I) the sponsor of 

the clinical trial (as defined in . . . 21 

[CFR 50.3] . . . (or any successor 

regulation)); or (II) the principal 

investigator of such clinical trial if so 

designated by a sponsor, grantee, 

contractor, or awardee, so long as the 

principal investigator is responsible for 

conducting the trial, has access to and 

control over the data from the clinical 

trial, has the right to publish the results 

of the trial, and has the ability to meet 

all of the requirements . . . [of this part] 

for the submission of clinical trial 

information.’’ We adopt this definition 

with minor, non-substantive 

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modifications in § 11.10 of this 

proposed rule. 

Given the significance of the role that 

the responsible party plays in 

complying with section 402(j) of the 

PHS Act, we elaborate on the meaning 

and interpretation of this term in section 

IV.A.5 of this preamble. We have 

codified parts of the elaboration of the 

definition of responsible party in 

proposed § 11.4(c), which specifies 

procedures for determining the 

responsible party. We have also 

included a definition of the term 

sponsor in proposed § 11.10. 

2. Modifications and Additions to the 

Elements of Clinical Trial Registration 

Information 

The clinical trial registration 

information required by section 

402(j)(2)(A)(ii) of the PHS Act includes 

25 specific data elements grouped into 

4 categories: Descriptive information, 

recruitment information, location and 

contact information, and administrative 

information. Additionally, section 

402(j)(2)(A)(iii) of the PHS Act 

authorizes the Secretary, by regulation, 

to modify the statutory requirements for 

clinical trial registration information if a 

rationale is provided as to ‘‘why such a 

modification improves and does not 

reduce’’ such information. Proposed 

§ 11.28 lists the clinical trial 

information that we propose to require 

at the time of registration. The 

definitions of specific data elements are 

provided in proposed § 11.10(b). For the 

most part, the proposed list of data 

items conforms to the list of items 

enumerated in section 402(j)(2)(A)(ii) of 

the PHS Act, restating, and, in many 

instances, clarifying the statutory data 

items. However, this proposed rule 

includes certain modifications and 

additions to the data items listed in 

402(j)(2)(A)(ii) of the PHS Act that we 

conclude improve the clinical trial 

information available to the public and 

implement the requirements of the 

statute. We do not believe that any of 

the proposed modifications and 

additions reduces the clinical trial 

information available to the public. As 

further explained in section IV.B.4 of 

this preamble, a number of the proposed 

modifications and additions to clinical 

trial registration information listed in 

section 402(j)(2)(A)(ii) of the PHS Act 

are not new to some responsible parties 

and other users of the data bank who 

submitted information to 

ClinicalTrials.gov prior to FDAAA; 

many of the data elements are the same 

or similar to those collected in 

ClinicalTrials.gov prior to enactment of 

FDAAA. 

Our proposed modifications and 

additions to clinical trial registration 

information take the following general 

forms. 

(1) Structuring data entry for 

registration data elements to help the 

public use the data bank and compare 

entries, as required by section 

402(j)(2)(B)(iv) of the PHS Act. We 

believe structured data entry for 

registration data elements helps satisfy 

the requirement at 402(j)(2)(B)(iv) to 

‘‘ensure that the registry data bank is 

easily used by the public, and that 

entries are easily compared,’’ because it 

will enable users to search the data bank 

using the criteria listed in section 

402(j)(2)(B)(i) of the PHS Act and will 

prompt responsible parties to submit 

complete and accurate information. We 

therefore propose to require responsible 

parties to enter defined components of 

certain data elements, such as study 

design, outcome measure, and IND or 

IDE number. For example, in 

§ 11.10(b)(35), we propose to define the 

Food and Drug Administration IND or 

IDE number, a data element expressly 

required to be submitted at the time of 

registration by section 

402(j)(2)(A)(ii)(IV)(cc) of the PHS Act 

(therein referred to as the ‘‘IND/IDE 

protocol number’’) to include the name 

of the FDA center that issued the IND 

or IDE (e.g., the Center for Drug 

Evaluation and Research (CDER), the 

Center for Biologics Evaluation and 

Research (CBER), or the Center for 

Devices and Radiological Health 

(CDRH)); the IND or IDE number; and 

any serial number that has been 

assigned by the sponsor to that filing. 

We believe these three components are 

necessary to provide complete 

information about IND/IDE number. 

(2) Additions to allow effective 

implementation of, or compliance with, 

other provisions of section 402(j) of the 

PHS Act. For example, this proposed 

rule in § 11.28(a)(1)(xv) requires 

information about whether a product 

under study in a clinical trial is 

manufactured in the U.S. or one of its 

Territories because this information is 

necessary in some situations to 

determine whether or not a clinical trial 

meets the definition of an applicable 

clinical trial or would be considered a 

voluntary submission under section 

402(j)(4)(A) of the PHS Act. 

(3) Additions to improve the quality 

and consistency of information available 

in the data bank and enabling users to 

better search for, retrieve, and 

understand it. For example, in 

§ 11.28(a)(1)(xi) of this proposed rule, 

we propose that responsible parties 

submit other current and former names 

for interventions studied in a clinical 

trial (if other such names exist) to help 

identify duplicative trial registrations 

and assist users in finding clinical trials 

for interventions that might be 

registered under different names (e.g., 

the name of the chemical compound, 

the brand name of an approved product, 

or an alias used during pre-marketing 

studies). 

(4) Addition to indicate the ethical 

and scientific review status of the 

clinical trials listed in the data bank. We 

believe that it is essential that patients 

and practitioners searching 

ClinicalTrials.gov for information about 

clinical trials retrieve information on 

whether a clinical trial registered in 

ClinicalTrials.gov is undergoing or has 

undergone review procedures with 

respect to ethical and scientific 

considerations. A small number of 

applicable clinical trials may not be 

required by applicable law, regulation, 

and/or institutional policy to seek 

approval from a human subjects 

protection review board (e.g., if a waiver 

has been provided, the clinical trial is 

determined to be exempt in accord with 

applicable law and regulation, or the 

clinical trial is not subject to laws, 

regulations, or institutional policies that 

require review by a human subjects 

protection review board). In such cases, 

the proposed rule would require 

responsible parties to indicate that 

human subjects protection review board 

approval is not required by applicable 

law, regulation, or institutional policy. 

We recognize that provision of 

information on human subjects review 

status cannot guarantee the quality of a 

clinical trial or the safety of human 

subjects who are enrolled in it. 

Nevertheless, we believe that requiring 

responsible parties to indicate whether 

a clinical trial registered in 

ClinicalTrials.gov is undergoing or has 

undergone review by a human subjects 

protection review board may provide 

some measure of assurance in most 

situations. 

We invite comments on our proposed 

modifications and additions to the data 

elements of clinical trial registration 

information, including the benefits and 

burdens associated with structuring 

certain registration data elements. 

3. Posting of Registration Information 

for Applicable Device Clinical Trials 

Section 402(j)(2)(D) of the PHS Act 

establishes the timelines for posting 

clinical trial registration information 

submitted by responsible parties in the 

data bank. For applicable drug clinical 

trials, section 402(j)(2)(D)(i) of the PHS 

Act requires NIH to post publicly 

clinical trial registration information not 

later than 30 days after it has been 

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submitted. For applicable device 

clinical trials of devices that previously 

have been approved or cleared by FDA, 

section 402(j)(2)(D)(ii)(II) of the PHS Act 

requires that clinical trial registration 

information be posted not later than 30 

days after clinical trial results 

information is required to be posted by 

NIH. As discussed in detail in section 

IV.B.5(b) of this preamble, NIH has 

interpreted this provision as allowing 

NIH to post clinical trial registration 

information for applicable device 

clinical trials of these devices as soon as 

practicable. For applicable device 

clinical trials of devices that have not 

previously been approved or cleared, 

NIH intends that, consistent with 

section 402(j)(2)(D)(ii)(I) of the PHS Act, 

clinical trial registration information 

will be posted not earlier than the date 

on which FDA approves or clears the 

device and not later than 30 calendar 

days after the date of such approval or 

clearance. 

While postponing the posting of 

clinical trial registration information for 

applicable device clinical trials for a 

device that previously has not been 

approved or cleared may protect the 

commercial interests of device 

manufacturers, there are a number of 

situations in which those who conduct 

such clinical trials may prefer to make 

such information publicly available in 

the data bank prior to the time frames 

allowed by section 402(j) of the PHS Act 

and this rulemaking. For example, based 

on experience to date, we believe that 

some sponsors and principal 

investigators prefer to make their 

registration information publicly 

available in the data bank because this 

would be an easy way to meet the ICMJE 

policy [Ref. 10], which requires public 

registration in a data bank prior to 

enrollment of the first patient as a 

precondition for consideration for 

publication. Others prefer to make 

registration information available to the 

public to assist with or expand upon 

efforts to recruit potential human 

subjects for a trial. In other cases, 

responsible parties might wish to make 

some of the registration information 

available to demonstrate to others (e.g., 

a funding organization or the sponsor) 

that a clinical trial has, in fact, been 

registered as required by section 402(j) 

of the PHS Act and this proposed 

regulation. 

We considered, but do not propose, 

two potential mechanisms for 

addressing these situations: (1) 

Allowing a responsible party to give 

voluntarily the NIH permission to 

release clinical trial registration 

information for an applicable device 

clinical trial of a device that previously 

has not been approved or cleared for 

public posting in the data bank, and (2) 

allowing any individual or entity to 

whom the responsible party provides 

the NCT number for such a trial (i.e., the 

unique identifier that is assigned to a 

trial upon registration in the data bank) 

to access a very limited set of data 

sufficient to verify that the clinical trial 

of interest has been registered, but 

without revealing substantive 

information about the clinical trial, such 

as the focus of the clinical trial or the 

products involved. However, section 

402(j)(2)(D)(ii) of the PHS Act provides 

that the ‘‘Director of NIH shall ensure 

that clinical trial information for an 

applicable device clinical trial of an 

unapproved or uncleared device 

submitted in accordance with . . . 

[section 402(j)(2) of the PHS Act not be] 

posted publicly . . .’’ before approval or 

clearance. Because neither of the 

mechanisms appears to be permissible 

under the statute, we have not proposed 

implementing either of these 

mechanisms in this rulemaking. We 

invite comments from the public on 

how, given the statutory language, the 

Agency may address the concerns of 

sponsors and responsible parties who 

wish to have clinical trial registration 

information for applicable device 

clinical trials of devices that previously 

have not been approved or cleared made 

publicly accessible in ClinicalTrials.gov 

when the responsible party so chooses. 

4. Application of Rule to a Pediatric 

Postmarket Surveillance of a Device 

That Is Not a Clinical Trial 

In section 801(c), FDAAA requires the 

Secretary of HHS to issue guidance on 

how section 402(j) of the PHS Act 

applies to a pediatric postmarket 

surveillance of a device that is not a 

clinical trial. Section 402(j)(1)(A)(ii)(II) 

of the PHS Act defines the term 

applicable device clinical trial to 

include ‘‘a pediatric postmarket 

surveillance as required under section 

522 of the [FD&C] Act.’’ This proposed 

rule in § 11.10 defines ‘‘pediatric 

postmarket surveillance of a device’’ as 

‘‘the active, systematic, scientifically 

valid collection, analysis, and 

interpretation of data or other 

information conducted under section 

522 of the [FD&C] Act about a marketed 

device that is expected to have 

significant use in patients who are 21 

years or younger at the time of diagnosis 

or treatment. A pediatric postmarket 

surveillance of a device may be, but is 

not always, a clinical trial.’’ 

FDA may order a pediatric postmarket 

surveillance of a device under section 

522 of the FD&C Act for any class II or 

class III device, as defined by 21 U.S.C. 

360c(a) and 21 CFR 860.3, meeting any 

of the following criteria: Its failure 

would be reasonably likely to have 

serious adverse health consequences; it 

is expected to have significant use in 

pediatric populations; it is intended to 

be implanted in the body for more than 

1 year; or it is intended to be a lifesustaining or life-supporting device 

outside a device user facility. (See 21 

U.S.C. 360l(a).) Pediatric postmarket 

surveillances under section 522 of the 

FD&C Act can take various forms, 

including a detailed review of the 

complaint history and the scientific 

literature, non-clinical testing, 

observational studies, and controlled 

clinical trials [Ref. 25]. 

Because section 402(j)(1)(A)(ii)(II) of 

the PHS Act defines the term 

‘‘applicable device clinical trial’’ to 

include pediatric postmarket 

surveillances of a device, such 

surveillances must be registered, and 

clinical trial results information must be 

submitted for them. Our proposed 

approach for applying the registration 

requirements to a pediatric postmarket 

surveillance of a device that is not a 

clinical trial is described in proposed 

§ 11.28(b). Our proposed approach for 

applying the results submission 

requirements to a pediatric postmarket 

surveillance of a device that is not a 

clinical trial is described in proposed 

§ 11.48(b). A pediatric postmarket 

surveillance of a device that is a clinical 

trial would be subject to the general 

requirements of this proposed rule, 

including the clinical trial registration 

and results submission requirements in 

proposed §§ 11.28(a) and 11.48(a), 

respectively. Further elaboration of 

these proposals is contained in section 

IV.B of this preamble. 

5. Submission of Results Information for 

Applicable Clinical Trials of 

Unapproved, Unlicensed, or Uncleared 

Products 

(a) General requirements and 

rationale. Section 402(j)(3)(D)(ii)(I) of 

the PHS Act requires the submission of 

results information for: (1) Each 

applicable drug clinical trial for a drug 

that is approved under section 505 of 

the FD&C Act or licensed under section 

351 of the PHS Act; and (2) each 

applicable device clinical trial for a 

device that is cleared under section 

510(k) of the FD&C Act or approved 

under section 515 or 520(m) of the 

FD&C Act. By contrast, section 

402(j)(3)(D)(ii)(II) of the PHS Act 

requires that the Secretary establish, 

through regulation, whether or not 

results information must be submitted 

for applicable clinical trials of 

unapproved, unlicensed, or uncleared 

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products, whether or not approval, 

licensure, or clearance was sought. If the 

Secretary requires, by regulation, the 

submission of results information for 

unapproved, unlicensed, or uncleared 

products, then section 

402(j)(3)(D)(iv)(III) of the PHS Act 

authorizes the Secretary to determine, 

by regulation, ‘‘the date by which such 

clinical trial information shall be 

required to be submitted,’’ taking into 

account (a) the process under section 

402(j)(3)(E)(iii) of the PHS Act for 

‘‘delayed submission of results with 

certification’’ when approval, licensure, 

or clearance is sought; and (b) whether 

there should be a delay of submission 

when approval, licensure, or clearance 

will not be sought. 

Pursuant to our authority under 

section 402(j)(3)(D)(ii)(II) of the PHS 

Act, we have decided to propose that 

results information be submitted for 

applicable clinical trials of drugs and 

devices that are not approved, licensed, 

or cleared by FDA, regardless of 

whether approval, licensure, or 

clearance is sought. In addition, 

pursuant to our authority under section 

402(j)(3)(D)(iv)(III) of the PHS Act, we 

propose deadlines for submitting this 

results information that, as required by 

statute, take into account both the 

certification process under section 

402(j)(3)(E)(iii) of the PHS Act for 

delayed submission of results when 

approval, licensure, or clearance is 

sought and whether there should be 

delayed submission of results when 

approval, licensure, or clearance will 

not be sought. As discussed in section 

III.D of this preamble, these proposals 

would apply to applicable clinical trials 

of unapproved, unlicensed, or uncleared 

products that reach their completion 

dates on or after the effective date of this 

rule, as well as certain applicable 

clinical trials of unapproved, 

unlicensed, or uncleared products that 

reach their completion dates prior to the 

effective date of the rule. 

We believe our proposal to require 

results submission for applicable 

clinical trials of unapproved, 

unlicensed, or uncleared products is in 

furtherance of the express statutory 

purpose of the expanded data bank, 

which states that the Secretary shall 

expand the registry and results data 

bank ‘‘[t]o provide more complete 

results information and to enhance 

patient access to and understanding of 

the results of clinical trials.’’ (See 

section 402(j)(3)(D)(i) of the PHS Act.) In 

developing our proposal, we considered 

a number of factors, many of which 

were raised at the Public Meeting [Ref. 

1], notably the potential public health 

benefits of timely disclosure of results 

information for clinical trials of drugs 

that are not approved, biological 

products that are not licensed, and 

devices that are not approved or cleared; 

the potential effects of disclosure on the 

competitive advantage of drug and 

device manufacturers, including 

incentives to invest in the development 

of new products intended to improve 

public health; and other results 

submission requirements and policies 

(e.g., those of the EMA). Other 

considerations include the relative 

burden on the responsible party of 

submitting results for clinical trials of 

unapproved drugs, unlicensed 

biological products, and unapproved or 

uncleared devices, the date by which 

results must be submitted, and practical 

issues of implementation and 

compliance. 

The Agency finds compelling the 

arguments in support of a requirement 

to submit the results of applicable 

clinical trials of unapproved, 

unlicensed, or uncleared products. The 

availability of such information in 

ClinicalTrials.gov could have several 

potential public health benefits. 

Systematic disclosure of results of 

applicable clinical trials of unapproved, 

unlicensed, or uncleared products 

would mitigate the bias in information 

available to the public about studied 

medical products that stems from 

selective disclosure of clinical trial 

results [Ref. 26]. Currently, sponsors, 

researchers, and product manufacturers 

often voluntarily and selectively release 

to the public partial information about 

the results of specific studies, including 

those of unapproved, unlicensed, or 

uncleared products, via scientific 

publications and abstracts, press 

releases, and other announcements. 

Requiring the submission of results of 

applicable clinical trials of unapproved, 

unlicensed, or uncleared products in a 

systematic and standardized format 

would provide a more current and 

complete picture of results of clinical 

trials of FDA-regulated products, 

therefore reducing a potential source of 

bias. 

The public availability of results 

information about trials of unapproved, 

unlicensed, and uncleared drugs 

(including biological products) and 

devices would also help protect the 

safety of participants who volunteer to 

be in clinical trials by reducing the 

likelihood that people will unknowingly 

design, approve, or participate in 

clinical trials that are unnecessary (e.g., 

because similar clinical trials have 

already been conducted but not 

published), or that are potentially 

harmful (e.g., because similar 

interventions have been shown to be 

harmful or ineffective in previous, 

unpublished clinical trials). It would 

also help potential human subjects 

make more informed decisions about 

participating in a clinical trial by 

providing them and their care providers 

with information about the results of a 

broader set of clinical trials of various 

interventions that have been studied for 

a disease or condition of interest. 

Investigators and human subjects 

protection review boards that already 

have access to unpublished information 

from the sponsor of a clinical trial or the 

manufacturer of a drug or device would 

have access via ClinicalTrials.gov to 

information about other clinical trials of 

similar unapproved, uncleared, or 

unlicensed products that might help 

them in designing or considering the 

potential risks and benefits of 

participation in a clinical trial. 

In addition, submission of results of 

clinical trials of unapproved, 

unlicensed, or uncleared products 

would broaden the evidence base for 

systematic reviewers and others 

involved in assessing the benefits and 

harms of classes of drugs and devices. 

Many clinical trials compare 

unapproved, unlicensed, or uncleared 

drugs and/or devices with approved, 

licensed, or cleared drugs and/or 

devices, and the submission of results of 

such clinical trials could increase access 

to additional information about the 

marketed products for their approved, 

licensed, or cleared uses. In addition, 

many unapproved, unlicensed, or 

uncleared products are similar to 

products that are approved, licensed, or 

cleared and in the marketplace. This is 

particularly true of the unapproved, 

unlicensed, or uncleared versions of 

products that are studied in clinical 

trials that contribute to the evidence 

base for subsequent approval, licensure, 

or clearance of a different version of the 

product. Preliminary or alternative 

versions of a drug, for example, may 

differ from the approved or licensed 

version in dose, form, or inactive 

ingredients, even if they contain the 

same active ingredient(s). Results of 

clinical trials of unapproved products 

could therefore enhance the knowledge 

base for understanding classes of 

products. 

There is also a compelling ethical 

rationale for making available to the 

public the results from clinical trials 

that involve human subjects, regardless 

of the approval status of the product. 

Part of the agreement made with human 

subjects who agree to participate in 

clinical trials is that knowledge that is 

obtained in the clinical trial will be 

available for use in advancing 

biomedical science [Ref. 27]. 

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Submission and subsequent posting of 

the results of applicable clinical trials of 

unapproved drugs, unlicensed 

biological products, and unapproved or 

uncleared devices to ClinicalTrials.gov 

that reach their completion dates on or 

after the effective date of a final rule 

would help to achieve that goal, 

especially for clinical trials for which 

results are never published in the 

scientific literature. 

We also are aware of ongoing 

regulatory efforts by the EMA to make 

results of clinical trials of drugs 

conducted within the EU available in a 

publicly accessible data bank, regardless 

of the approval status of the drug [Ref. 

28, 29, 30]. Already, all clinical trials of 

drugs performed within the EU are 

registered in EMA’s EudraCT database, 

with information on phase 2, 3, and 4 

clinical trials and all pediatric clinical 

trials made public through the EU 

Clinical Trials Register (https://www.

clinicaltrialsregister.eu/). In June 2010, 

EMA issued for public comment the 

draft implementing technical guidance 

on the EudraCT results data bank. The 

technical guidance specifies summary 

results information that would be 

submitted to the data bank for public 

posting. The specified summary results 

information differs from the detailed 

information that would be submitted to 

EMA as part of a Marketing 

Authorization Application. As noted in 

that document, EMA has worked with 

ClinicalTrials.gov staff to harmonize 

common data elements used by the two 

results data banks, which we view as a 

way of simplifying the process of 

submitting results to EudraCT and 

ClinicalTrials.gov, for those trial that are 

required to submit results to both data 

banks. Many clinical trials that would 

be subject to EMA regulations requiring 

the disclosure of clinical trial results 

would likely be applicable clinical trials 

subject to section 402(j) of the PHS Act. 

We believe that if clinical trial results 

information is available via another 

publicly accessible data bank (such as 

EudraCT), a number of the concerns that 

have been expressed about disclosure in 

ClinicalTrials.gov would no longer be 

applicable. The use of common data 

elements would promote harmonization 

of results information in EudraCT and 

ClinicalTrials.gov and simplify data 

submission for clinical trials that would 

be summarized in both databases. 

We recognize that the posting of 

results information about clinical trials 

of unapproved, unlicensed, and 

uncleared products presents special 

challenges. Such information would be 

accessible to care providers and their 

patients and would describe uses of 

products that are not approved, cleared, 

or licensed. Even for approved, cleared, 

or licensed uses the posted result 

information would contain information 

that is not included in approved 

labeling and that requires further 

interpretation for understanding 

potential risks and benefits. We believe 

that the results information from any 

individual clinical trial should be 

considered not on its own, but in the 

context of the broader set of information 

available about the product and 

alternative products. In keeping with 

current practice, we intend to establish 

links from clinical trial records in 

ClinicalTrials.gov additional sources of 

information, including but not limited 

to the FDA and NIH information 

specified in section 402(j)(3)(A)(ii) of 

the PHS Act (we would indicate that the 

links were added by the NIH and not by 

the responsible party). As discussed 

further in section III.C.11, we would 

also provide information to assist users 

in better understanding and interpreting 

the information available in 

ClinicalTrials.gov, including materials 

that describe the general purpose and 

content of the data bank, the limitations 

of the data presented, and cautions that 

the information should be used in 

conjunction with advice from healthcare 

professionals. 

We believe that all of these benefits 

can be best achieved by requiring the 

submission of results information for all 

applicable clinical trials involving 

unapproved, unlicensed, or uncleared 

products, regardless of whether FDA 

approval, licensure, or clearance is 

sought. Limiting results submission to 

those applicable clinical trials of 

unapproved, unlicensed, or uncleared 

products for which product 

development has been abandoned by 

industry would minimize industry 

concerns about disclosing potentially 

valuable information to competitors, but 

would do little to address concerns 

about bias in the disclosure of 

information. Considerable information 

of potential scientific, clinical, and 

public significance would still be 

hidden from public view and would 

continue to be unavailable for 

consideration by human subjects 

protection review boards in assessing 

proposed clinical trials, by individuals 

considering participation in them, or by 

other researchers who are planning 

similar clinical trials or clinical trials of 

similar products. Even if investigators 

and human subjects protection review 

boards have access to information from 

a clinical trial sponsor, they will not 

have access to the full range of 

unpublished results of other clinical 

trials that might be relevant to a clinical 

trial under consideration. We believe 

that concerns about commercial 

competitiveness resulting from 

disclosure of results information from 

clinical trials of products that are not 

approved, licensed, or cleared by the 

FDA can be mitigated by delaying the 

results submission deadline for 

applicable clinical trials of products that 

are still under development, as 

described later in this section. Indeed, 

disclosure of results information for 

clinical trials of products that are still 

under development could improve the 

efficiency of research and development 

(R&D) investments by reducing the 

likelihood that private companies, 

universities, and the U.S. Government 

will waste resources repeating studies of 

interventions that have already been 

conducted. In addition, limiting 

disclosure to applicable clinical trials of 

products for which product 

development has been abandoned 

would be difficult to administer because 

only the sponsor and/or manufacturer 

are in a position to determine that 

product development has been 

abandoned for all potential uses. 

Moreover, as noted by some industry 

commenters, product development is 

often suspended for periods of time 

before being resumed when company 

priorities change or a developmental 

product is transferred to another 

company. Information about 

unapproved products still in product 

development pipelines might therefore 

remain undisclosed for long periods of 

time, depriving the public of the 

benefits that could result from 

disclosure even in situations where nondisclosure might provide little 

commercial advantage. 

We therefore propose, as authorized 

by section 402(j)(3)(D)(ii)(II) of the PHS 

Act and as specified in proposed 

§ 11.42(a), to require submission of 

clinical trial results information for 

applicable clinical trials that reach their 

completion dates on or after the 

effective date of the rule and that 

involve a drug, biological product, or 

device that is not approved, licensed, or 

cleared for any indication, regardless of 

whether the sponsor seeks approval, 

licensure, or clearance. We believe that 

requiring this information to be 

submitted is consistent with the 

statute’s stated purpose in expanding 

the registry and results data bank ‘‘[t]o 

provide more complete results 

information and to enhance patient 

access to and understanding of the 

results of clinical trials.’’ (See section 

402(j)(3)(D)(i) of the PHS Act). 

In considering the deadlines for 

submitting results information for 

applicable clinical trials of unapproved, 

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unlicensed, or uncleared products, as 

required by section 402(j)(3)(D)(iv)(III) 

of the PHS Act, the Agency recognized 

a need to balance several considerations 

namely: Commercial interests in 

protecting information about products 

under development, public health 

benefits of timely access to results 

information, the burden associated with 

submission of results information, and 

administrative burden. We also 

considered the statutory requirements of 

section 402(j)(3)(D)(iv)(III) of the PHS 

Act to take into account: (1) the 

certification process for delayed 

submission of results under section 

402(j)(3)(E)(iii) of the PHS Act ‘‘when 

approval, licensure, or clearance is 

sought’’ for a product studied in an 

applicable clinical trial; and (2) 

‘‘whether there should be a delay of 

submission when approval, licensure or 

clearance will not be sought.’’ 

As further described below, we 

propose to require results submission 

for applicable clinical trials involving 

unapproved, unlicensed, or uncleared 

products not later than 1 year after the 

completion date of the clinical trial, 

unless the responsible party submits a 

certification under section 

402(j)(3)(E)(iii) of the PHS Act prior to 

that deadline indicating that initial 

approval, licensure, or clearance is 

being sought or may at a future date be 

sought. 

Delayed submission of results of 

applicable clinical trials involving 

products that are unapproved, 

unlicensed, or uncleared would be 

permitted only if the responsible party 

certifies under section 402(j)(3)(E)(iv) of 

the PHS Act that the sponsor or 

manufacturer intends to continue with 

product development, meaning that it is 

either seeking, or may at a future date 

seek, initial approval, licensure, or 

clearance of the product under study in 

an applicable clinical trial. For 

applicable clinical trials of unapproved, 

unlicensed, or uncleared products, 

results submission may be delayed only 

if section 402(j)(3)(E)(iv) of the PHS Act 

applies. In determining whether section 

402(j)(3)(E)(iv) of the PHS Act applies to 

a particular applicable clinical trial, we 

took into consideration the fact that 

section 402(j)(3)(D)(iv)(III)(aa) of the 

PHS Act indicates that the certification 

process under section 402(j)(3)(E)(iii) of 

the PHS Act applies ‘‘when approval, 

licensure, or clearance is sought’’ 

(emphasis added), whereas section 

402(j)(3)(D)(iv)(III)(bb) of the PHS Act 

states that the Secretary shall determine, 

by regulation, ‘‘whether there should be 

a delay of submission when approval, 

licensure, or clearance will not be 

sought’’ (emphasis added). We consider 

these two provisions together to mean 

that delayed submission of results with 

certification is allowable if initial 

approval, licensure, or clearance is 

sought, meaning that the sponsor or 

manufacturer intends to continue with 

product development and thus either is 

seeking, or may at a future date seek, 

approval, licensure, or clearance. This 

proposed rule does not include a 

provision extending delayed submission 

when approval, licensure, or clearance 

will not be sought. 

Delayed submission of results would 

not be available to a responsible party 

who either meets the criteria in section 

402(j)(3)(E)(iv) of the PHS Act to certify 

but does not submit a certification prior 

to the deadline under the process set 

forth in section 402(j)(3)(E)(iii) of the 

PHS Act, or who does not meet the 

statutory criteria to submit a 

certification. In such instances, we 

propose that results be due not later 

than 1 year after the completion date, 

unless an extension for good cause is 

requested and granted under section 

402(j)(3)(E)(vi) of the PHS Act. This 

deadline is consistent with the time 

frame in section 402(j)(3)(E)(i) of the 

PHS Act for submitting results 

information. Specifically with regard to 

applicable clinical trials of drugs 

(including, biological products) or 

devices for which approval, licensure, 

or clearance will not be sought, we 

interpret the phrase ‘‘will not be 

sought’’ to mean that the sponsor or 

manufacturer has no intention of 

developing a marketable product or 

otherwise has abandoned product 

development. For these trials, the 

Agency believes that the public benefits 

of disclosure of results information 

outweigh any private, commercial 

interests. We recognize that, in many 

cases, whether initial approval, 

licensure, or clearance is, or may at a 

future date be, sought is information 

that will be known only to the sponsor 

or manufacturer of the drug, biological 

product, or device and may not even be 

known to them at the time a clinical 

trial is completed, especially for an 

earlier stage trial, such as a phase 2 

applicable drug clinical trial. Instead, 

the sponsor or manufacturer may know 

only that it intends to continue with 

product development, such as through 

the conduct of a subsequent clinical 

trial. Accordingly, the Agency needs a 

way to verify that the sponsor or 

manufacturer is seeking, or may at a 

future date seek, initial approval, 

licensure, or clearance. Therefore, as a 

condition of delaying results submission 

for unapproved, unlicensed, or 

uncleared products, we propose in 

§ 11.44(c), to require the responsible 

party to certify that the sponsor or 

manufacturer intends to continue with 

product development and either is 

seeking, or may at a future date seek, 

approval, licensure, or clearance. See 

section 402(j)(3)(E)(iv) of the PHS Act. If 

the responsible party elects to submit a 

certification for delayed submission, it 

is the responsible party’s obligation to 

verify that the particular applicable 

clinical trial meets the proposed 

§ 11.44(c) criteria, as explained in this 

preamble. We recommend that if the 

sponsor has designated the PI as the 

responsible party under the process 

described under proposed § 11.4(c), the 

sponsor should be prepared to 

communicate with the responsible party 

to help ensure the accuracy of any 

certification that is made. 

If after submission of a certification 

that section 402(j)(3)(E)(iv) of the PHS 

Act applies to a specific applicable 

clinical trial, the drug, biological 

product, or device studied in the 

applicable clinical trial becomes 

approved, licensed, or cleared for the 

indication studied in the applicable 

clinical trial, results information would 

be due 30 calendar days after approval, 

licensure, or clearance. If, after 

submission of a certification that section 

402(j)(3)(E)(iv) applies to the applicable 

clinical trial, initial approval is no 

longer being sought (i.e., product 

development is abandoned), we 

likewise do not believe that continued 

delays in results submission are 

warranted, and we recommend that the 

responsible party should submit results 

information as soon as practicable. 

Furthermore, we do not believe that a 

delay in submitting results for 

applicable clinical trials of unapproved, 

unlicensed, or uncleared products 

should be indefinite, enduring until a 

responsible party proactively asserts 

that product development has been 

abandoned or until the product is 

approved, licensed, or cleared. We 

therefore propose to limit the allowable 

delay period for results submission for 

applicable clinical trials of unapproved, 

unlicensed, or uncleared products to 2 

years after the submission of a 

certification for delayed results 

submission. The certification would 

have to be submitted prior to the date 

on which results information would 

otherwise be due (e.g., 12 months after 

the completion date), and we would 

permit only one certification to be 

submitted for each clinical trial. Product 

development can extend over long 

periods of time and may even be 

suspended or remain inactive for 

significant periods of time, whether due 

to limited financing, changes in 

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corporate policy, revised strategic plans, 

or other reasons. While sponsors or 

manufacturers may find commercial 

advantage in protecting clinical trial 

results during this extended period, 

those advantages must be weighed 

against the disadvantages of denying 

access to results information to the 

research community, healthcare 

providers, and the public for an 

extended period. 

The proposed 2-year time limitation 

reflects a balance between the need to 

protect competitive advantage and the 

desire for public access to clinical trial 

results. Within this time frame, a 

sponsor or manufacturer would often 

make a decision about whether to 

initiate another clinical trial or submit 

a marketing application or premarket 

notification to the FDA. A subsequent 

pre-market clinical trial of a drug would 

likely be an applicable clinical trial that 

would be registered at 

ClinicalTrials.gov, making public 

information about the sponsor’s 

intention to pursue product 

development. The total delay in 

disclosure of results of up to 3 years 

after the completion date would provide 

sponsors with significant lead time in 

product development over potential 

competitors. 

(b) Additional results information for 

applicable clinical trials of unapproved 

or uncleared devices. Once clinical trial 

results information is submitted, section 

402(j)(3)(G) of the PHS Act requires 

public posting of that information no 

later than 30 days after the date of 

submission (See proposed § 11.52, 

which implements this statutory 

requirement). Thus, clinical trial results 

information for applicable clinical trials 

of both approved, licensed, and cleared, 

products and unapproved, unlicensed, 

and uncleared products will be publicly 

posted no later than 30 calendar days 

after submission. Section 

402(j)(2)(D)(ii)(I) of the PHS Act requires 

the clinical trial information submitted 

upon registration of applicable device 

clinical trials of devices that have not 

previously been approved or cleared not 

be posted earlier than the date on which 

FDA approves or clears the device 

studied in the applicable clinical trial. 

(See section III.C.3. of this preamble.) 

Therefore the proposed timelines for 

submitting and publicly posting clinical 

trial results information in §§ 11.44 and 

11.52 may result in the public 

availability of clinical trial results 

information for applicable device 

clinical trials for unapproved or 

uncleared devices before the 

information submitted during 

registration is posted for these same 

trials. 

We believe that posting clinical trial 

results information without the 

corresponding public availability of 

certain descriptive information that is 

the same type of information that is 

included as part of registration would 

fail to provide the necessary context for 

understanding clinical trial results 

information and would significantly 

limit access to and understanding of 

posted results data. This is why journal 

articles and other reports of the results 

of clinical trials routinely include 

information about the disease or 

condition and interventions under 

study, the inclusion and exclusion 

criteria for participants, the location(s) 

of the trial, etc. Without such 

information, results data about patient 

demographics, outcomes, and adverse 

events would be uninterpretable and 

inaccessible. For example, patients and 

other users typically access clinical trial 

results by searching for (and retrieving) 

clinical trials with specific 

characteristics, e.g., that involve a 

particular intervention or type of 

intervention, study a particular disease 

or condition, recruit certain types of 

subjects, take place during a particular 

time period, are conducted in a specific 

location or particular facility, are 

sponsored by a particular organization, 

or match a title or identification number 

they have found in other public sources. 

This type of information is not included 

as part of clinical trial results 

information under proposed § 11.48(a) 

but is the same type of descriptive 

information submitted upon 

registration, e.g., Brief Title, 

Intervention Name, Study Start Date, 

Completion Date. 

Similarly, to enhance their 

understanding of the clinical trial 

results, researchers, healthcare 

providers, patients and other users of 

ClinicalTrials.gov need information 

about the purpose of the study, its 

design, the intervention(s) studied, the 

types of subjects eligible to participate, 

the duration of the study, and the 

outcome measures. They need to know 

whether the clinical trial is completed, 

if data are still being collected for other 

outcome measures, or if the clinical trial 

was terminated prematurely. They need 

to understand whether information has 

been submitted for all anticipated 

outcome measures and corresponds to 

the outcome measures that the clinical 

trial was designed to achieve (or did the 

outcome measures change during the 

course of the study). They also need 

information to assist them in comparing 

results with the results of other clinical 

trials and with other publicly available 

information about a clinical trial of 

interest and other trials. They also need 

to know whether the clinical trial was 

reviewed for human subjects protection 

and who had authority over the conduct 

of the trial. In addition, they need to 

know who submitted the information 

and when it was last verified (i.e., to 

indicate whether it might be out of 

date). Such information is not readily 

available from submitted results 

information, but is the same type of 

descriptive information provided during 

registration, e.g., Primary Purpose, 

Study Design, Primary Outcome 

Measure(s), Secondary Outcome 

Measure(s), Eligibility Criteria, Overall 

Recruitment Status, Oversight 

Authorities, Human Subjects Protection 

Review Board Status, Responsible Party, 

by Official Title, and Record 

Verification Date (See proposed 

§ 11.28(a). 

Section 402(j)(3)(D)(i) of the PHS Act 

states that the purpose of granting the 

Secretary rulemaking authority to 

expand the results information in the 

data bank is ‘‘[t]o provide more 

complete results information and to 

enhance patient access to and 

understanding of the results of clinical 

trials.’’ We believe it would be 

extremely challenging for the public to 

understand clinical trial results 

information without having access to 

certain descriptive information that is 

the same type of information submitted 

during trial registration. Thus, to 

‘‘enhance patient access to and 

understanding of the results,’’ it is 

necessary for patients to have access to 

this descriptive information when 

clinical trial results information is 

posted, not only for applicable drug 

clinical trials of both approved and 

unapproved drugs (See section 

402(j)(2)(D)(i) and section IV.B.5 of this 

preamble), but also for applicable device 

clinical trials of both approved or 

cleared devices and unapproved or 

uncleared devices. 

Section 402(j)(3)(D)(ii)(II) of the PHS 

Act grants the Secretary discretion in 

what can be required through 

rulemaking to be submitted as part of 

clinical trial results information for 

applicable device clinical trials of 

devices that have not been approved or 

cleared. Specifically, it allows the 

Secretary to require the submission of 

results information that is ‘‘described in 

clause (iii).’’ Clause (iii), or section 

402(j)(3)(D)(iii) of the PHS Act, states 

that the regulations ‘‘shall require, in 

addition to the elements described in 

[section 402(j)(3)(C)]. . .[s]uch other 

categories as the Secretary determines 

appropriate’’ (section 402(j)(3)(D)(iii)(IV) 

of the PHS Act). Thus, for applicable 

device clinical trials of unapproved or 

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uncleared devices, the Secretary can 

require, through rulemaking, 

submission of not only those results that 

are required under section 402(j)(3)(C) 

of the PHS Act, but ‘‘such other 

categories’’ of information as the 

Secretary determines appropriate. 

To ‘‘enhance patient access to and 

understanding of the results of the 

clinical trials’’ as required by section 

402(j)(3)(D)(i) of the PHS Act, we 

interpret ‘‘such other categories’’ of 

results information for applicable device 

clinical trials of unapproved or 

uncleared devices to include, among 

other things, certain descriptive 

information that is the same type of 

information that was required to be 

submitted under section 402(j)(2)(A)(ii) 

of the PHS Act. Accordingly, we 

propose under § 11.48(a)(6) to require 

responsible parties to submit this 

descriptive information as part of 

clinical trial results information for 

applicable device clinical trials of 

unapproved or uncleared devices. 

Because this descriptive information 

would be defined as part of clinical trial 

results information, it would be posted 

no later than 30 calendar days after it 

has been submitted, pursuant to section 

402(j)(3)(G) of the PHS Act. See 

proposed § 11.48(a)(6) and section 

IV.C.4(g) of this preamble for a list of 

proposed required data elements. 

Requiring responsible parties for 

applicable device clinical trials of 

unapproved or uncleared devices to 

resubmit information they would have 

submitted previously to the data bank 

under proposed § 11.28(a), in order to 

comply with proposed § 11.48(a)(6), 

would be inefficient and impose an 

unnecessary burden on responsible 

parties. It would also introduce the 

possibility that information provided at 

the time of results submission would be 

inconsistent with the information 

provided at the time of registration and 

require the Agency to perform a second 

quality review of information submitted 

at registration. To promote efficiency 

and lessen the burden on responsible 

parties, we propose to require these 

responsible parties to fulfill the 

proposed requirement under 

§ 11.48(a)(6) by affirming in the data 

bank when submitting clinical trial 

results information that they are 

submitting information that is already 

contained in the databank as part of 

their submission of clinical trial results 

information and that such information 

has been updated as specified in 

§ 11.64(c) and is to be included as 

clinical trial results information. Once 

this affirmation is made, the information 

listed in proposed § 11.48(a)(6) that had 

been previously submitted to the data 

bank, would automatically populate the 

results information data fields and be 

posted when results information is 

posted. This proposal would help us 

ensure that the clinical trial results 

information necessary ‘‘to enhance 

patient access to and understanding of 

the results of clinical trials,’’ consistent 

with section 402(j)(3)(D)(i) of the PHS 

Act is available to the public. 

6. Submission of Non-Technical and 

Technical Summaries of Trial Results 

Section 402(j)(3)(D)(iii)(I) of the PHS 

Act specifies that the regulations shall 

require ‘‘[a] summary of the clinical trial 

and its results that is written in nontechnical, understandable language for 

patients, if the Secretary determines that 

such types of summary can be included 

without being misleading or 

promotional.’’ Section 

402(j)(3)(D)(iii)(II) of the PHS Act 

specifies that the regulations shall 

require ‘‘a summary of the clinical trial 

and its results that is technical in 

nature, if the Secretary determines that 

such types of summary can be included 

without being misleading or 

promotional. 

We interpret the provisions in 

sections 402(j)(3)(D)(iii)(I) and (II) of the 

PHS Act to mean that the proposed 

regulations are to require the 

submission of non-technical and 

technical narrative summaries if such 

summaries can be produced in such a 

way that they will not be misleading or 

promotional to potential users of the 

data bank. We believe it is necessary to 

demonstrate that narrative summaries of 

applicable clinical trials can be 

consistently produced in a way that will 

not be misleading or promotional. 

If non-technical or technical narrative 

summaries can be consistently 

produced without being misleading or 

promotional, patients, members of the 

general public, clinicians and 

researchers might benefit from brief, 

well-written, accurate, and objective 

summaries of the results of individual 

clinical trials. Such summaries might 

assist the public, clinicians, and 

researchers in understanding salient 

information about the characteristics of 

the participants in a specific applicable 

clinical trial and the benefits and harms 

experienced by those participants in 

that clinical trial. In fact, some users of 

ClinicalTrials.gov might find narrative 

summaries easier to understand than the 

summary results tables. Although 

summarized evidence from multiple 

clinical trials and observational studies, 

when available, would provide a more 

complete overall picture of a clinical 

trial’s results, summaries of individual 

trials that are accurate and objective 

could also be useful, particularly for 

clinical trials that present the first 

evidence of benefits and harms for 

specific products or population groups, 

based on the experience of participants 

in that clinical trial. 

Another consideration is the optimum 

format for narrative, non-technical 

summaries. For example, two existing 

widely-endorsed and used formats 

intended for reporting results of 

individual clinical trials for technical or 

expert audiences are the CONsolidated 

Standards for Reporting Trials 

(CONSORT) Statement [Ref. 31], a 

checklist of best practices for producing 

journal articles that report the results of 

clinical trials of any type of 

intervention; and the International 

Conference on Harmonisation of 

Technical Requirements for Registration 

of Pharmaceuticals for Human Use (ICH) 

topic E3—Structure and Content of 

Clinical Study Reports (ICH E3) [Ref. 

23], a required format for summarizing 

results of individual clinical trials of 

drugs in submissions to FDA and to 

agencies that regulate the use of drugs 

in other countries. Both of these formats 

require narratives and data tables, 

including information that is already 

submitted to ClinicalTrials.gov to meet 

the registration and results submission 

requirements under section 402(j) of the 

PHS Act. 

The CONSORT Statement specifically 

addresses various ways in which reports 

of clinical trial results can be misleading 

and how to avoid these pitfalls, 

generally by providing additional types 

of information, such as limitations in 

trial design, participant populations, 

etc. The CONSORT Statement strongly 

recommends ‘‘that at a minimum, 

authors should discuss the results of 

their trial in the context of existing 

evidence. This discussion should be as 

systematic as possible and not limited to 

studies that support the results of the 

current trial. Ideally, we recommend a 

systematic review and an indication of 

the potential limitation of the 

discussion if this cannot be completed’’ 

[Ref. 31]. The ICH E3 format does not 

specifically address the potential for 

misleading narratives, but it does 

emphasize the need to address many 

specific topics whose omission might 

lead to a misleading summary, e.g., 

appropriateness of measurements, 

statistical analysis plans, determination 

of sample size, protocol deviations. The 

ICH E3 guidance document also 

addresses the importance of context by 

stating that ‘‘Clinical relevance and 

importance of the results should be also 

discussed in light of other existing data’’ 

[Ref. 23]. 

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Another question to be addressed is 

whether a single, brief summary of an 

individual clinical trial can provide 

sufficient background or context to 

avoid being potentially misleading to a 

clinician or patient interested in the 

clinical significance of the results. 

Individual trials can contain a large 

number of primary and secondary 

outcome measures (more than 120 in 

some submissions to ClinicalTrials.gov), 

which would make it extremely difficult 

to prepare succinct summaries without 

presenting selective information about 

the outcome measures or adverse 

events, a process that can introduce bias 

into the summary. On the other hand, 

all of the data required in results 

reporting would be available alongside 

the technical and non-technical 

summaries, providing all data on 

outcome measures. In addition, we rely 

on publication of clinical trials results 

through scientific journals so scientists 

are accustomed to analyzing and 

reporting often complex data from their 

clinical trials. ClinicalTrials.gov links to 

publications where available to provide 

the user with additional information. 

In addition to reviewing the relevant 

literature, we consulted with the FDA 

Risk Communication Advisory 

Committee (meeting summary available 

at: http://www.fda.gov/Advisory

Committees/CommitteesMeeting

Materials/RiskCommunicationAdvisory

Committee/ucm116558.htm) and 

considered public comments from the 

public meeting held in April 2009 [Ref. 

1]. We agree with those who commented 

that further research on this complex 

issue is warranted. Accordingly, NIH 

plans to undertake an evaluation to 

assess the value to the public of such 

summaries and whether they can be 

provided in a manner that is objective 

and not misleading. We are therefore 

deferring the decision about whether or 

not to require the submission of 

narrative summaries. We invite further 

public comment on methods that we 

might employ to help answer this 

question so that we can explore this 

issue more thoroughly before making a 

final determination. 

Consistent with section 

402(j)(3)(A)(ii)(II), NIH will continue to 

provide links, where possible, from 

individual clinical trials listed in 

ClinicalTrials.gov to related peerreviewed literature and other 

authoritative information related to the 

intervention(s) studied or the disease or 

condition addressed. To avoid potential 

confusion, such links are indicated to 

have been added by the Agency and not 

by the responsible party. 

7. Submission of the Full Protocol 

Section 402(j)(3)(D)(iii)(III) of the PHS 

Act provides that the regulations shall 

require submission of ‘‘[t]he full 

protocol or such information on the 

protocol for the trial as may be 

necessary to help to evaluate the results 

of the trial.’’ This requirement could be 

satisfied in any of several ways: (1) 

Requiring submission of additional 

structured data elements derived from, 

or describing, the protocol; (2) requiring 

submission of portions of the final 

protocol or other narrative information 

about the conduct of the study that is 

associated with the protocol (e.g., a 

statistical analysis plan, if not part of 

the protocol); or (3) requiring 

submission of the full protocol at the 

time of results submission, meaning the 

final version of the protocol, including 

all protocol amendments, in a format 

such as PDF. 

Evaluating the results of a clinical 

trial involves the careful study and 

appraisal of the clinical trial 

methodology, so that results can be 

interpreted and their significance 

assessed. It can require detailed 

information about the conduct of a 

clinical trial, including the methods of 

participant selection, randomization, 

and assignment to arms; methods of 

collecting baseline and clinical trial 

data; specific information about the 

interventions used in the clinical trial 

(e.g., other elements of care that were 

provided in addition to the specified 

interventions studied in the clinical 

trial); and assessment of adverse events. 

It can also require information on the 

statistical techniques used to analyze 

collected results information. 

We received comments on submission 

of protocols at the public meeting in 

April 2009 [Ref. 1]. At that time, 

commenters did not know what other 

registration and results information 

would be proposed in this NPRM for 

submission to ClinicalTrials.gov and 

could not take those requirements into 

account in their comments. Most 

comments addressed the question of 

whether or not to require submission of 

the full protocol and did not consider 

other approaches to meeting the 

statutory requirement in section 

402(j)(3)(D)(iii)(III) of the PHS Act. 

Given the proposals for submission of 

additional registration and results 

information detailed in section IV of 

this preamble, we are not proposing to 

require submission of the full protocol 

or other ‘‘information on the protocol.’’ 

We invite public comment on 

whether the registration and results 

information that is proposed for 

submission in this NPRM is sufficient to 

meet the statutory requirement in 

section 402(j)(3)(D)(iii)(III) of the PHS 

Act to provide ‘‘information on the 

protocol’’ as may be necessary to help 

evaluate the results of the clinical trial 

or whether submission of additional 

information, including submission of 

the full protocol, should be required. 

Comments should address the relative 

benefits and burdens of preparing and 

submitting any additional information 

and should indicate how such 

information will help evaluate the 

results of the clinical trial. We will 

consider such input in formulating the 

final rule. 

8. Increasing the Time Period for 

Submitting Results Information 

Section 402(j)(3)(D)(iv)(I) of the PHS 

Act requires that the Secretary 

determine, by regulation, whether the 

deadline for submission of clinical trial 

results information of 1 year after the 

completion date of the applicable 

clinical trial—the deadline established 

in section 402(j)(3)(E)(i) of the PHS Act, 

which does not apply when a 

certification for delay is submitted or a 

request for extension is granted—should 

be increased from 1 year to a period not 

to exceed 18 months. The public 

comments on this matter helped inform 

our view [Ref. 1]. We believe there is 

value in making results information for 

primary outcome measures available 

within 1 year of the completion date. 

We therefore have decided not to 

propose lengthening the deadline for 

submitting results information, but to 

propose specific mechanisms for 

accommodating extended data 

collection for secondary outcomes to 

avoiding the premature unblinding of 

trials. 

Proposed § 11.44(a)(1) provides that 

clinical trial results must be submitted 

no later than 1 year after the completion 

date of the clinical trial, unless a 

certification for delay is submitted or a 

request for extension is granted. In 

accordance with the statutory definition 

in section 402(j)(1)(A)(v) of the PHS Act, 

the term ‘‘[c]ompletion date’’ is defined 

in proposed § 11.10—for a clinical 

trial—to mean ‘‘the date that the final 

subject was examined or received an 

intervention for the purposes of final 

collection of data for the primary 

outcome, whether the clinical trial 

concluded according to the prespecified protocol or was terminated. In 

the case of clinical trials with more than 

one primary outcome measure with 

different completion dates, this term 

refers to the date upon which data 

collection is completed for all of the 

primary outcomes.’’ 

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We interpret the phrase ‘‘primary 

outcome’’ to be synonymous with the 

phrase ‘‘primary outcome measure.’’ In 

the event that clinical trial results data 

for all pre-specified secondary outcome 

measures have not been collected by the 

completion date, proposed § 11.44(a)(2) 

provides a process for submitting 

‘‘partial results’’ to the data bank. In 

particular, the responsible party will 

remain responsible for submitting 

results information for each remaining 

secondary outcome measure until the 

responsible party has submitted results 

data, including associated adverse event 

data, for all pre-specified outcome 

measures. Such results information 

must be submitted no later than 1 year 

after the date on which the final subject 

was examined or received an 

intervention for purposes of final data 

collection for the secondary outcome 

measure at issue. In cases where results 

submission under our proposed 

schedule would necessitate unblinding 

a trial, and doing so would affect a prespecified secondary outcome measure, 

responsible parties should submit a 

request for an extension of the deadline 

for good cause, which must contain the 

elements outlined in proposed 

§ 11.44(e). As discussed in greater detail 

in section IV.C.3(d) of this preamble, we 

believe that the need to preserve the 

scientific integrity of an applicable 

clinical trial for which data collection is 

ongoing would, in general, constitute 

good cause for an extension. 

Based on our experience with 

approximately 1,200 data providers who 

have submitted results data to 

ClinicalTrials.gov, 1 year after the 

completion date of a clinical trial 

appears to be a reasonable amount of 

time for electronic data submission. We 

are aware of other results submission 

requirements (e.g., in Germany and the 

European Union) that define completion 

date as last patient, last visit (LPLV), 

instead of the final data collection for 

primary outcome as defined in section 

402(j)(1)(A)(v) of the PHS Act. The 

European Union proposal would require 

results to be submitted within 6 months 

of the LPLV date of completion [Ref. 

28]. 

To inform our proposal, we reviewed 

in the summer of 2009 a set of 230 

randomly selected clinical trials 

registered in ClinicalTrials.gov. We 

found that about 80 percent of the 

clinical trials listed a single time frame 

for all pre-specified primary and 

secondary outcome measures. In other 

words, completion date as defined in 

section 402(j)(1)(A)(v) of the PHS Act 

and LPLV are identical for most of the 

clinical trials. 

We recognize that many factors, such 

as rate of participant enrollment, may 

contribute to when final data are 

collected for the primary outcome 

measure. Thus, we propose that the 

responsible party: (1) As specified in 

§ 11.10(b)(17) provide a reasonable 

estimate of the completion date upon 

registering the clinical trial (the Agency 

interprets ‘‘estimated completion date’’ 

as used in section 402(j)(3)(E)(i)(I) of the 

PHS Act to be synonymous with 

‘‘expected completion date’’ as used in 

section 402(j)(2)(A)(ii)(I)(jj) of the PHS 

Act); and (2) update the information to 

indicate the actual completion date in 

accordance with the time frame 

established in § 11.64(b)(1)(viii). We 

note, if the estimated completion date of 

a clinical trial changes before or during 

the clinical trial, the responsible party 

would be required to update estimated 

completion date information consistent 

with § 11.64. 

Updating the estimated completion 

date promptly to reflect the actual 

completion date is important because, 

as proposed, responsible parties would 

need to submit clinical trial results 

information not later than 1 year after 

the actual completion date (unless they 

submit a certification for delayed results 

submission or a request for a good-cause 

extension is granted). Hence, as 

described in proposed § 11.64, we 

propose to require that responsible 

parties update the completion date in 

ClinicalTrials.gov not later than 30 

calendar days after a change. As with 

other data elements at 

ClinicalTrials.gov, all changes to posted 

information are tracked publicly at the 

ClinicalTrials.gov archive. 

9. Retroactive Submission of Additional 

Results Information 

Section 402(j)(3)(D)(iv)(II) of the PHS 

Act provides that the Secretary shall, by 

regulation, determine ‘‘whether the 

clinical trial information described in 

[section 402(j)(3)(D)(iii) of the PHS Act] 

should be required to be submitted for 

an applicable clinical trial for which the 

clinical trial information described in 

[section 402(j)(3)(C) of the PHS Act] is 

submitted to the registry and results 

data bank before the effective date of the 

regulations.’’ The clinical trial 

information described in section 

402(j)(3)(D)(iii) of the PHS Act refers to: 

(1) technical and non-technical 

narrative summaries of the clinical trial, 

(2) the protocol or other information on 

the protocol to help evaluate the results 

of the trial, and (3) other categories of 

information as determined to be 

appropriate by the Secretary. 

As explained in sections III.C.6 and 

III.C.7 of this preamble, we do not 

propose in this rule a requirement for 

the submission of technical or 

nontechnical narrative summaries or for 

the submission of the full protocol 

(although we invite public comment on 

both topics). We propose to require 

submission of ‘‘other categories of 

information’’ in two situations: When a 

responsible party submits results for 

applicable clinical trial of a device that 

has not been cleared or approved (see 

section IV.C.4.f of this preamble); and 

when a responsible party submits 

results information voluntarily under 

section 402(j)(4)(A) of the PHS Act. 

Neither of these situations would apply 

to clinical trials for which results 

information is submitted prior to the 

effective date of the rule because 

responsible parties would not be 

required prior to the effective date of the 

rule to submit results of applicable 

clinical trials of devices that are not 

approved or cleared; nor would they be 

subject to the voluntary submissions 

provisions in section 402(j)(4)(A) of the 

PHS Act. Therefore, we do not propose 

to require the submission of clinical 

trial information described in section 

402(j)(3)(D)(iii) of the PHS Act for an 

applicable clinical trial for which the 

clinical trial results information is 

submitted to ClinicalTrials.gov before 

the effective date of the regulations. As 

described in section III.D of this 

preamble on Effective Date, we do, 

however, propose to require the 

responsible party for an applicable 

clinical trial that reaches its completion 

date prior to the effective date of the 

final rule to submit all of the results 

information specified in proposed 

§ 11.48 if the responsible party has not 

submitted results information prior to 

the effective date of the rule. Requiring 

the submission of this information 

would improve the uniformity and 

consistency of information available in 

the data bank for applicable clinical 

trials. 

10. Standard Data Formats 

Section 402(j)(3)(D)(v)(I) of the PHS 

Act provides that regulations regarding 

the submission of expanded results 

information shall also establish ‘‘a 

standard format for the submission of 

clinical trial information under [section 

402(j)(3)(D)(v)(I) of the PHS Act] to the 

registry and results data bank.’’ 

Proposed § 11.48 of this proposed rule 

implements standard data formats for 

results information, including adverse 

event information, taking into 

consideration comments made at the 

public meeting [Ref. 1]. 

As discussed in sections II.B and 

III.C.12 of this preamble, NLM is 

adopting a tabular, structured data entry 

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system to promote objective reporting, 

optimize data display, permit effective 

searching of ClinicalTrials.gov, and 

facilitate cross-trial comparisons. To the 

extent possible, our proposal for 

submitting adverse event information is 

consistent with ICH–E3 formats (see 

http://www.fda.gov/downloads/Drugs/

GuidanceComplianceRegulatory

Information/Guidances/

UCM073113.pdf) and Body Organ 

System Class for grouping adverse 

events by organ system, as required by 

the statutory default provisions in 

section 402(j)(3)(I)(iii) of the PHS Act. 

We have developed a mechanism for 

uploading results data in an automated 

electronic fashion using eXtensible 

Markup Language (XML) files. We do 

not believe that uploads of data tables 

in other formats will allow for the 

comparability and consistency desired 

across trials and do not include such a 

mechanism in our proposal. 

11. Additional Information to Improve 

Patient Understanding of Submitted 

Information 

Section 402(j)(3)(D)(v)(II) of the PHS 

Act requires that the regulations 

establish ‘‘additional information on 

clinical trials and results that is written 

in nontechnical, understandable 

language for patients[.]’’ We interpret 

this provision to mean, in part, that the 

regulations must specify additional 

expanded results information that 

responsible parties would be required to 

submit to ClinicalTrials.gov to assist 

patients in understanding and 

interpreting other submitted clinical 

trial information. 

As discussed elsewhere in this 

preamble (see sections III.C.2 and 

III.C.15) and in several sections of this 

proposed rule, we propose additional 

data elements or types of information 

that responsible parties must submit to 

enhance the interpretability of 

submitted information related to 

registration and results, including 

adverse events. In developing the 

proposed regulation, we took into 

account numerous suggestions that were 

made at the public meeting about 

resources that could be included in the 

data bank to assist patients in 

understanding and interpreting 

information in the data bank [Ref. 1]. 

Although section 402(j)(3)(D)(v)(II) of 

the PHS Act does not require the 

Agency to develop and provide 

additional information in 

ClinicalTrials.gov to assist users in 

better understanding and interpreting 

the submitted clinical trial information, 

we have paid careful attention to 

comments about how the 

ClinicalTrials.gov Web site might be 

improved. ClinicalTrials.gov already 

contains site-level resources to assist 

patients and other users in obtaining 

and understanding information on 

clinical trials in the data bank, e.g., 

FAQs on understanding clinical trials, a 

glossary of clinical trial terms, and an 

introduction that describes the general 

purpose and content of the data bank 

and cautions that the information 

should be used in conjunction with 

advice from healthcare professionals. In 

addition, each clinical trial record 

contains links to definitions that explain 

to the public standard terms such as 

‘‘condition’’ and ‘‘intervention;’’ and, 

where it exists, to information at select 

consumer health Web sites that is 

relevant to the clinical trial. Such 

information includes: resources related 

to the conditions being studied, from 

MedlinePlus (http://www.nlm.nih.gov/

medlineplus/) and the Genetics Home 

Reference (http://ghr.nlm.nih.gov/); 

resources related to the intervention(s) 

being investigated, from the NLM Drug 

Information Portal (http://druginfo.

nlm.nih.gov/) and FDA’s Web site 

(www.fda.gov); and publications related 

to the clinical trial, including freely 

available abstracts if available, from 

PubMed (http://www.ncbi.nlm.nih.gov/

pubmed/). As noted in section III.C.6 of 

this preamble, we intend to add links 

from clinical trial records to other 

sources of related, authoritative health 

information (e.g., information from 

government sources and/or peer 

reviewed publications). Such 

information will be labeled as being 

added by NLM. 

12. Quality Control Procedures 

Section 402(j)(3)(D)(v)(III) of the PHS 

Act provides that the regulations shall 

also establish procedures for quality 

control ‘‘with respect to completeness 

and content of clinical trial 

information,’’ including using 

representative samples, in order ‘‘to 

help ensure that data elements are not 

false or misleading and are nonpromotional[.]’’ In developing such 

procedures, the Agency is to consider 

the experience gained through the pilot 

quality control project, described in 

section 402(j)(5)(C)(i) of the PHS Act. 

The pilot quality control project is ‘‘to 

determine the optimal method of 

verification to help ensure that the 

clinical trial information submitted 

under . . . [section 402(j)(3)(C) of the 

PHS Act] is non-promotional and is not 

false or misleading in any particular 

. . .’’ (See section 402(j)(5)(C)(i) of the 

PHS Act). Comments submitted to the 

docket and discussed at the public 

meeting also have been considered in 

developing the quality control 

procedures [Ref. 1]. 

We note that Section 801(d)(2) of 

FDAAA includes a Rule of 

Construction, which states that the 

‘‘submission of clinical trial 

information, if submitted in compliance 

with [section 402(j) of the PHS Act], that 

relates to the use of a drug or device not 

included in the official labeling of the 

approved drug or device shall not be 

construed by the Secretary of Health 

and Human Services or in any 

administrative or judicial proceeding, as 

evidence of a new intended use of the 

drug or device that is different from the 

intended use of the drug or device set 

forth in the official labeling of the drug 

or device.’’ Public Law 110–85, section 

801(d)(2) (emphasis added). Section 

801(d)(2) further states that the 

availability of clinical trial information 

through the data bank, if submitted in 

compliance with such subsection, shall 

not be considered as labeling, 

adulteration, or misbranding of the drug 

or device under the FD&C Act. 

Consistent with many of the 

comments we received, we have 

designed the ClinicalTrials.gov results 

submission system to encourage 

objective reporting. As discussed in 

section III.C.10 of this preamble, the 

tabular, structured data entry system 

developed for ClinicalTrials.gov 

promotes objective reporting, optimizes 

the data display and permits effective 

searching of the data bank. In addition, 

as discussed in section III.C.6 of this 

preamble we have not included a 

proposed requirement to submit nontechnical and technical narrative 

summaries of the results of a clinical 

trial. We intend to study this issue 

further and are inviting additional 

public comment on it. At present, 

procedures for quality control relate to 

the review of structured data that would 

be required to be submitted to 

ClinicalTrials.gov under this proposed 

rule. 

(a) Pilot Quality Control Project. As a 

preliminary step toward satisfying the 

required pilot quality control project 

under section 402(j)(5)(C)(i) of the PHS 

Act, we conducted a quality control 

study that consisted of two parts as 

follows: (1) review of the results of more 

than 4,500 clinical trials submitted 

under section 402(j)(3)(C) of the PHS 

Act after September 27, 2008; and (2) an 

initial validation study of the 

ClinicalTrials.gov results data bank, 

conducted under contract by researchers 

at the Oregon Health Science University 

[Ref. 32]. 

The first part of the quality control 

study led to the development of detailed 

quality review criteria [Ref. 33, 34]. 

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Since the launch of the 

ClinicalTrials.gov results data bank, 

each submission of results information 

has been reviewed for apparent validity, 

meaningful entries, logical and internal 

consistency, and formatting. We have 

tried to ensure that submitted results 

information is objective and contains no 

comments about conclusions, clinical 

implications, or comparisons with other 

studies or other data. Table 1 lists 

common types of errors, deficiencies 

and inconsistencies with specific 

examples that were seen during this 

time period. Data submitters were 

notified of errors, deficiencies and/or 

inconsistencies found during this first 

part of the quality control study and 

asked to revise their submissions. 

During this period, clinical trial results 

information was not posted in 

ClinicalTrials.gov until the errors, 

deficiencies and/or inconsistencies 

identified by the quality review had 

been addressed by responsible parties. 

In some cases, corrected information 

was not provided until more than 30 

days had passed from the initial 

submission. 

To assist responsible parties in 

avoiding such errors, deficiencies and 

inconsistencies, we developed and 

continue to refine documentation 

explaining how to meet the quality 

review criteria; identified and compiled 

lists of frequent errors, deficiencies and 

inconsistencies in submitted results 

information; and provided system 

support to help responsible parties 

minimize such errors, deficiencies and 

inconsistencies. We also have provided 

intensive user support for responsible 

parties who are new to the online 

results submission process, whether 

through data entry using Web-based 

forms or automated uploading of data 

files. We have developed and posted 

draft educational materials, such as tips 

on improving results submissions and 

ways to avoid common errors, 

deficiencies and inconsistencies 

observed in submissions to date. All 

such documents are available at http:// 

prsinfo.clinicaltrials.gov/fdaaa.html. We 

will continue to provide support to 

responsible parties and, based on these 

interactions, develop new or updated 

materials in order to facilitate and 

streamline preparation of results data 

for submission to ClinicalTrials.gov and 

to help ensure that the submissions 

meet the quality review criteria. 

TABLE 1—SOME COMMON TYPES OF ERRORS, DEFICIENCIES AND INCONSISTENCIES IDENTIFIED IN RESULTS SUBMISSIONS

Data quality category Description Example Explanation 

Lack of apparent validity ..... Data not plausible based 

on information provided.

Outcome measure indicating a mean 

value of 263 hours per day of sleep.

Measure of mean hours per day can 

only have values in the range of 0–24. 

Value of ‘‘263’’ is not valid. 

Incomplete Information ........ Information insufficient to 

convey intended meaning.

Outcome measure description states 

‘‘clinical evaluation of adverse events, 

laboratory parameters and imaging’’; 

data reported as 100 and 96 participants, in each arm.

Data are uninformative. Unclear to what 

counts of 100 and 96 participants 

refer. Outcome measure description 

not sufficiently descriptive to understand specific outcome. 

Incomplete information ........ Information insufficient to 

convey intended meaning.

Outcome measure assessed on a scale, 

which is not explained; data reported 

as mean values of 3.2 and 4.1 in the 

two arms.

Data are uninformative without an explanation of what the scale is assessing 

and the range and direction of scores 

(e.g., whether 3.2 is better or worse 

than 4.1 on a 5-point scale). 

Internal inconsistency .......... Data not consistent with 

descriptive information.

Outcome measure title is ‘‘time to disease progression;’’ data reported as 

42 & 21 participants, in each arm.

A time-to-event measure requires a unit 

of time such as days or months. 

Internal inconsistency .......... Data in one section are not 

consistent with data in 

another section.

Baseline characteristics & participant 

flow entered as 2-armed study with a 

total of 400 participants; outcomes entered for 3 arms with 600 participants.

If there is a third group, then Baseline 

Characteristics and Participant Flow 

modules must reflect this or group descriptions in Outcomes should explain 

their origin. 

These efforts have produced 

significant improvements in the quality 

of initial submissions of results 

information to ClinicalTrials.gov. 

Whereas in 2008 only 5 percent of 

submissions met the quality review 

criteria when first submitted, by 2012 

approximately 36 percent of initial 

submissions met the quality review 

criteria. Improvements in the percentage 

of initial results submission that meet 

our quality review criteria may be a 

consequence of three factors: (1) greater 

familiarity among responsible parties 

and sponsors with the system and the 

associated rules, (2) better resource 

materials from ClinicalTrials.gov, and 

(3) growing awareness that the task of 

entering results requires involvement of 

personnel with a full understanding of 

the trial design and results. The number 

of responsible parties submitting data 

has increased each quarter. 

The second part of the quality control 

study compared the consistency of 

posted results information for phase 3 or 

4 clinical trials of drugs that were 

completed prior to January 1, 2009 and 

had submitted results by November 17, 

2010 with results information published 

in peer reviewed journals and 

documents made publicly available on 

the FDA Web site, such as medical 

reviews. A publication was identified 

for only 32 percent of the 342 trials that 

were sampled, and in 82 percent of the 

publication-trial pairs at least one 

discrepancy was found between the data 

submitted to ClinicalTrials.gov and the 

data contained in the peer-reviewed 

journal article. Discrepancies occurred 

in almost all fields analyzed, including 

number of arms, primary and secondary 

outcome measures (the name of the 

measure as well as the actual data), total 

enrollment, and number of serious 

adverse events. In cases where the 

publication addresses a subset of the 

data in the trial, the apparent 

discrepancies could be correct 

reflections of the clinical trial results for 

the population covered [Ref.38]. 

The study results demonstrate that 

comparisons with publications cannot 

be used in real time to validate results 

submissions to ClinicalTrials.gov. For 

the great majority of clinical trials, no 

publications are available for 

comparison at the time results are 

submitted to the data bank. In addition, 

for clinical trials of products that have 

not been approved, licensed, or cleared, 

or for which a new indication is being 

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studied but has not yet been approved, 

licensed, or cleared, information about 

the clinical trial ordinarily is not 

available on FDA’s Web site at the time 

results are submitted to 

ClinicalTrials.gov. Thus, we do not 

believe that comparisons with 

publications or FDA documents would 

provide a feasible or effective method of 

routinely screening submitted clinical 

trial records with results to help ensure 

that the clinical trial information is nonpromotional and not false or misleading 

in any particular. 

As required by section 402(j)(5)(C)(i), 

we plan to continue conducting the 

pilot quality control project in 

coordination with the Commissioner of 

Food and Drugs until the effective date 

of this regulation to determine the 

optimal method of verification to help 

ensure that the clinical trial information 

submitted under section 402(j)(3)(C) of 

the PHS Act is non-promotional and is 

not false or misleading in any particular. 

In addition, we will continue to use 

comparisons with random samples of 

publications or public FDA documents 

to identify problems and improve our 

procedures. In addition, if we become 

aware of a publication or FDA 

document that appears to contain 

information that is inconsistent with a 

submitted clinical trial record, we will 

consult with FDA on the appropriate 

next steps. 

(b) Proposed Quality Control 

Procedures. Based on the public 

comments we received, experience with 

the preliminary steps of the pilot quality 

control project, and consistent with 

current practice, we intend to continue 

a form of quality control at the time of 

clinical trial registration or submission 

of clinical trial results information that 

is similar to the procedures we have 

been using for the past several years. 

The quality control process will not 

affect the statutory deadlines for 

submitting or publicly posting 

submitted clinical trial information. 

Our quality control process cannot 

determine the veracity of the data 

submitted, and all entries in 

ClinicalTrials.gov will carry a 

disclaimer to that effect. Our quality 

control process is intended to help 

ensure that clinical trial information 

posted on ClinicalTrials.gov has face 

validity and is free from obvious errors. 

The identification of two or more data 

elements within a clinical trial record 

that are internally inconsistent is an 

effective method of identifying errors 

since, by logic, both pieces of data 

cannot be correct. By providing 

responsible parties with information as 

to which elements of submitted clinical 

trial information do not meet specified 

quality review criteria, we can better 

facilitate access by the public to 

information that is not obviously 

incomplete, incorrect, or inconsistent. 

Overall, our proposed quality control 

process for submission of clinical trial 

registration information or clinical trials 

results information will consist of two 

sequential components as follows: (1) an 

automated system-based check, 

followed by (2) a detailed, manual 

review. In the first component, the 

ClinicalTrials.gov system would alert 

responsible parties to machinedetectable errors in the data entered 

(e.g., certain types of missing 

information that is required, certain 

types of impossible values, certain types 

of internally inconsistent data). The 

number of automated checks the system 

performs has increased over time as we 

have gained experience with the types 

of errors that occur and devised 

additional automated rules for 

detection. We will continue to refine the 

automated checks in order to assist 

submitters in detecting and minimizing 

errors, deficiencies, and inconsistencies 

in the information they are submitting. 

Once clinical trial information has 

passed the automated checks and been 

submitted, we would begin the second 

component of quality control: the 

detailed, manual review. We would 

review all data submissions that pass 

the automated system checks in order to 

identify, based on detailed quality 

review criteria, additional apparent 

errors, deficiencies, or inconsistencies 

that are not detected by the automated 

checks. If problems are identified in the 

detailed, manual review, we would send 

an electronic notification to the 

responsible party, indicating that the 

submission contains apparent errors, 

deficiencies and/or inconsistencies 

listing the errors, deficiencies and/or 

inconsistencies found, and requesting 

correction. Consistent with the proposal 

in § 11.66 regarding correction of 

clinical trial information, responsible 

parties would be required to correct the 

errors, deficiencies and/or 

inconsistencies not later than 15 

calendar days after being informed of 

them by the Agency or otherwise 

becoming aware of them (e.g., if they 

discover the errors, inconsistencies, 

and/or deficiencies themselves), 

whichever is later. (See the discussion 

of the corrections provision in section 

IV.D.4 of this preamble). 

We expect to complete the quality 

control process and to receive 

submissions of corrected clinical trial 

information prior to the deadlines for 

posting such information publicly, as 

established by sections 402(j)(2)(D) and 

402(j)(2)(G) of the PHS Act. We 

recognize that in some situations, the 

quality review process may not be 

completed prior to the statutory posting 

deadlines, and we will have to post 

submitted information that has not been 

corrected. Clinical trial information 

posted without having completed the 

quality control review and any 

necessary correction by the responsible 

party will include a statement 

indicating that it has not completed the 

quality control process. Users searching 

ClinicalTrials.gov will be able to elect to 

include or exclude clinical trial 

registrations or clinical trial results 

information that have not yet completed 

the quality control process proposed in 

this NPRM. When revised information 

correcting the noted errors has been 

submitted and the revised information 

has passed the quality control process, 

the statement that the clinical trial 

record has not completed the quality 

control process would be removed from 

the posted record. However, the 

information that was initially posted 

prior to completion of the quality 

control review would appear in the 

archived history for that clinical trial 

entry, and the archived version would 

indicate that it had been posted with a 

notice. The electronic notification sent 

to the responsible party would inform 

responsible parties of these facts. 

We believe additional precautions 

must be taken with clinical trial 

registration information that has not 

completed quality review. Clinical trial 

registration information may be used by 

patients and healthcare providers who 

are considering enrollment in a clinical 

trial. Although we will post information 

submitted when clinical trials are 

registered consistent with the time 

frames in section 402(j)(2)(D) of the PHS 

Act and with the statement described 

above, we will not assign an NCT 

number until information submitted has 

completed our quality control process. 

Thus, if the quality control process and 

any necessary data correction by the 

responsible party have not been 

completed within calendar 30 days after 

an applicable drug clinical trial has 

been registered, the information 

submitted will be posted without an 

NCT number. This approach is 

consistent with the practice that has 

been in effect since ClinicalTrials.gov 

was launched in 2000. This approach 

would ensure that the existence of an 

NCT number for a specific clinical trial 

remains an indicator both that a 

publicly posted clinical trial has been 

registered and that the registration of the 

clinical trial has gone through the 

proposed two-stage quality control 

process. Use of NCT numbers is 

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required in certain submissions to FDA 

and in reports to NIH and other HHS 

agencies from relevant grantees and 

contractors as evidence that clinical 

trials have been publicly registered, as 

required by section 402(j) of the PHS 

Act, and by other stakeholders, 

including journal editors, as evidence of 

public disclosure of certain protocol 

information. In our experience in 

operating the registry component of 

ClinicalTrials.gov, we have found that 

clinical trial registration information 

can be reviewed quickly and that 

responsible parties can submit corrected 

information in a matter of days. 

Other elements of quality control are 

described in proposed § 11.66 and 

section IV.D.4 of this preamble. We 

recognize that clinical trial data 

elements that are submitted as free-text 

could be phrased in a manner that might 

be considered promotional or 

misleading. We solicit comment on 

ways in which the descriptions of the 

data elements in the proposed codified 

could be improved to help ensure that 

submitted clinical trial information is 

not promotional or misleading. We also 

seek comment on standards we could 

use for determining when clinical trial 

information should be considered to be 

promotional. Finally, we solicit 

comment regarding how the pilot 

quality control project may help ensure 

that the clinical trial information 

submitted under paragraph (j)(3)(C) is 

non-promotional and not false or 

misleading under paragraph (j)(5)(D). 

We note that compliance with our 

quality control process, including the 

requirements set forth in § 11.66, does 

not necessarily constitute a legal 

defense to enforcement pursuant to 

section 301(jj) of the FD&C Act (21 

U.S.C. 331) and 303(f) of the FD&C Act 

(21 U.S.C. 333(f)). 

13. Updating Submitted Clinical Trial 

Information 

Section 402(j)(3)(D)(v)(IV) of the PHS 

Act provides that the regulations shall 

also establish ‘‘the appropriate timing 

and requirements for updates of clinical 

trial information, and whether and, if 

so, how such updates should be 

tracked.’’ Section 402(j)(4)(C) of the PHS 

Act, separately requires responsible 

parties to submit updates of clinical trial 

registration information to 

ClinicalTrials.gov not less than once 

every 12 months (except for certain 

specified data elements for which more 

rapid updates are required), and the 

Director to post such updates publicly 

in the data bank. With regard to the 

requirement in section 

402(j)(3)(D)(v)(IV) of the PHS Act to 

establish, by regulation, ‘‘the 

appropriate timing and requirements for 

updates of clinical trial information 

. . .,’’ we interpret the term ‘‘clinical 

trial information’’ to mean both 

information submitted when a clinical 

trial is registered and clinical trial 

results information, consistent with the 

definition of ‘‘clinical trial information’’ 

in section 402(j)(1)(A)(iv) of the PHS 

Act. In addition, our proposed 

requirements for updates apply to 

adverse event information because 

adverse event information is deemed to 

be clinical trial results information 

under section 402(j)(3)(I)(v) of the PHS 

Act. Our proposals take into 

consideration comments made at the 

public meeting [Ref. 1]. 

Proposed § 11.64(a)(1) provides that, 

in general, updates of clinical trial 

information must be provided every 12 

months, unless there are no changes 

during the previous 12 months. 

Proposed § 11.64(a)(2) specifies that a 

responsible party must submit updates 

until the final clinical trial results 

information has been submitted for all 

primary and secondary outcome 

measures and all adverse events 

collected in accordance with the 

protocol. After all such results 

information has been submitted, a 

responsible party’s obligation to update 

the record would end unless and until 

the responsible party becomes aware of 

errors in the submitted clinical trial 

information. In that case, the 

responsible party would need to submit 

corrected information as specified in 

proposed § 11.66. 

Proposed § 11.64(b) identifies several 

data elements that must be updated not 

later than 30 days after a change occurs 

(e.g., Overall Recruitment Status and 

Availability of Expanded Access), 

requires updates to U.S. FDA Approval, 

Licensure, or Clearance Status not later 

than 15 calendar days after the change 

occurred, and specifies that if a protocol 

is amended in such a manner that 

changes are communicated to 

participants in the clinical trial, updates 

to relevant clinical trial information 

must be submitted no later than 30 

calendar days after the protocol 

amendment is approved by the human 

subjects protection review board. A 

responsible party would also be 

required to update the Record 

Verification Date any time the 

responsible party reviews the complete 

clinical trial record for accuracy, even if 

no other updates are submitted at that 

time. The above exceptions to the 12- 

month period for updates are 

considered important for patients using 

the data bank to search for clinical trials 

for which they might qualify and for the 

Agency in administering other 

provisions of section 402(j) of the PHS 

Act. In addition, proposed § 11.64(c) 

would require a responsible party to 

update, as necessary, any previously 

submitted clinical trial information at 

the time results information is 

submitted to ClinicalTrials.gov (the 

responsible party would then be 

required to update the Record 

Verification Date data element). Doing 

so will improve the accuracy of 

information that is used by 

ClinicalTrials.gov to automatically 

prepopulate some elements of results 

information. Further discussion of these 

update requirements appears in the 

description of proposed § 11.64 in 

section IV of this preamble. 

As set forth in proposed § 11.64(d)(2), 

all prior clinical trial information, 

including past updates of posted 

submissions, are tracked in the 

ClinicalTrials.gov archive, in which the 

full history of changes to clinical trial 

information for any clinical trial is 

accessible to the public. Note that, as 

discussed in section III.C.13 of this 

preamble, the time frames for updating 

registration and results information do 

not apply to corrections of errors, 

corrections of falsified data, and other 

corrections of clinical trial information, 

which should be made in accordance 

with the time frames proposed in 

§ 11.66. (See section 402(j)(5)(D)(i) of the 

PHS Act.) 

14. Statement To Accompany Certain 

Trials and Other Issues Related to 

Voluntary Submissions 

Section 402(j)(3)(D)(v)(V) of the PHS 

Act provides that the regulations shall 

also establish ‘‘a statement to 

accompany the entry for an applicable 

clinical trial when the primary and 

secondary outcome measures for such 

clinical trial are submitted under 

paragraph (4)(A) [voluntary 

submissions] after the date specified for 

the submission of such information in 

paragraph (2)(C)[.]’’ Some applicable 

clinical trials are not subject to 

mandatory registration or submission of 

results information because they were 

not initiated after, or ongoing as of, the 

dates established in section 402(j)(2)(C) 

of the PHS Act (i.e., 90 days after the 

date of enactment of FDAAA). They 

would be considered ‘‘submitted under 

paragraph (4)(A)’’ if the responsible 

party submits the information 

voluntarily to ClinicalTrials.gov or if the 

responsible party is required to submit 

the information under section 

402(j)(4)(A) of the PHS Act because the 

applicable clinical trial is included in a 

marketing application or premarket 

notification submitted to FDA. 

Submitted information might consist of 

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registration information and/or results 

information. We interpret section 

402(j)(3)(D)(v)(V) of the PHS Act to 

require a statement to be posted with 

the clinical trial registration and/or the 

results information for such applicable 

clinical trials because primary and 

secondary outcome measures are 

required at the time of both registration 

and submission of results information. 

See 402(j)(2)(A)(ii)(ll) and (3)(C)(ii) of 

the PHS Act. 

We note that for applicable clinical 

trials subject to section 402(j)(4)(A) of 

the PHS Act, it would be permissible for 

information about the primary and 

secondary outcome measures to be 

submitted after the deadline established 

for clinical trial registration under 

section 402(j)(2)(C) of the PHS Act. We 

interpret section 402(j)(3)(D)(v)(V) of the 

PHS Act to require a statement that 

clarifies that the submission was not 

subject to the deadlines imposed by 

section 402(j) of the PHS Act for clinical 

trial registration and submission of 

results information. Such a statement 

would be valuable in demonstrating to 

users of ClinicalTrials.gov that the 

submitted information is not out-ofcompliance with the statutory deadlines 

for submitting information about the 

primary and secondary outcomes. Some 

commenters recommended specific 

language for the statement to 

accompany these voluntary submissions 

(Ref. 1). 

We propose in § 11.60(b) that the 

following statement accompany each 

applicable clinical trial for which 

clinical trial information is submitted 

voluntarily to ClinicalTrials.gov under 

section 402(j)(4)(A) of the PHS Act or 

proposed § 11.60(a): ‘‘Clinical trial 

information for this applicable clinical 

trial was submitted under section 

402(j)(4)(A) of the Public Health Service 

Act and 42 CFR 11.60 and is not subject 

to the deadlines established by sections 

402(j)(2) and (3) of the Public Health 

Service Act or 42 CFR 11.24 and 11.44.’’ 

Proposed § 11.60 provides that a 

responsible party may voluntarily 

submit complete clinical trial 

information for trials of FDA-regulated 

drugs or devices that are not applicable 

clinical trials, such as phase 1 trials, but 

only if certain conditions are met. If a 

responsible party registers or submits 

clinical trial results information 

voluntarily for such a clinical trial, 

section 402(j)(4)(A) of the PHS Act 

requires that such information be 

complete, and that clinical trial 

information be submitted with respect 

to certain ‘‘triggered’’ applicable clinical 

trials. These requirements are discussed 

further in section IV.D.1 of this 

preamble. 

15. Adverse Event Information 

Section 402(j)(3)(I)(i) of the PHS Act 

requires the Secretary, by regulation, to 

‘‘determine the best method for 

including in the registry and results data 

bank appropriate results information on 

serious adverse and frequent adverse 

events for applicable clinical trials . . . 

in a manner and form that is useful and 

not misleading to patients, physicians, 

and scientists.’’ Such regulations are to 

be issued not later than 18 months after 

the date of enactment of FDAAA (i.e., by 

March 27, 2009). Section 402(j)(3)(I)(ii) 

of the PHS Act specifies that if such 

regulations are not issued by the date 

that is 24 months after the date of the 

enactment of FDAAA (i.e., by 

September 27, 2009), a set of default 

provisions in sections 402(j)(3)(I)(iii)(I) 

and (II) of the PHS Act (referred to 

hereinafter as ‘‘the statutory default 

provisions’’) take effect. The statutory 

default provisions require submission of 

two tables of information, as follows: (1) 

‘‘A table of anticipated and 

unanticipated serious adverse events 

grouped by organ system, with number 

and frequency of such event in each arm 

of the clinical trial’’ (section 

402(j)(3)(I)(iii)(I) of the PHS Act), 

referred to hereinafter as the ‘‘serious 

adverse events table’’; and (2) ‘‘A table 

of anticipated and unanticipated 

adverse events that are not included in 

the [serious adverse events] table . . . 

that exceed a frequency of 5 percent 

within any arm of the clinical trial, 

grouped by organ system, with number 

and frequency of such event in each arm 

of the clinical trial’’ (section 

402(j)(3)(I)(iii)(II) of the PHS Act). In 

this proposed rule and in 

ClinicalTrials.gov, we refer to adverse 

events that do not fit the definition of 

a serious adverse event as ‘‘other 

adverse events,’’ and we refer to the 

adverse event table in (2) as the ‘‘other 

adverse events table.’’ 

The statutory default provisions set 

forth in sections 402(j)(3)(I)(iii)(I) and 

(II) of the PHS Act became mandatory as 

of September 27, 2009. For a year prior 

to this date, responsible parties were 

able to submit adverse event data 

voluntarily and adjust the threshold for 

other adverse events to the level of their 

choice. Such an approach allowed us to 

test whether frequency thresholds other 

than 5 percent were better suited to the 

submission of information about other 

adverse events and might constitute the 

‘‘best method’’ for submitting 

information about other adverse events. 

Responsible parties were also able to 

submit comments on the way 

ClinicalTrials.gov collected adverse 

event information so that we could 

improve the design and implementation 

of the system. [See: Docket NIH–2009– 

0002] 

Our proposal for submitting adverse 

event information in § 11.48(a)(4) is 

based on the statutory default 

provisions in sections 402(j)(3)(I)(iii)(I) 

and (II) of the PHS Act, with some 

modifications. We believe that the 

Secretary has authority to modify the 

statutory default provisions by 

regulation under section 

402(j)(3)(D)(v)(VI) of the PHS Act, which 

specifies that the regulations shall 

establish ‘‘additions or modifications to 

the manner of reporting of the data 

elements established under [section 

402(j)(3)(C) of the PHS Act].’’ Section 

402(j)(3)(I)(v) of the PHS Act deems 

adverse event information to be 

‘‘clinical trial information included in 

[the] data bank pursuant to . . . [section 

402(j)(3)(C) of the PHS Act],’’ and we 

believe that this clinical trial 

information is coextensive with the 

‘‘data elements established under . . . 

[section 402(j)(3)(C) of the PHS Act][,]’’ 

referred to in section 402(j)(3)(D)(v)(VI) 

of the PHS Act. Therefore, we conclude 

that the Secretary has authority, under 

section 402(j)(3)(D)(v)(VI) of the PHS 

Act, to modify the statutory default 

provisions for submission of adverse 

event information via regulation, 

provided that such modifications 

represent ‘‘additions or modifications to 

the manner of reporting [adverse event 

information] . . .’’ 

We propose to maintain the 

requirement under the statutory default 

provisions in sections 402(j)(3)(I)(iii)(I) 

and (II) of the PHS Act to submit two 

tables of information summarizing 

anticipated and unanticipated adverse 

events that were collected in accordance 

with the protocol, i.e., one table for all 

serious adverse events and one table for 

other adverse events that exceed a 

frequency of 5 percent within any arm 

of the trial. We would continue to allow 

the submission of other adverse events 

with a frequency of less than 5 percent 

on a voluntary basis, as many data 

submitters have continued to do. 

Consistent with the statutory default 

provisions, our proposal would require 

submission of information on all such 

adverse events, not only those that are 

unanticipated or considered attributable 

to interventions studied in the clinical 

trial, to the extent that the collection of 

these data was specified in the protocol 

for the trial. By including information 

on adverse events, regardless of whether 

or not they were considered anticipated 

or attributed to the intervention(s) 

studied in the clinical trial, 

ClinicalTrials.gov would provide an 

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objective summary of the adverse events 

that were collected during the trial. 

We do not intend for our proposal to 

cause an investigator to collect adverse 

event information of a type or in a way 

that is not specified in the protocol. For 

clinical trials for which the protocol 

specifies collection of only a limited set 

of adverse events (e.g. unanticipated 

adverse reactions), we would require the 

responsible party to submit to 

ClinicalTrials.gov a summary of the 

information that was collected during 

the clinical trial about serious adverse 

events and other adverse events that 

exceed a frequency of 5 percent within 

any arm of the trial. In addition, as 

specified in proposed 

§ 11.48(a)(4)(ii)(H), we would require 

the responsible party to describe how 

the types of adverse events collected in 

the clinical trial differ from the types of 

adverse events and serious adverse 

events defined in proposed § 11.10. We 

believe this proposal would provide 

responsible parties with a convenient 

means of submitting required adverse 

event information without causing them 

to collect and submit information that is 

not specified in the protocol. It would 

also permit users of ClinicalTrials.gov to 

understand how submitted adverse 

event information differs in scope and 

kind from the adverse event information 

defined in this part. 

Implementing the statutory default 

provisions for adverse event information 

entails an interpretation of the 

requirement to submit information 

describing the ‘‘number and frequency’’ 

of adverse events. Sections 

402(j)(3)(I)(iii)(II) and (III) of the PHS 

Act do not specify whether the number 

and frequency of adverse events refer to 

the number of participants who 

experience an adverse event and the 

frequency relative to the number of 

participants assessed for that adverse 

event (i.e., the number of participants 

who were ‘‘at risk’’ for experiencing that 

adverse event) or to the absolute number 

of adverse events or occurrences, 

independent of the number of 

participants involved. When an adverse 

event occurs only once in a participant, 

the two methods of summarizing 

adverse event data are equivalent (i.e., 

the number of participants experiencing 

an adverse event is equal to the number 

of events that occurred). However, when 

an adverse event occurs multiple times 

in a single participant, information 

about the number of adverse events 

without information about the number 

of affected participants could be 

confusing. For example, if the submitted 

information indicates that 20 headaches 

occurred in an arm with 100 

participants, it would be unclear how 

many participants experienced 

headaches: the number could range 

from as many as 20 participants with 

one headache each to as few as one 

participant with 20 headaches. 

We interpret the statutory default 

provisions to require submission of 

information about the number of 

participants who experienced an 

adverse ‘‘event’’ and the total number of 

participants at risk for the adverse 

event. This interpretation is consistent 

with existing conventions for 

summarizing adverse event information 

(e.g., CONSORT Statement on Harms) 

and supports the important objective of 

summary results submission, which is 

to allow users to compare the number of 

participants who may have benefited 

from a particular intervention with the 

number who experienced adverse 

events during a trial. Consistent with 

requirements in effect at 

ClinicalTrials.gov since September 

2009, we propose that responsible 

parties submit both the number of 

participants who experienced an 

adverse event and the total number of 

participants at risk for the adverse 

event. ClinicalTrials.gov provides 

features to simplify submission of the 

number at risk (e.g., when the number 

at risk is the same for all adverse events 

submitted) and would use this 

information in combination with the 

number of participants affected to 

compute the frequency automatically. 

We also believe there is value in 

making information available about the 

number of adverse events. Since 

September 2009, responsible parties 

have had the option of voluntarily 

submitting the total number of 

occurrences of each adverse event in 

addition to the number of participants 

affected. Many responsible parties have 

submitted this information voluntarily; 

nearly half of the results submitted in 

2012 for clinical trials that appear to 

meet the definition of applicable 

clinical trials included the total number 

of occurrences for adverse events. We 

will continue to provide a mechanism 

for responsible parties to voluntarily 

provide event level information for 

adverse events. 

We considered, but do not propose, 

requirements for responsible parties to 

provide the total number of occurrences 

of each serious adverse event and the 

number of such occurrences considered, 

as of a specific date, to be attributable 

to the intervention(s) under study. 

Participants in many clinical trials have 

serious conditions that cause adverse 

events; they are also subject to the 

accidents and other unpredictable 

health events that affect the general 

population. During the course of a 

clinical trial, participants may die or 

suffer other serious adverse events due 

to causes that are unrelated to the 

interventions they are receiving as part 

of the clinical trial. Evaluating whether 

a specific adverse event is likely to have 

been caused by an intervention studied 

in the clinical trial can be valuable 

while the clinical trial is ongoing and 

data are still being collected because it 

can lead to modifications in the clinical 

trial to better protect the human 

subjects. The value of attribution at the 

level of an individual adverse event is 

less certain after a clinical trial has 

completed and all clinical trial data 

have been collected. The determination 

of attribution is, by its nature, 

subjective, influenced by various biases, 

and can change over time within a given 

clinical trial. The ‘‘gold standard’’ for 

assessing possible causal relationships 

between an adverse event (or a series of 

adverse events) and an intervention 

after completion of a clinical trial is an 

empirical comparison of the adverse 

events that occurred in different arms of 

the clinical trial. Because adverse event 

information would be submitted to 

ClinicalTrials.gov after completion of a 

clinical trial (as long as three years after 

the completion date if the responsible 

party submits a certification for delayed 

results submission), we do not propose 

a requirement for including attribution 

information. We invite public comment 

on any aspect of this issue, as well as 

information about current practices for 

attribution of serious adverse events that 

might help us to refine proposed 

requirements for submission of adverse 

event information. 

To further assist users in 

understanding and interpreting 

submitted adverse event information, 

we propose to require the submission of 

additional information, based on our 

experience in operating 

ClinicalTrials.gov to-date. Some of this 

information is already collected on a 

voluntary basis in ClinicalTrials.gov, 

and some has been required since 

September 2009, but one data element is 

new. 

We propose to continue to require 

responsible parties to submit 

information about adverse events by 

organ class for each arm and for each 

table (serious adverse events and other 

adverse events), as required by the 

statutory default provisions in section 

402(j)(3)(I)(iii)(I) and (II) of the PHS Act. 

We propose to require responsible 

parties to use the organ system classes 

specified in the Medical Dictionary for 

Regulatory Affairs (MedDRA) (http://

www.meddramsso.com/) to classify the 

specific adverse event terms (e.g., 

nausea) by organ system. Our 

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experience with voluntary and 

mandatory adverse events submission 

since September 2008 indicates that 

responsible parties are able to use these 

classes effectively and that a single set 

of organ system classes provides a 

consistent way to display information 

about adverse events between tables for 

a trial and across trials. 

We also propose to require 

responsible parties to submit the total 

number of participants affected by an 

adverse event at the organ system level. 

This information would be required for 

each arm of the clinical trial and for 

each adverse event table (serious 

adverse events and other adverse 

events). Section 402(j)(3)(I)(iii) of the 

PHS Act requires the listing of adverse 

events by organ system. We believe that 

one purpose of this provision is to 

enable comparisons across arms even 

when there are variations in the level of 

specificity or granularity of the data 

submitted. Unless the total number of 

participants with adverse events is 

provided at the level of the organ 

system, the serious adverse event and 

other adverse event tables will not be 

able to support such comparisons. For 

example, if one trial lists 5 participants 

with ‘‘rash’’ under the ‘‘Skin and 

subcutaneous tissue disorders’’ organ 

system category and another lists 2 

participants for each of three specific 

types of rashes under the same category, 

it is not possible to know which trial 

had more participants with adverse 

events affecting the skin, because 

certain participants in the second trial 

could have suffered more than one type 

of rash. Thus, in order to obtain an 

important benefit of listing adverse 

events by organ system, we believe that 

it is necessary to require responsible 

parties to submit the total number of 

participants affected by any adverse 

event within each organ system for 

which adverse event data were 

collected. For organ systems that do not 

have a submitted adverse event, 

ClinicalTrials.gov will automatically 

assume that the total number of 

participants affected by that organ 

system is 0 (zero) for serious adverse 

events, and less than the 5 percent 

threshold for other adverse events, 

which will reduce the burden of this 

proposed requirement. 

We also propose to continue to 

require responsible parties to submit 

information about the total number of 

participants affected by any adverse 

event for each arm in each table. As 

described earlier in this section, it is our 

view that this information permits better 

interpretation of the adverse event data 

by clearly presenting how many 

participants were affected by any 

adverse event in a given arm of the 

clinical trial. 

We also considered, but do not 

propose to require submission of several 

other types of information describing 

the collection of adverse events in a 

clinical trial. Responsible parties are 

currently able to submit some of this 

information voluntarily. We invite 

public comment on the potential benefit 

and burden of requiring that the 

following types of information be 

submitted to ClinicalTrials.gov. We will 

consider comments in preparing the 

final rule. 

Time frame: Time frame information 

would specify when during the clinical 

trial adverse event information was 

collected. Information on different types 

of adverse events may be collected 

during different time frames in a clinical 

trial. Some adverse events are recorded 

only during specific portions of the trial, 

while others may be recorded 

throughout the duration of the trial [Ref. 

35, 36, 37]. Time frame information 

could assist users of ClinicalTrials.gov 

in interpreting correctly and comparing 

the relative occurrence of adverse events 

across different clinical trials. 

Submission of this information is 

currently optional. Responsible parties 

provided time frame information with 

more than half of the results information 

submitted in 2012 for probable 

applicable clinical trials. 

Collection approach: Collection 

approach information would indicate 

the type of approach taken to collect 

adverse event information, either 

‘‘systematic assessment’’ or ‘‘nonsystematic assessment.’’ Systematic 

assessment involves use of a specific 

method of ascertaining the presence of 

an adverse event, e.g., the use of 

checklists, questionnaires, or specific 

laboratory tests at regular intervals. 

Non-systematic assessment relies on 

spontaneous reporting of adverse 

events, such as unprompted selfreporting by participants. The approach 

used to assess adverse events affects 

comparability of information across 

clinical trials. For example, clinical 

trials using non-systematic assessment 

typically will record fewer adverse 

events than those using systematic 

assessment [Ref. 37]. Therefore, 

knowledge of the type of approach used 

to identify adverse events may help 

users of ClinicalTrials.gov to interpret 

differences in the rates of adverse events 

in different clinical trials. Submission of 

assessment type information currently is 

optional in ClinicalTrials.gov. 

Responsible parties who choose to 

submit this information select from the 

set of descriptors available in 

ClinicalTrials.gov (either ‘‘systematic 

assessment’’ or ‘‘non-systematic 

assessment’’). To simplify data entry, 

responsible parties are able to indicate 

the assessment type for the adverse 

event table as a whole or by each 

adverse event in the table. Of results for 

probable applicable clinical trials 

submitted in 2012, 76 percent included 

information about the approach to 

collecting some adverse events. 

All-cause mortality information: An 

all-cause mortality table would 

consolidate information about all 

participant deaths from any cause 

following assignment to an arm, by arm, 

for the clinical trial. Although 

information related to deaths may be 

part of other clinical trial results 

information, the total number of deaths 

that occurred during the clinical trial 

might not be readily apparent (e.g., 

submitted adverse event information 

might indicate a number of subjects who 

experienced a myocardial infarction, but 

would not necessarily indicate how 

many of the subjects died from the 

event). Submission of all-cause 

mortality information would be 

consistent with some clinical trial 

reporting guidelines [Ref. 23, 38], but it 

might need to be accompanied by 

additional explanatory information that 

would assist users in interpreting it 

correctly, e.g., to indicate that deaths 

may not have been associated with the 

interventions studied in the clinical 

trial. 

Standard vocabulary for adverse 

event terms. We also considered, but do 

not propose to require that adverse 

event terms be submitted according to a 

standard vocabulary. Although use of a 

single vocabulary might improve the 

comparability of adverse event data 

across trials represented in 

ClinicalTrials.gov, we do not believe it 

is reasonable to require responsible 

parties to submit adverse event data 

using a specific vocabulary. There is no 

agreed-upon standard adverse event 

vocabulary that is used in collecting and 

categorizing adverse event data for the 

full range of clinical trials. 

ClinicalTrials.gov currently allows 

responsible parties to indicate 

voluntarily any standardized vocabulary 

they have used when collecting adverse 

event data. Examination of the data 

voluntarily provided to date confirms 

that various versions of MedDRA are 

widely used by the pharmaceutical 

industry as the source of adverse event 

terms, but not by other entities (e.g., 

device manufacturers, non-industry 

organizations) that sponsor and conduct 

clinical trials. Other organizations use a 

variety of vocabularies, including 

SNOMED CT, which is an HHS-required 

standard for certification of electronic 

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health record products, or use no 

standard vocabulary at all. A 

requirement to submit adverse event 

data using a particular vocabulary 

would add significantly to the data 

submission burden for any responsible 

party who had used a different (or no) 

standard terminology in collecting 

adverse event data. In addition, 

requiring data collected under one 

terminology to be converted to a 

different terminology for submission to 

the data bank would carry unacceptable 

risks of data loss or misrepresentation. 

Such conversion is also a potentially 

much more difficult and timeconsuming task than assigning highlevel organ system classes to individual 

adverse event terms. As an alternative, 

we considered proposing that a single 

standard vocabulary be used to submit 

adverse event data for all clinical trials 

that are initiated after some date in the 

future (e.g., 2017). We rejected this 

approach because we do not think there 

is sufficient consensus on a standard 

vocabulary that is suitable for the full 

range of applicable clinical trials, and 

because ideally, data submission 

standards should follow data collection 

standards. 

We understand that adverse event 

data from individual clinical trials are 

inherently difficult to interpret or to 

compare with similar data from other 

trials of the same intervention. Many 

factors may contribute to differences in 

the adverse events data collected in 

different trials, including differences in 

patient populations, differences in the 

methods or duration of adverse events 

collection, or in the types of adverse 

events collected. In addition, adverse 

event information available in 

ClinicalTrials.gov for a clinical trial 

most likely will differ from the adverse 

event data included in published 

reports or FDA documents discussing 

the same clinical trial, which may 

contain information on only a subset of 

adverse events for specific trials or 

provide aggregated information from 

multiple clinical trials. To avoid 

confusion with adverse event 

information available from sources other 

than ClinicalTrials.gov and to assist 

ClinicalTrials.gov users with varying 

degrees of expertise in clinical trial 

design and data analysis in 

understanding the adverse event data 

contained in the data bank, we will 

include a prominent notice and 

explanation in ClinicalTrials.gov 

describing the types of adverse events 

that are listed in clinical trial records 

and how they might differ between 

clinical trials and from information 

available in other sources. In addition, 

we will consider steps such as (1) 

linking to and offering on the 

ClinicalTrials.gov site other resource 

materials describing issues that need to 

be considered when interpreting 

adverse event information (e.g., issues of 

attribution, participants at risk); (2) 

creating a default public display that 

highlights certain data (e.g., all serious 

adverse events and other adverse events 

with frequencies above a certain 

threshold, such as 20 percent); and (3) 

providing mechanisms to allow the user 

to customize the display (e.g., by 

adjusting the frequency threshold). 

We invite comments on all aspects of 

our proposed requirements for 

submission of adverse events 

information for clinical trials, including: 

(1) The benefit and burden of the 

proposed modifications to the statutory 

default provisions, including the 

number of participants affected by 

adverse events at the organ system level 

for both serious adverse events and 

other adverse events; (2) the potential 

benefit and burden of the additional 

information considered but not 

included in the proposal, such as the 

number of occurrences of each serious 

adverse event (in addition to the 

number of participants affected by a 

serious adverse event), the number of 

occurrences of each serious adverse 

event considered causally related to the 

intervention(s) studied, the time frame 

for collecting adverse events, the 

collection approach (systematic vs. nonsystematic), and all-cause mortality 

information; (3) ways to reduce the data 

submission burden without reducing 

the value of the data submitted; and (4) 

approaches to increasing 

standardization in the vocabularies used 

in submitting adverse event 

information. We also invite and 

encourage the submission of any other 

information on current practices for 

collection, attribution, and 

summarization of adverse event data 

that might help us to refine the 

proposed requirements for submission 

of summary adverse event information. 

16. Privacy Considerations 

We believe that, in general, the 

information submitted to 

ClinicalTrials.gov for the vast majority 

of applicable clinical trials subject to 

this proposed rule would pose no 

privacy concerns. Registration and 

results information submitted to 

ClinicalTrials.gov pursuant to this 

proposed rule would consist of 

summary level data only and would not 

contain personally identifiable 

information. It would consist of the 

same type of information that would be 

expected to be included in a journal 

article or other routine form of public 

scientific communication. In addition, 

participants would be aware that 

summary data would be posted at 

ClinicalTrials.gov. FDA regulations 

require that informed consent forms for 

applicable clinical trials of drugs and 

devices include a specific statement to 

inform potential participants that 

certain information about the clinical 

trial will be submitted to 

ClinicalTrials.gov, where it will be 

publicly posted [see 21 CFR § 50.25(c)]. 

We also believe that in most cases it 

would not be possible to re-identify 

individuals who participated in a 

clinical trial based on the data 

submitted to ClinicalTrials.gov. For 

clinical trials of common diseases, or 

that recruit large numbers of 

participants, and/or recruit participants 

from multiple locations, the summary 

information submitted to 

ClinicalTrials.gov would be unlikely to 

contain characteristics that would 

enable re-identification of study 

participants. Even the information 

submitted for small trials with limited 

numbers of sites and few study 

participants would, in general, provide 

no clear basis for re-identification. 

The risk of re-identification could be 

greater in particular types of clinical 

trials, such as small clinical trials that 

study treatments for rare diseases and 

have few recruitment sites or that 

recruit subjects from only small, welldefined populations. For some such 

clinical trials, we believe that a 

responsible party could submit required 

results information in a way that 

minimizes opportunities for reidentification. For example, if a trial of 

a rare disease recruits a participant of 90 

years or more, the responsible party 

could consider submitting demographic 

information by grouping subjects into 

broader age categories or providing the 

mean age of all subjects in each arm of 

the trial, rather than breaking out the 

data for that one subject. 

In those situations in which a 

responsible party believes results 

information could not be submitted in a 

way that is consistent with this 

proposed rule without risk of reidentification, the responsible party 

could alternatively request a waiver of 

results submission requirements, as 

permitted by section 402(j)(3)(H) of the 

PHS Act and proposed in § 11.54 of this 

rule. We believe such situations would 

be rare and such a waiver request would 

need to be evaluated on a case-by-case 

basis. 

We invite public comment on other 

situations that might raise privacy 

concerns and on other approaches that 

we could propose to address them in a 

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way that is consistent with the 

requirements of section 402(j) of the 

PHS Act. 

D. Effective Date/Compliance Date 

1. Effective Date 

We propose that the effective date of 

these regulations be established as 45 

days after the date on which the final 

rule is published in the Federal 

Register. As of the effective date, the 

ClinicalTrials.gov system would be 

modified to be consistent with the final 

rule. As such, a responsible party that 

submits information into the data bank 

on or after the effective date must do so 

consistent with the final rule. 

2. Compliance Date 

We propose that the compliance date 

for these regulations be established as 

90 days after the effective date of the 

rule. We interpret this to mean that a 

responsible party would have until the 

compliance date of the rule to come into 

compliance with the requirements of 

this proposed Part. Accordingly, by the 

compliance date of the rule: (a) 

Responsible parties for all applicable 

clinical trials initiated on or after, or 

ongoing as of, the effective date would 

have to comply with the clinical trial 

registration information requirements of 

proposed subpart B; (b) responsible 

parties for all applicable clinical trials 

required to submit clinical trial results 

information by a date that is on or after 

the effective date of the rule (including 

such trials whose completion dates were 

prior to the effective date of the rule, but 

for which results are due on or after the 

effective date of the rule under section 

402(j)(3)(E) of the PHS Act) would have 

to comply with the clinical trial results 

information requirements of proposed 

subpart C; (c) responsible parties that 

make voluntary submissions of clinical 

trial information on or after the effective 

date of the rule would have to comply 

with proposed § 11.60 and any other 

applicable provisions of the final rule; 

and (d) responsible parties that submit 

clinical trial information to 

ClinicalTrials.gov, for both applicable 

clinical trials and clinical trials 

voluntarily submitted to the data bank 

under proposed § 11.60, on or after the 

effective date of the rule, would be 

required to update such clinical trial 

information in accordance with the 

requirements of proposed § 11.64(c). 

Consistent with the foregoing, in 

instances in which submission of 

clinical trial registration or results 

information ordinarily would have been 

due between the effective date and the 

compliance date of the rule, the 

responsible party would have until the 

compliance date to submit the required 

clinical trial information. For example, 

if under this proposed part, clinical trial 

results information were due for an 

applicable clinical trial on a date that is 

30 days after the effective date of the 

rule, the responsible party for that 

applicable clinical trial would have 

until the compliance date to submit 

such information. That said, because we 

propose to modify ClinicalTrials.gov 

consistent with the final rule as of the 

effective date of the rule, responsible 

parties seeking to come into compliance 

with the final rule after the effective 

date but prior to the compliance date 

would be able to do so. 

We recognize that there will be 

situations in which the determination of 

one submission deadline will be 

conditioned upon an earlier submission 

deadline. In such situations, the Agency 

would consider the deadline pursuant 

to section 402(j) of the PHS Act and the 

final rule, notwithstanding the 

compliance date, as the applicable date 

for purposes of determining a 

subsequent deadline. For example, 

responsible parties that submit a 

certification to delay results submission 

under section 402(j)(3)(E)(v) of the PHS 

Act or proposed § 11.44(b)(1) must 

subsequently submit clinical trial 

results information no later than two 

years after the date of the certification. 

(See section 402(j)(3)(E)(v)(III) of the 

PHS Act and proposed § 11.44(b)(2).) If 

the deadline for the certification to 

delay results submission falls between 

the effective date and compliance date 

of the rule, then the responsible party 

would have until the compliance date to 

submit the certification. However, the 

subsequent deadline—i.e., the date by 

which clinical trial results information 

is due—would remain 2 years after the 

certification would have been due 

absent the compliance date. 

We believe that the proposed 90-day 

delay between the effective date and the 

compliance date of the final rule would 

provide ample time for responsible 

parties of applicable clinical trials to 

come into compliance with the final 

rule. This proposed 90-day delay is the 

same number of days provided after the 

date of enactment of section 402(j) of the 

PHS Act for ongoing applicable clinical 

trials to submit registration information. 

3. Registration Information 

Clinical trial registration information 

submitted on or after the effective date 

of the rule would need to comply with 

the clinical trial registration information 

requirements of proposed subpart B. 

Furthermore, if an applicable clinical 

trial is ongoing as of the effective date 

of the rule and clinical trial registration 

information for that trial had been 

submitted prior to the effective date of 

the rule, the responsible party would 

need to submit any revised or additional 

registration information necessary to 

comply with proposed § 11.28 by the 

compliance date. This would help 

ensure that complete clinical trial 

registration information, as defined in 

this proposed rule, is available to the 

public for all ongoing applicable clinical 

trials subject to this proposed part. This 

also would ensure that certain 

information that was not previously 

required in order to register a clinical 

trial with ClinicalTrials.gov, but which 

is essential to the implementation of the 

proposed regulation, will be included in 

the data bank for all applicable clinical 

trials ongoing as of the effective date of 

the rule. 

By contrast, if an applicable clinical 

trial reached its completion date prior to 

the effective date of the rule, and thus 

would not be ongoing as of the effective 

date of the rule, the responsible party 

would not be required to submit the 

additional registration information that 

would be required by proposed § 11.28. 

The responsible party would 

nevertheless be expected to have 

provided, at minimum, registration 

information containing all of the data 

elements specified in section 

402(j)(2)(A)(ii) of the PHS Act, as they 

were available in ClinicalTrials.gov at 

the time of registration, namely, Brief 

Title, Brief Summary, Primary Purpose, 

Study Design, Study Phase (for an 

applicable drug clinical trial), Study 

Type, Primary Disease or Condition or 

Focus of the Study, Intervention Name, 

Intervention Type, Study Start Date, 

Completion Date (listed in 

ClinicalTrials.gov as ‘‘Study Completion 

Date’’), Target Number of Subjects 

(listed in ClinicalTrials.gov as 

‘‘Enrollment’’), Primary and Secondary 

Outcome Measures, Eligibility Criteria, 

Gender, Age Limits, Whether the Trial 

Accepts Healthy Volunteers (listed in 

ClinicalTrials.gov as ‘‘Accepts Healthy 

Volunteers?’’), Overall Recruitment 

Status, Individual Site Status, 

Availability of Expanded Access (for an 

applicable drug clinical trial) (listed in 

ClinicalTrials.gov as ‘‘expanded access 

record’’), Name of the Sponsor, 

Responsible Party by Official Title 

(listed in ClinicalTrials.gov as 

‘‘Responsible Party Information’’), 

Facility Name and Facility Contact 

Information (either facility-specific or 

central contact information), Unique 

Protocol Identification Number, 

Secondary ID, IND/IDE number (listed 

in ClinicalTrials.gov as ‘‘IND/IDE 

Protocol’’), and Record Verification 

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Date. We also would expect the 

responsible party to have updated these 

data elements as necessary, consistent 

with the section 402(j)(4)(C) of the PHS 

Act. For example, for each of the 

applicable clinical trials in this 

category, we would expect that the 

Completion Date data element would 

have been updated not later than 30 

calendar days after the completion date 

of the clinical trial to reflect the 

‘‘actual’’ completion date of the clinical 

trial. See section 402(j)(4)(C)(i)(IV) of the 

PHS Act. 

We recognize that the data elements 

listed in the previous paragraph do not 

provide sufficient information for the 

responsible party to demonstrate (or for 

the Agency to determine) in all cases 

whether a clinical trial that was 

registered in ClinicalTrials.gov prior to 

the effective date of the rule meets the 

definition of an applicable clinical trial 

and thus whether results information 

was required to be submitted. The need 

to determine whether a clinical trial is 

an applicable clinical trial, in all cases, 

is one of the reasons we have proposed 

in § 11.28 to require the submission of 

several additional data elements as part 

of clinical trial registration information, 

e.g., Single Arm Controlled as part of 

Study Design (for single-armed studies); 

Product Manufactured in U.S.?; and 

U.S. FDA Approval, Clearance, or 

Licensure Status. Responsible parties 

may voluntarily submit such additional 

data elements for clinical trials that 

were registered and reached their 

completion dates before the effective 

date of this rule. Submission of this 

information will enable the clinical trial 

record to indicate whether or not the 

clinical trial is an applicable clinical 

trial subject to section 402(j) of the PHS 

Act. 

4. Results Information 

We interpret the approval status of a 

product studied in an applicable 

clinical trial (i.e., either ‘‘unapproved, 

unlicensed, or uncleared’’ or ‘‘approved, 

licensed, or cleared’’) to be the approval 

status of the product on any given date. 

For example, if a drug being studied in 

an applicable clinical trial was 

unapproved as of the completion date, 

at that time, the applicable clinical trial 

would be of an unapproved product. 

However, if and when the study drug 

receives FDA approval (for any 

indication), the applicable clinical trial 

would be of an approved product as of 

the date of FDA approval. 

(a) Applicable clinical trials that reach 

their completion dates on or after the 

effective date of the rule. Responsible 

parties would be required to submit 

clinical trial results information 

specified in proposed subpart C for all 

applicable clinical trials that are 

required to be registered in 

ClinicalTrials.gov under section 402(j) 

of the PHS Act or this proposed rule 

that reach their completion dates on or 

after the effective date of the rule. This 

requirement would apply to applicable 

clinical trials of unapproved, 

unlicensed, or uncleared products as 

well as approved, licensed, or cleared 

products. 

(b) Applicable clinical trials that 

reach their completion dates prior to the 

effective date of the rule—approved, 

licensed, or cleared products. In general, 

the responsible party for an applicable 

clinical trial of an approved, licensed, or 

cleared product that reaches its 

completion date prior to the effective 

date of the rule would not be required 

to submit the additional clinical trial 

results information required under 

proposed § 11.48 if the responsible party 

has already submitted the clinical trial 

results information required under 

section 402(j)(3)(C) of the PHS Act. This 

reflects the Agency’s decision, as further 

described in section III.C.9 of this 

preamble, not to exercise its authority 

under section 402(j)(3)(D)(iv)(II) of the 

PHS Act to require ‘‘the clinical trial 

information described in [section 

402(j)(3)(D)(iii) of the PHS Act] . . . to 

be submitted for an applicable clinical 

trial for which the clinical trial 

information described in [section 

402(j)(3)(C) of the PHS Act] is submitted 

to the registry and results data bank 

before the effective date of the 

regulations.’’ We interpret the phrase ‘‘is 

submitted’’ to mean ‘‘is required to be 

submitted,’’ in order to make clear that 

this provision would also apply to those 

responsible parties who were required 

to submit results under section 

402(j)(3)(C) of the PHS Act, but failed to 

do so. 

There are three scenarios in which we 

propose to require the responsible party 

for an applicable clinical trial of an 

approved, licensed, or cleared product 

that reaches its completion date prior to 

the effective date of the rule to submit 

the additional clinical trial results 

information under proposed § 11.48: 

First, in certain cases, an applicable 

clinical trial may reach its completion 

date prior to the effective date of the 

rule, but the clinical trial results 

information is neither due nor 

submitted until after the effective date 

of the rule. For example, under section 

402(j)(3)(E)(i) of the PHS Act, clinical 

trial results information is due for an 

applicable clinical trial of an approved, 

licensed, or cleared product not later 

than 1 year after the completion date of 

the trial. Thus, if clinical trial results 

information is submitted after the 

effective date of the rule, consistent 

with this deadline, the responsible party 

would be required to submit the clinical 

trial results information required by 

proposed § 11.48. 

Second, there may be situations 

consistent with proposed § 11.44(a)(2) 

in which an applicable clinical trial of 

an approved, licensed, or cleared 

product reaches its completion date 

prior to the effective date of the rule, has 

partial results information (i.e., primary 

outcome measures) submitted before the 

effective date of the rule, but has other 

partial results information (i.e., 

secondary outcome measures) that is 

neither due nor submitted until on or 

after the effective date of the rule. The 

Agency proposes to exercise its 

authority under section 

402(j)(3)(D)(iv)(II) of the PHS Act in 

situations when partial results are due 

on or after the effective date of the rule 

to require the responsible party to 

submit clinical trial results information 

under proposed § 11.48 for all outcome 

measures, including primary outcome 

measures submitted prior to the 

effective date of the rule. We make this 

proposal so that, for any such trial, the 

data bank ultimately will contain the 

same required data elements for both 

primary and secondary outcome 

measures. 

Third, as a result of modifications that 

would be made to the ClinicalTrials.gov 

data bank upon implementation of the 

final rule, the responsible party would 

be required to submit clinical trial 

results information as specified in 

proposed § 11.48 for any applicable 

clinical trial of an approved, licensed, or 

cleared product for which results 

information was required to be 

submitted under section 402(j)(3)(C) of 

the PHS Act prior to the effective date 

of the rule, but for which the 

responsible party failed to do so. Such 

responsible parties would be required to 

submit the clinical trial results 

information specified in § 11.48, even 

though only the clinical trial results 

information specified in section 

402(j)(3)(C) of the PHS Act would have 

been required had results information 

been submitted on time. Accordingly, 

we are electing to exercise our authority 

under section 402(j)(3)(D)(iv)(II) of the 

PHS Act to require such responsible 

parties of applicable clinical trials of 

approved, licensed, or cleared products 

to submit the additional results data 

elements specified in proposed § 11.48. 

As discussed in section III.C.9 of this 

preamble, section 402(j)(3)(D)(iv)(II) of 

the PHS Act provides that the Secretary 

shall by regulation determine ‘‘whether 

the clinical trial information described 

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in [section 402(j)(3)(D)(iii) of the PHS 

Act] should be required to be submitted 

for an applicable clinical trial for which 

the clinical trial information described 

in [section 402(j)(3)(C) of the PHS Act] 

is submitted to the registry and results 

data bank before the effective date of the 

regulations.’’ We interpret the phrase ‘‘is 

submitted’’ to mean ‘‘is required to be 

submitted,’’ in order to make clear that 

this provision would also apply to those 

responsible parties who were required 

to submit results information under 

section 402(j)(3)(C) of the PHS Act, but 

failed to do so. 

(c) Results information for applicable 

clinical trials that reach their 

completion dates prior to the effective 

date of the rule—unapproved, 

unlicensed, or uncleared products. With 

respect to applicable clinical trials of 

unapproved, unlicensed, or uncleared 

products that reach their completion 

dates prior to the effective date of the 

final rule, whether clinical trial results 

information is required under this 

proposed rule would depend on 

whether the product under study gets 

approved, licensed, or cleared. If the 

drug or device under study in an 

applicable clinical trial that reached its 

completion date prior to the effective 

date of the rule is never approved, 

licensed, or cleared by FDA, then 

submission of results information would 

not be required. However, if the drug or 

device under study is subsequently 

approved, licensed, or cleared after the 

effective date of the rule, then, 

consistent with section 402(j)(3)(E)(iv) 

of the PHS Act, clinical trial results 

information required by proposed 

§ 11.48 would be due by the earlier of 

1 year after the completion date or 30 

calendar days after the date of initial 

FDA approval, licensure or clearance. In 

addition, the clinical trial results 

information under § 11.48 would be 

required if results were due and 

submitted after the effective date of this 

proposed rule. 

5. Voluntary Submissions 

If on or after the effective date, a 

responsible party voluntarily submits 

clinical trial information for a clinical 

trial that is not an applicable clinical 

trial, or that is an applicable clinical 

trial but is not required to register in 

ClinicalTrials.gov under section 

402(j)(2)(C) of the PHS Act, the 

voluntary submissions provision of 

section 402(j)(4)(A) of the PHS Act and 

proposed § 11.60 apply to that 

submission, regardless of the 

completion date of such trial. 

6. Updates and Corrections to Clinical 

Trial Information 

With respect to clinical trial 

registration information or clinical trial 

results information that is due on or 

after the effective date of the rule, the 

Agency intends to require responsible 

parties to update such information, in 

accordance with proposed § 11.64. 

With respect to clinical trial 

information that is due prior to the 

effective date of the rule, the Agency 

intends to continue requiring 

responsible parties to update such 

information in accordance with the 

requirements set forth in section 

402(j)(4)(C) of the PHS Act. Because 

responsible parties that submitted 

clinical trial information to the data 

bank prior to the effective date of the 

final rule would have submitted only 

those data elements required under 

sections 402(j) of the PHS Act, which 

excludes any additional data elements 

required under the final rule, they 

would be required to update only that 

information that was required to be 

submitted prior to the effective date of 

the rule and only to the extent required 

under section 402(j)(4)(C) of the PHS 

Act. 

In the event that a clinical trial 

reaches its completion date prior to the 

effective date of the rule but clinical 

trial results information is due after the 

effective date of the rule, the responsible 

party would be required to update the 

clinical trial registration information in 

accordance with the requirements of 

section 402(j)(4)(C) of the PHS Act, but 

it would be required to update the 

clinical trial results information 

submitted after the effective date in 

accordance with the requirements of 

proposed § 11.64(c). As discussed 

earlier in this section, a responsible 

party of a clinical trial that is registered 

but ongoing as of the effective date of 

the rule would be required to submit 

registration information consistent with 

proposed § 11.28 by the compliance 

date of the rule; consistent with this 

approach, responsible parties would be 

required to update the clinical trial 

registration information for such trials 

in accordance with the requirements of 

proposed § 11.64(c). 

Notwithstanding the foregoing, if a 

responsible party becomes aware of 

previously submitted clinical trial 

information that contains errors that 

need to be corrected or that may have 

been falsified, the Agency proposes to 

require responsible parties to correct 

such previously submitted clinical trial 

information in accordance with 

proposed § 11.66(c), regardless of when 

such clinical trial information was 

submitted to data bank. We believe our 

proposed approaches outlined in this 

part balance the differing positions 

expressed in comments made at the 

public meeting. We invite public 

comment on the advantages and 

disadvantages of this proposed 

approach and on other approaches that 

might be considered by the Agency in 

establishing the effective date and the 

compliance date. 

IV. Detailed Description of This 

Proposed Rule 

Proposed Subpart A, General 

Provisions, sets forth the purpose of the 

regulations; to whom the regulations 

apply; the form and manner for 

submission of clinical trial information; 

the requirement that the submission of 

information under this part be truthful 

and not false or misleading; and the 

definitions applicable to this part. 

Proposed Subpart B, Registration, sets 

forth the requirements related to clinical 

trial registration information. It 

delineates who must submit clinical 

trial registration information; which 

applicable clinical trials must be 

registered in ClinicalTrials.gov; when 

clinical trial registration information 

must be submitted; where clinical trial 

registration information must be 

submitted; what constitutes clinical trial 

registration information; and by when 

NIH will post submitted clinical trial 

registration information. 

Proposed Subpart C, Results 

Submission, addresses the submission 

of clinical trial results information. It 

delineates who must submit clinical 

trial results information for applicable 

clinical trials; which applicable clinical 

trials are subject to the results 

submission requirement; when the 

clinical trial results information must be 

submitted; where and in what format 

clinical trial results information must be 

submitted; what constitutes clinical trial 

results information; by when NIH will 

post submitted clinical trial results 

information; and under what 

circumstances a waiver of the 

regulations will be granted. 

Proposed Subpart D, Additional 

Submissions of Clinical Trial 

Information, sets forth the requirements 

and procedures for voluntary 

submissions of clinical trial information 

for clinical trials of FDA-regulated drugs 

and devices, submissions required to 

protect the public health, and updates to 

previously-submitted clinical trial 

registration and results information. 

A detailed discussion of this proposed 

rule, its statutory basis, and the purpose 

of its provisions follows. 

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Federal Register / Vol. 79, No. 225 / Friday, November 21, 2014 / Proposed Rules 69595 

A. General Provisions—Subpart A 

1. What is the purpose of this part— 

§ 11.2 

As set forth in proposed § 11.2, the 

purpose of this part is to implement 

section 402(j) of the PHS Act [42 U.S.C. 

282(j)], by providing requirements and 

procedures for the submission of 

clinical trial information for certain 

applicable clinical trials and other 

specified clinical trials to the Director of 

NIH to be made publicly available 

through ClinicalTrials.gov, the Internetaccessible clinical trial registry and 

results data bank established by NLM at 

http://www.clinicaltrials.gov. 

2. To whom does this part apply?— 

§ 11.4 

Proposed § 11.4(a) specifies that this 

proposed rule applies to any person or 

entity that is considered to be the 

‘‘responsible party’’ for an applicable 

clinical trial that is required to be 

registered under § 11.22 or a clinical 

trial for which clinical trial information 

is submitted voluntarily under § 11.60. 

The responsible party would be either 

the sponsor of the clinical trial or a 

principal investigator who meets the 

criteria specified in proposed 

§ 11.4(c)(2) and has been so designated 

by the sponsor. (See proposed § 11.4(c).) 

Proposed § 11.22 specifies which 

applicable clinical trials are required to 

submit registration information to 

ClinicalTrials.gov (i.e., applicable drug 

clinical trials and applicable device 

clinical trials that were initiated after 

September 27, 2007, or that were 

initiated on or before September 27, 

2007, and ‘‘ongoing’’ (as such term is 

defined by this proposed rule) on 

December 26, 2007, consistent with 

section 402(j)(2)(C) of the PHS Act. 

Proposed § 11.60 specifies requirements 

for voluntary submissions of clinical 

trial information for applicable clinical 

trials that are not required to register 

under section 402(j) of the PHS Act (e.g., 

because they were completed prior to 

September 27, 2007), and for clinical 

trials that do not meet the definition of 

an applicable clinical trial. The 

voluntary submission of clinical trial 

registration or results information for 

such clinical trials, triggers a 

requirement to submit clinical trial 

registration or results information for 

certain other trials, as required by 

section 402(j)(4)(A) of the PHS Act. (See 

proposed § 11.60(a)(2)(ii)).) 

In no case would this proposed rule 

apply to the sponsor or principal 

investigator or other individual or entity 

associated with a clinical trial of a 

health intervention that is not subject to 

FDA jurisdiction. Although section 

402(j)(4)(A) of the PHS Act directs the 

NIH to permit ‘‘[v]oluntary 

submissions’’ of clinical trial 

information for ‘‘a clinical trial that is 

not an applicable clinical trial or that is 

an applicable clinical trial that is not 

subject to’’ the registration provisions of 

section 402(j)(2) of the PHS Act, we 

interpret section 402(j) of the PHS Act 

and thus this proposed rule as not 

applying to anyone who submits 

information to ClinicalTrials.gov about 

trials of interventions that are not 

subject to FDA jurisdiction under 

sections 505, 510(k), 515, 520(m), or 522 

of the FD&C Act, or section 351 of the 

PHS Act. Moreover, we interpret section 

402(j) of the PHS Act and thus this 

proposed rule as not applying to anyone 

who submits information to 

ClinicalTrials.gov for a study that is 

neither an interventional clinical trial 

nor a pediatric postmarket surveillance 

of a device as defined in this part (e.g., 

for a study that is an observational 

study), even if it involves a drug or 

device subject to sections 505, 510(k), 

515, 520(m), or 522 of the FD&C Act, or 

section 351 of the PHS Act. Consistent 

with other statutory authorities of the 

NIH and long-standing practice, 

however, ClinicalTrials.gov may, and 

does, accept registration and results 

information on clinical studies and 

interventions that are not subject to the 

requirements of section 402(j) of the 

PHS Act and this proposed rule. 

Proposed § 11.4(b) implements 

section 402(j)(1)(B) of the PHS Act, 

which provides that the Secretary ‘‘shall 

develop a mechanism by which the 

responsible party for each applicable 

clinical trial shall submit the identity 

and contact information of such 

responsible party to the Secretary at the 

time of submission of clinical trial 

[registration] information.’’ Proposed 

§ 11.4(b) provides that the responsible 

party’s identity and contact information 

must be included as part of the clinical 

trial information that is submitted in 

accordance with subpart B and updated 

in accordance with § 11.64(b)(1)(ix) and 

(x). We propose in § 11.28(a)(4)(vii), to 

require submission of a data element 

entitled Responsible Party Contact 

Information that, as specified in 

proposed § 11.10(b)(38) includes the 

name, official title, organizational 

affiliation, physical address (i.e., street 

address), mailing address, phone 

number, and email address of the 

responsible party. To minimize 

redundant data entry, we will provide a 

mechanism for the responsible party to 

indicate if the mailing address is the 

same as the physical address. In those 

cases in which the responsible party is 

an organization, as opposed to an 

individual, we would require the name 

and official title to correspond to a 

designated contact person for the 

organization. As described in section 

IV.B.4(a) of this preamble, if the 

responsible party is an individual, we 

intend to make the name of responsible 

party publicly available in the data 

bank, but we do not propose to make the 

other contact information publicly 

available (i.e., the physical address, 

mailing address, phone number, and 

email address). The other contact 

information will be used for internal 

administrative processes (e.g., for 

necessary communications). We note 

that the official title and organizational 

affiliation of the responsible party will 

also be made publicly available as part 

of the Responsible Party, By Official 

Title data element, which is required to 

be submitted to ClinicalTrials.gov at the 

time of registration. See section 

402(j)(2)(A)(ii)(III)(bb) of the PHS Act. 

Proposed § 11.4(c) outlines 

procedures for determining the 

responsible party for each applicable 

clinical trial or other clinical trial 

subject to this part. We believe that 

there must be one (and only one) 

responsible party for each applicable 

clinical trial or other clinical trial. 

Absent a responsible party, the 

objectives of registration and results 

submission cannot be met. Because the 

definition of responsible party under 

section 402(j) of the PHS Act specifies, 

first, that the sponsor will be the 

responsible party and, second, that the 

PI is the responsible party if delegated 

this role through a designation ‘‘by a 

sponsor, grantee, contractor, or 

awardee,’’ with regard to clinical trials, 

the Agency looks first to determine who 

is the sponsor of the clinical trial, 

consistent with the definition proposed 

in this part, and assumes that such 

individual or entity is the responsible 

party, unless the PI has been designated 

the responsible party in accordance 

with the procedure established in 

proposed § 11.4(c)(2). For a pediatric 

postmarket surveillance of a device that 

is not a clinical trial, the responsible 

party would be considered the entity 

whom FDA orders to conduct the 

pediatric postmarket surveillance of a 

device. 

Proposed § 11.4(c)(1) specifies who 

will be considered the sponsor. The 

Agency believes that there must be a 

sponsor, as that term is used in section 

402(j)(1)(A)(ix) of the PHS Act, for each 

clinical trial, and that there can be only 

one sponsor. Without a defined sponsor, 

there cannot be a responsible party for 

a clinical trial because responsible party 

is defined as either the sponsor or the 

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principal investigator who has been so 

designated by the sponsor. The 

proposed definition of sponsor in 

§ 11.10(a), includes both a ‘‘sponsor’’ 

and a ‘‘sponsor-investigator’’ as those 

terms are defined in 21 CFR 50.3. Both 

definitions in 21 CFR 50.3 refer to the 

sponsor as, in part, the person or entity 

who ‘‘initiates’’ the clinical 

investigation. For purposes of this 

proposed rule, if a clinical trial is being 

conducted under an IND or IDE, the 

IND/IDE holder would be considered to 

be the individual or entity who initiated 

the clinical trial and, therefore, the 

sponsor, regardless of how the clinical 

trial is being funded. For clinical trials 

not conducted under an IND or IDE, the 

sponsor would be considered to be the 

person or entity who initiated the trial 

and would be identified as follows. 

(1) Where the clinical trial is being 

conducted by an entity under a research 

assistance funding agreement such as a 

grant or sponsored research agreement, 

the funding recipient generally would 

be considered to be the initiator of the 

clinical trial, and therefore, the sponsor. 

This is because, as a general rule, when 

a clinical trial is funded in this manner, 

the funding recipient ‘‘initiates’’ the 

clinical trial process by, for example, 

submitting a funding proposal and 

designing the clinical trial. 

(2) Where the clinical trial is being 

conducted by an entity under a 

procurement funding agreement such as 

a contract, the party obtaining the goods 

or services for its direct benefit or use 

(the funder) generally would be 

considered to be the initiator of the trial, 

and therefore, the sponsor. This is 

because, as a general rule, when a 

clinical trial is funded in this manner, 

it is the funder of the clinical trial that 

initiates the clinical trial process by, for 

example, contracting with another 

entity for that entity to conduct a 

clinical trial meeting the specifications 

of the funder. 

(3) Where there is no funding 

agreement supporting the clinical trial, 

the person or entity who initiated the 

clinical trial by preparing and/or 

planning the clinical trial, and who has 

appropriate authority and control over 

the clinical trial to carry out the 

responsibilities under section 402(j) of 

the PHS Act and this proposed part 

would be the sponsor. 

Proposed § 11.4(c)(2) establishes the 

procedures for designation of a 

principal investigator as the responsible 

party. Section 402(j)(1)(A)(ix) of the PHS 

Act defines the responsible party, as 

either ‘‘the sponsor of the clinical trial 

(as defined in . . . 21 [CFR 50.3] (or any 

successor regulation);’’ or, as ‘‘the 

principal investigator of such clinical 

trial if so designated by the sponsor, 

grantee, contractor, or awardee. . .’’ In 

order to give practical effect to this 

provision, we believe that, for any given 

applicable clinical trial, only one 

entity—the sponsor—can designate the 

PI as the responsible party. We believe 

that this interpretation is consistent 

with section 402(j) of the PHS Act 

because in many situations the sponsor 

of the clinical trial will also be a 

grantee, contractor, or awardee (e.g., in 

a situation in which there is no IND/IDE 

holder, and the sponsor is considered 

the ‘‘initiator’’ of the trial). In addition, 

interpreting this provision in a different 

manner could result in situations in 

which both a sponsor (e.g., an IND/IDEholder) and a PI (designated by a 

separate grantee, contractor, or awardee) 

consider themselves the responsible 

party and submit information for the 

same clinical trial. This would not only 

increase the overall burden associated 

with registration, but more importantly 

would undermine the integrity of the 

data bank and potentially cause 

confusion to users of the system. 

Section 402(j)(1)(A)(ix) of the PHS Act 

permits a PI to serve as a responsible 

party only if he or she ‘‘is responsible 

for conducting the trial, has access to 

and control over the data from the 

clinical trial, has the right to publish the 

results of the trial, and has the ability to 

meet all of the requirements under [this 

proposed part] for the submission of 

clinical trial information.’’ Accordingly, 

if the PI does not meet the specified 

conditions for serving as the responsible 

party, the sponsor cannot designate the 

PI as the responsible party, and the 

sponsor must remain the responsible 

party. In proposed § 11.10(a) we define, 

for purposes of this part, the term 

principal investigator (PI) to mean ‘‘the 

individual who is responsible for the 

scientific and technical direction of the 

study.’’ We note that under section 

402(j)(1)(A)(ix) of the PHS Act, in order 

to be designated the responsible party, 

the PI must be responsible for 

‘‘conducting the trial’’ and must have 

‘‘access to and control over the data 

from the clinical trial.’’ We interpret 

‘‘the trial’’ to mean ‘‘the entire trial,’’ 

and ‘‘the data’’ to mean ‘‘all of the data’’, 

including data collected at all sites of a 

multi-site trial. 

We wish to clarify our understanding 

of section 402(j)(3)(C)(iv) of the PHS 

Act, as it relates to whether a PI would 

be eligible to serve as the responsible 

party under this proposed part. Section 

402(j)(3)(C)(iv) of the PHS Act requires 

the responsible party to indicate, as an 

element of clinical trial results 

information, whether there exist 

‘‘certain agreements,’’ which are 

described as ‘‘an agreement . . . that 

restricts in any manner the ability of the 

principal investigator, after the 

completion date of the trial, to discuss 

the results of the trial at a scientific 

meeting or any other public or private 

forum, or to publish in a scientific or 

academic journal information 

concerning the results of the trial.’’ We 

do not view the presence of such an 

agreement as necessarily disqualifying a 

PI from serving as the responsible party. 

Rather, we view only those agreements 

that prevent the PI from performing the 

functions described in section 

402(j)(1)(A)(ix)(II) of the PHS Act or 

from submitting clinical trial 

information or any updates to such 

information required by section 402(j) of 

the PHS Act and this proposed part as 

preventing the PI from serving as the 

responsible party. 

To provide for the orderly 

implementation of section 

402(j)(1)(A)(ix)(II) of the PHS Act, 

pursuant to which the sponsor may 

designate a PI as responsible party, and 

ensure that the PI has notice of the 

designation, we have proposed a 

process in § 11.4(c)(2) for designating a 

PI, as follows: the sponsor shall provide 

notice of the designation to the PI and 

obtain acknowledgement of the PI’s 

responsibilities under this proposed 

part. We intend to continue to provide 

mechanisms in the PRS for the sponsor 

and the PI to indicate the designation 

and the acknowledgement, respectively. 

The designation by the sponsor is 

currently reflected in ClinicalTrials.gov 

by having the PI submit clinical trial 

information via the sponsor’s 

organizational account (the sponsor 

must provide an account for the PI 

within the sponsor’s PRS organizational 

account). The acknowledgement is 

reflected by having the PI list his/her 

name as the responsible party and 

indicate that he/she was designated as 

responsible party by the sponsor. This 

approach has been implemented in 

ClinicalTrials.gov since 2011. 

If and when a designated principal 

investigator becomes unable to meet all 

of the requirements of a responsible 

party, proposed § 11.04(c)(3) outlines 

the mechanisms by which the sponsor 

would become the responsible party. 

This might occur if, for example, a 

principal investigator dies, retires, 

changes jobs, or turns control of the 

clinical trial data over to the sponsor. 

We note that even if a sponsor 

designates a principal investigator as the 

responsible party for an applicable 

clinical trial registered under proposed 

§ 11.22, there may be times when the 

sponsor would need to provide the 

principal investigator with certain 

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information in order for the principal 

investigator to meet his or her 

obligations as responsible party under 

section 402(j) of the PHS Act and/or this 

proposed part. For example, the sponsor 

would likely have to provide the 

principal investigator with information 

to describe an expanded access program 

for which information is required to be 

submitted and updated pursuant to 

proposed §§ 11.28(a)(2)(viii) and 11.64. 

In some cases, a principal investigator 

who is the responsible party would rely 

upon the sponsor to obtain information 

necessary to determine if the applicable 

clinical trial meets the criteria for 

delayed submission of results 

information under proposed §§ 11.44(b) 

or (c). Although we would expect a 

principal investigator who is a 

responsible party to request such 

information from the sponsor, we also 

would expect a sponsor who has 

designated a principal investigator as 

the responsible party to provide such 

information. A principal investigator 

who is not provided the information 

necessary to enable him or her to meet 

all of the requirements for submitting 

and updating clinical trial information 

would not meet the criteria set forth in 

proposed § 11.4(c)(2)(i) to serve as the 

responsible party. If the sponsor does 

not provide the principal investigator 

with the requisite information to meet 

the criteria under proposed 

§ 11.4(c)(2)(i), the principal investigator 

cannot be designated as a responsible 

party and the responsible party 

designation either would remain with or 

revert back to the sponsor. 

3. What are the requirements for the 

submission of truthful information?— 

§ 11.6 

Section 402(j)(5)(D) of the PHS Act 

specifies that ‘‘clinical trial information 

submitted by a responsible party under 

this subsection shall not be false or 

misleading in any particular.’’ In 

addition, it is a prohibited act under 

section 301(jj)(3) of the FD&C Act to 

submit clinical trial information under 

section 402(j) of the PHS Act that is 

false or misleading in any particular 

under section 402(j)(5)(D) of the PHS 

Act. Other Federal laws also govern the 

veracity of information or claims 

submitted to the Federal Government, 

such as 18 U.S.C. 1001 (making it a 

crime to make certain false statements to 

the executive, legislative, or judicial 

branch of the U.S. Government) and 31 

U.S.C. 3802 (referencing civil and 

potential administrative liability of 

persons making certain false claims to 

the U.S. Government). Thus, we propose 

in § 11.6(a) to require that ‘‘[t]he clinical 

trial information submitted by a 

responsible party under this part shall 

not be false or misleading in any 

particular.’’ In addition, proposed 

§ 11.6(b) provides that ‘‘[s]ubmission of 

false and/or misleading information 

would subject the responsible party to 

civil, criminal, and/or administrative 

liability under U.S. law.’’ Specifically, 

all information submitted by a 

responsible party to ClinicalTrials.gov 

must be truthful, including information 

submitted voluntarily and other 

information that may not fall under the 

definition of clinical trial information, 

such as certifications for delayed 

submission and requests for good-cause 

extensions. Note, however, that this part 

does not require inclusion of 

information from any source other than 

the applicable clinical trial or other 

clinical trial that is the subject of the 

submission. 

To help ensure that responsible 

parties are aware of this requirement 

and to provide an opportunity for them 

to attest to the veracity of the 

information at the time of submission, 

we propose in § 11.6(b) to require the 

responsible party, each time he or she 

submits clinical trial information or 

other information to ClinicalTrials.gov, 

to ‘‘certify that, to the best of his or her 

knowledge, the information submitted is 

truthful and not misleading and that he 

or she is aware that the submission of 

false and/or misleading information 

would subject the responsible party to 

civil, criminal, and/or administrative 

liability under U.S. law.’’ This 

requirement is similar to requirements 

to certify to the truthfulness of 

information about FDA-regulated 

products submitted to FDA, and we 

believe is an important component of 

efforts to help ensure that submitted 

information is not false or misleading, 

as required by section 402(j)(5)(D) of the 

PHS Act, 18 U.S.C. 1001, and 31 U.S.C. 

3802. We plan to implement this 

requirement in ClinicalTrials.gov by 

integrating a certification statement into 

the mechanism for submitting 

information electronically through the 

Protocol Registration System. The 

requirement of proposed § 11.6 would 

be met by the responsible party making 

an attestation such as the following: ‘‘I 

certify that the information I have 

submitted is, to the best of my 

knowledge, truthful and not misleading, 

and I am aware that the submission of 

false and/or misleading information 

would subject me to civil, criminal, 

and/or administrative liability under 

U.S. law.’’ 

4. In what form and manner must 

clinical trial information be 

submitted?—§ 11.8 

Proposed § 11.8 sets forth 

requirements for the form and manner 

of submitting clinical trial information 

to ClinicalTrials.gov. It specifies that 

information submitted under this 

proposed part must be submitted 

electronically to ClinicalTrials.gov in 

the form and manner specified at 

http://prsinfo.clinicaltrials.gov. No other 

form or manner of submission will be 

accepted. Proposed §§ 11.10, 11.28 and 

11.48, specify the individual data 

elements of clinical trial information 

that must be submitted to 

ClinicalTrials.gov at the time of 

registration and results submission (and 

updated in accordance with proposed 

§ 11.64), including the subelements that 

are considered to be part of a data 

element (e.g., proposed § 11.10 specifies 

that the Study Design data element 

includes subelements of Interventional 

Study Model, Number of Arms, Arm 

Information, Allocation, Masking, and 

Single Arm Controlled). 

Sections IV.B.4 and IV.C.4 of this 

preamble describe the specific form and 

manner in which data elements and 

subelements would be required to be 

submitted to ClinicalTrials.gov. For 

some data elements and subelements, 

responsible parties would be required to 

submit information in the form of freetext; for other data elements and 

subelements, responsible parties would 

be required to select the best response 

from menus of options presented in 

ClinicalTrials.gov. Some menus would 

offer a fixed set of options without an 

‘‘other’’ option; others would offer a 

prespecified set of options plus an 

‘‘other’’ option. In most cases, 

responsible parties selecting the ‘‘other’’ 

option would be required to provide an 

additional free-text response to 

elaborate on their other selections. Some 

data elements without an ‘‘other’’ option 

would also include an optional free-text 

field in which responsible parties could 

voluntarily provide additional 

information about the option selected. 

The use of menu options is intended to 

promote the entry of data in a structured 

manner that allows users to search 

ClinicalTrials.gov and retrieve 

comparable information, consistent with 

the requirements of sections 402(j)(2)(B) 

and (3)(D)(v)(I) of the PHS Act. 

Menu options have been used in 

ClinicalTrials.gov since its launch. They 

are routinely used to improve the 

quality and help ensure the 

completeness of data submitted to 

information systems. Their use can 

reduce typographical errors in data 

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entry and minimize the data entry 

burden on responsible parties by 

providing a set of predefined options for 

common entries. By standardizing the 

set of available responses, they also 

promote the use of consistent 

terminology across entries and can 

improve the ability of users to search 

the data bank and compare entries 

easily across clinical trials, consistent 

with the requirements of sections 

402(j)(2)(B)(iv) and (3)(D)(v)(I) of the 

PHS Act. 

In describing the registration and 

results information to be submitted to 

ClinicalTrials.gov, the preamble 

specifies whether information would be 

submitted as free text or as menu 

selections. For data elements with menu 

options, the preamble specifies the 

complete set of options proposed, 

including whether or not an ‘‘other’’ 

option would be offered. The choice of 

providing menu options versus free-text 

fields and the set of menu options 

offered for specific data elements and 

subelements are based on our 

experience in operating 

ClinicalTrials.gov and on comments 

received from users of 

ClinicalTrials.gov, including those who 

commented on the draft guidance 

documents that were issued in 2002 and 

2004 [Ref. 3, 4] (see section II.A of the 

preamble) and the preliminary version 

of the results database and adverse 

event module that were available for 

testing beginning in the spring of 2008 

(see section II.B. of this preamble). 

We anticipate that, from time to time, 

we might make minor changes to the 

specific form and manner in which 

responsible parties would submit 

individual data elements and 

subelements to ClinicalTrials.gov. Such 

changes would not require a responsible 

party to submit different or more 

clinical trial information than is 

specified in this proposed rule, but 

would alter the way in which the 

information is entered, with the general 

aim of making sure the menu options 

contain the most relevant, useful, and 

convenient options for responsible 

parties and users of the system. For 

example, if the research community 

develops a new type of clinical trial 

design, we might expand the list of 

menu options under the Interventional 

Study Model subelement of the Study 

Design data element to include it. If we 

find that many of the free-text entries for 

the Why Study Stopped data element 

fall into a small number of categories, 

we might offer them as menu options (in 

addition to accepting free-text for 

‘‘other’’ reasons) to reduce the burden of 

data entry and improve the consistency 

and comparability of responses across 

registered clinical trials. We would 

provide prior notice and seek public 

comment on any proposed changes to 

the form and manner of submitting 

clinical trial information, and any 

changes would ultimately be reflected 

in the ClinicalTrials.gov data entry 

system at http://prsinfo.

clinicaltrials.gov. 

We invite comment on the specific 

form and manner described in this 

proposed rule for submitting data 

elements and subelements of proposed 

clinical trial information, including 

comment on the benefits and burden 

associated with providing proposed data 

elements and subelements, whether 

proposed menu options are sufficient to 

accommodate the range of potential 

entries (e.g., for different trial designs), 

and whether ‘‘other’’ options are needed 

for additional data elements. We also 

invite comment on the proposed 

approach described in this section for 

modifying the form and manner of 

submitting clinical trial information 

over time. 

We further note that to reduce the 

burden on responsible parties related to 

the submission of information to the 

data bank, ClinicalTrials.gov 

accommodates both interactive, online 

entry of information for a specific 

clinical trial and automated uploading 

of information that is prepared in a 

specified electronic format. Responsible 

parties submitting information on 

multiple clinical trials may upload 

information that is prepared as a batch 

submission. We expect this feature will 

be of interest to large entities (e.g., drug 

and device manufacturers) who might 

be the responsible party for multiple 

clinical trials. Additional information 

about submitting information to 

ClinicalTrials.gov is available at http:// 

prsinfo.clinicaltrials.gov. 

5. What definitions apply to this part?— 

§ 11.10 

Proposed § 11.10 defines certain terms 

and data elements used in this proposed 

part. The terms defined in proposed 

§ 11.10(a) includes terms explicitly 

defined in section 402(j) of the PHS Act 

(e.g., ‘‘applicable clinical trial’’ and 

‘‘responsible party’’); terms used but not 

defined in section 402(j) of the PHS Act 

(e.g., ‘‘clinical trial’’); and terms not 

specifically found in section 402(j) of 

the PHS Act but which are important for 

implementing the statutory provisions. 

With respect to terms not defined in the 

statute, we propose definitions to fit 

within the proposed framework for the 

expanded data bank and for purposes of 

satisfying the statutory goals, clarifying 

the application and operation of this 

proposed rule, in particular as related to 

information to be submitted to 

ClinicalTrials.gov, and/or for 

convenience. We also reference some 

terms defined under the PHS Act and 

the FD&C Act and implementing 

regulations, as necessary. 

In March 2009 the Agency provided 

an elaboration of its then-current 

thinking about the definitions of the 

terms ‘‘applicable clinical trial,’’ 

‘‘applicable device clinical trial,’’ 

‘‘applicable drug clinical trial,’’ and 

‘‘responsible party’’ in a document 

entitled ‘‘Elaboration of the Definitions 

of Responsible Party and Applicable 

Clinical Trial’’ that was posted on the 

ClinicalTrials.gov Web site. The posted 

document invites comments on the 

elaborations, but no written comments 

were received by the Agency. We 

discuss below a number of the proposed 

definitions. 

Adverse event is a term used but not 

defined in section 402(j)(3)(I) of the PHS 

Act to describe a certain category of 

clinical trial results information. 

Current FDA regulations define the term 

‘‘adverse event’’ with respect to drugs, 

but not to devices. (FDA regulations for 

devices include a different but related 

term, ‘‘suspected adverse device effect,’’ 

that is discussed below in the definition 

of the term ‘‘serious adverse event’’). 

FDA regulations for IND safety reporting 

requirements that were issued on 

September 29, 2010 (see 75 FR 59935, 

Sept. 29, 2010) and took effect on March 

28, 2011 define an adverse event as 

‘‘any untoward medical occurrence 

associated with the use of a drug in 

humans, whether or not considered 

drug related’’ (21 CFR 312.32(a)). In 

addition to defining the term ‘‘adverse 

event,’’ those FDA regulations have the 

additional purpose of identifying 

circumstances in which certain adverse 

events (such as those that are serious 

and unexpected and that also meet the 

definition of a ‘‘suspected adverse 

reaction,’’ meaning the adverse event 

must have a reasonable possibility of 

being caused by the drug) must be 

reported in an expedited fashion while 

the trial is ongoing. 

Because this proposed rule includes a 

requirement to submit to 

ClinicalTrials.gov summary information 

about anticipated and unanticipated 

adverse events observed during a 

clinical trial (as well as a requirement to 

submit information about serious 

adverse events), regardless of attribution 

(i.e., whether or not the investigator 

believes they are related to the 

intervention(s)), our proposed definition 

cannot be limited to adverse events that 

are anticipated, are likely to have been 

caused by the drug or device (or other 

type of intervention used in the clinical 

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trial), or that have a reasonable 

possibility of being related to the 

intervention under study. Instead, the 

proposed definition of adverse event 

must include all adverse events 

regardless of possible attribution and 

regardless of whether they were 

anticipated. 

The HHS Office for Human Research 

Protections (OHRP) has a definition of 

adverse event that covers drug, device, 

and other interventions and has the 

same scope of adverse events addressed 

by section 402(j) of the PHS Act, i.e., it 

includes both anticipated and 

unanticipated event(s) regardless of 

whether they are attributed to the 

intervention(s) studied in the clinical 

trial. As discussed in OHRP’s 

‘‘Guidance on Reviewing and Reporting 

Unanticipated Problems Involving Risks 

to Subjects or Others and Adverse 

Events’’ (January 2007), an adverse 

event means ‘‘[a]ny untoward or 

unfavorable medical occurrence in a 

human subject, including any abnormal 

sign (for example, abnormal physical 

exam or laboratory finding), symptom, 

or disease, temporally associated with 

the subject’s participation in the 

research, whether or not considered 

related to the subject’s participation in 

the research’’ [Ref. 39]. The OHRP 

definition was adapted from the 

definition used by the International 

Conference on Harmonization (ICH) 

Guideline E6, Good Clinical Practice: 

Consolidated Guidance [Ref. 40], which 

was published by FDA as a guidance 

document in the Federal Register in 

1997 (62 FR 25692, May 9, 1997). The 

definition, therefore, is consistent with 

international norms. Although the ICH 

Guidelines are intended to apply to 

pharmaceutical products, the OHRP 

definition is intended to apply broadly 

to research in humans that involves any 

type of intervention. 

Our proposed definition of adverse 

event derives from the OHRP definition. 

We propose to define an adverse event 

as ‘‘any untoward or unfavorable 

medical occurrence in a human subject, 

including any abnormal sign (for 

example, abnormal physical exam or 

laboratory finding), symptom, or 

disease, temporally associated with the 

subject’s participation in the research, 

whether or not considered related to the 

subject’s participation in the research.’’ 

This interpretation helps improve 

consistency in the submission of 

adverse event information for applicable 

device clinical trials and applicable 

drug clinical trials. It is consistent with, 

although not identical to, the definition 

of adverse event included in FDA’s IND 

regulations. We invite public comment 

on this proposed definition. 

Applicable clinical trial is the term 

used in section 402(j)(1)(A)(i) of the PHS 

Act to designate the scope of clinical 

trials that may be subject to the 

requirements to submit clinical trial 

registration and results information as 

specified in this proposed part. Not all 

applicable clinical trials are subject to 

clinical trial registration and results 

submission requirements. For example, 

an applicable clinical trial that reached 

its completion date on or before 

September 27, 2007, is not subject to 

registration under section 402(j) of the 

PHS Act, nor is an applicable clinical 

trial that was ongoing as of September 

27, 2007, and reached its completion 

date prior to December 26, 2007. This 

proposed rule adopts the definition of 

applicable clinical trial from section 

402(j)(1)(A)(i) of the PHS Act, which 

relies on two other terms defined in that 

section of the PHS Act and this 

proposed rule, namely applicable device 

clinical trial and applicable drug 

clinical trial. In addition, in proposed 

§ 11.22(b), we propose an approach for 

determining whether a clinical study or 

trial meets the definition of an 

applicable clinical trial. 

Applicable device clinical trial is the 

term used in section 402(j)(1)(A) of the 

PHS Act to designate the clinical trial of 

a device and FDA-ordered pediatric 

postmarket surveillance of a device for 

which clinical trial information must be 

submitted to ClinicalTrials.gov under 

section 402(j) of the PHS Act. The term 

‘‘device’’ is defined in section 

402(j)(1)(A)(vi) as ‘‘a device as defined 

in section 201(h) of the [FD&C] Act.’’ 

We have adopted this definition of 

‘‘device’’ in proposed § 11.10. In 

addition, this proposed rule adopts, in 

§ 11.10, the definition of applicable 

device clinical trial, as provided in 

section 402(j)(1)(A)(ii) of the PHS Act: 

‘‘(I) a prospective clinical study of 

health outcomes comparing an 

intervention with a device subject to 

section 510(k), 515, or 520(m) of the 

[FD&C] Act against a control in human 

subjects (other than a small clinical trial 

to determine the feasibility of a device, 

or a clinical trial to test prototype 

devices where the primary outcome 

measure relates to feasibility and not to 

health outcomes); and (II) a pediatric 

postmarket surveillance as required 

under section 522 of the [FD&C] Act.’’ 

The first part of the definition in 

section 402(j)(1)(A)(ii)(I) defines a 

clinical study as an applicable device 

clinical trial if it meets the following 

four criteria: (1) It is a prospective 

clinical study of health outcomes; (2) it 

compares an intervention with a device 

against a control in human subjects; (3) 

the studied device is subject to section 

510(k), 515, or 520(m) of the FD&C Act; 

and (4) it is other than a small clinical 

trial to determine the feasibility of a 

device or a clinical trial to test prototype 

devices where the primary outcome 

measure relates to feasibility and not to 

health outcomes. Except as described 

below with regard to pediatric 

postmarket surveillances of a device, if 

a clinical investigation fails to meet one 

or more of these criteria, it would not 

be considered an applicable device 

clinical trial. We have considered the 

meaning of these criteria carefully and 

our interpretation follows. 

(1) ‘‘Prospective clinical study of 

health outcomes.’’ First, we interpret the 

term ‘‘clinical study,’’ with respect to a 

device. We interpret ‘‘clinical study’’ 

with respect to a device to mean an 

investigation in which a device is used 

in one or more human subjects. For 

purposes of interpreting the term 

‘‘clinical study,’’ we consider the term 

‘‘human subject’’ to have the same 

meaning as the term ‘‘subject,’’ which is 

defined in FDA regulations as a ‘‘human 

who participates in an investigation, 

either as an individual on whom or on 

whose specimen an investigational 

device is used or as a control. A subject 

may be in normal health or may have a 

medical condition or disease.’’ (See 21 

CFR 812.3(p).) For purposes only of the 

requirements under section 402(j) of the 

PHS Act and this proposed rule, the 

term ‘‘human subject’’ does not include 

de-identified human specimens (see 

[Ref. 41]). Note that we use the term 

‘‘participant’’ interchangeably with 

‘‘human subject’’ in this document. 

The term ‘‘study’’ is often used 

interchangeably with the term 

‘‘investigation.’’ As pertaining to 

devices, ‘‘investigation’’ is defined as ‘‘a 

clinical investigation or research 

involving one or more subjects to 

determine the safety or effectiveness of 

a device.’’ (See 21 CFR 812.3(h).) 

Although FDA regulations pertaining to 

devices do not specifically define the 

term ‘‘clinical investigation,’’ that term 

is defined in FDA regulations pertaining 

to clinical investigations of drugs and 

biological products as ‘‘any experiment 

in which a drug is administered or 

dispensed to, or used involving, one or 

more human subjects,’’ where 

‘‘experiment’’ is defined as ‘‘any use of 

a drug except for the use of a marketed 

drug in the course of medical practice.’’ 

(See 21 CFR 312.3.) In our view, these 

definitions can be applied to device 

trials by defining a ‘‘clinical study of a 

device’’ as ‘‘any experiment in which a 

device is administered, dispensed to, or 

used involving, one or more human 

subjects,’’ defining an ‘‘experiment’’ as 

‘‘any use of a device except for the use 

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of a marketed device in the course of 

medical practice,’’ and using the 

definition of ‘‘subject’’ described above 

(from 21 CFR 812.3(p)). This 

interpretation helps improve 

consistency between definitions of the 

terms applicable device clinical trial 

and applicable drug clinical trial. In 

addition, our proposed interpretation of 

a ‘‘clinical study’’ of a device would 

include studies in which subjects are 

assigned to specific interventions 

according to a study protocol. Studies in 

which a device is used on a patient as 

part of routine medical care and not 

because of a study or protocol would 

not be considered ‘‘clinical studies’’ for 

purposes of this rulemaking. An 

example of studies that would not be 

considered clinical investigations 

include situations in which, after a 

device has been administered to a 

patient in the course of routine medical 

practice by a healthcare provider, a 

researcher not associated with the 

administration of the device reviews the 

records of the patients in order to assess 

certain effects, interviews the patients to 

assess certain impacts, or collects 

longitudinal data to assess health 

outcomes. 

Second, turning to our interpretation 

of ‘‘prospective,’’ we consider a 

‘‘prospective’’ clinical study to be any 

study that is not retrospective or, in 

other words, one in which subjects are 

followed forward in time from a welldefined point (i.e., the baseline of the 

study) or are assessed at the time the 

study intervention is provided. A 

‘‘prospective clinical study’’ also may 

have non-concurrent (e.g., historical) 

control groups. An example of a 

retrospective study, and thus not an 

applicable device clinical trial, is a 

study in which subjects are selected 

based on the presence or absence of a 

particular event or outcome of interest 

(e.g., from hospital records or other data 

sources) and their past exposure to a 

device is then studied. 

Third, we interpret ‘‘of health 

outcomes.’’ For purposes of the 

definition of applicable device clinical 

trial, a ‘‘prospective clinical study of 

health outcomes’’ is a clinical study in 

which the primary objective is to 

evaluate a defined clinical outcome 

directly related to human health. For 

example, a clinical study of a diagnostic 

device (such as an in vitro diagnostic 

(IVD)) in which the primary purpose is 

to evaluate the ability of the device to 

make a diagnosis of a disease or 

condition is related directly to human 

health and, therefore, would be 

considered a clinical study ‘‘of health 

outcomes’’ for purposes of this proposed 

rule. 

(2) ‘‘Comparing an intervention with 

a device against a control in human 

subjects.’’ We interpret an ‘‘intervention 

with a device’’ to be one in which a 

device is used on a human subject in the 

course of a study. As stated above, the 

meaning of the term ‘‘human subject’’ is 

consistent with the definition of 

‘‘subject’’ in 21 CFR 812.3(p), except 

that for purposes only of the 

requirements under this part, the term 

‘‘human subject’’ does not include deidentified human specimens. We 

interpret the term ‘‘intervention’’ 

broadly, to include various techniques 

of using the device such as, among other 

things, device regimens and procedures 

and use of prophylactic, diagnostic, or 

therapeutic agents. 

A clinical study is considered to 

‘‘compare an intervention with a device 

against a control in human subjects’’ 

when it compares differences in the 

clinical outcomes, or diagnosis, between 

human subjects who received an 

intervention that included a device and 

human subjects who received other 

interventions, or no intervention (i.e., 

the control group). The intervention 

under study may be with a device that 

has never been cleared or approved or 

with a device that has been cleared or 

approved, regardless of whether the 

clearance or approval is for the 

indication being studied. Such 

controlled clinical studies include not 

only concurrent control groups, but also 

non-concurrent controls such as 

historical controls (e.g., literature, 

patient records, human subjects as their 

own control) or validated objective 

outcomes using objective performance 

criteria, by which we mean performance 

criteria based on broad sets of data from 

historical databases (e.g., literature or 

registries) that are generally recognized 

as acceptable values. 

Expanded access protocols under 

section 561 of the FD&C Act, under 

which investigational devices are made 

available to individuals under certain 

conditions, generally are not controlled 

clinical investigations and therefore 

generally are not applicable device 

clinical trials. In those instances in 

which use of an investigational device 

in an expanded access program is 

controlled and the program otherwise 

meets the definition of an applicable 

device clinical trial, the expanded 

access program would be considered an 

applicable clinical trial and would be 

registered as such. Similarly, continued 

access protocols, under which an 

investigational device continues to be 

made available after completion of a 

controlled trial while a marketing 

application is being prepared or 

reviewed, are, by definition, not 

controlled clinical investigations and, 

therefore, not applicable device clinical 

trials. 

(3) ‘‘A device subject to section 

510(k), 515, or 520(m)’’ of the FD&C Act. 

A device is considered to be subject to 

section 510(k), 515, or 520(m) of the 

FD&C Act if any of the following is 

required before it may be legally 

marketed in the U.S.: (1) a finding of 

substantial equivalence under section 

510(k) permitting the device to be 

marketed; (2) an order under section 515 

of the FD&C Act approving a pre-market 

approval application for the device; or 

(3) a humanitarian device exemption 

under section 520(m) of the FD&C Act. 

Such devices that are considered to be 

subject to section 510(k), 515, or 520(m) 

of the FD&C Act include significant risk 

devices for which approval of an 

investigational device exemption (IDE) 

is required under section 520(g) of the 

FD&C Act; non-significant risk devices 

that are considered to have an approved 

IDE in accordance with 21 CFR 812.2(b); 

or devices that are exempt from the 

submission requirements of 21 CFR 812. 

If a clinical study of a device (1) 

includes sites both within the U.S. 

(including any territory of the U.S.) and 

outside of the U.S., and (2) any of those 

sites is using (for purposes of the 

clinical study) a device that is subject to 

section 510(k), 515, or 520(m) of the 

FD&C Act, we would consider the entire 

clinical study to be an applicable device 

clinical trial, provided that it meets all 

of the other criteria of the definition 

under this part. However, a clinical 

study of a device that is being 

conducted entirely outside of the U.S. 

(i.e., does not have any sites in the U.S. 

or in any territory of the U.S.) and is not 

conducted under an IDE may not be a 

clinical study of a device subject to 

section 510(k), 515, or 520(m) of the 

FD&C Act, and thus not an applicable 

device clinical trial, depending on 

where the device being used in the 

clinical study is manufactured. If the 

device is manufactured in the U.S. or 

any territory of the U.S., and is exported 

for study in another country (whether it 

is exported under section 801(e) or 

section 802 of the FD&C Act), then the 

device is considered to be subject to 

section 510(k), 515, or 520(m) of the 

FD&C Act. If the device is manufactured 

outside of the U.S. or its territories, and 

the clinical study sites are all outside of 

the U.S. and/or its territories, then the 

device would not be considered to be 

subject to section 510(k), 515, or 520(m) 

of the FD&C Act. 

(4) ‘‘Other than a small clinical trial 

to determine the feasibility of a device, 

or a clinical trial to test prototype 

devices where the primary outcome 

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measure relates to feasibility and not to 

health outcomes.’’ Clinical studies 

designed primarily to determine the 

feasibility of a device or to test a 

prototype device are considered by the 

Agency to be clinical studies conducted 

to confirm the design and operating 

specifications of a device before 

beginning a full clinical trial. Feasibility 

studies are sometimes referred to as 

phase 1 studies, pilot studies, prototype 

studies, or introductory trials. 

Feasibility studies are not considered 

applicable device clinical trials under 

this proposed part. 

The second part of the definition in 

section 402(j)(1)(A)(ii)(II) specifies that 

an applicable device clinical trial 

includes ‘‘pediatric postmarket 

surveillance as required under section 

522 of the Federal Food, Drug, and 

Cosmetic Act.’’ Postmarket surveillances 

can take many forms, from literature 

reviews to controlled clinical trials. 

Based on the statutory language, any 

pediatric postmarket surveillance under 

section 522 of the FD&C Act, regardless 

of its design, is an applicable device 

clinical trial. 

Applicable drug clinical trial is the 

term used in section 402(j) of the PHS 

Act to designate a clinical trial 

involving a drug (including a biological 

product) for which clinical trial 

information must be submitted to 

ClinicalTrials.gov, if the trial is subject 

to the registration and results 

submission requirements under section 

402(j) of the PHS Act. Section 

402(j)(1)(A)(iii)(I) of the PHS Act 

provides the following detailed 

definition of the term applicable drug 

clinical trial: ‘‘a controlled clinical 

investigation, other than a phase I 

clinical investigation, of a drug subject 

to section 505 of the Federal Food, Drug, 

and Cosmetic Act or to section 351 of 

th[e] [PHS] Act.’’ Sections 

402(j)(1)(A)(iii)(II) and (III) of the PHS 

Act further clarify that the term 

‘‘clinical investigation’’ has the meaning 

given in 21 CFR 312.3 (or any successor 

regulation) and ‘‘phase I’’ has the 

meaning given in 21 CFR 312.21 (or any 

successor regulation). We propose to 

adopt the statutory definition of this 

term, replacing ‘‘phase I’’ with ‘‘phase 

1,’’ to be consistent with the numbering 

scheme used in FDA regulations (21 

CFR 312.21). We provide additional 

elaboration of the interpretation of 

applicable clinical trial below. 

We interpret the definition of 

applicable drug clinical trial under 

section 402(j)(1)(A)(iii) of the PHS Act 

as having four operative elements: (1) 

‘‘controlled’’; (2) ‘‘clinical 

investigation’’; (3) ‘‘other than a phase 

[1] clinical investigation’’; and (4) ‘‘drug 

subject to section 505 of the Federal 

Food, Drug, and Cosmetic Act or section 

351 of th[e] [Public Health Service] 

Act.’’ A clinical investigation that meets 

all four elements is considered to be an 

‘‘applicable drug clinical trial.’’ 

Conversely, a clinical investigation that 

does not meet one or more of these 

criteria would not be considered an 

applicable drug clinical trial. We have 

carefully considered these four criteria, 

and our interpretation follows in an 

order that facilitates the explanation. 

(1) First, with regard to a ‘‘drug 

subject to section 505 of the Federal 

Food, Drug, and Cosmetic Act or section 

351 of th[e] [Public Health Service] 

Act,’’ proposed § 11.10 adopts the 

definition of the term ‘‘drug’’ in section 

402(j)(1)(A)(vii) of the PHS Act as 

follows: ‘‘drug as defined in section 

201(g) of the [FD&C Act] or a biological 

product as defined in section 351 of 

th[e] [PHS] Act.’’ In keeping with the 

requirements of the FD&C Act and 

section 351 of the PHS Act, a drug or a 

biological product is considered to be 

‘‘subject to section 505 of the [FD&C] 

Act or section 351 of th[e] [PHS] Act,’’ 

as applicable, if it is the subject of an 

approved new drug application (NDA) 

or licensed biologics license application 

(BLA), or if an approved NDA or 

licensed BLA would be required in 

order for that drug or biological product 

to be legally marketed. A nonprescription drug that is or could be 

marketed under an existing over-thecounter (OTC) drug monograph (See 21 

CFR 330–358) is not considered ‘‘subject 

to section 505 of the [FD&C] Act.’’ 

A drug or a biological product that is 

subject to section 505 of the FD&C Act 

or to section 351 of the PHS Act, and 

therefore would require an approved 

NDA or licensed BLA in order to be 

marketed legally, can be shipped for the 

purpose of conducting a clinical 

investigation of that product if an 

investigational new drug application 

(IND) is in effect. Drugs (including 

biological products) that are being 

studied under an IND are considered 

‘‘subject to section 505’’ both because 

(in most situations) the drug being 

studied would need an approved NDA 

or licensed BLA to be marketed legally, 

and because INDs are issued by FDA 

pursuant to the authority in section 

505(i) of the FD&C Act. However, 

whether a drug or biological product is 

subject to section 505 of the FD&C Act 

or section 351 of the PHS Act is a 

different question from whether a 

clinical investigator would need to 

obtain an IND from FDA before 

beginning to enroll human subjects in 

that clinical investigation. Therefore, a 

drug (or biological product) being 

studied in a clinical investigation can be 

subject to section 505 of the FD&C Act 

or section 351 of the PHS Act, even if 

a clinical investigation of that drug or 

biological product is ‘‘IND exempt’’ (i.e., 

does not require an IND because that 

clinical investigation falls within 21 

CFR 312.2(b)). Hence, provided it meets 

all other criteria of the definition, a 

clinical investigation of a drug 

(including a biological product) can be 

an applicable drug clinical trial under 

section 402(j) of the PHS Act and this 

part, even if it does not require an IND. 

Furthermore, if a sponsor chooses to 

obtain an IND (issued under section 505 

of the FD&C Act) for a clinical 

investigation of a drug (including a 

biological product) that is not otherwise 

subject to section 505 or to section 351 

of the PHS Act, the sponsor, in so doing, 

agrees to regulation under section 505 of 

the FD&C Act, and that clinical 

investigation thus will be considered an 

applicable drug clinical trial, provided 

that it meets all other criteria of the 

definition under this part. 

If a clinical investigation of a drug 

(including a biological product) (1) 

includes sites both within the U.S. 

(including any territory of the U.S.) and 

outside of the U.S., and (2) any of those 

sites is using (for purposes of the 

clinical investigation) a drug or 

biological product that is subject to 

section 505 of the FD&C Act or section 

351 of the PHS Act, we would consider 

the entire clinical investigation to be an 

applicable drug clinical trial, provided 

that it meets all other criteria of the 

definition under this part. However, a 

clinical investigation of a drug 

(including a biological product) that is 

being conducted entirely outside of the 

U.S. (i.e., does not have any sites in the 

U.S. or in any territory of the U.S.) may 

or may not be a clinical investigation of 

a drug or biological product subject to 

section 505 of the FD&C Act or section 

351 of the PHS Act, and thus not an 

applicable drug clinical trial, depending 

on where the drug (including biological 

product) being used in the clinical 

investigation is manufactured. If the 

drug (including a biological product) is 

manufactured in the U.S. or any 

territory of the U.S., and is exported for 

study in another country under an IND 

(whether pursuant to 21 CFR 312.110 or 

section 802 of the FD&C Act), the drug 

or biological product is considered to be 

subject to section 505 of the FD&C Act 

or section 351 of the PHS Act (as 

applicable), and the clinical 

investigation may be an applicable drug 

clinical trial, provided that it meets all 

other criteria of the definition under this 

part. If the drug (including a biological 

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product) is manufactured outside of the 

U.S. or its territories, the clinical 

investigation sites are all outside of the 

U.S., and the clinical investigation is 

not being conducted under an IND, the 

drug or biological product would not be 

considered to be subject to section 505 

of the FD&C Act or section 351 of the 

PHS Act, and the clinical investigation 

would not be an applicable drug clinical 

trial. 

(2) Second, with regard to ‘‘clinical 

investigation,’’ section 

402(j)(1)(A)(iii)(II) of the PHS Act 

provides that ‘‘clinical investigation’’ 

has the meaning given that term in 21 

CFR 312.3, which defines ‘‘[c]linical 

investigation’’ as ‘‘any experiment in 

which a drug is administered or 

dispensed to, or used involving, one or 

more human subjects.’’ The regulation 

further defines an ‘‘experiment’’ as ‘‘any 

use of a drug except for the use of a 

marketed drug in the course of medical 

practice.’’ 

The FDA definition of ‘‘clinical 

investigation’’ of a drug includes studies 

in which human subjects are assigned to 

specific interventions according to a 

protocol. However, a situation in which 

a drug is administered or provided to a 

patient as part of routine medical care 

and not under a study or protocol would 

not be considered a ‘‘clinical 

investigation’’ for purposes of this 

rulemaking. Examples of studies that 

might fall under this description 

include situations in which, after a drug 

has been administered to a patient in 

the course of routine medical practice 

by a healthcare provider, a researcher 

not associated with the administration 

of the drug reviews the records of the 

patients to assess certain effects, 

interviews the patients to assess certain 

impacts, or collects longitudinal data to 

track health outcomes. Similarly, a 

situation in which a healthcare provider 

only observes and records the effects of 

the use of a marketed drug in the course 

of his or her routine medical practice 

would not be considered a ‘‘clinical 

investigation’’ under this definition. 

Because these activities would not be 

considered ‘‘clinical investigations’’ 

under 21 CFR 312.3, they would not be 

considered applicable drug clinical 

trials under section 402(j) of the PHS 

Act and this proposed part. 

Accordingly, in the approach described 

below in § 11.22(b)(2), we consider an 

‘‘interventional’’ study (or investigation) 

of a drug to be an applicable drug 

clinical trial. 

(3) Third, with regard to ‘‘controlled,’’ 

we consider a controlled clinical 

investigation to be one that is designed 

to permit a comparison of a test 

intervention with a control to provide a 

quantitative assessment of the drug 

effect. The purpose of the control is to 

distinguish the effect of a drug from 

other influences, such as the 

spontaneous change in the course of the 

diseases, placebo effect, or biased 

observation. The control will provide 

data about what happens to human 

subjects who have not received the test 

intervention or who have received a 

different intervention. Generally, the 

types of controls that are used in 

clinical investigations are: (1) Placebo 

concurrent control; (2) dose-comparison 

control; (3) no intervention concurrent 

control; (4) active intervention 

concurrent control; and (5) historical 

control. (See 21 CFR 314.126(b).) 

In our view, a clinical investigation 

designed to demonstrate that an 

investigational drug product is 

bioequivalent to a previously approved 

drug product, or to demonstrate 

comparative bioavailability of two 

products (such as for purposes of 

submitting an abbreviated new drug 

application under 21 U.S.C. 355(j) or a 

new drug application as described in 21 

U.S.C. 355(b)(2)) is considered to be a 

controlled clinical investigation. In this 

case, the control generally would be the 

previously approved drug product. 

However, as discussed below, 

bioequivalent or comparative 

bioanalysis studies that fall within the 

scope of studies described in 21 CFR 

320.24(b)(1), (2), and (3) share many of 

the characteristics of a phase 1 study 

and would be considered phase 1 trials 

(and thus not applicable clinical trials) 

in this proposed rule. 

Similar to expanded access to 

investigational devices, as discussed 

above in the definition of applicable 

device clinical trial, the use of an 

investigational drug in an expanded 

access program under section 561 of the 

FD&C Act is generally not ‘‘controlled,’’ 

and generally does not meet the 

definition of a ‘‘controlled clinical 

investigation.’’ In those instances in 

which use of an investigational drug in 

an expanded access program is 

controlled and the program otherwise 

meets the definition of an applicable 

drug clinical trial, the expanded access 

program would be considered an 

applicable clinical trial. 

(4) Fourth, with regard to the ‘‘other 

than a phase [1] clinical investigation’’ 

element, an applicable drug clinical trial 

is defined in section 402(j)(1)(A)(iii) of 

the PHS Act to exclude phase 1 clinical 

investigations, consistent with 21 CFR 

312.21. Under 21 CFR 312.21(a)(1), a 

phase 1 study ‘‘includes the initial 

introduction of an investigational new 

drug into humans. Phase 1 studies are 

typically closely monitored and may be 

conducted in patients or normal 

volunteer subjects. These studies are 

designed to determine the metabolism 

and pharmacologic actions of the drug 

in humans, the side effects associated 

with increasing doses, and, if possible, 

to gain early evidence on effectiveness. 

During phase 1, sufficient information 

about the drug’s pharmacokinetics and 

pharmacological effects should be 

obtained to permit the design of wellcontrolled, scientifically valid, phase 2 

studies. The total number of subjects 

and patients included in phase 1 studies 

varies with the drug, but is generally in 

the range of 20 to 80.’’ Under 21 CFR 

312.21(a)(2), ‘‘[p]hase 1 studies also 

include studies of drug metabolism, 

structure-activity relationships, and 

mechanism of action in humans, as well 

as studies in which investigational 

drugs are used as research tools to 

explore biological phenomena or 

disease processes.’’ Studies that are 

phase 1 studies under 21 CFR 312.21 are 

not applicable drug clinical trials. 

Studies that are phase 1/phase 2 studies 

are not considered phase 1 studies and 

may be applicable drug clinical trial if 

they meet the other specified criteria. 

Under certain circumstances, a 

clinical investigation designed to 

demonstrate that an investigational drug 

product is bioequivalent to a previously 

approved drug product, or to 

demonstrate comparative bioavailability 

of two products (such as for purposes of 

submitting an abbreviated new drug 

application under 21 U.S.C. 355(j) or a 

new drug application as described in 21 

U.S.C. 355(b)(2)) will be considered to 

be a phase 1 clinical investigation under 

21 CFR 312.21 for purposes of 

determining whether a particular 

clinical trial is an applicable drug 

clinical trial under section 

402(j)(1)(A)(iii) of the PHS Act. 

Although phase 1 clinical investigations 

are generally designed to fit sequentially 

within the development plan for a 

particular drug, and to develop the data 

that will support beginning phase 2 

studies, 21 CFR 312.21(a) does not limit 

phase 1 trials to that situation. 

Bioequivalence or comparative 

bioavailability studies that fall within 

the scope of the studies described in 21 

CFR 320.24(b)(1), (2), and (3) share 

many of the characteristics of phase 1 

clinical investigations as described in 21 

CFR 312.21(a), and therefore will be 

considered to be phase 1 trials for 

purposes of section 402(j) of the PHS 

Act. However, bioequivalence or 

comparative bioavailability trials that 

fall within the scope of 21 CFR 

320.24(b)(4) do not share the 

characteristics of phase 1 trials as 

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described in 21 CFR 312.21(a), and thus 

would not be considered to be phase 1 

trials for purposes of section 402(j) of 

this proposed part. 

In addition, for purposes of 

implementing this proposed rule, we 

propose to treat certain clinical trials of 

combination products as applicable 

drug clinical trials. Combination 

products are defined in 21 CFR 3.2(e). 

A combination product is comprised of 

a drug and device; a biological product 

and device; a drug and biological 

product; or a drug, biological product, 

and device that, for example, are 

physically, chemically, or otherwise 

combined or mixed and produced as a 

single entity or are separate products 

packaged together in a single package or 

as a unit. (See 21 CFR 3.2(e)(1) and (2)). 

Because the definition of drug in 

proposed § 11.10 includes a biological 

product, a combination product under 

this proposed rule would always 

consist, in part, of a drug. For this 

reason, we propose to treat clinical trials 

of combination products that meet the 

definition in 21 CFR 3.2(e) as applicable 

drug clinical trials, for purposes of 

implementing this proposed rule, so 

long as the clinical trial of the 

combination product is a controlled 

clinical investigation, other than a phase 

1 clinical investigation (as described in 

above), and the combination product is 

subject to sections 505 of the FD&C Act 

and/or section 351 of the PHS Act (as 

described above) and/or section 510(k), 

515, or 520(m) of the FD&C Act (as 

described in the definition of an 

applicable device clinical trial). Such 

clinical trials of combination products 

would therefore be subject to the 

registration and results submission 

requirements, including requirements 

for posting clinical trial information, for 

applicable drug clinical trials as 

described in this proposed part. We 

believe this approach will provide 

clarity to responsible parties conducting 

clinical trials of combination products. 

Approved drug is defined to mean ‘‘a 

drug that is approved for any indication 

under section 505 of the FD&C Act or 

a biological product licensed for any 

indication under section 351 of the PHS 

Act.’’ 

Approved or cleared device. Section 

402(j)(2)(D)(ii)(II) of the PHS Act uses 

the phrase ‘‘a device that was previously 

cleared or approved’’ to refer to a subset 

of devices that, if studied in an 

applicable device clinical trial, would 

trigger certain requirements under this 

proposed part with respect to the 

submission and public posting of 

clinical trial information. Accordingly, 

we believe that it is helpful to define the 

term ‘‘approved or cleared device.’’ 

Specifically, we want to clarify that our 

definition of approved or cleared device 

refers to any device that has been 

approved or cleared under the 

applicable section of the FD&C Act for 

any indication, even if the applicable 

device clinical trial studies the device 

for an unapproved or uncleared use. 

Consistent with the reference in section 

402(j)(2)(D)(ii) of the PHS Act to 

approval or clearance of a device under 

the designated sections of the FD&C Act, 

we propose to define an approved or 

cleared device as ‘‘a device that is 

cleared under section 510(k) of the 

FD&C Act or approved under section 

515 or 520(m) of the FD&C Act for any 

indication.’’ 

Arm is defined to mean ‘‘a prespecified group or subgroup of human 

subjects in a clinical trial assigned to 

receive specific intervention(s) (or no 

intervention) according to a protocol.’’ 

Clinical trial is defined to mean ‘‘a 

clinical investigation or a clinical study 

in which human subjects are 

prospectively assigned, according to a 

protocol, to one or more interventions 

(or no intervention) to evaluate the 

effects of the interventions on 

biomedical or health-related outcomes.’’ 

The proposed definition explicitly 

includes ‘‘biomedical’’ in addition to 

‘‘health-related’’ outcomes because we 

have defined the term ‘‘clinical trial’’ to 

include phase 1 studies, which may 

measure physiological changes that are 

biomedical in nature but may not be 

related to health effects. We have 

defined the term ‘‘clinical trial’’ to 

include phase 1 studies, in part, because 

phase 1 studies may be voluntarily 

submitted under section 402(j)(4)(A) of 

the PHS Act. The restriction of the 

scope of this definition to clinical 

investigations or studies in which 

human subjects are prospectively 

assigned to interventions is intended to 

distinguish clinical trials (interventional 

studies) from observational studies, in 

which the investigator does not assign 

human subjects to interventions, but, for 

example, observes patients who have 

been given interventions in the course 

of routine clinical care. Observational 

studies may also include retrospective 

reviews of patient medical records or 

relevant literature. 

Further, in terms of defining the scope 

of a clinical trial, we recognize that it is 

sometimes difficult to determine the 

boundaries of a single clinical trial 

when there are two or more closely 

related clinical trials. In general, a 

clinical trial has an explicit group of 

human subjects who are assigned to 

interventions based on a protocol. The 

data from these human subjects are 

assessed and analyzed based on a 

protocol. However, when two different 

clinical trials share the same protocol, 

but the groups of human subjects are 

different and the outcomes will be 

analyzed separately, then they should 

be considered separate clinical trials. 

This is distinct from a situation in 

which multiple sites of the same clinical 

trial follow the same protocol with 

different groups of human subjects, but 

the intention is to analyze the primary 

outcome measure(s) with pooled data 

from all of the study sites. When some 

(or all) human subjects from a clinical 

trial are offered the opportunity to 

participate in an additional clinical trial 

that was not part of the original protocol 

(e.g., a follow-on study), and that 

requires a separate consent process, it 

would be considered a separate clinical 

trial. 

Clinical trial information is the term 

defined in section 402(j) of the PHS Act 

to designate those data elements that the 

responsible party is required to submit 

to ClinicalTrials.gov when registering or 

submitting results information for a 

clinical trial, as described in §§ 11.28 

and 11.48 of this proposed rule, 

respectively. Section 402(j)(1)(A)(iv) of 

the PHS Act expressly provides that 

‘‘[c]linical trial information’’ means 

‘‘those data elements that the 

responsible party is required to submit 

under paragraph (2) or under paragraph 

(3)’’ of section 402(j) of the PHS Act. 

Paragraph (2) refers to registration 

requirements and paragraph (3) refers to 

results submission requirements. 

Section 402(j)(3)(I)(v) of the PHS Act 

also expressly provides that adverse 

event information included in the data 

bank pursuant to the paragraph (3)(I) ‘‘is 

deemed to be clinical trial information 

included in such data bank pursuant to 

subparagraph (C).’’ Therefore, for 

purposes of this proposed rule, clinical 

trial information means ‘‘the data 

elements, including clinical trial 

registration information and clinical 

trial results information that the 

responsible party is required to submit 

to ClinicalTrials.gov under this part.’’ 

Clinical trial registration information 

is defined to mean ‘‘the data elements 

that the responsible party is required to 

submit to ClinicalTrials.gov under 

§ 11.28.’’ The full set of data elements 

under § 11.28 must be submitted in 

order to register under proposed subpart 

B. 

Clinical trial results information is 

defined to mean ‘‘the data elements that 

the responsible party is required to 

submit to ClinicalTrials.gov under 

§ 11.48 or, if applicable, 

§ 11.60(a)(2)(i)(B).’’ The full set of data 

elements under § 11.48 must be 

submitted when providing results 

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information under proposed subpart C. 

Clinical trial results information 

includes the adverse event information 

set forth in proposed § 11.48(a)(4). We 

include adverse event information as 

part of clinical trial results information 

pursuant to section 402(j)(3)(I)(v) of the 

PHS Act, which indicates that the 

adverse event information included in 

the registry and results data bank under 

section 402(j)(3)(I) of the PHS Act ‘‘is 

deemed to be clinical trial information 

included in [the] data bank pursuant to 

[section 402(j)(3)(C) of the PHS Act].’’ 

As discussed in greater detail in section 

IV.D.1 of this preamble, if, under 

proposed § 11.60, a responsible party 

seeks to submit clinical trial results 

information voluntarily for a clinical 

trial for which clinical trial registration 

information specified in § 11.28(a) is not 

submitted, clinical trial results 

information is defined to include the 

data elements in proposed § 11.48(a) 

and the data elements set forth in 

proposed § 11.60(a)(2)(i)(B). 

Comparison group is defined in this 

proposed rule to mean ‘‘a grouping of 

human subjects in a clinical trial, other 

than an arm, that is used in analyzing 

the results data collected during the 

clinical trial.’’ In some trials, results 

data are not analyzed according to the 

arms to which human subjects were 

assigned; the data may be combined into 

other groupings for analysis. For 

example, in a cross-over study, human 

subjects in one arm of a trial may 

receive intervention X for a period of 

time followed by intervention Y, while 

human subjects in another arm of the 

trial may receive intervention Y for a 

period of time followed by intervention 

X. In such studies, results data are often 

analyzed by intervention (e.g., results 

for human subjects when receiving 

intervention X versus results for human 

subjects when taking intervention Y), 

rather than by arm. When submitting 

results information to ClinicalTrials.gov 

under proposed § 11.48, we believe 

responsible parties should submit the 

data in the same way in which it was 

analyzed, whether by arm (as defined 

above) or by comparison group. We do 

expect that the set of comparison groups 

for a particular trial would account for 

all of the participants in the analysis. 

Completion date is defined in section 

402(j)(1)(A)(v) of the PHS Act as ‘‘the 

date that the final subject was examined 

or received an intervention for the 

purposes of final collection of data for 

the primary outcome, whether the 

clinical trial concluded according to the 

pre-specified protocol or was 

terminated.’’ This term has particular 

significance because the responsible 

party is required to submit ‘‘the 

expected completion date’’ to 

ClinicalTrials.gov upon registration (See 

section 402(j)(2)(A)(ii)(I)(jj) of the PHS 

Act) and to submit clinical trial results 

information for certain applicable 

clinical trials not later than 1 year after 

the earlier of the estimated or the actual 

completion date, See sections 

402(j)(3)(E)(i)(I)&(II) of the PHS Act 

(unless the deadline is delayed or 

extended using one of the mechanisms 

described in proposed § 11.44). For 

purposes of this proposed rule, we 

interpret ‘‘expected completion date’’ to 

be synonymous with ‘‘estimated 

completion date.’’ 

This proposed rule adopts the 

statutory definition of completion date 

with respect to applicable clinical trials 

that are clinical trials with one 

modification. If a clinical trial has 

multiple primary outcome measures, 

each with a different date on which the 

final human subject is examined or 

receives an intervention for purposes of 

final data collection, the ‘‘completion 

date’’ refers to the date upon which data 

collection is completed for all of the 

primary outcomes. While this approach 

may delay somewhat the submission 

and public availability of clinical trial 

results information for the earliest 

primary outcomes, we expect any such 

delays to be minimal. Most clinical 

trials registered at ClinicalTrials.gov to 

date specify only a single primary 

outcome, and those with multiple 

primary outcomes have measurement 

time frames that are relatively close in 

time. Moreover, the proposed approach 

avoids cases in which the submission of 

clinical trial results information would 

be required before data collection has 

been completed for all of the primary 

outcomes in a clinical trial and before 

all of the results data for the primary 

outcomes have been ‘‘unblinded,’’ a 

situation that could threaten the 

scientific integrity of the clinical trial. 

While a responsible party could request 

a good-cause extension of the results 

submission deadline in such a situation 

under proposed § 11.44(e), the proposed 

definition should reduce the number of 

good-cause extension requests that 

responsible parties might be expected to 

file. Submission of results data for all 

primary outcomes at the same time will 

also aid in the interpretation of clinical 

trial results information by providing 

users of ClinicalTrials.gov with a more 

comprehensive set of data from the 

clinical trial, rather than data for only 

some of the primary outcomes. Thus, for 

purposes of this proposed rule, 

completion date means ‘‘for a clinical 

trial, the date that the final subject was 

examined or received an intervention 

for the purposes of final collection of 

data for the primary outcome, whether 

the clinical trial concluded according to 

the pre-specified protocol or was 

terminated. In the case of clinical trials 

with more than one primary outcome 

measure with different completion 

dates, this term refers to the date upon 

which data collection is completed for 

all of the primary outcomes.’’ 

We note that the current 

implementation of ClinicalTrials.gov 

uses the term ‘‘primary completion 

date’’ to refer to ‘‘completion date,’’ as 

defined in section 402(j)(1)(A)(v) of the 

PHS Act. This was done to alert those 

submitting data to ClinicalTrials.gov 

under section 402(j) of the PHS Act that 

the definition of completion date differs 

from that of the term, ‘‘study completion 

date,’’ which refers to the date on which 

the last subject makes the last visit as 

part of the clinical trial (commonly 

referred to as ‘‘last patient, last visit’’ or 

LPLV) and is also collected by 

ClinicalTrials.gov. To improve 

concordance with section 402(j) of the 

PHS Act and to be consistent with our 

proposed definition, ClinicalTrials.gov 

will begin to use the term completion 

date once the final regulations take 

effect. We will include a notice in 

ClinicalTrials.gov to alert responsible 

parties to this change in data element 

name. 

For a pediatric postmarket 

surveillance of a device that is not a 

clinical trial, completion date means 

‘‘the date on which the final report 

summarizing the results of the pediatric 

postmarket surveillance is submitted to 

FDA.’’ (See proposed § 11.10.) 

Control or Controlled are terms used 

in sections 402(j)(1)(A)(ii)(I) and (iii)(I) 

of the PHS Act as part of the definitions 

of ‘‘applicable device clinical trial’’ and 

‘‘applicable drug clinical trial,’’ 

respectively. For purposes of this 

proposed rule, the term ‘‘controlled’’ 

means, ‘‘with respect to a clinical trial, 

that data collected on human subjects in 

the clinical trial will be compared to 

concurrently collected data or to nonconcurrently collected data (e.g., 

historical controls, including a human 

subject’s baseline data), as reflected in 

the pre-specified primary or secondary 

outcome measures.’’ This is consistent 

with FDA regulations that define the 

related concepts of ‘‘adequate and wellcontrolled studies’’ for drugs (21 CFR 

314.126(b)(1) and (2)) and ‘‘a wellcontrolled clinical investigation’’ for 

devices (21 CFR 860.7(f)). FDA has also 

adopted as guidance the International 

Conference on Harmonization E10: 

Choice of Control Group and Related 

Issues in Clinical Trials (ICH E10), 

which describes considerations to be 

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used in choosing a control group. In 

FDA regulations, the critical attribute of 

a well-controlled clinical trial, which is 

the intent of any controlled trial, is ‘‘a 

design that permits a valid comparison 

with a control to provide a quantitative 

assessment’’ of the effect of the 

investigational intervention. (See 21 

CFR 314.126(b)(2).) The FDA 

regulations recognize several types of 

concurrent controls (e.g., active control) 

and the non-concurrent, historical 

control. This can refer to a control group 

for which data were collected at a 

different time or place but can also refer 

to a clinical trial in which subjects serve 

as their own controls (e.g., the clinical 

trial measures change from baseline). 

Our proposed definition of controlled 

is consistent with the types of controls 

recognized by FDA and the ICH E10 

guidance, but is potentially broader in 

that it does not require that the study be 

‘‘adequate,’’ i.e., that the control allows 

a valid comparison of the two 

treatments. It is consistent in that it 

explicitly recognizes both concurrent 

and non-concurrent controls. We 

recognize that this interpretation may 

differ from common use of the term 

‘‘controlled’’ by some researchers, who 

may consider only studies with 

concurrent controls to be ‘‘controlled,’’ 

but we believe it is important to 

maintain consistency with the approach 

of the FDA and ICH E10 and to include 

non-concurrent controls. Our definition 

of controlled is broader than that of 

‘‘well-controlled’’ used by FDA and ICH 

E10 because FDA regulations and the 

ICH E10 guidance describe the more 

limited circumstances in which use of a 

non-concurrent control constitutes a 

‘‘well-controlled’’ clinical trial, i.e., one 

that might serve to support marketing. 

Although FDA regulations state that 

historical controls are usually reserved 

for special circumstances, such as 

studies of a disease with ‘‘high and 

predictable mortality’’ (e.g., certain 

malignancies) or in which the effect of 

the drug is ‘‘self-evident’’ (e.g., 

anesthesia, cardioversion), our proposed 

definition of controlled would include 

all studies using an historical control, 

regardless of whether the study is of a 

disease with a ‘‘high and predictable 

mortality’’ or in which the effect of the 

drug is self-evident. Our proposed 

definition would encompass all studies 

and investigations with a placebo 

concurrent control, dose-comparison 

concurrent control, no treatment 

concurrent control, active treatment 

concurrent control, and historical 

control, but it would not reflect a 

consideration of the adequacy or 

appropriateness of the control or the 

adequacy of the study design, e.g., 

whether adequate steps were taken to 

minimize bias. Hence it would cover all 

trials that are controlled, using 

concurrent or non-concurrent controls, 

regardless of whether they would be 

considered ‘‘well-controlled.’’ 

Under our proposed definition, any 

clinical trial with two or more arms 

would be considered controlled because 

it would involve the comparison of data 

collected concurrently from different 

arms of the study. Some single-arm 

trials that meet the other components of 

the definition of an applicable clinical 

trial, e.g., not phase 1 or a feasibility 

study, could also meet this definition of 

controlled. These include the single-arm 

trials of FDA-regulated products that 

have as a stated objective in their 

protocol to evaluate a response rate to 

an intervention, to measure 

effectiveness of an intervention at 

specific endpoints, and/or to compare 

the effect of an intervention against an 

identified baseline. Thus, single-arm 

clinical trials that explicitly identify 

primary or secondary outcomes in the 

protocol that involve comparisons to 

historical data (including baseline data) 

would be considered controlled. 

Enroll or Enrolled is a term used in 

section 402(j)(1)(A)(viii)(I) of the PHS 

Act as part of the definition of 

‘‘[o]ngoing’’ and in 402(j)(2)(C)(ii) of the 

PHS Act as one of the criteria used to 

establish the deadline by which a 

responsible party is required to submit 

clinical trial registration information. 

For purposes of this proposed rule, the 

term ‘‘enrolled’’ means ‘‘a human 

subject’s agreement to participate in a 

clinical trial, as indicated by the signing 

of the informed consent document(s).’’ 

(See proposed § 11.10.) 

Human subjects protection review 

board is defined in § 11.10 of this 

proposed rule to mean an ‘‘institutional 

review board (IRB) as defined in 21 CFR 

50.3 and 45 CFR 46.102 (or any 

successor regulation), as applicable, or 

equivalent independent ethics 

committee that is responsible for 

ensuring the protection of the rights, 

safety, and well-being of human subjects 

involved in a clinical investigation and 

is adequately constituted to provide 

assurance of that protection.’’ We 

propose to include this definition to 

clarify the scope of the review boards 

for which Human Subjects Protection 

Review Board Status must be submitted 

under proposed § 11.28 (see section 

IV.B.4(a)(4) of this preamble). For 

clinical trials conducted in the U.S. or 

under an IND or IDE, the term human 

subjects protection review board would 

mean an institutional review board, as 

defined in the cited regulations issued 

by the FDA and OHRP within HHS. For 

clinical trials conducted outside the 

United States or otherwise outside the 

scope of the regulations for institutional 

review boards, the term would refer to 

other independent ethics committees 

that are responsible for ensuring the 

protection of the rights, safety, and wellbeing of human subjects involved in a 

clinical investigation and are adequately 

constituted to provide assurance of that 

protection. This phrasing is consistent 

with, but not identical to, the definition 

of the term ‘‘independent ethics 

committee,’’ in FDA regulations for 

INDs (See 21 CFR 312.3). It is also 

consistent with longstanding use of the 

term ‘‘human subjects protection review 

board’’ at ClinicalTrials.gov, which 

instructed registrants to provide 

information about ‘‘[a]ppropriate review 

boards[, including] an Institutional 

Review Board, an ethics committee or 

an equivalent group that is responsible 

for review and monitoring of this 

protocol to protect the rights and 

welfare of human research subjects.’’ 

[Ref 50] 

Interventional is defined in this 

proposed rule to mean, ‘‘with respect to 

a clinical study or a clinical 

investigation that participants are 

assigned prospectively to an 

intervention or interventions according 

to a protocol to evaluate the effect of the 

intervention(s) on biomedical or other 

health related outcomes.’’ We propose 

to define this term to distinguish 

interventional studies from 

observational studies, as those terms are 

used in the clinical research 

community. Observational studies 

include those in which a patient 

receives an intervention as part of 

routine medical care, and a researcher 

studies the effect of the intervention. 

They also include retrospective reviews 

of patient medical records or relevant 

literature, as may occur in a pediatric 

postmarket surveillance of a device. 

Interventional studies are those in 

which a researcher assigns subjects to 

specific interventions (or to no 

intervention) according to a study 

protocol for purposes of the 

investigation. For purposes of this part, 

we use the term ‘‘clinical trial’’ to refer 

to interventional studies to the 

exclusion of observational studies. (See 

the proposed definition of clinical trial). 

The term ‘‘interventional’’ is one of the 

responses that can be submitted as part 

of the Study Type data element that is 

included as clinical trial registration 

information under proposed § 11.28 and 

defined in § 11.10. Responsible parties 

must indicate whether a study being 

registered is ‘‘interventional’’ or 

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‘‘observational,’’ or is an expanded 

access program that does not meet the 

definition of an applicable clinical trial. 

A study that is designated as 

‘‘interventional’’ can be an applicable 

clinical trial if it meets the other criteria 

for an applicable clinical trial that are 

specified in this part. (See the proposed 

definitions of applicable device clinical 

trial and applicable drug clinical trial). 

A study should be designated 

interventional if it meets the proposed 

definition even if the medical products 

being studied are being used in a 

manner considered to be the standard of 

care. A study that is designated 

‘‘observational’’ can be an applicable 

clinical trial only if it is a pediatric 

postmarket surveillance of a device as 

defined in this part. (See the proposed 

definition of pediatric postmarket 

surveillance of a device). 

NCT number is the term used in this 

proposed part to refer to the term 

‘‘National Clinical Trial number[,]’’ 

which is used in section 

402(j)(2)(B)(i)(VIII) of the PHS Act. 

Since its launch in 2000, 

ClinicalTrials.gov has assigned each 

submitted clinical trial record a unique 

identifier once the information has 

completed quality review procedures. 

While the identifier originally was 

called a National Clinical Trial number, 

that nomenclature was soon changed to 

‘‘NCT number’’ in recognition of the fact 

that ClinicalTrials.gov also receives 

clinical trial information about trials 

being conducted in countries other than 

the United States. We propose to 

maintain the term ‘‘NCT number’’ in 

this part. NCT numbers are used in 

many contexts to refer to clinical trial 

records or other types of records (e.g., 

observational studies, expanded access 

programs) that are accepted by 

ClinicalTrials.gov. Under the ICMJE 

registration policy, for example, journals 

publishing original papers on the results 

of clinical trials require their authors to 

include in their manuscripts a unique 

identification number assigned by a 

recognized clinical trial registry as 

evidence that the trial has been 

registered in compliance with the ICMJE 

policy [Ref. 10]. For trials registered in 

ClinicalTrials.gov, this unique identifier 

is the NCT number. When published in 

journal articles, NCT numbers are also 

included in MEDLINE records and are 

searchable through PubMed [Ref. 42]. 

For purposes of this proposed rule, NCT 

number means ‘‘the unique 

identification code assigned to each 

record in ClinicalTrials.gov, including a 

record for an applicable clinical trial, a 

clinical trial, or an expanded access 

program.’’ The NCT number is assigned 

to clinical trials and expanded access 

records once registration information 

has been submitted to the Director and 

the Director’s quality control process 

has been completed, with the exception 

that if a responsible party voluntarily 

submits only clinical trial results 

information under § 11.60(a)(2)(i)(B), the 

NCT number is assigned once complete 

clinical trial results information has 

been submitted to the Director and the 

Director’s quality control process has 

been completed. 

Ongoing is defined in this proposed 

rule in § 11.10 to mean, ‘‘with respect to 

a clinical trial of a drug or a device and 

to a date, that one or more human 

subjects is enrolled in the clinical trial, 

and the date is before the completion 

date of the clinical trial.’’ This 

definition is the same as the statutory 

definition except the term ‘‘human 

subjects’’ has been substituted for the 

term ‘‘patients’’ that is used in section 

402(j)(1)(A)(viii) of the PHS Act. The 

reason for this change is that clinical 

trials may include healthy volunteers as 

well as human subjects who might be 

considered ‘‘patients.’’ 

With respect to a pediatric postmarket 

surveillance of a device, we define the 

term ‘‘ongoing’’ to mean ‘‘a date 

between the date on which FDA 

approves the plan for conducting the 

surveillance and the date on which the 

final report is submitted to FDA.’’ 

Outcome measure is defined in this 

proposed rule to mean ‘‘a pre-specified 

measurement that will be used to 

determine the effect of experimental 

variables on the human subjects in a 

clinical trial.’’ The experimental 

variables may be the specific 

intervention(s) used in the clinical trial 

or other elements of the clinical trial 

that vary between arms, e.g., diagnostic 

or other procedures provided to 

participants in different arms. In this 

proposed part, outcome measure refers 

to measurements taken on those human 

subjects who are enrolled in the clinical 

trial of interest. Although it is not 

uncommon to compare data derived 

from human subjects enrolled in a 

clinical trial with data derived from 

other sources (e.g., literature, other 

clinical trials), we believe that only 

measurements taken from participants 

in the clinical trial of interest should be 

submitted as results information to 

ClinicalTrials.gov. In our view, 

comparisons of such data with results 

data derived from other sources are 

more appropriately described in forums 

other than ClinicalTrials.gov (e.g., 

journal articles) where the other 

comparator can be explained in detail. 

Clinical trial information submitted for 

a clinical trial of interest would not 

describe the human subjects studied in 

another clinical trial (i.e., the clinical 

trial record would not contain baseline 

and demographic information about 

them, nor would it describe how they 

were allocated to arms of the clinical 

trial to receive interventions). See the 

definitions of primary outcome, 

measure and secondary outcome 

measure below. 

Pediatric postmarket surveillance of a 

device is a term used in section 

402(j)(1)(A)(ii)(II) of the PHS Act to 

describe a type of applicable device 

clinical trial. The term ‘‘[a]pplicable 

device clinical trial’’ includes ‘‘a 

pediatric postmarket surveillance as 

required under . . . [section 522 of the 

FD&C Act].’’ Pursuant to section 522, 

FDA defines the term ‘‘postmarket 

surveillance’’ as ‘‘the active, systematic, 

scientifically valid collection, analysis, 

and interpretation of data or other 

information about a marketed device.’’ 

(See 21 CFR 822.3(h).) In Title III of 

FDAAA, Congress directed that the term 

‘‘pediatric,’’ when used with respect to 

devices, refers to patients 21 and 

younger. (See Title III of FDAAA 

(‘‘Pediatric Medical Device Safety and 

Improvement Act of 2007’’), amending 

section 520(m) of the FD&C Act). Thus, 

for purposes of this proposed rule, the 

term pediatric postmarket surveillance 

of a device is defined to mean ‘‘the 

active, systematic, scientifically valid 

collection, analysis, and interpretation 

of data or other information conducted 

under section 522 of the [FD&C] Act 

about a marketed device that is expected 

to have significant use in patients who 

are 21 years of age or younger at the 

time of diagnosis or treatment. A 

pediatric postmarket surveillance of a 

device may be, but is not always, a 

clinical trial.’’ (See proposed § 11.10.) 

Primary outcome measure(s) is a term 

used, but not defined, in section 402(j) 

of the PHS Act. Section 

402(j)(2)(A)(ii)(I)(ll) of the PHS Act 

expressly requires primary outcome 

measures to be submitted as a clinical 

trial registration information data 

element. In addition, section 

402(j)(1)(A)(v) of the PHS Act defines 

the completion date in relation to the 

‘‘final collection of data for the primary 

outcome.’’ Primary outcome measure(s) 

also expressly is required as a clinical 

trial results information data element by 

section 402(j)(3)(C)(ii) of the PHS Act. 

We believe this enables users of 

ClinicalTrials.gov to identify the prespecified primary outcome measure(s) 

for the clinical trial submitted as part of 

the clinical trial registration information 

and to examine the results data 

collected for those outcome measures 

and submitted to the data bank as part 

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of clinical trial results information. We 

propose to define primary outcome 

measure to mean ‘‘the outcome 

measure(s) of greatest importance 

specified in the protocol, usually the 

one(s) used in the power calculation. 

Most clinical trials have one primary 

outcome measure, but a clinical trial 

may have more than one . . .’’ (See 

proposed § 11.10.) We note that for the 

purpose of this proposed rule, ‘‘primary 

outcome’’ has the same meaning as 

‘‘primary outcome measure.’’ (See 

proposed § 11.10.) See also the 

discussion in part IV of this preamble 

regarding primary outcome measure as 

a clinical trial registration information 

data element in proposed 

§ 11.28(a)(1)(xix) and as a clinical trial 

results information data element in 

proposed § 11.48(a)(3). 

Principal Investigator (PI) is a term 

used in the definition of responsible 

party in section 402(j)(1)(A)(ix) of the 

PHS Act. For purposes of this proposed 

rule, principal investigator means ‘‘the 

individual who is responsible for the 

scientific and technical direction of the 

study.’’ (See proposed § 11.10.) This 

proposed definition uses terminology 

derived from 42 CFR 52.2, which 

defines principal investigator in the 

context of an NIH grant as ‘‘the 

individual(s) judged by the applicant 

organization to have the appropriate 

level of authority and responsibility to 

direct the project or program supported 

by the grant and who is or are 

responsible for the scientific and 

technical direction of the project.’’ We 

have modified that definition to remove 

references to ‘‘applicant organization’’ 

and ‘‘project or program supported by 

the grant’’ that are specific to NIHfunded grants and would not 

necessarily apply to applicable clinical 

trials that are funded by industry or 

other non-governmental organizations. 

We use the term ‘‘study’’ in place of 

‘‘project’’ because the projects of 

relevance to this rule would be clinical 

studies, whether clinical trials or 

pediatric postmarket surveillances of a 

device. We have also modified the 

definition in order to indicate that it 

applies to only a single individual. This 

is consistent with our interpretation that 

there cannot be more than one 

responsible party for a clinical trial. We 

would expect a principal investigator to 

have full responsibility for the treatment 

and evaluation of human subjects in the 

study and for the integrity of the 

research data for the full study. In 

keeping with this approach, an 

investigator for an individual site in a 

multi-site clinical trial would not be 

considered the PI unless he or she also 

has overall responsibility for the clinical 

trial at all sites at which it is being 

conducted. This interpretation is 

consistent with the requirement in 

section 402(j)(1)(A)(ix) of the PHS Act 

that a principal investigator may be a 

responsible party only if he or she is 

responsible for conducting the trial, has 

access to and control over the data from 

the clinical trial, has the right to publish 

the clinical trial results, and has the 

ability to meet all the requirements for 

the submission of clinical trial 

information under section 402(j) of the 

PHS Act and this proposed part. 

We note that the PI of a grant awarded 

by a Federal Government agency that 

funds a clinical trial may not necessarily 

be the PI for that clinical trial for 

purposes of this proposed rulemaking. 

For example, the PI on a federal grant 

who has responsibility for only one site 

of a multi-site clinical trial (See, e.g., 42 

CFR 52.2.) would neither have the 

requisite responsibility for conducting 

the entire trial nor the requisite access 

to data from all sites involved in the 

clinical trial, both of which are required 

by section 402(j) of the PHS Act and this 

proposed part in order to meet the 

definition of responsible party. 

Accordingly, the PI on such a grant 

would not be considered to be the 

responsible party for purposes of 

registering and submitting clinical trial 

results information under section 402(j) 

of the PHS Act and this proposed part. 

Protocol is the document that 

describes the design of a clinical trial. 

It may be, and frequently is, amended 

after a clinical trial has begun. For 

purposes of this proposed rule, protocol 

means ‘‘the written description of the 

clinical trial, including objective(s), 

design, and methods. It may also 

include relevant scientific background 

and statistical considerations.’’ This 

proposed definition is derived from ICH 

E6(R1): Good Clinical Practice: 

Consolidated Guideline [Ref. 40], which 

defines the term as ‘‘[a] document that 

describes the objective(s), design, 

methodology, statistical considerations, 

and organization of a trial. The protocol 

usually also gives the background and 

rationale for the trial, but these could be 

provided in other protocol referenced 

documents.’’ The protocol generally 

addresses major statistical 

considerations, such as the number of 

human subjects required to provide 

adequate statistical power, but it may or 

may not include detailed information 

about the specific statistical analyses to 

be performed as part of the clinical trial. 

Such information may be contained in 

a separate statistical analysis plan. 

Responsible party is the term used in 

section 402(j) of the PHS Act in order 

to refer to the entity or individual who 

is responsible for registering a clinical 

trial or a pediatric postmarket 

surveillance of a device that is not a 

clinical trial and for submitting clinical 

trial information to ClinicalTrials.gov. 

Consistent with the definition provided 

in section 402(j)(1)(A)(ix) of the PHS 

Act, this proposed rule defines the term 

‘‘responsible party’’ to mean, ‘‘with 

respect to a clinical trial, (i) the sponsor 

of the clinical trial, as defined in 21 CFR 

50.3 (or any successor regulation); or (ii) 

the principal investigator of such 

clinical trial if so designated by a 

sponsor, grantee, contractor, or awardee, 

so long as the principal investigator is 

responsible for conducting the trial, has 

access to and control over the data from 

the clinical trial, has the right to publish 

the results of the trial, and has the 

ability to meet all of the requirements 

under this part for the submission of 

clinical trial information. For a pediatric 

postmarket surveillance of a device that 

is not a clinical trial, the responsible 

party is the entity whom FDA orders to 

conduct the pediatric postmarket 

surveillance of a device.’’ Proposed 

procedures for determining which 

individual or entity meets the definition 

of responsible party are specified in 

§ 11.4(c) and described in section IV.A.2 

of this preamble. 

Secondary outcome measure(s) is a 

term used, but not defined, in section 

402(j) of the PHS Act. Section 

402(j)(2)(A)(ii)(I)(ll) of the PHS Act 

expressly requires secondary outcome 

measures to be submitted as a clinical 

trial registration information data 

element, as a component of the outcome 

measures data element. In addition, 

secondary outcome measure(s) also is 

expressly required as a clinical trial 

results information data element by 

section 402(j)(3)(C)(ii) of the PHS Act. 

We believe this structure enables users 

of ClinicalTrials.gov to identify the prespecified secondary outcome measures 

for the clinical trial submitted as part of 

the clinical trial registration information 

and to examine the results data 

collected for those outcome measures 

and submitted to the data bank as part 

of clinical trial results information. Our 

proposed definition of ‘‘secondary 

outcome measure’’ means ‘‘an outcome 

measure that is of lesser importance 

than a primary outcome measure, but is 

part of a pre-specified plan for 

evaluating the effects of the intervention 

or interventions under investigation in a 

clinical trial. A clinical trial may have 

more than one secondary outcome 

measure.’’ This definition is consistent 

with the WHO Trial Registration 

standard and ICMJE registration policies 

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[Ref. 10, 13]. We note that for the 

purpose of this proposed rule, 

‘‘secondary outcome’’ has the same 

meaning as ‘‘secondary outcome 

measure.’’ 

The specification in proposed § 11.10 

that a secondary outcome measure is 

‘‘specifically planned to be analyzed as 

part of the clinical trial’’ is intended to 

help responsible parties differentiate 

between secondary outcome measures 

and tertiary or other lesser outcome 

measures that are more exploratory in 

nature. We consider secondary outcome 

measures to be those outcome measures 

(other than the primary outcome 

measures) that are not considered 

exploratory and for which there is a 

specific analysis plan. In general, the 

analysis plan would be specified in the 

protocol or statistical analysis plan, but 

protocols do not always contain detailed 

information about statistical analysis, 

and statistical analysis plans may not be 

complete at the time a trial is registered. 

Hence, the plan to analyze the 

secondary outcome measure may be 

expressed only in other formal trial 

documentation (e.g., a grant application, 

contract, or published journal article). 

We view outcomes measures that are 

not part of an analysis plan or are 

indicated to be exploratory as tertiary or 

lower level outcome measures that do 

not need to be submitted to 

ClinicalTrials.gov, but for which 

information may be submitted 

voluntarily. See discussion in sections 

IV.B.4 and IV.C.4 of this preamble, 

respectively, regarding secondary 

outcome measure(s) as a clinical trial 

information data element to be 

submitted at the time of registration 

following proposed § 11.28(a)(1)(xx) and 

at the time of results submission, 

following proposed § 11.48(a)(3). 

Serious adverse event is a term used 

but not defined in section 402(j)(3)(I) of 

the PHS Act. Section 402(j)(3)(I)(iii)(I) of 

the PHS Act requires the submission to 

ClinicalTrials.gov of specific 

information about ‘‘anticipated and 

unanticipated serious adverse events’’ 

for applicable clinical trials of drugs as 

well as devices. In defining the term 

‘‘serious adverse event’’ in its IND 

Safety Reporting regulations at 21 CFR 

312.32(a), FDA considers an adverse 

event to be ‘‘serious’’ when, in the view 

of either the sponsor or the investigator, 

it ‘‘results in any of the following 

outcomes: Death, a life-threatening 

adverse event, inpatient hospitalization 

or prolongation of existing 

hospitalization, a persistent or 

significant incapacity or substantial 

disruption of the ability to conduct 

normal life functions, or a congenital 

anomaly/birth defect. Important medical 

events that may not result in death, be 

life-threatening, or require 

hospitalization may be considered 

serious when, based upon appropriate 

medical judgment, they may jeopardize 

the patient or subject and may require 

medical or surgical intervention to 

prevent one of the outcomes listed in 

this definition. Examples of such 

medical events include allergic 

bronchospasm requiring intensive 

treatment in an emergency room or at 

home, blood dyscrasias or convulsions 

that do not result in inpatient 

hospitalization, or the development of 

drug dependency or drug abuse.’’ A 

‘‘serious adverse event’’, as defined in 

21 CFR 312.32(a), applies only in the 

context of drugs (including biological 

products). No fully equivalent term is 

defined in FDA regulations for medical 

devices. In 21 CFR 812.3(s), FDA 

defines an ‘‘unanticipated adverse 

device effect’’ as, in part, ‘‘any serious 

adverse effect on health or safety or any 

life-threatening problem or death caused 

by, or associated with, a device’’ that 

‘‘was not previously identified . . . in 

the investigational plan or application 

. . . or any other unanticipated serious 

problem associated with a device that 

relates to the rights, safety, or welfare of 

subjects.’’ However, because it is 

restricted to unanticipated effects, we 

do not consider this definition sufficient 

to meet the statutory requirement in 

section 402(j)(3)(I)(iii) of the PHS Act for 

submission of serious adverse event 

information that encompasses both 

anticipated and unanticipated events. 

Although we are relying on an FDA 

drug regulation, we emphasize that 

‘‘serious adverse event,’’ as defined for 

purposes of this proposed rulemaking, 

applies to both drugs and devices. 

Therefore, for purposes of this 

rulemaking, we draw upon the FDA 

definition of ‘‘serious adverse event’’ in 

21 CFR 312.32(a), because it more fully 

characterizes the criteria for ‘‘other 

serious problems’’ as well as ‘‘any lifethreatening problem’’ or ‘‘[d]eath.’’ Our 

proposed rule defines serious adverse 

event to mean ‘‘an adverse event that 

results in any of the following 

outcomes: death, a life-threatening 

adverse event as defined in 21 CFR 

312.32 (or any successor regulation), 

inpatient hospitalization or 

prolongation of existing hospitalization, 

a persistent or significant incapacity or 

substantial disruption of the ability to 

conduct normal life functions, or a 

congenital anomaly/birth defect. 

Important medical events that may not 

result in death, be life-threatening, or 

require hospitalization may be 

considered serious when, based upon 

appropriate medical judgment, they may 

jeopardize the human subject and may 

require medical or surgical intervention 

to prevent one of the outcomes listed in 

this definition. Examples of such 

medical events include allergic 

bronchospasm requiring intensive 

treatment in an emergency room or at 

home, blood dyscrasias or convulsions 

that do not result in inpatient 

hospitalization, or the development of a 

substance use disorder.’’ We use the 

phrase ‘‘a substance use disorder’’ 

instead of the phrase ‘‘drug dependency 

or drug abuse,’’ which is used in the 

FDA definition, for consistency with the 

latest version (fifth edition) of the 

Diagnostic and Statistical Manual of 

Mental Disorders (DSM V). By referring 

to adverse events (and thus the 

definition of that term in this proposed 

part), our proposed definition of serious 

adverse event is broader than the FDA 

definition of serious adverse event in 21 

CFR 312.32(a) because it encompasses 

any untoward or unfavorable medical 

occurrences associated with any 

intervention included in a clinical trial 

(not just the use of the FDA-regulated 

product), including any intervention(s) 

in any arm of the clinical trial that does 

not involve FDA-regulated products. In 

addition, as with our proposed 

definition of adverse event, our 

proposed definition of serious adverse 

event encompasses both anticipated and 

unanticipated effects regardless of 

attribution or association with the 

intervention. 

Sponsor is a term used in section 

402(j) of the PHS Act to define 

responsible party. Section 

402(j)(1)(A)(ix)(I) of the PHS Act 

explicitly defines ‘‘sponsor’’ as such 

term is defined at 21 CFR 50.3 or any 

successor regulation. There are two 

types of sponsors defined in 21 CFR 

50.3, both of which meet the definition 

of sponsor for purposes of this proposed 

rule. The first type is a ‘‘sponsor,’’ 

which is defined as ‘‘a person who 

initiates a clinical investigation but who 

does not actually conduct the 

investigation, i.e., the test article is 

administered or dispensed to or used 

involving, a subject under the 

immediate direction of another 

individual. A person other than an 

individual (e.g., corporation or agency) 

that uses one or more of its own 

employees to conduct a clinical 

investigation it has initiated is 

considered to be a sponsor (not a 

sponsor-investigator), and the 

employees are considered to be 

investigators.’’ The second is a 

‘‘sponsor-investigator,’’ which is 

defined as ‘‘an individual who both 

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initiates and actually conducts, alone or 

with others, a clinical investigation, i.e., 

under whose immediate direction the 

test article is administered or dispensed 

to, or used involving, a subject. The 

term does not include any person other 

than an individual, e.g., corporation or 

agency.’’ We believe that the definition 

of sponsor used in this proposed rule, 

must encompass both a sponsor and a 

sponsor-investigator because both terms 

are relevant in determining who 

initiates the clinical trial. Hence, we 

propose to define sponsor as ‘‘either a 

‘sponsor’ or ‘sponsor-investigator’, as 

each is defined 21 CFR 50.3 or any 

successor regulation.’’ Procedures for 

determining which individual or entity 

would be considered the sponsor of a 

applicable clinical trial or other clinical 

trial subject to this part are specified in 

proposed § 11.4(c) and described in 

section IV.A.2 of this preamble. As 

those sections explain, the individual or 

entity that is the sponsor will be 

considered to be the responsible party of 

an applicable clinical trial or other 

clinical trial, unless and until that 

responsibility is delegated to the PI, 

consistent with the requirements of 

section 402(j)(1)(A)(ix) of the PHS and 

this proposed part. 

Proposed § 11.10(b) defines certain 

data elements that are part of the 

clinical trial information that must be 

submitted to ClinicalTrials.gov under 

this proposed part. 

B. Registration—Subpart B 

Proposed subpart B sets forth the 

requirements for registration. It 

identifies who must submit clinical trial 

registration information; which 

applicable clinical trials must be 

registered in ClinicalTrials.gov; when 

clinical trial registration information 

must be submitted; where clinical trial 

registration information must be 

submitted; what constitutes clinical trial 

registration information; and by when 

NIH will post submitted clinical trial 

registration information. 

1. Who must submit clinical trial 

registration information?—§ 11.20 

Proposed § 11.20 requires that ‘‘[t]he 

responsible party for an applicable 

clinical trial specified in § 11.22 must 

register the applicable clinical trial 

[. . .] .’’ This approach is consistent 

with section 402(j)(2)(C) of the PHS Act, 

which states that the ‘‘responsible party 

for an applicable clinical trial . . . shall 

submit to the Director of NIH for 

inclusion in the registry data bank the 

[clinical trial registration information].’’ 

2. Which applicable clinical trials must 

be registered?—§ 11.22 

(a) General specification. Proposed 

§§ 11.22(a)(1) and (2) specify which 

applicable clinical trials must be 

registered with ClinicalTrials.gov. They 

state that registration is required for: (1) 

‘‘[a]ny applicable clinical trial that is 

initiated after September 27, 2007;’’ and 

(2) [a]ny applicable clinical trial that is 

initiated on or before September 27, 

2007 and is ongoing on December 26, 

2007 [. . .] .’’ This is consistent with 

section 402(j)(2)(C) of the PHS Act. We 

note that under section 402(j)(2)(C)(iii) 

of the PHS Act, in the case of an 

applicable clinical trial for a non-serious 

or non-life-threatening disease or 

condition that was ongoing as of 

September 27, 2007, clinical trial 

registration information was not 

required to be submitted until 

September 27, 2008. However, this 

distinction is no longer relevant because 

any such trial already should have been 

registered in the data bank. 

We note that this proposal differs 

from guidance that the Agency 

originally provided regarding its 

interpretation of section 402(j)(2)(C) of 

the PHS Act. The original interpretation 

may have resulted in some responsible 

parties registering applicable clinical 

trials that we no longer believe are 

subject to the registration requirement of 

section 402(j)(2)(C) of the PHS Act and 

this proposed part (i.e., applicable 

clinical trials for non-serious or nonlife-threatening diseases or conditions 

that were ongoing as of September 27, 

2007, but not as of December 26, 2007). 

We believe that our revised, proposed 

interpretation more accurately 

implements the text of section 

402(j)(2)(C) of the PHS Act. This revised 

interpretation was announced to the 

public in October 2009 through the NIH 

Guide [Ref. 43], the ClinicalTrials.gov 

Listserv [Ref. 44], and 

ClinicalTrials.gov. Although there is no 

legal requirement for responsible parties 

to keep clinical trial information for 

such previously-registered applicable 

clinical trials in ClinicalTrials.gov, we 

anticipate that many responsible parties 

will want to continue to make clinical 

trial information for such applicable 

clinical trials available to the public 

through the data bank. We do not intend 

to remove these clinical trial records 

from ClinicalTrials.gov, but we note that 

the clinical trial information for such 

clinical trials would be considered 

voluntary submissions of clinical trial 

information under section 402(j)(4)(A) 

of the PHS Act and would be subject to 

all of the requirements applicable to 

voluntarily-submitted clinical trial 

information under section 402(j)(4)(A) 

of the PHS Act, including but not 

limited to the requirements that such 

information be truthful and not 

misleading in accordance with proposed 

§ 11.6 and updated in accordance with 

proposed § 11.64. The Agency 

recognizes that some responsible parties 

for applicable clinical trials described in 

this paragraph may not want to be 

subject to the requirements that apply to 

clinical trial information submitted 

under 402(j)(4)(A) of the PHS Act or 

proposed § 11.60. To address this 

situation, any responsible party who 

wishes to remove an active clinical trial 

record from ClinicalTrials.gov for such 

an applicable clinical trial must submit 

an electronic request to the Agency at 

register@clinicaltrials.gov to have the 

record removed from the data bank. We 

note that if the Agency removes a 

clinical trial record from 

ClinicalTrials.gov as a result of such a 

request, the clinical trial record would 

continue to be available to the public in 

the ClinicalTrials.gov archives; 

however, the responsible party for such 

an applicable clinical trial would not be 

subject to the requirements of section 

402(j) of the PHS Act or this proposed 

part. For example, clinical trial results 

information is not required to be 

submitted for these clinical trials. 

Proposed § 11.22(a)(3) provides 

clarification for determining the date on 

which an applicable clinical trial is 

initiated. This date is important for 

determining if an applicable clinical 

trial is required to register in 

ClinicalTrials.gov, because, as described 

above, the registration requirements of 

section 402(j) of the PHS Act and this 

proposed part apply only to applicable 

clinical trials initiated after September 

27, 2007, and to applicable clinical 

trials that were initiated prior to 

September 27, 2007 and ongoing on 

December 26, 2007. However, section 

402(j) of the PHS Act does not define 

how to determine when an applicable 

clinical trial is ‘‘initiated.’’ We 

considered several possibilities for 

determining the date of initiation, 

including our longstanding practice for 

ClinicalTrials.gov which was to 

consider the date of initiation to be the 

date that an applicable clinical trial is 

open to recruitment. In order to be 

consistent with the definitions of 

‘‘ongoing’’ and ‘‘enrolled’’ and these 

proposed regulations, we propose 

instead that for any applicable clinical 

trial, other than a pediatric postmarket 

surveillance of a device that is not a 

clinical trial, the date of initiation 

means the date on which the first 

human subject is enrolled in the clinical 

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trial. For any pediatric postmarket 

surveillance of a device that is not a 

clinical trial, we propose that the date 

of initiation be the date on which FDA 

approves the plan for conducting the 

surveillance. This date will be welldocumented in correspondence with 

FDA and represents the first date on 

which the pediatric postmarket 

surveillance of a device could be started 

in accordance with an approved plan. 

(b) Determination of applicable 

clinical trial. Proposed § 11.22(b) sets 

forth an approach for determining 

whether or not a clinical trial or study 

meets the definition of an applicable 

clinical trial. By relying on certain 

aspects of the detailed discussions in 

section IV.A.5 regarding the definitions 

of applicable device clinical trial and 

applicable drug clinical trial, this 

approach outlines specific data 

elements that would be submitted as 

part of the registration process. For 

clinical trials and studies that are 

registered with ClinicalTrials.gov, it 

would provide a simple mechanism for 

determining whether or not the clinical 

trial or study is an applicable clinical 

trial that is subject to section 402(j) of 

the PHS Act and this part, and we could 

indicate such status in 

ClinicalTrials.gov. The order in which 

the data elements are considered would 

not influence the outcome: A clinical 

trial for which the submitted 

information meets the criteria specified 

below would be considered an 

applicable clinical trial. 

Other than situations where a clinical 

trial that is not an applicable clinical 

trial is registered voluntarily (see 

proposed § 11.60), there is no 

requirement under section 402(j) of the 

PHS Act or this proposed part for a 

responsible party to submit clinical trial 

registration information to 

ClinicalTrials.gov for a clinical trial or 

study that does not meet the definition 

of an applicable clinical trial. 

Algorithms following the approach 

outlined here could be developed to 

allow potential registrants to determine 

a priori whether their clinical trial or 

study meets the definition of an 

applicable clinical trial, without having 

to go through the registration process. 

To this end, we would make such 

algorithms accessible on 

ClinicalTrials.gov outside of the 

registration system. 

The proposed approach of using 

specified data elements to determine 

whether a clinical trial or study meets 

the definition of an applicable clinical 

trial is intended to amend and replace 

the approach currently implemented in 

ClinicalTrials.gov, which asks potential 

registrants to indicate whether their trial 

is an applicable clinical trial. We 

believe our proposed approach 

accurately reflects the proposed 

definitions of the terms applicable 

device clinical trial and applicable drug 

clinical trial. We invite public comment 

on this proposed approach and on 

whether there are any types of clinical 

trials or studies which might be errantly 

classified as applicable clinical trials 

that do not in fact meet the definitions 

of applicable device clinical trial or 

applicable drug clinical trial, or, 

conversely, any types of clinical trials or 

studies that do in fact meet the 

definitions of applicable device clinical 

trial or applicable drug clinical trial that 

might fail to be classified as applicable 

clinical trials. 

Consistent with the elaboration 

provided in section IV.A.5 of this 

preamble for the proposed definition of 

applicable device clinical trial, under 

proposed § 11.22(b)(1), a study would 

meet the definition of an applicable 

device clinical trial if (1) it is a Pediatric 

Postmarket Surveillance of a Device 

required by FDA under section 522 of 

the FD&C Act (regardless of whether the 

pediatric postmarket surveillance is a 

clinical trial), (2) it meets all of the 

following criteria for the submitted data 

elements: (a) The Study Type is 

interventional; (b) the Primary Purpose 

selected is other than feasibility; (c) 

either the Number of Arms is two or 

more, or the Number of Arms is one and 

Single Arm Controlled is selected; (d) 

the Intervention Type selected is 

something other than a combination 

product; (e) the clinical trial Studies an 

FDA-regulated Device; and (f) one or 

more of the following applies: At least 

one Facility Location is within the U.S. 

or one of its territories, the device under 

investigation is a Product Manufactured 

in the U.S. or one of its territories and 

is exported for study in another country, 

or the clinical trial has a U.S. Food and 

Drug Administration IDE Number. 

Taking a similar approach for 

applicable drug clinical trials, and 

consistent with the elaboration provided 

in section IV.A.5 of this preamble for 

the proposed definition of applicable 

drug clinical trial, proposed 

§ 11.22(b)(2) states that a clinical trial 

meets the definition of an applicable 

drug clinical trial if it meets all of the 

following criteria for the submitted data 

elements: (1) The Study Type is 

interventional; (2) the Study Phase is 

other than phase 1; (3) either the 

Number of Arms is two or more, or the 

Number of Arms is one and Single Arm 

Controlled is selected; (4) the clinical 

trial Studies an FDA-regulated Drug; 

and (5) one or more of the following 

applies: At least one Facility Location is 

within the U.S. or one of its territories, 

the drug under investigation is a 

Product Manufactured in the U.S. and is 

exported for study in another country, 

or the clinical trial has a U.S. Food and 

Drug Administration IND Number. 

With respect to Study Phase, we do 

not consider a phase 1/phase 2 study to 

be a phase 1 study; therefore, a clinical 

trial that is indicated to be phase 1/

phase 2 would be considered an 

applicable drug clinical trial if it meets 

the other conditions listed in (1) 

through (5) above and would be 

required to register at ClinicalTrials.gov 

if it also meets the conditions specified 

in proposed § 11.22(a). If a clinical trial 

is registered as phase 1/phase 2, and the 

trial subsequently proceeds through 

only the phase 1 stage and/or is 

terminated before reaching phase 2, the 

Study Phase data element may be 

updated to indicate that the trial is a 

phase 1 trial, in which case it would not 

be considered an applicable drug 

clinical trial and would not be subject 

to the requirements for results 

submission specified in subpart C. 

However, submitted registration 

information would continue to be 

posted in ClinicalTrials.gov. 

While most applicable clinical trials 

will meet the definition of either an 

applicable device clinical trial or an 

applicable drug clinical trial, some 

applicable clinical trials that study 

multiple intervention types (e.g., in 

different arms of the clinical trial) could 

meet both definitions. For example, a 

clinical trial with facility locations in 

the U.S. that studies an FDA-regulated 

drug in one arm and studies an FDAregulated device in another arm and 

compares outcomes of the two arms 

would meet both definitions. If the 

device studied in such an applicable 

clinical trial is not approved or cleared 

by FDA for any use and is not a 

component of a combination product, it 

would be treated as an applicable device 

clinical trial in that we would not post 

clinical trial registration information for 

that clinical trial prior to the date of 

approval or clearance of the device, 

consistent with proposed § 11.35(b)(2). 

We consider this situation to differ from 

that of an applicable clinical trial in 

which a studied device is part of a 

combination product. As explained in 

the discussion of the definition of an 

applicable drug clinical trial in section 

IV.A.5 of this preamble, any applicable 

clinical trial that studies a combination 

product would be treated as an 

applicable drug clinical trial under this 

proposed rule. 

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3. When must clinical trial registration 

information be submitted?—§ 11.24 

Proposed § 11.24 specifies the 

deadlines by which a responsible party 

must submit clinical trial registration 

information to register an applicable 

clinical trial in ClinicalTrials.gov. 

Consistent with section 402(j)(2)(C) of 

the PHS Act, proposed § 11.24(a) 

requires that clinical trial registration 

information be submitted on the later of 

December 26, 2007, or 21 calendar days 

after the first human subject is enrolled 

in the clinical trial. However, section 

402(j)(2)(C)(iii) of the PHS Act provides 

an exception to this deadline. For any 

applicable clinical trial that was not for 

a serious or life-threatening disease or 

condition (e.g., was not for indications 

such as acquired immunodeficiency 

syndrome (AIDS), all other stages of 

human immunodeficiency virus (HIV), 

Alzheimer disease, cancer, or heart 

failure; See [Ref. 4]), was initiated on or 

before September 27, 2007, and was still 

ongoing on December 26, 2007, the 

responsible party must submit clinical 

trial registration information by the later 

of September 27, 2008, or 21 calendar 

days after the first human subject is 

enrolled in the clinical trial. This 

proposed rule mirrors this standard in 

§ 11.24(b)(1). 

With regard to registering a pediatric 

postmarket surveillance of a device that 

is not a clinical trial, the submission 

deadlines described above may not be 

applicable because such surveillances 

may not entail formal recruitment of 

human subjects. We propose in 

§ 11.24(b)(2), therefore, that registrations 

of pediatric postmarket surveillances of 

a device that are not clinical trials be 

submitted ‘‘not later than December 26, 

2007, or 21 calendar days after FDA 

approves the postmarket surveillance 

plan, whichever date is later.’’ This 

provides a clear deadline for submission 

of clinical trial registration information, 

and the 21-day period is consistent with 

the requirement in section 

402(j)(2)(C)(ii) of the PHS Act that 

clinical trials be registered 21 days after 

enrollment of the first human subject. 

4. What constitutes clinical trial 

registration information?—§ 11.28 

Proposed § 11.28 identifies the 

structured information, or data 

elements, that constitute clinical trial 

information that a responsible party 

must submit in order to register an 

applicable clinical trial. Section 

402(j)(2)(A)(ii) of the PHS Act specifies 

a number of data elements that must be 

submitted to ClinicalTrials.gov for 

registration. In general, the proposed 

data elements in § 11.28 conform to the 

items enumerated in section 

402(j)(2)(A)(ii) of the PHS Act. In many 

instances, the Agency, through this 

proposed rulemaking has restated or 

clarified the registration data elements 

required by section 402(j)(2)(A)(ii) of the 

PHS Act. In addition, section 

402(j)(2)(A)(iii) of the PHS Act expressly 

authorizes the Secretary to modify the 

registration data elements, by 

regulation, if a rationale is provided as 

to why such a modification ‘‘improves 

and does not reduce’’ such information. 

In developing the proposed set of data 

elements for registration, we carefully 

considered the items enumerated in 

section 402(j)(2)(A)(ii) of the PHS Act, 

the mandate in section 402(j)(2)(A)(i) to 

‘‘expand’’ the existing registration data 

bank, and the intent to expand the data 

bank ‘‘to enhance patient enrollment 

and provide a mechanism to track 

subsequent progress of clinical trials.’’ 

(See section 402(j)(2)(A)(i) of the PHS 

Act). We have also taken into 

consideration the WHO trial registration 

standards and have sought to maintain 

consistency with the clinical trial 

registration requirements of the ICMJE 

[Ref. 13, 10]. 

Careful consideration was given to the 

data elements that were part of the data 

bank prior to passage in 2007 of section 

402(j) of the PHS Act, some of which are 

not expressly required under section 

402(j)(2)(A)(ii) of the PHS Act, but 

which we consider necessary to fulfill 

both the purpose of the expansion of 

registration information contained in 

ClinicalTrials.gov and certain other 

requirements of section 402(j) of the 

PHS Act. We believe, in general, that 

maintaining consistency with the preexisting data elements for 

ClinicalTrials.gov is consistent with the 

intent of section 402(j) of the PHS Act. 

Not only do we presume that Congress 

was familiar with those existing 

definitions when it developed and 

passed section 402(j) of the PHS Act, but 

also we believe that maintaining 

consistency will minimize confusion for 

those who submitted registration 

information previously to 

ClinicalTrials.gov prior to enactment of 

section 402(j) of the PHS Act. It will also 

minimize the level of effort required by 

those who previously established 

automated computer-based processes for 

submitting and updating registration 

data in ClinicalTrials.gov, rather than 

entering the data manually into the data 

bank. It will serve the public by 

facilitating cross-comparison of entries 

made before and after enactment of 

section 402(j) of the PHS Act. It also will 

ensure that the proposed clinical trial 

registration information requirements 

would not have the effect of reducing 

the amount of information available for 

newly-registered clinical trials as 

compared to those registered prior to the 

passage in 2007 of section 402(j) of the 

PHS Act, a result that we believe would 

be contrary to the intent of section 402(j) 

of the PHS Act. For these reasons, we 

believe that requiring the submission of 

data elements that were expected to be 

submitted to ClinicalTrials.gov prior to 

the passage in 2007 of section 402(j) of 

the PHS Act in order to register a 

clinical trial would improve and not 

reduce the clinical trial information 

submitted to ClinicalTrials.gov. 

As further discussed in section III.C.2 

of this preamble, in developing our 

proposed set of data elements for 

clinical trial registration information, 

we have decided to exercise our 

authority under section 402(j)(2)(A)(iii) 

of the PHS Act to modify the section 

402(j)(2)(A)(ii) requirements for 

registration information in order to 

achieve the following objectives: 

(1) Specify a particular structure for 

submitting certain clinical trial 

registration information in order to: (a) 

Help the public use the data bank more 

easily and be able to compare entries, 

consistent with section 402(j)(2)(B)(iv) 

of the PHS Act; (b) enable searching of 

the data bank using criteria listed in 

sections 402(j)(2)(B)(i) and (ii) of the 

PHS Act; and (c) facilitate the 

submission of complete and accurate 

information by responsible parties; 

(2) Enable effective implementation 

of, or compliance with, other provisions 

of section 402(j) of the PHS Act and this 

part, e.g., proposing to add data 

elements to indicate whether a product 

under study in a clinical trial in 

manufactured in the U.S. and whether 

a study is a pediatric postmarket 

surveillance of a device, both of which 

are important to help determine 

whether a study meets the definition of 

an applicable clinical trial; 

(3) Improve the quality and 

consistency of clinical trial registration 

information, e.g., proposing to add 

Other Intervention Name(s) and 

Intervention Description to help users 

identify and differentiate among similar 

interventions studied in registered 

clinical trials; or 

(4) Demonstrate whether clinical trials 

registered in the data bank have 

complied with ethical and scientific 

review procedures in accordance with 

applicable statutes and regulations, e.g., 

proposing to add Human Subjects 

Protection Review Board Status to 

indicate to potential human subjects 

and other users whether an applicable 

clinical trial has received needed 

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approvals or is not subject to such 

requirements. 

(a) Registration data elements for 

applicable clinical trials other than 

pediatric postmarket surveillances of a 

device that are not clinical trials. 

Proposed § 11.28(a) specifies the data 

elements that a responsible party would 

be required to submit to 

ClinicalTrials.gov to register an 

applicable clinical trial other than a 

pediatric postmarket surveillance of a 

device that is not a clinical trial. A 

pediatric postmarket surveillance of a 

device that does not take the form of a 

clinical trial would be registered by 

submitting the clinical trial information 

specified in § 11.28(b). The clinical trial 

registration information data elements 

in § 11.28(a) are grouped into the four 

categories used in section 402(j)(2)(A)(ii) 

of the PHS Act: (1) Descriptive 

information, (2) recruitment 

information, (3) location and contact 

information, and (4) administrative data. 

Additional data elements that the 

Agency proposes via this rule are listed 

in the categories in which they best fit. 

The clinical trial registration 

information data elements, grouped by 

category, are as follows. 

(1) Descriptive Information 

Brief Title. Section 

402(j)(2)(A)(ii)(I)(aa) of the PHS Act 

specifically requires the submission of a 

brief title as part of the clinical trial 

information submitted at registration, 

but does not define the term, other than 

to indicate that the title is ‘‘intended for 

the lay public.’’ We interpret this 

requirement to mean that potential 

human subjects should be able to 

understand, from the brief title, the 

general purpose of the clinical trial and 

distinguish it from others listed in the 

data bank. Prior to FDAAA, those 

submitting information to the 

ClinicalTrials.gov registry pursuant to 

FDAMA, were requested to include a 

‘‘brief title’’ of the trial [Ref. 2]. This 

term was defined to mean a ‘‘protocol 

title intended for the lay public’’ [Ref. 

2]. This definition of ‘‘brief title’’ also is 

consistent with ‘‘public title’’ (data item 

#9) of the WHO Trial Registration 

standard and ICMJE registration policies 

[Ref. 13, 10]. 

Based on our experience to date with 

ClinicalTrials.gov, we recognize that 

acronyms are frequently used to refer to 

clinical trials (e.g., ‘‘ACCORD’’ for the 

Action to Control Cardiovascular Risk in 

Diabetes trial or ‘‘STAR*D’’ for the 

Sequenced Treatment Alternatives to 

Relieve Depression trial), and believe it 

is important for such acronyms to be 

included in the registry to enable users 

of the data bank to identify clinical 

trials that they might see referenced in 

other media (e.g., news reports, journal 

articles). As such, we consider an 

acronym used to identify a clinical trial 

to be part of the brief title. Therefore, in 

proposed § 11.10(b)(1), Brief Title is 

described as ‘‘a short title of the clinical 

trial written in language intended for 

the lay public, including any acronym 

or abbreviation used publicly to identify 

the clinical trial.’’ Although we do not 

specify what type of information must 

be conveyed by the Brief Title, we 

believe that a Brief Title intended for 

the lay public should include, where 

possible, information on the 

participants, condition being evaluated, 

and intervention(s) studied. 

Official Title. Using the authority in 

section 402(j)(2)(A)(iii) of the PHS Act 

we propose to require a responsible 

party to submit an ‘‘official title’’ as part 

of clinical trial information when 

registering an applicable clinical trial at 

ClinicalTrials.gov. In proposed 

§ 11.10(b)(2), we define Official Title as: 

‘‘The title of the clinical trial, 

corresponding to the title of the 

protocol.’’ We believe that the official 

title will complement the Brief Title that 

is intended for the lay public, by 

providing a technical title that will help 

researchers understand the general 

purpose of the study. The official title 

would also be helpful in associating the 

clinical trial in ClinicalTrials.gov with 

information about the clinical trial that 

is contained in other sources, such as 

scientific publications, regulatory 

submissions, and media reports, which 

often use the official title of the study 

protocol. Those who learn about a 

clinical trial from one of these other 

sources could more easily search for the 

trial in ClinicalTrials.gov using the 

Official Title. Prior to passage of 

FDAAA, those submitting information 

to ClinicalTrials.gov were able to submit 

an ‘‘official title’’ as an optional data 

element, defined to mean ‘‘Official 

name of the protocol provided by the 

study principal investigator or sponsor’’ 

[Ref. 2]. This submission of an official 

title is also consistent with the WHO 

Trial Registration standard and ICMJE 

registration policies, which require the 

submission of a ‘‘scientific title’’ (data 

item #10) [Ref. 13, 10]. 

Brief Summary. Section 

402(j)(2)(A)(ii)(I)(bb) of the PHS Act 

expressly requires a ‘‘brief summary’’ to 

be submitted as clinical trial registration 

information, but it does not define the 

term other than to indicate that the brief 

summary is ‘‘intended for the lay 

public.’’ Prior to FDAAA, those 

submitting information to the 

ClinicalTrials.gov registry pursuant to 

FDAMA were requested to include a 

‘‘brief summary’’ of the clinical trial 

[Ref. 4]. This term was defined to mean 

a ‘‘short description of the protocol 

intended for the lay public, including a 

brief statement of the study hypothesis’’ 

[Ref. 2]. We propose to continue to use 

that definition. Accordingly, in 

proposed § 11.10(b)(3), Brief Summary 

is described as ‘‘a short description of 

the clinical trial, including a brief 

statement of the clinical trial’s 

hypothesis, written in language 

intended for the lay public.’’ 

Primary Purpose. Section 

402(j)(2)(A)(ii)(I)(cc) of the PHS Act 

expressly requires the ‘‘primary 

purpose’’ of the intervention(s) to be 

submitted as clinical trial registration 

information, but it does not define the 

term. Prior to passage of section 402(j) 

of the PHS Act in 2007, those 

submitting information to the registry 

were requested to indicate the primary 

purpose of the clinical trial. This term 

was defined to mean the ‘‘reason for the 

protocol’’ [Ref. 2], and those submitting 

information were given a choice of 

selections, including ‘‘treatment,’’ 

‘‘prevention,’’ ‘‘diagnostic,’’ ‘‘supportive 

care,’’ ‘‘screening,’’ ‘‘health services 

research,’’ and ‘‘basic science.’’ Data 

submitters could also indicate ‘‘other’’ 

and include a description of the purpose 

in the detailed description portion of 

the clinical trial record. We found this 

approach effective for indicating the 

primary purpose of the intervention(s) 

studied in the clinical trials registered 

with ClinicalTrials.gov and believe this 

approach would apply well to clinical 

trials being registered pursuant to this 

proposed part. Therefore, under 

proposed § 11.10(b)(4), Primary Purpose 

refers to ‘‘the main objective of the 

intervention(s) being evaluated by the 

clinical trial.’’ We would require a 

responsible party to provide a response 

selected from the following set of 

options: ‘‘treatment’’ (for a protocol 

designed to evaluate one or more 

interventions for treating a disease, 

syndrome or condition), ‘‘prevention’’ 

(for a protocol designed to assess one or 

more interventions aimed at preventing 

the development of a specific disease or 

health condition), ‘‘diagnostic’’ (for a 

protocol designed to evaluate one or 

more interventions aimed at identifying 

a disease or health condition), 

‘‘supportive care’’ (for a protocol 

designed to evaluate one or more 

interventions where the primary intent 

is to maximize comfort, minimize side 

effects or mitigate against a decline in 

the subject’s health or function), 

‘‘screening’’ (for a protocol designed to 

assess or examine methods of 

identifying a condition, or risk factors 

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for a condition, in people who are not 

yet known to have the condition or risk 

factor), ‘‘health services research’’ (for a 

protocol designed to evaluate the 

delivery, processes, management, 

organization or financing of health care), 

‘‘basic science’’ (for a protocol designed 

to examine the basic mechanism of 

action, e.g., physiology or biomechanics, 

of an intervention), ‘‘feasibility’’ (for a 

protocol designed to determine the 

feasibility of a device or test prototype 

devices where the primary outcome 

measure relates to feasibility and not to 

health outcomes), or ‘‘other’’. The 

inclusion of ‘‘feasibility’’ on the list of 

options is intended to permit the 

responsible party for a clinical trial of a 

device to indicate whether such clinical 

trial is a feasibility study. Feasibility 

studies do not meet the definition of an 

applicable device clinical trial as 

specified in section 402(j)(1)(A)(ii) of 

the PHS Act and § 11.10(a) of this 

proposed part. A responsible party may 

nevertheless voluntarily register a 

clinical trial that is a feasibility study of 

a device. Such registration would be a 

voluntary submission of clinical trial 

information under section 402(j)(4)(A) 

of the PHS Act and proposed § 11.60. 

Study Design. Section 

402(j)(2)(A)(ii)(I)(dd) of the PHS Act 

expressly requires ‘‘study design’’ to be 

submitted as part of clinical trial 

registration information, but does not 

define the term. There are many 

important aspects of a study design, and 

information about each is relevant to 

ensuring that the descriptions of study 

designs are complete and comparable 

across clinical trials. Hence, we propose 

to require that several components of 

study design be submitted. Prior to 

FDAAA, those submitting information 

to ClinicalTrials.gov pursuant to 

FDAMA were requested to include the 

interventional study characteristics of 

the trial [Ref. 4]. This term was defined 

to mean the ‘‘[p]rimary investigative 

techniques used in the protocol,’’ and 

data submitters were instructed to 

provide information describing several 

key attributes of the study design, 

including the study model, number of 

arms, masking, and allocation [Ref. 2]. 

This definition of study design, 

including the key attributes, conforms to 

ICH Guidelines [Ref. 23] and is 

consistent with ‘‘study type’’ (data item 

#15) of the WHO Trial Registration 

standard (version 1.0) and ICMJE 

registration policies [Ref. 13, 10]. 

Consistent with this approach, proposed 

§ 11.10(b)(5) requires that Study Design 

include information about several 

important aspects of a clinical trial: 

interventional study model, number of 

arms, arm information, allocation, 

masking, and whether a single-armed 

clinical trial is controlled. None of these 

terms is used in section 402(j) of the 

PHS Act, but we believe each is key 

component of study design. We propose 

the following meanings for these terms. 

(a) Interventional Study Model 

characterizes the approach used for 

assigning groups of human subjects to 

interventions during the clinical trial. In 

proposed § 11.10(b)(5)(i), the data item 

is defined as ‘‘[t]he strategy for assigning 

interventions to human subjects.’’ In 

ClinicalTrials.gov, responsible parties 

would be required to select an entry 

from the following limited set of 

proposed options: ‘‘single group’’ (i.e., 

clinical trials with a single arm), 

‘‘parallel’’ (i.e., participants are assigned 

to one of two or more groups in parallel 

for the duration of the study), ‘‘crossover’’ (i.e., participants receive one of 

two alternative interventions during the 

initial phase of the study and receive 

the other intervention during the second 

phase of the study), or ‘‘factorial’’ (i.e., 

two or more interventions, each alone 

and in combination, are evaluated in 

parallel against a control group). No 

‘‘other’’ option is proposed. To address 

those situations in which a clinical trial 

might use a modified version of one of 

these models or the responsible party 

might wish to provide more information 

about the specific implementation of the 

model, responsible parties would also 

be able to provide voluntarily additional 

free-text description containing more 

specific details about the interventional 

study model. We invite public comment 

on whether the proposed set of options 

adequately addresses existing and 

emerging interventional study models, 

including dose escalation study designs, 

and whether it would provide suitable 

selections, without an ‘‘other’’ option 

for all types of applicable clinical trials 

and voluntarily registered trials that are 

subject to this proposed regulation. 

(b) Number of Arms specifies the total 

number of arms in a clinical trial. We 

define the term ‘‘arm’’ in proposed 

§ 11.10(a). Some clinical trials contain 

multiple periods or phases, each of 

which might use different numbers of 

arms. Hence, in proposed 

§ 11.10(b)(5)(ii), the data element is 

defined as ‘‘[t]he number of arms in the 

clinical trial. For a trial with multiple 

periods or phases that have different 

numbers of arms, the maximum number 

of arms during any period or phase.’’ 

We note that historical controls are not 

considered to be an ‘‘arm’’ of a clinical 

trial and thus are not counted in the 

number of arms. 

(c) Arm Information provides key 

information about each arm in the 

clinical trial. In proposed 

§ 11.10(b)(5)(iii), the data element is 

defined as ‘‘[a] description of each arm 

of the clinical trial that indicates its role 

in the clinical trial, provides an 

informative title, and, if necessary, 

additional descriptive information to 

differentiate each arm from other arms 

in the clinical trial.’’ Responsible parties 

would be required to select from the 

following list of options for describing 

the role of each arm in the clinical trial: 

‘‘experimental,’’ ‘‘active comparator,’’ 

‘‘placebo comparator,’’ ‘‘sham 

comparator,’’ ‘‘no intervention,’’ or 

‘‘other.’’ The informative title would 

consist of a label or short name to 

identify the arm in the clinical trial 

record (e.g., the name of the 

experimental intervention used in the 

arm or placebo). Additional descriptive 

information would be required if the 

informative title does not sufficiently 

differentiate among arms in the clinical 

trial (e.g., in a clinical trial that 

compares two different dosages of the 

same investigational drug, the 

descriptive information would have to 

indicate which is the higher dose arm 

versus the lower dose arm). Even if the 

informative title and/or additional 

descriptive information vary sufficiently 

among the arms of the clinical trial, 

responsible parties may voluntarily 

include additional details about the 

interventions or the arms in this field. 

(d) Allocation describes how human 

subjects are assigned to interventions. In 

proposed § 11.10(b)(5)(iv), the data item 

is defined as ‘‘[t]he method by which 

human subjects are assigned to arms in 

a clinical trial.’’ Responsible parties 

would be required to select from the 

following limited set of options: 

‘‘randomized’’ (participants are assigned 

to intervention groups by chance), or 

‘‘nonrandomized’’ (participants are 

expressly assigned to intervention 

groups through a non-random method, 

such as physician choice), or ‘‘not 

applicable’’ (for a single arm study). No 

‘‘other’’ option is proposed. We invite 

public comment on whether this limited 

set of options would provide suitable 

selections for all types of applicable 

clinical trials and voluntarily registered 

clinical trials that are subject to this 

proposed rule. 

(e) Masking specifies which entities, if 

any, involved in the clinical trial are not 

informed of the intervention 

assignments (i.e., who is ‘‘blinded’’ in 

the clinical trial). In proposed 

§ 11.10(b)(5)(v), the data item is defined 

as ‘‘[t]he party or parties, if any, 

involved in the clinical trial who are 

prevented from having knowledge of the 

interventions assigned to individual 

human subjects.’’ In the data bank, 

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responsible parties would be required to 

select from the following limited menu 

of choices for describing which 

party(ies) is/are blinded: ‘‘human 

subject,’’ ‘‘care provider,’’ 

‘‘investigator,’’ and/or an ‘‘outcomes 

assessor’’ (i.e., another individual who 

evaluates the outcome(s) of interest). No 

‘‘other’’ option is proposed, but 

responsible parties would have the 

ability to voluntarily provide additional, 

free-text, information about other parties 

who might be blinded in clinical trial. 

(f) Single Arm Controlled? is not a 

data element that is explicitly listed in 

section 402(j) of the PHS Act as part of 

clinical trial information, but we 

propose it as a sub-element part of 

Study Design to enable the Agency to 

determine whether a registered clinical 

trial is an applicable clinical trial when 

such a determination cannot be made 

based on other submitted registration 

data elements. This data element, which 

is described in proposed 

§ 11.10(b)(5)(vi) as ‘‘[f]or a single-armed 

clinical trial only, whether or not the 

clinical trial is controlled, as specified 

by the protocol or statistical analysis 

plan,’’ would assist the Agency, 

responsible parties, and users of the 

data bank in determining whether a 

clinical trial with only one arm meets 

the definition of an applicable clinical 

trial. As explained in section IV.A.5 of 

this preamble, a study of a device that 

is not a pediatric postmarket 

surveillance of a device can meet the 

definition of an applicable device 

clinical trial only if it ‘‘compar[es] an 

intervention with a device . . . against 

a control in human subjects.’’ (See 

402(j)(1)(A)(ii)(I) of the PHS Act.) 

Similarly, a clinical trial of a drug can 

meet the definition of an applicable 

drug clinical trial only if it is ‘‘a 

controlled clinical investigation . . .’’ 

(See 402(j)(1)(A)(iii)(I)). 

As explained in the definition of the 

term ‘‘controlled’’ in section IV.A.5 of 

this preamble, we consider any clinical 

trial with two or more arms to be 

controlled and/or to compare an 

intervention against a control. A clinical 

trial with only one arm (a single-armed 

study) may or may not be controlled 

and/or compare an intervention against 

a control, depending on whether or not 

the data collected on human subjects in 

the clinical trial will be compared to 

non-concurrently collected data. To 

determine whether a clinical trial with 

only one arm meets this criterion, we 

propose to require the responsible party 

for a single-armed study to indicate 

whether the clinical trial is controlled, 

as defined in this part. In doing so, the 

responsible party would consider 

whether the protocol or statistical 

analysis plan for the clinical trial 

indicates that data collected in the 

single-arm clinical trial will be 

compared to non-concurrently collected 

data, such as an historical control group. 

To reduce the burden on responsible 

parties, we would require this element 

of Study Design to be submitted only if 

the other clinical trial information 

submitted by the responsible party 

indicates that the clinical trial has one 

arm and otherwise meets the criteria for 

an applicable clinical trial, as listed in 

proposed § 11.22(b) (section IV.B.2(b) of 

this preamble). If other submitted 

registration data elements demonstrate 

that the clinical trial is not an applicable 

clinical trial or that it includes two or 

more arms, the Single Arm Controlled? 

data element would not need to be 

submitted. 

Study Phase. Section 

402(j)(2)(A)(ii)(I)(ee) of the PHS Act 

expressly requires, for an applicable 

drug clinical trial, the ‘‘study phase’’ to 

be submitted as a clinical trial 

registration information data element, 

but it does not define the term. Prior to 

FDAAA, those submitting registration 

information to ClinicalTrials.gov 

pursuant to FDAMA were requested to 

include the study phase of the clinical 

trial [Ref. 4]. This term was interpreted 

to mean ‘‘phase of investigation, as 

defined by FDA for trials involving 

investigational new drugs’’ [Ref. 2]. In 

proposed § 11.10(b)(6), the data item is 

defined as ‘‘for a clinical trial of a drug, 

the numerical phase of such clinical 

trial, consistent with terminology in 21 

CFR 312.21, or any successor regulation, 

such as phase 2 or phase 3, and in 21 

CFR 312.85, or any successor regulation, 

for phase 4 studies.’’ Responsible parties 

would be required to select one 

response from a limited list of options 

that includes phases 1, 2, 3, and 4, 

consistent with the terminology in 21 

CFR 312.21 and 21 CFR 312.85. In 

addition, they would be able to select 

from other options that are commonly 

used in practice: Phase 1/phase 2 (for 

trials that are a combination of phases 

1 and 2; as discussed previously, phase 

1/phase 2 studies are not considered 

phase 1 studies and may be applicable 

drug clinical trials); and phase 2/phase 

3 (for trials that are a combination of 

phases 2 and 3). No ‘‘other’’ option is 

proposed. Although we are aware that 

the term ‘‘phase 0’’ is used in practice 

(e.g., to refer to clinical trials that are 

exploratory in nature and are not 

designed to evaluate therapeutic or 

diagnostic intent), any trial that would 

be referred to as ‘‘phase 0’’ meets the 

definition of a phase 1 trial under FDA’s 

regulations (21 CFR 312.21). Therefore, 

we do not propose to include ‘‘phase 0’’ 

as an option for the Study Phase data 

element, and responsible parties 

registering a clinical trial that might be 

referred to as ‘‘phase 0’’ should indicate 

the Study Phase as ‘‘phase 1’’. Study 

phases are not intended for use in 

describing clinical trials of devices, and 

therefore, consistent with section 

402(j)(2)(A)(ii)(I)(ee) of the PHS Act, 

responsible parties for applicable device 

clinical trials would not be required to 

submit this data element. 

Study Type. Section 

402(j)(2)(A)(ii)(I)(ff) of the PHS Act 

expressly requires ‘‘study type’’ to be 

submitted as clinical trial information at 

the time of registration, but it does not 

define the term. Prior to FDAAA, those 

submitting information to the registry 

pursuant to FDAMA were requested to 

include the study type of the record 

being submitted to the registry by 

indicating whether the record 

corresponded to an interventional study 

(i.e., a clinical trial), an observational 

study, or an expanded access program. 

The study type selected would 

determine which other data elements to 

submit [Ref. 4]. Consistent with prior 

practice, proposed § 11.10(b)(7) defines 

the Study Type date element as ‘‘the 

type of study for which clinical trial 

information is being submitted.’’ 

Responsible parties would be required 

to select one of the following limited set 

of options: ‘‘interventional,’’ 

‘‘observational,’’ or ‘‘expanded access 

program.’’ No ‘‘other’’ option is 

proposed. We believe that all applicable 

clinical trials and all other clinical 

studies that might be registered 

voluntarily with ClinicalTrials.gov can 

be characterized accurately as either 

‘‘interventional’’ or ‘‘observational,’’ 

depending on whether human subjects 

studied are assigned to interventions 

based on a study protocol 

(interventional) or patients receive 

interventions as part of routine medical 

care, and a researcher studies the effect 

of the intervention (observational). We 

would consider observational studies to 

include a wide range of noninterventional studies, including 

retrospective reviews of patient records 

or relevant literature. (See the 

elaboration of the terms applicable 

device clinical trial and applicable drug 

clinical trial in section IV.A.5 of this 

preamble). A study that is designated as 

‘‘interventional,’’ as that term is defined 

in this proposed part, may or may not 

be an applicable clinical trial, 

depending on whether it meets the other 

criteria for an applicable clinical trial 

that are specified in this part. A study 

that is designated ‘‘observational’’ 

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would be an applicable clinical trial 

only if it is a pediatric postmarket 

surveillance of a device as defined in 

this part. (See the proposed definition of 

pediatric postmarket surveillance of a 

device in § 11.10, the discussion of 

proposed § 11.28(b), and the discussion 

of observational studies in section 

IV.A.5 of this preamble). Conversely, 

any applicable clinical trial other than 

a pediatric postmarket surveillance of a 

device must always have a Study Type 

of ‘‘interventional.’’ An applicable 

clinical trial that is a pediatric 

postmarket surveillance of a device 

could have a Study Type of 

‘‘interventional’’ or ‘‘observational.’’ 

The term, ‘‘expanded access program,’’ 

is proposed as an option for Study Type 

because responsible parties are required 

to enter the data elements describing an 

expanded access program that is not an 

applicable clinical trial by creating an 

expanded access record if there is an 

expanded access program for the drug or 

biological product under study in the 

clinical trial being registered, consistent 

with section 402(j)(2)(A)(ii)(II)(gg) of the 

PHS Act, and if such a record does not 

already exist. As discussed in section 

IV.A.5 of this preamble, we expect that 

most expanded access programs will not 

meet the definition of an applicable 

clinical trial. The appropriate Study 

Type for expanded access programs that 

do not meet the definition of applicable 

clinical trial would be ‘‘expanded access 

program.’’ The appropriate Study Type 

for an expanded access program that 

does meet the definition of applicable 

clinical trial would be ‘‘interventional.’’ 

An expanded access program must be 

registered under only one Study Type. 

(See discussion of proposed § 11.28(c)). 

We invite public comment on our 

proposal for Study Type, including 

whether the limited set of options 

proposed would provide suitable 

selections for all types of applicable 

clinical trials and voluntarily registered 

clinical trials that are subject to this 

proposed rule. 

Whether the Study is a Pediatric 

Postmarket Surveillance of a Device. We 

propose, in § 11.28(a)(1)(viii), to add a 

requirement for responsible parties of a 

study of a device to indicate if the study 

is a pediatric postmarket surveillance of 

a device. As we stated previously, the 

term ‘‘applicable device clinical trial’’ is 

defined, in part, as ‘‘a pediatric 

postmarket surveillance as required 

under section 522 of the Federal Food, 

Drug, and Cosmetic Act.’’ (See section 

402(j)(1)(A)(ii)(II) of the PHS Act). A 

responsible party would be required to 

provide this data element only if the 

study is a pediatric postmarket 

surveillance of a device; a responsible 

party would not be required to submit 

this data element if the device study is 

not a pediatric postmarket surveillance 

of a device. 

By indicating that a study is a 

pediatric postmarket surveillance of a 

device, users of the data bank and the 

Agency would be able to confirm that 

the study is an applicable device 

clinical trial. In addition, by combining 

this information with other submitted 

clinical trial registration information, 

e.g., the Study Type data element 

(interventional, observational), the 

Agency could confirm whether the 

pediatric postmarket surveillance of a 

device is a clinical trial and indicate 

which other data elements must be 

submitted at the time of registration. If 

a pediatric postmarket surveillance of a 

device is a clinical trial, the clinical trial 

registration information data elements 

set forth at proposed § 11.28(a) are 

required to be submitted. If a pediatric 

postmarket surveillance of a device is 

not a clinical trial (i.e. it is a form of 

observational study, including a 

retrospective review of patient records 

or relevant literature), the clinical trial 

registration information data elements 

set forth in § 11.28(b) are required to be 

submitted. 

Primary Disease or Condition Being 

Studied in the Trial, or the Focus of the 

Study. Section 402(j)(2)(A)(ii)(I)(gg) of 

the PHS Act expressly requires ‘‘the 

primary disease or condition being 

studied, or the focus of the study’’ to be 

submitted as part of clinical trial 

registration information, but it does not 

define the term. Section 402(j)(2)(B)(i)(I) 

of the PHS Act further requires the data 

bank to be searchable by one or more of 

eight listed criteria, including ‘‘the 

disease or condition being studied in 

the clinical trial, using Medical Subject 

Headers (MeSH) descriptors.’’ To 

support searching using MeSH 

descriptors, the primary disease or 

condition being studied in the clinical 

trial, or the focus of the study, must be 

described using either MeSH 

terminology (http://www.nlm.nih.gov/

mesh/) or another terminology that has 

been mapped to MeSH, when possible 

(if the other terminology is mapped to 

MeSH, the data bank can be searched 

using MeSH terms and retrieve the 

correct record(s)). SNOMED CT 

(Systematized Nomenclature of 

Medicine—Clinical Terms) (http://www.

ihtsdo.org/snomed-ct/) meets the 

criteria of having been mapped to MeSH 

and has been designated as a U.S. 

standard for certified electronic health 

records that meet specified criteria for 

meaningful use of health information 

technology. (See http://www.gpo.gov/

fdsys/pkg/FR-2012-09-04/pdf/2012- 

20982.pdf). Other vocabularies have 

also been mapped to MeSH within the 

NLM’s Unified Medical Language 

System® (UMLS®) Metathesaurus. 

While it is possible that not all primary 

diseases or conditions or study foci can 

be expressed using MeSH, SNOMED CT, 

or another vocabulary that is mapped to 

MeSH within the UMLS Metathesaurus, 

we believe such terminology would 

accommodate most clinical trials and 

must be used when available. When a 

suitable term is unavailable in MeSH, 

SNOMED CT, or another vocabulary 

that is included in the UMLS 

Metathesaurus, ClinicalTrials.gov can 

accept another English language entry 

that accurately describes the primary 

disease or condition being studied, or 

the focus of the study. ClinicalTrials.gov 

could then use the information to enable 

searching by MeSH terms. Therefore, 

under proposed § 11.10(b)(9), we define 

Primary Disease or Condition Being 

Studied in the Trial, or the Focus of the 

Study as ‘‘the name(s) of the disease(s) 

or condition(s) studied in the clinical 

trial, or the focus of the clinical trial, 

using, if available, appropriate 

descriptors from the National Library of 

Medicine’s Medical Subject Headings 

(MeSH) controlled vocabulary thesaurus 

http://www.nlm.nih.gov/mesh/, or terms 

from another vocabulary, such as the 

Systematized Nomenclature of 

Medicine—Clinical Terms (SNOMED 

CT), that has been mapped to MeSH 

within the Unified Medical Language 

System (UMLS) Metathesaurus (https:// 

uts.nlm.nih.gov).’’ This definition is 

consistent with ‘‘health condition(s) or 

problem(s) studied’’ (data item #12) of 

the WHO Trial Registration standard 

(version 1.0) and ICMJE registration 

policies [Ref. 13, 10]. It is also 

consistent with the terminology used in 

ClinicalTrials.gov prior to FDAAA when 

those submitting information to the 

registry in response to FDAMA were 

requested to include ‘‘conditions or 

focus of study,’’ which were described 

as the ‘‘primary disease or condition 

being studied, or focus of the study,’’ 

and submitters were directed to describe 

the diseases or conditions using MeSH 

controlled vocabulary when possible 

[Ref. 2, 4]. 

Intervention Name(s). Section 

402(j)(2)(A)(ii)(I)(hh) of the PHS Act 

expressly requires ‘‘intervention name’’ 

to be submitted as part of clinical trial 

information at the time of registration, 

but it does not define the term. We 

believe the purpose of this data element 

is to enable interested parties to readily 

identify the intervention(s) being 

studied in each arm of a clinical trial 

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and compare clinical trials by 

intervention. While some clinical trials 

compare a single intervention against a 

placebo (which would not need to be 

listed as a separate intervention), many 

compare multiple interventions (e.g., a 

new drug versus standard treatment, or 

different dosages of the same drug). We 

believe it is important for the names of 

all interventions studied in a clinical 

trial to be submitted to the data bank. 

Based on our previous experience in 

operating ClinicalTrials.gov, we 

recognize that there are inherent 

difficulties in determining the level of 

detail that should be required for 

naming interventions, especially those 

without non-proprietary (i.e., generic) 

names [Ref. 4]. We believe that nonproprietary names must be provided for 

interventions (e.g., drugs, biological 

products, and devices) when available. 

For interventions for which a nonproprietary name is not available, our 

prior experience suggests that a brief 

descriptive name can suffice. In either 

case, additional descriptive information 

is often needed to distinguish the 

intervention(s) under study from other 

similar interventions used in practice or 

studied in the same or other clinical 

trials. Therefore, under proposed 

§ 11.10(b)(10), Intervention Name(s) is 

specified as ‘‘a brief descriptive name 

used to refer to the intervention(s) 

studied in each arm of the clinical trial. 

A non-proprietary name of the 

intervention must be used, if available. 

If a non-proprietary name is not 

available, a brief descriptive name or 

identifier must be used.’’ Examples of a 

brief descriptive name or identifier 

include a chemical name, company 

code or serial number. This description 

of Intervention Name is consistent with 

the ‘‘intervention(s)’’ (data item #13) of 

the WHO Trial Registration standard 

(version 1.0) and ICMJE registration 

policies [Ref. 13, 10]. It is also 

consistent with use of the term in 

ClinicalTrials.gov prior to FDAAA when 

those submitting information to the 

ClinicalTrials.gov registry pursuant to 

FDAMA were requested to include the 

intervention name for each intervention 

involved in the trial [Ref. 4], and the 

term was defined to mean the ‘‘generic 

name of the precise intervention being 

studied. For investigational new drugs 

that do not yet have a generic name, a 

chemical name, company code or serial 

number may be used on a temporary 

basis.’’ Our current proposal is 

consistent with this approach. 

Other Intervention Name(s) is a term 

that is not used in section 402(j) of the 

PHS Act, but is proposed as a data 

element that responsible parties must 

submit if the sponsor has used more 

than one name publicly to identify the 

intervention under study in a clinical 

trial. Based on our prior experience 

operating ClinicalTrials.gov, we are 

aware that interventions often have 

multiple names, including, for example, 

a sponsor code name, brand name(s), or 

a name or identifier from a standard 

vocabulary, such as RxNorm for drugs 

(http://www.nlm.nih.gov/research/umls/

rxnorm/index.html). Accordingly, 

providing only a single name for each 

intervention (as is required under the 

Intervention Name(s) data element) does 

not necessarily provide enough 

information to allow users to find and 

compare all clinical trials in 

ClinicalTrials.gov that involve a specific 

intervention, as a different clinical trial 

with the same intervention may have 

been registered by another responsible 

party under a different intervention 

name. Therefore, we believe that adding 

a requirement to submit Other 

Intervention Name(s) improves and does 

not reduce the clinical trial information 

available in the data bank. Under 

proposed § 11.10(b)(11), this term is 

defined as ‘‘other current and former 

name(s) or alias(es), if any, different 

from the Intervention Name(s), that the 

sponsor has used publicly to identify 

the intervention, including, but not 

limited to, past or present names such 

as brand name(s), serial numbers, or 

chemical descriptions.’’ This 

requirement could mean that, in some 

circumstances (e.g., when the 

responsible party is a designated 

principal investigator), the responsible 

party would need to communicate with 

the sponsor or the manufacturer of the 

intervention(s) to determine whether 

another name has been used publicly. 

We do not believe such additional 

communication would be frequent or 

onerous. This proposal would not 

require a responsible party to submit 

names that have not been used publicly 

because users of ClinicalTrials.gov 

would be unlikely to search for a 

clinical trial using such names. We seek 

comment on this approach. 

Intervention Description. The term 

‘‘intervention description’’ is not used 

in section 402(j) of the PHS Act, but we 

propose it as an additional data element 

to be submitted as clinical trial 

information at the time of registration. 

Based on prior experience, we recognize 

that the Intervention Name(s) and Other 

Intervention Name(s) data elements, 

whether providing information on brand 

or non-proprietary names, do not always 

provide enough information to allow 

potential human subjects or other users 

to differentiate among similar 

interventions used in different arms of 

a clinical trial, or to distinguish the 

intervention used in one clinical trial 

from a similar intervention used in 

another clinical trial, or to understand 

the differences between interventions 

studied in a clinical trial and those used 

in routine medical practice. For 

example, a clinical trial might compare 

two or more dosages of the same drug 

or two different clinical trials might 

examine drug-eluting stents that are 

similar to those used in standard 

medical practice. To reduce this 

ambiguity, additional descriptive 

information is needed about the 

intervention, such as information about 

the dosage, dosage form, frequency of 

administration, route of administration, 

and/or duration of administration of a 

drug, or a general description of the 

device, including how the device 

functions, the scientific concepts that 

form the basis for the device, and the 

significant physical and performance 

characteristics of the device, such as its 

key components and general types of 

materials used. The submission of such 

information will enable users (whether 

subjects, patients, physicians, 

researchers, or others) to understand key 

elements of a clinical trial, and compare 

information among clinical trials. For 

these reasons, requiring submission of 

an Intervention Description would 

improve but not reduce the clinical trial 

information available in the data bank. 

Under proposed § 11.10(b)(12), the term 

is defined to mean ‘‘details that can be 

made public about the intervention, 

other than the Intervention Name and 

Other Intervention Name(s), sufficient to 

distinguish it from other, similar 

interventions studied in the same or 

another clinical trial.’’ The information 

should be sufficiently detailed to 

differentiate the specified intervention 

from other similar interventions, but 

should not include information that the 

responsible party cannot make public. 

For example, if the specific dosage of a 

drug being studied cannot be divulged, 

a responsible party could instead 

indicate if the dosage is higher or lower 

than that used in an approved or 

licensed drug or in another arm of the 

study. If an experimental device uses 

different material than previous 

versions of the device, or than other 

marketed devices, the responsible party 

could provide a general description of 

the new material without including its 

specific formulation. 

Intervention Type. Section 

402(j)(2)(A)(ii)(I)(hh) of the PHS Act 

expressly requires ‘‘intervention type’’ 

to be submitted as part of clinical trial 

information at the time of registration, 

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but it does not define the term. Prior to 

FDAAA, those submitting information 

to the ClinicalTrials.gov registry were 

requested to specify the intervention 

type for each intervention studied in the 

clinical trial. Under proposed 

§ 11.10(b)(13) Intervention Type would 

be defined as ‘‘for each intervention 

studied in the clinical trial, the general 

type of intervention.’’ When submitting 

this information, responsible parties 

would be required to select one of the 

following options for each intervention 

studied: ‘‘drug’’ (including placebo), 

‘‘device’’ (including sham), ‘‘biological/ 

vaccine,’’ ‘‘procedure/surgery,’’ 

‘‘radiation,’’ ‘‘behavioral’’ (e.g., 

psychotherapy, lifestyle counseling), 

‘‘genetic’’ (including gene transfer, stem 

cell and recombinant DNA), ‘‘dietary 

supplement’’ (e.g., vitamins, minerals), 

‘‘combination product’’ (combining a 

drug and device, a biological product 

and device; a drug and biological 

product; or a drug, biological product, 

and device), ‘‘diagnostic test’’ (e.g., 

imaging in-vitro), and ‘‘other.’’ Note that 

when the intervention used is a 

combination product (e.g., drug-eluting 

stent), the responsible party must select 

‘‘combination product’’ as the 

Intervention Type. As specified in 

proposed § 11.28(a)(1)(xiii), selection of 

an Intervention Type would be required 

for each intervention studied in each 

arm of the clinical trial. Some clinical 

trials will therefore include multiple 

Intervention Types. As discussed in 

section IV.B.2(b) of this preamble, a 

clinical trial that studies a drug and a 

device as separate, independent 

interventions would list both ‘‘drug’’ 

and ‘‘device’’ as Intervention Types and 

may meet the definitions of both an 

applicable device clinical trial and an 

applicable drug clinical trial. 

Studies an FDA-Regulated Device. 

Section 402(j) of the PHS Act does not 

explicitly require submission of a 

clinical trial registration information 

data element to indicate whether or not 

a clinical trial studies an FDA-regulated 

device. We propose to require such a 

data element using our authority under 

section 402(j)(2)(A)(iii) of the PHS Act 

to assist responsible parties, users of 

ClinicalTrials.gov, and the Agency in 

determining whether or not a clinical 

trial is an applicable device clinical 

trial, using the approach specified in 

proposed § 11.22(b)(1). As specified in 

the elaboration of the definition of an 

applicable device clinical trial in 

section IV.A.5 of this preamble, one 

criterion for an applicable device 

clinical trial is that the clinical trial 

studies a device ‘‘subject to section 

510(k), 515, or 520(m) of the [FD&C 

Act].’’ It is possible that a clinical trial 

with an Intervention Type of ‘‘device’’ 

would not be an applicable device 

clinical trial because the device is not 

subject to section 510(k), 515, or 520(m) 

of the FD&C Act. Conversely, it is 

possible that a clinical trial could be an 

applicable device clinical trial even if 

none of the specified Intervention Types 

is ‘‘device.’’ For example, a clinical trial 

for which a responsible party indicates 

the Intervention Type is ‘‘radiation,’’ 

‘‘genetic,’’ or ‘‘procedure’’ could in fact 

be an applicable device clinical trial 

studying a device subject to section 

510(k), 515, or 520(m) of the FD&C Act 

(e.g., an x-ray device, a genetic test, or 

a surgical device). If the responsible 

party has obtained an IDE and 

submitted an IDE number to 

ClinicalTrials.gov, it would be clear that 

the clinical trial is an applicable device 

clinical trial as defined in this part 

(assuming, as discussed previously, that 

the clinical trial is not a clinical trial of 

a combination product). If the 

responsible party does not submit an 

IDE number, however, ambiguity would 

arise because the lack of an IDE number 

(or an IDE) does not per se indicate that 

a clinical trial is not an applicable 

device clinical trial. 

To avoid this ambiguity and help 

ensure that applicable clinical trials can 

be properly identified, we propose to 

require a responsible party to 

specifically indicate whether or not a 

clinical trial studies an FDA-regulated 

device by submitting the Studies an 

FDA-regulated Device data element. The 

data element is defined in proposed 

§ 11.10(b)(39) to mean that ‘‘a clinical 

trial studies a device that is subject to 

section 510(k), 515, or 520(m) of the 

Federal Food, Drug, and Cosmetic Act.’’ 

Consistent with the elaboration of the 

term applicable device clinical trial in 

section IV.A.4 of this preamble, we 

interpret this definition to mean that the 

clinical trial studies a device that would 

require any of the following before it 

may be legally marketed in the U.S.: (1) 

A finding of substantial equivalence 

under section 510(k) of the FD&C Act; 

(2) an order under section 515 of the 

FD&C Act approving a premarket 

approval application for the device, or 

(3) a humanitarian device exemption 

under section 520(m) of the FD&C Act. 

We believe that submission of this 

information would improve and not 

reduce the clinical trial information 

submitted at the time of registration by 

making it clear to the responsible party, 

the Agency, and users of 

ClinicalTrials.gov whether or not a 

clinical trial without an IDE studies an 

FDA-regulated device. This information 

would, in turn, be used in determining 

whether a clinical trial meets the 

definition of an applicable device 

clinical trial, following the approach 

specified in proposed § 11.22(b)(1). To 

reduce the data entry burden on 

responsible parties, ClinicalTrials.gov 

could automatically pre-populate this 

data field to indicate ‘‘yes’’ if a 

responsible party submits an IDE 

number as part of the FDA IND or IDE 

Number data element specified in 

proposed § 11.10(b)(35). 

We are aware that devices may be 

used in clinical trials even though they 

are not the intervention studied in the 

clinical trial or the experimental 

variable of interest in the study. For 

example, clinical trials of procedures 

involving surgical devices may not be 

designed to study the effect of these 

devices. Therefore, when considering 

whether a clinical trial Studies an FDAregulated Device a responsible party 

should consider whether: (a) The study 

is designed to examine the effect or 

performance of an FDA-regulated 

device, or differences in the intended 

use, e.g., variations in frequency of use, 

method of administration, design 

specifications, and other characteristics 

(e.g., used in one or more, but not all, 

arms in a multi-arm study); and/or (b) 

at least one pre-specified primary or 

secondary outcome measure reflects a 

characteristic, effect, or performance of 

an FDA-regulated device (e.g., need for 

replacement or maintenance of the 

device). 

Studies an FDA-Regulated Drug. 

Section 402(j) of the PHS Act does not 

explicitly require submission of a 

clinical trial registration information 

data element to indicate whether or not 

a clinical trial studies an FDA-regulated 

drug. We propose to require such a data 

element using our authority under 

section 402(j)(2)(A)(iii) of the PHS Act 

to assist responsible parties, users of 

ClinicalTrials.gov, and the Agency in 

determining whether or not a clinical 

trial is an applicable drug clinical trial 

using the approach specified in 

proposed § 11.22(b)(1). As specified in 

the elaboration of the definition of an 

applicable drug clinical trial in section 

IV.A.5 of this preamble, one criterion for 

an applicable drug clinical trial is that 

the clinical trial studies a drug ‘‘subject 

to section 505 of the [FD&C] Act or [a 

biological product subject] to section 

351 of [the PHS] Act.’’ It is possible that 

a clinical trial with an Intervention 

Type of ‘‘drug’’ or ‘‘biological product’’ 

would not be an applicable drug clinical 

trial because the drug is not subject to 

section 505 FD&C Act (e.g., a nonprescription drug that is marketed under 

an over-the-counter drug monograph) 

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and/or the biological product is not 

subject to section 351 of the PHS Act. 

Conversely, it is possible that a clinical 

trial could be an applicable drug clinical 

trial even if none of the specified 

Intervention Types is ‘‘drug’’ or 

‘‘biological product.’’ A clinical trial for 

which the responsible party indicates 

the Intervention Type to be ‘‘dietary 

supplement’’ or ‘‘genetic’’ or 

‘‘procedure’’ could in fact be an 

applicable drug clinical trial studying a 

drug subject to section 505 of the FD&C 

Act or a biological product subject to 

section 351 of the PHS Act. For 

example, a dietary supplement could be 

studied for treatment of cancer, or a 

genetic trial could study a gene therapy. 

If the responsible party has obtained an 

IND and submitted an IND number to 

ClinicalTrials.gov, then it would be 

clear (assuming, as discussed 

previously, that the clinical trial is not 

a clinical trial of a combination product) 

that the clinical trial is an applicable 

drug clinical trial as defined in this part. 

If the responsible party does not submit 

an IND number, however, ambiguity 

would arise because the lack of an IND 

number (or an IND) does not per se 

indicate that a trial is not an applicable 

drug clinical trial. To avoid this 

ambiguity and help ensure that 

applicable clinical trials can be properly 

identified, we propose to require a 

responsible party to specifically indicate 

whether or not a clinical trial studies an 

FDA-regulated drug by submitting the 

Studies an FDA-regulated Drug data 

element. The data element is defined in 

proposed § 11.10(b)(40) to mean that ‘‘a 

clinical trial studies a drug that is 

subject to section 505 of the Federal 

Food, Drug, and Cosmetic Act or section 

351 of the Public Health Service Act.’’ 

Consistent with the elaboration of the 

term applicable drug clinical trial in 

section IV.A.4 of this preamble, we 

interpret this definition to mean that the 

clinical trial studies a drug that is the 

subject of an approved new drug 

application (NDA) or biologics license 

application (BLA) or that would require 

an approved NDA or BLA to be legally 

marketed in the U.S. We believe that 

submission of this information would 

improve and not reduce the clinical trial 

information submitted at the time of 

registration by making it clear to the 

responsible party, the Agency, and users 

of ClinicalTrials.gov whether or not a 

clinical trial without an IND studies an 

FDA-regulated drug or biological 

product. This information would, in 

turn, be used in determining whether a 

clinical trial meets the definition of an 

applicable drug clinical trial, following 

the approach specified in proposed 

§ 11.22(b)(2). To reduce the data entry 

burden on responsible parties, 

ClinicalTrials.gov could automatically 

pre-populate this data field to indicate 

‘‘yes’’ if a responsible party submits an 

IND number as part of the FDA IND or 

IDE Number data element specified in 

proposed § 11.10(b)(35). 

We are aware that a clinical trial may 

include an FDA-regulated drug even 

though the drug is not a variable of 

interest. For example, a clinical trial of 

a device may involve the surgical 

insertion of the device under anesthesia, 

but the anesthesia drug is not studied in 

the clinical trial. In determining 

whether a clinical trial Studies an FDAregulated Drug a responsible party 

should consider whether: (a) The 

clinical trial is designed to examine the 

effect of the FDA-regulated drug(s), or of 

differences in the intended use, 

including differences in dosing, 

frequency of use, or route of 

administration; and/or (b) at least one of 

the pre-specified primary or secondary 

outcome measures reflects a 

characteristic or effect of the FDAregulated drug(s). 

U.S. FDA Approval, Licensure, or 

Clearance Status. We propose U.S. FDA 

Approval, Licensure, or Clearance 

Status to be submitted as clinical trial 

information to indicate whether any 

intervention regulated by FDA and 

studied in the clinical trial has been 

approved, licensed, or cleared for any 

use. Such information would help in 

ensuring that the data bank operates in 

compliance with statutory requirements. 

For example, knowledge of the approval 

or clearance status of a device is 

necessary to determine when clinical 

trial registration information submitted 

for an applicable device clinical trial 

may be posted publicly in the data bank. 

(See section 402(j)(2)(D)(ii) of the PHS 

Act.) This information also would be 

helpful for users of ClinicalTrials.gov, 

including potential participants, who 

might wish to know whether or not the 

product(s) under study have been 

approved, licensed, or cleared for the 

use studied in the clinical trial. 

Requiring submission of the approval, 

licensure, or clearance status for each 

drug or device studied in an applicable 

clinical trial would therefore improve 

and not reduce the clinical trial 

information available in the data bank, 

consistent with section 402(j)(2)(A)(iii) 

of the PHS Act for proposed 

modifications to clinical trial 

registration information. We propose 

referring explicitly to the ‘‘U.S.’’ FDA to 

provide clarification for those 

submitting information about foreign 

clinical trials to ClinicalTrials.gov. In 

proposed § 11.10(b)(14), we therefore 

define U.S. FDA Approval, Licensure, or 

Clearance Status, to mean, ‘‘for each 

drug or device studied in the clinical 

trial, whether that drug or device is 

approved, licensed, or cleared by the 

U.S. Food and Drug Administration for 

any use.’’ We would require responsible 

parties to select a response from the 

following limited list of choices: ‘‘for 

studied use(s)’’ (the drug, biological 

product, or device is approved, 

licensed, or cleared for the use studied 

in the clinical trial; ‘‘for other use(s)’’ 

(the drug, biological product, or device 

is approved, licensed, or cleared for 

use(s) other than those studied in the 

clinical trial, e.g., the clinical trial 

studies a new use of the product); ‘‘No’’ 

(the product has not been approved, 

licensed, or cleared for any use). No 

‘‘other’’ option is proposed, but a 

responsible party would also be able to 

provide voluntarily additional free-text 

information to further describe the 

approval, licensure, or clearance status, 

e.g., to indicate that the product has 

been approved in another dose or 

dosage form, or to list the indications for 

which it has been approved. We invite 

public comment on whether the set of 

proposed options is sufficient to 

describe the approval, licensure, or 

clearance status of FDA-regulated drugs 

or devices that would be studied in 

applicable clinical trials or voluntarily 

registered clinical trials that are subject 

to this proposed rule. 

Product Manufactured in the U.S. 

Section 402(j) of the PHS Act does not 

explicitly require a data element to be 

submitted as part of clinical trial 

information to indicate whether a 

product under study is manufactured in 

the U.S, but we propose to include it 

using our authority under section 

402(j)(2)(A)(iii) of the PHS Act to allow 

users to determine whether a registered 

clinical trial is an applicable clinical 

trial. This data element, which is 

defined in § 11.10(b)(15) as ‘‘for a drug 

or device studied in a clinical trial, 

whether or not the drug or device is 

manufactured in the U.S. or one of its 

territories,’’ will assist the Agency in 

determining whether a clinical trial 

meets the definition of an applicable 

clinical trial. As explained above in the 

definitions of ‘‘applicable device 

clinical trial’’ and ‘‘applicable drug 

clinical trial,’’ even if a clinical trial is 

being conducted entirely outside of the 

U.S. or one of its territories, it may be 

considered an applicable clinical trial 

where the drug or device is subject to 

regulation under the FD&C Act. A drug 

or device is considered to be subject to 

regulation under the FD&C Act if the 

product under investigation is 

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manufactured in the U.S. or one of its 

territories and is exported for study in 

another country, either under an IND, 

pursuant to 21 CFR 312.110, or any 

successor regulation, or under section 

801(e) or 802 of the FD&C Act. Thus, 

information indicating whether each 

intervention studied in a clinical trial is 

manufactured in the U.S. or one of its 

territories would be essential in some 

situations to determine whether such 

trial is subject to FDA jurisdiction and 

meets the definition of an applicable 

clinical trial. 

To reduce data submission burden, 

this data element would need to be 

submitted to ClinicalTrials.gov only if 

the entry submitted for the U.S. Food 

and Drug Administration IND or IDE 

Number data element indicates that 

there is no IND or IDE for the clinical 

trial, and the entry(ies) for the Facility 

Information data element include no 

facility locations in the U.S. or its 

territories. In those situations in which 

a responsible party would be required to 

submit information about whether the 

product(s) under study is manufactured 

in the U.S., including this information 

in the data bank would improve and not 

reduce clinical trial information by 

publicly providing data necessary to 

determine whether or not such trial is 

an applicable clinical trial. Accordingly, 

we propose the addition of this data 

element as clinical trial registration 

information pursuant to our authority to 

modify the requirements for clinical 

trial registration information under 

section 402(j)(2)(A)(iii) of the PHS Act. 

Study Start Date. Section 

402(j)(2)(A)(ii)(I)(ii) of the PHS Act 

expressly requires ‘‘study start date’’ to 

be submitted as clinical trial 

information at the time of registration, 

but it does not define this term. Prior to 

passage in 2007 of section 402(j) of the 

PHS Act, those submitting information 

to ClinicalTrials.gov were requested to 

include the study start date of the trial, 

which was defined as the ‘‘date that 

enrollment to the protocol begins’’ [Ref. 

2], meaning the date on which the 

clinical trial is open to enrollment, even 

if no subjects are enrolled on that date. 

The WHO Trial Registration standard 

(version 1.0) and ICMJE registration 

policies, in contrast, define the term 

study start date (data item #16) as the 

‘‘date of first enrollment’’ [Ref. 13, 10]. 

Section 402(j)(2)(C)(ii) of the PHS Act 

and proposed § 11.24(a) generally 

require that clinical trial registration 

information be submitted to 

ClinicalTrials.gov not later than 21 

calendar days after the first human 

subject is enrolled in the clinical trial. 

In practice, however, many responsible 

parties submit clinical trial registration 

information to ClinicalTrials.gov before 

the first subject is enrolled. In some 

cases, at the time the clinical trial is 

registered, the responsible party might 

not have information about when the 

first subject will be enrolled or when the 

first subject was enrolled (for example, 

in a large multi-site trial) but might 

know only when the clinical trial was 

or will be opened for enrollment. To 

account for these potential scenarios, we 

propose that responsible parties be 

required to provide an estimated study 

start date (i.e., the estimated date on 

which the clinical trial will be open to 

enrollment of human subjects), unless 

and until the responsible party knows 

the actual study start date (i.e., the 

actual date on which the first human 

subject is enrolled). Not later than 21 

days after the first human subject is 

enrolled, the responsible party would be 

required to update the Study Start Date 

data element to reflect the actual study 

start date, consistent with proposed 

§ 11.64. Providing the estimated study 

start date to the public, even before the 

first subject is enrolled, has important 

benefits to potential human subjects 

because it will allow them to know 

when a clinical trial likely will be open 

to enrollment. Hence, in proposed 

§ 11.10(b)(16) we define Study Start 

Date to mean: ‘‘the estimated date on 

which the clinical trial will be open to 

enrollment of human subjects. If the 

clinical trial has enrolled the first 

human subject, the actual date on which 

the first human subject was enrolled.’’ 

The Study Start Date must include the 

day, month, and year. We note that if a 

clinical trial is registered with an 

estimated study start date but the 

clinical trial then is halted before 

enrolling the first subject (e.g., because 

of difficulties in recruitment, loss of 

funding, etc.), the responsible party 

would not be expected to update the 

study start date; rather, responsible 

party would be expected to update the 

Overall Recruitment Status data element 

specified in proposed § 11.10(b)(25) to 

indicate that the clinical trial has been 

‘‘withdrawn,’’ as such term is used for 

the purpose of this regulation, and to 

update the Why Study Stopped data 

element specified in proposed 

§ 11.10(b)(26). 

Completion Date. Section 

402(j)(2)(A)(ii)(I)(jj) of the PHS Act 

requires the responsible party to submit 

information on the ‘‘expected 

completion date’’ of an applicable 

clinical trial when registering a clinical 

trial. The public availability of 

information about the expected 

completion date is important for an 

ongoing clinical trial because it provides 

an indication of the relative progress of 

the clinical trial and the expected date 

on which results information may be 

submitted to the data bank because 

section 402(j)(3)(E)(i) of the PHS Act 

requires that, in general, clinical trial 

results information be submitted not 

later than 1 year after the earlier of the 

estimated completion date of the 

applicable clinical trial or the actual 

completion date of the applicable 

clinical trial. We note, as described in 

the discussion of proposed § 11.44, that 

certain exceptions apply to this general 

deadline for the submission of clinical 

trial results information. In addition, we 

note that we interpret the phrase 

‘‘estimated completion date,’’ as such 

term is used in section 402(j)(3)(E)(i)(I) 

of the PHS Act, to have the same 

meaning as ‘‘expected completion date,’’ 

as such term is used in section 

402(j)(2)(A)(ii)(I)(jj) of the PHS Act, 

because both indicate the date on which 

the responsible party anticipates that 

the clinical trial will be completed. 

In addition, we believe it is important 

for users to have information about the 

actual completion date of a clinical trial, 

so that they can know when clinical 

trial results information ordinarily 

would be due under section 

402(j)(3)(E)(i) of the PHS Act and 

proposed § 11.44(a), absent certain 

specified circumstances in which 

submission of clinical trial results 

information may be delayed. Because 

clinical trial results information 

generally is required under section 

402(j)(3)(E)(i) of the PHS Act and 

proposed § 11.44 to be submitted not 

later than 1 year after the estimated or 

actual completion date, whichever is 

earlier, we believe it is important for the 

Completion Date data element to be 

updated promptly after the completion 

date is reached. We therefore propose in 

§ 11.28(a)(1)(xvii) that when registering 

a clinical trial, a responsible party must 

submit the Completion Date for the 

clinical trial, which is defined in 

§ 11.10(b)(17) to mean: ‘‘the estimated 

completion date. Once the clinical trial 

has reached the completion date, the 

responsible party must update the 

Completion Date data element to reflect 

the actual completion date.’’ The 

Completion Date must include the day, 

month, and year. We would require the 

responsible party to take the following 

steps with regard to the Completion 

Date data element: (1) Provide a 

reasonable estimated completion date at 

the time of registration; (2) update the 

estimated completion date at least once 

every 12 months during the course of 

the clinical trial, in accordance with 

proposed § 11.64(b)(1)(viii)(A), if the 

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estimate changes; and (3) update the 

Completion Date information to indicate 

the actual completion date not later than 

30 days after the clinical trial reaches its 

completion date, in accordance with 

proposed § 11.64(b)(1)(viii)(B). Finally, 

we note that, consistent with the 

requirement in section 402(j)(4)(C)(ii) of 

the PHS Act, ClinicalTrials.gov will 

maintain an archive of all of the updates 

made to the Completion Date data 

element. 

Enrollment. Section 

402(j)(2)(A)(ii)(I)(kk) of the PHS Act 

expressly requires submission of ‘‘the 

target number of subjects’’ to be enrolled 

in an applicable clinical trial, but this 

phrase is not defined. We believe this 

data element is intended to describe the 

intended or estimated size of the 

clinical trial, in terms of the estimated 

total number of human subjects 

(including healthy volunteers) or target 

number of human subjects who will be 

enrolled in the clinical trial. We 

therefore propose in § 11.28(a)(1)(xviii) 

to require the submission of enrollment 

information at the time of registration, 

which is described in proposed 

§ 11.10(b)(18) as ‘‘the estimated total 

number of human subjects to be 

enrolled or target number of human 

subjects in the clinical trial.’’ 

We expect that the estimated or target 

enrollment in a clinical trial might 

change either before or during the 

clinical trial, e.g., as recruitment 

continues. Consistent with section 

402(j)(4)(C) of the PHS Act and 

proposed § 11.64(a)(1), a responsible 

party would be required to update the 

Enrollment data element not less than 

once every 12 months, if the anticipated 

or target enrollment in the clinical trial 

changes. This update would be in 

addition to the requirement in proposed 

§ 11.64(b) that a responsible party 

submit the Actual Enrollment data 

element when recruitment for a clinical 

trial has ended, i.e., when the Overall 

Recruitment Status of the trial is 

changed to ‘‘active, no longer 

recruiting’’ or ‘‘terminated.’’ This latter 

requirement is intended to provide 

users of ClinicalTrials.gov with 

additional information about the total 

number of participants enrolled in the 

clinical trial, which may differ from the 

target enrollment. (See proposed 

§ 11.64(b) and the discussion below of 

‘‘Overall Recruitment Status’’ for a 

discussion of this requirement.) Our 

proposal for Enrollment is similar to 

procedures in place for 

ClinicalTrials.gov prior to FDAAA. 

Primary Outcome Measures and 

Secondary Outcome Measures are data 

elements expressly required by section 

402(j)(2)(A)(ii)(I)(ll) of the PHS Act to be 

submitted as part of clinical trial 

information at the time of registration. 

Definitions of the terms Outcome 

Measure, Primary Outcome Measure, 

and Secondary Outcome Measure are 

provided and elaborated upon earlier in 

this preamble and in proposed subpart 

A. 

Section 402(j) of the PHS Act does not 

specify what specific information about 

primary and secondary outcome 

measures must be submitted to 

ClinicalTrials.gov at the time of 

registration. We therefore have 

attempted to develop requirements that 

are consistent with what we believe to 

be the intent of section 402(j) of the PHS 

Act, with data submission standards for 

ClinicalTrials.gov prior to passage in 

2007 of section 402(j) of the PHS Act, 

and with our understanding of common 

practice in the clinical trials 

community. 

Under proposed §§ 11.28(a)(1)(xix) 

and (xx), responsible parties would be 

required to submit the information 

specified in §§ 11.10(b)(19) and (20) for 

each primary or secondary outcome 

measure in their clinical trials, namely: 

(1) The name of the specific outcome 

measure (e.g., systolic blood pressure); 

(2) a description of the metric used to 

characterize the specific outcome 

measure (e.g., mean value of systolic 

blood pressure); and (3) the time 

point(s) at which the measurement is 

assessed for the specific metric used 

(e.g., 24 weeks after initiation of 

treatment). These requirements are 

consistent with the WHO Data Elements 

Version 1.2.1, which specifies that each 

outcome include the name of the 

outcome, the metric or method of 

measurement used, and the time 

point(s) of primary interest. 

Furthermore, based on our experience 

in operating ClinicalTrials.gov, we 

believe these three elements are key 

attributes of an outcome measure. Not 

only might certain outcome measures 

can be assessed in different ways (e.g., 

systolic blood pressure can be measured 

as a mean value or as a change from 

baseline), but also a single clinical trial 

may assess a single attribute at multiple 

points in time, e.g., systolic blood 

pressure may be measured 3 months, 6 

months, and 12 months after beginning 

treatment. Each of these would be 

considered a different outcome measure. 

Ensuring that the primary and 

secondary outcome measures include 

descriptions of the measures and the 

time points of assessment is therefore 

necessary for differentiating between 

similar measures and for subsequently 

ensuring that results information is 

provided for all of them and in a 

manner that is consistent with the way 

in which they were pre-specified in the 

registry. It also ensures that any changes 

in the outcome measure are recorded as 

updates to the registration information, 

consistent with the purpose of the data 

bank ‘‘to track subsequent progress of 

clinical trials,’’ section 402(j)(2)(A)(i) of 

the PHS Act. Defining Primary Outcome 

Measure Information and Secondary 

Outcome Measure Information to 

include these three pieces of 

information also retains consistency 

with data submission prior to FDAAA, 

when those submitting information to 

ClinicalTrials.gov were requested to 

provide ‘‘the specific measure that will 

be used to determine the effect of the 

intervention(s), along with the 

timeframe for taking measurements’’ 

[Ref. 2]. 

(2) Recruitment Information 

Eligibility criteria. Section 

402(j)(2)(A)(ii)(II)(aa) of the PHS Act 

expressly requires ‘‘eligibility criteria’’ 

to be submitted for registration in 

ClinicalTrials.gov, but it does not define 

the term. We believe the purpose of this 

data element is to enable users of the 

data bank to determine key 

characteristics of potential participants 

in the clinical trial and to assist 

prospective participants in identifying 

clinical trials that may be of interest. 

Consistent with the stated objective of 

section 402(j)(2)(A)(i) of the PHS Act to 

‘‘enhance patient enrollment,’’ we 

interpret the requirement to include an 

‘‘eligibility criteria’’ data element as part 

of clinical trial registration information 

to refer to information that can be of 

practical use to prospective participants 

who wish to determine if they 

potentially qualify to participate in a 

clinical trial and who might be 

interested in seeking additional 

information about a clinical trial. 

Clinical trial protocols typically 

contain lengthy, detailed descriptions of 

inclusion and exclusion requirements 

for participants, including, for example, 

specific laboratory test result values. 

The requirements are often complex and 

must be assessed by a clinician or 

researcher involved in the clinical trial. 

We believe the submission of all 

eligibility criteria would be burdensome 

for responsible parties and, instead of 

helping prospective participants, would 

instead prove confusing or 

overwhelming. We believe that 

prospective participants would be better 

served by including a more limited list 

of inclusion and exclusion criteria in 

the data bank, in order to assist 

prospective participants in identifying 

clinical trials of possible interest. 

Prospective participants who believe 

they meet the criteria listed in the data 

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bank could discuss the clinical trial 

with their physician or other healthcare 

advisor and contact the facility-specific 

contact or central contact for the clinical 

trial for more information and a more 

complete assessment of eligibility. 

While there may be other users of the 

data bank who wish to have more 

detailed information about eligibility 

criteria for purposes of interpreting 

clinical trial results information and 

better understanding the population of 

human subjects studied, they could 

request such information from the 

Results Point of Contact, whose 

information would be submitted under 

proposed § 11.48(a)(5), and/or request a 

copy of the protocol. 

Therefore, in proposed § 11.10(b)(21), 

Eligibility Criteria is described as ‘‘a 

limited list of criteria for selection of 

human subjects to participate in the 

clinical trial, provided in terms of 

inclusion and exclusion criteria and 

suitable for assisting potential human 

subjects in identifying clinical trials of 

interest.’’ For entry of eligibility criteria 

information, we would prefer that 

responsible parties list inclusion and 

exclusion criteria (e.g., inclusion 

criteria: Clinical diagnosis of 

Alzheimer’s Disease, and must be able 

to swallow tablets; exclusion criteria: 

Insulin dependent diabetes and thyroid 

disease). 

Our proposed definition of ‘‘eligibility 

criteria’’ is consistent with ‘‘key 

inclusion and exclusion criteria’’ (data 

item #14) of the WHO Trial Registration 

standard (version 1.0) and ICMJE 

registration policies [Ref. 13, 10]. This 

proposed interpretation is also 

consistent with longstanding practice in 

ClinicalTrials.gov and the international 

clinical trial community. Prior to 

FDAAA, those submitting information 

to the ClinicalTrials.gov registry 

pursuant to FDAMA were requested to 

include ‘‘key eligibility criteria’’ for the 

trial [Ref. 4]. This term was defined to 

mean ‘‘summary criteria for participant 

selection’’ including inclusion and 

exclusion criteria [Ref. 2]. 

Gender. Section 402(j)(2)(A)(ii)(II)(bb) 

of the PHS Act expressly requires 

‘‘gender’’ to be submitted as clinical 

trial information at the time of 

registration, but it does not define this 

term. In proposed § 11.10(b)(22) we 

define the term to mean, ‘‘the biological 

sex of the human subjects who may 

participate in the clinical trial.’’ This is 

consistent with practice prior to 

FDAAA, when those submitting 

information to the ClinicalTrials.gov 

registry were requested to include the 

gender of participants of the trial [Ref. 

4], which was defined to mean, 

‘‘physical gender of individuals who 

may participate in the protocol’’ [Ref. 2]. 

Responsible parties would select from 

the following limited set of choices: 

‘‘male,’’ ‘‘female,’’ or ‘‘both.’’ No ‘‘other’’ 

option is proposed, but responsible 

parties would be able to provide 

voluntarily additional, free-text 

information about the gender of 

participants who may participate in the 

clinical trial. 

Age limits. Section 

402(j)(2)(A)(ii)(II)(cc) of the PHS Act 

expressly requires ‘‘age limits’’ to be 

submitted as a clinical trial information 

at the time of registration, but it does 

not define the term. In proposed 

§ 11.10(b)(23) we define the term to 

mean, ‘‘the minimum and maximum age 

of human subjects who may participate 

in the clinical trial, provided in relevant 

units of time.’’ Examples of ‘‘relevant 

units of time’’ include but are not 

limited to years, months, or weeks. This 

description of age limits is consistent 

with that used prior to FDAAA, when 

those submitting information to the 

ClinicalTrials.gov registry were 

requested to include the age limits for 

participants in the trial [Ref. 4]. At that 

time, the term was defined to mean a 

‘‘minimum age’’ and ‘‘maximum age of 

participants’’ using ‘‘a number and a 

unit of time (years, months, weeks, 

days, hours or minutes)’’ [Ref. 2]. 

Accepts Healthy Volunteers? Section 

402(j)(2)(A)(ii)(II)(dd) of the PHS Act 

requires the submission of information 

about ‘‘whether the trial accepts healthy 

volunteers.’’ In proposed § 11.10(b)(24), 

we define a data element called Accepts 

Healthy Volunteers to mean ‘‘whether 

human subjects who do not have a 

disease or condition, or related 

conditions or symptoms, under study in 

the clinical trial are permitted to 

participate in the clinical trial.’’ This 

definition is consistent with practice 

prior to FDAAA, when those submitting 

information to the ClinicalTrials.gov 

registry were required to indicate ‘‘if 

persons who have not had the 

condition(s) being studied or otherwise 

related conditions or symptoms, as 

specified in the eligibility requirements, 

may participate in the study’’ [Ref. 4]. 

Note that we consider any human 

participant in a clinical trial to be a 

human subject regardless of whether he 

or she is a healthy volunteer. 

Overall Recruitment Status. Section 

402(j)(2)(A)(ii)(II)(ee) of the PHS Act 

requires ‘‘overall recruitment status’’ to 

be submitted as clinical trial 

information at the time of registration, 

but it does not define this term. Prior to 

FDAAA, those submitting registration 

information to ClinicalTrials.gov were 

requested to indicate the overall 

recruitment status of the trial [Ref. 4]. 

This term was defined to mean ‘‘overall 

accrual activity for the protocol’’ [Ref. 

2]. This definition of overall recruitment 

status is consistent with ‘‘recruitment 

status’’ (data item #18) of the WHO Trial 

Registration standard (version 1.0) and 

ICMJE registration policies [Ref. 13, 10]. 

Therefore, under proposed 

§ 11.10(b)(25) we define the Overall 

Recruitment Status data element as ‘‘the 

recruitment status for the clinical trial 

as a whole, based upon the status of the 

individual sites. If at least one facility in 

a multi-site clinical trial has an 

individual site status of ‘recruiting,’ 

then the overall recruitment status for 

the trial must be ‘recruiting.’ 

To facilitate user searching by 

recruitment status and allow 

information to be compared across 

clinical trials, responsible parties would 

be required to select from the following 

limited set of choices: ‘‘Not yet 

recruiting’’ (participants are not yet 

being recruited); ‘‘Recruiting’’ 

(participants are currently being 

recruited); ‘‘Enrolling by invitation’’ 

(participants are being, or will be 

selected from a predetermined 

population); ‘‘Active, not recruiting’’ 

(study is ongoing, meaning participants 

are being treated or examined, but new 

participants are not currently being 

recruited or enrolled); ‘‘Completed’’ (the 

study has concluded normally; 

participants are no longer being 

examined or treated, i.e., last patient’s 

last visit has occurred); ‘‘Suspended’’ 

(recruiting or enrolling participants has 

halted prematurely but potentially will 

resume), ‘‘Terminated’’ (recruiting or 

enrolling participants has halted 

prematurely and will not resume; 

participants are no longer being 

examined or treated), and ‘‘Withdrawn’’ 

(study halted prematurely, prior to 

enrollment of first participant). No 

‘‘other’’ option is proposed. We believe 

this list includes all relevant choices for 

Overall Recruitment Status, but we 

invite public comment on whether the 

proposed options are sufficient to 

accurately describe the Overall 

Recruitment Status of applicable 

clinical trials and other voluntarily 

registered clinical trials that would be 

subject to this proposed rule. 

If a clinical trial is registered before it 

is open to enrollment, we would expect 

the Overall Recruitment Status to be 

listed as ‘‘Not yet recruiting.’’ When the 

clinical trial opens for enrollment, we 

would expect the Overall Recruitment 

Status to be listed as ‘‘Enrolling by 

invitation’’ if human subjects are 

selected from a predetermined 

population, or as ‘‘Recruiting’’ if the 

study is open to volunteers who meet 

the study’s eligibility criteria. As 

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indicated in the discussion of the Study 

Start Date data element, in the context 

of this rulemaking, if a clinical trial is 

registered prior to enrollment of the first 

subject and the clinical trial is 

subsequently halted before the first 

subject is enrolled, we would expect the 

responsible party to update the Overall 

Recruitment Status data element to 

‘‘Withdrawn.’’ 

When indicating that recruitment to a 

clinical trial has stopped, we believe it 

is important to distinguish between 

several different situations: (1) ‘‘Active, 

not recruiting,’’ in which enrollment has 

closed, but enrolled human subjects are 

continuing to be examined or treated 

according to the study protocol; (2) 

‘‘Completed,’’ in which the clinical trial 

has concluded according to its protocol 

and human subjects are no longer being 

enrolled, treated, or examined; (3) 

‘‘Suspended,’ in which the clinical trial 

is temporarily halted after one or more 

human subjects is enrolled but may 

potentially resume enrollment and in 

which enrolled human subjects may 

continue to be treated or examined; and 

(4) ‘‘Terminated,’’ in which the study is 

permanently halted after one or more 

subjects is enrolled in the clinical trial 

but before the trial is completed as 

anticipated in the protocol. We would 

therefore require responsible parties to 

provide such information. We believe 

that updating the Overall Recruitment 

Status data element would provide 

users of ClinicalTrials.gov with an 

effective means of tracking the progress 

of clinical trials, as the data bank is 

intended to do (section 402(j)(2)(A)(i) of 

the PHS Act). In the case of a clinical 

trial that is halted before the first subject 

is enrolled (i.e., withdrawn), this 

information would explain why no 

results information is to be expected or 

is required to be submitted. In the case 

of a clinical trial for which recruitment 

is prematurely halted (i.e., suspended or 

terminated), this information would 

allow potential human subjects to 

determine whether enrollment is likely 

to resume. Such information would also 

assist in the interpretation of results 

information, for example, by providing 

an explanation of why some clinical 

trial outcomes were not achieved and/ 

or enrollment was significantly below 

the target. 

Why Study Stopped? In situations in 

which a clinical trial is suspended, 

terminated, or withdrawn prior to its 

completion as anticipated by the 

protocol, we propose to require that 

responsible parties not only submit or 

update the Overall Recruitment Status 

data element but also provide a brief 

explanation for why the clinical trial 

was stopped. While this information is 

not required for submission by section 

402(j) of the PHS Act, we believe it is 

important to communicate to users of 

the data bank why a clinical trial was 

suspended, terminated, or withdrawn, 

e.g., because of safety concerns, 

difficulties in recruitment, or for 

financial reasons. Such information also 

furthers the statutory objective stated in 

section 402(j)(2)(A)(i) of the PHS Act to 

enable users ‘‘to track subsequent 

progress of clinical trials.’’ For these 

reasons, requiring this information 

improves and does not reduce the 

clinical trial information available in the 

data bank, consistent with section 

402(j)(2)(A)(iii) of the PHS Act. 

In our experience operating 

ClinicalTrials.gov, we have found that 

users often wish to have information 

describing why a clinical trial stopped 

prematurely and that clinical trial 

sponsors often wish to submit such 

information voluntarily so they may 

explain why a clinical trial was 

prematurely stopped. We are concerned 

that if submission of this information is 

not required then some responsible 

parties might submit it selectively, 

resulting in users having information 

about why clinical trials are stopped for 

only some registered clinical trials. In 

order to reduce confusion and 

inconsistencies in the information 

available for registered clinical trials, we 

believe that submission of such 

information should be required in each 

instance in which a clinical trial is 

stopped prematurely (i.e., not according 

to the protocol). Accordingly, proposed 

§§ 11. 28(a)(2)(vi) and 11.64(b) specify 

that a brief explanation for why the 

clinical trial was stopped must be 

submitted if the overall recruitment 

status is ‘‘suspended’’ or ‘‘terminated,’’ 

or ‘‘withdrawn.’’ In most cases, the 

overall recruitment status of a clinical 

trial would be other than ‘‘suspended,’’ 

‘‘terminated,’’ or ‘‘withdrawn’’ at the 

time of registration (e.g., ‘‘not yet 

recruiting’’ or ‘‘recruiting’’). The 

responsible party would not be required 

to complete the ‘‘why study stopped’’ 

data element unless and until there is a 

change in overall recruitment status to 

‘‘suspended,’’ ‘‘terminated,’’ or 

‘‘withdrawn.’’ (The Why Study Stopped 

data element would be presented 

neither to a responsible party during the 

registration process nor to the public in 

the posted clinical trial record, unless 

and until the overall recruitment status 

indicates that the clinical trial is 

‘‘suspended,’’ ‘‘terminated,’’ or 

‘‘withdrawn’’). However, we note that if 

a clinical trial is ‘‘suspended,’’ 

‘‘terminated,’’ or ‘‘withdrawn,’’ the 

responsible party would be required to 

update the Overall Recruitment Status 

data element and, consistent with 

proposed § 11.64(b), submit the Why 

Study Stopped data element not later 

than 30 calendar days after the date of 

such suspension, termination, or 

withdrawal, to explain why the study 

stopped. We propose to allow 

responsible parties to enter this 

information as free-text, to provide them 

with the flexibility to explain the 

reason(s) why a clinical trial stopped 

prematurely. We define the data to be 

submitted in proposed § 11.1(b)(26) as 

‘‘for a clinical trial that is suspended or 

terminated or withdrawn prior to its 

completion as anticipated by the 

protocol, a brief explanation of the 

reason(s) why such clinical trial was 

stopped.’’ 

Actual Enrollment. When enrollment 

of human subjects to a clinical trial ends 

because recruitment was completed in 

accordance with the protocol or because 

the clinical trial was terminated prior to 

its completion as anticipated by the 

protocol, we propose to require 

responsible parties to submit the actual 

number of human subjects enrolled in 

the clinical trial by completing the 

Actual Enrollment data element. The 

actual enrollment data element does not 

need to be completed until such time as 

the overall recruitment status data 

element is updated to ‘‘active, not 

recruiting’’ or ‘‘terminated.’’ See 

proposed § 11.64(b). (The Actual 

Enrollment data element would be 

presented neither to a responsible party 

during the registration process nor to 

the public in the posted clinical trial 

record, unless and until the overall 

recruitment status indicates that the 

clinical trial is ‘‘active, not recruiting’’ 

or ‘‘terminated.’’) We believe 

submission of actual enrollment 

information is consistent with the 

objective of the expanded registry data 

bank to ‘‘provide a mechanism to track 

subsequent progress of clinical trials’’ 

(section 402(j)(2)(A)(i) of the PHS Act). 

It would offer a means of measuring 

how actual enrollment compares with 

the target or estimated enrollment in the 

clinical trial (collected under proposed 

§ 11.28(a)(1)(xviii)). 

Our proposal would require a 

responsible party to submit the actual 

enrollment figure only after enrollment 

is closed. Although requiring more 

frequent updates while recruitment is 

ongoing would allow tracking of 

enrollment progress, we believe it 

would be burdensome for responsible 

parties, especially for clinical trials with 

multiple sites, and provide limited 

value to users. The data could become 

quickly outdated as enrollment for the 

clinical trial continues, potentially 

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leading users to believe that enrollment 

is lower than is the case. We believe that 

providing the actual enrollment figure 

once, at the time recruitment ends, 

would provide an effective means for 

tracking the progress of clinical trials 

registered in ClinicalTrials.gov. When 

combined with information about target 

enrollment, the actual enrollment data 

would indicate the degree to which the 

clinical trial met its enrollment target. 

By requiring the submission of actual 

enrollment data when enrollment 

closes, rather than when results 

information is submitted (which could 

be several years after enrollment 

closed), users would be able to gauge in 

advance their level of interest in the 

results of the clinical trial: The results 

of a clinical trial for which actual 

enrollment is substantially below the 

target enrollment might be of less 

interest than one in which recruitment 

targets were met. In proposed 

§ 11.10(b)(27) we define Actual 

Enrollment as ‘‘for a clinical trial for 

which recruitment of human subjects 

has terminated or completed, the actual 

number of human subjects enrolled in 

the clinical trial.’’ 

Individual Site Status. Section 

402(j)(2)(A)(ii)(II)(ff) of the PHS Act 

expressly requires ‘‘individual site 

status’’ to be submitted as a clinical trial 

information at the time of registration, 

but it does not define this term. Prior to 

FDAAA, those submitting information 

to the ClinicalTrials.gov registry were 

requested to include a recruitment 

status for each site of the trial [Ref. 4]. 

This term was defined to mean 

‘‘protocol accrual activity at a facility’’ 

[Ref. 2]. In proposed § 11.28(a)(2)(viii), 

we would require the submission of 

Individual Site Status, which is defined 

in § 11.10(b)(28) as ‘‘the recruitment 

status of each participating facility in a 

clinical trial.’’ Consistent with the 

proposed Overall Recruitment Status 

data element, responsible parties would 

be required to indicate individual site 

status by selecting from the following 

limited set of choices: ‘‘Not yet 

recruiting,’’ ‘‘Recruiting,’’ ‘‘Enrolling by 

invitation,’’ ‘‘Active, not recruiting,’’ 

‘‘Completed,’’ ‘‘Suspended,’’ 

‘‘Terminated,’’ and ‘‘Withdrawn.’’ No 

‘‘other’’ option is proposed, but we 

invite public comment on whether the 

proposed options are sufficient to 

accurately describe the Individual Site 

Status of applicable clinical trials and 

other voluntarily registered clinical 

trials that would be subject to this 

proposed rule. (See the discussion of 

Overall Recruitment Status for a 

description of these categories.) 

Availability of Expanded Access. 

Section 402(j)(2)(A)(ii)(II)(gg) of the PHS 

Act specifies that, if a drug (including 

a biological product) being investigated 

in an applicable clinical trial is not 

approved under section 505 of the FD&C 

Act or licensed under section 351 of the 

PHS Act, the responsible party must 

specify: (1) ‘‘whether or not there is 

expanded access to the drug under 

section 561 of the Federal Food, Drug, 

and Cosmetic Act for those who do not 

qualify for enrollment in the clinical 

trial’’; and, if so, (2) ‘‘how to obtain 

information about such access.’’ We 

believe the purpose of this requirement 

is to allow prospective human subjects 

and other users of the data bank to 

readily identify unapproved drugs that 

are available through an expanded 

access program under section 561 of the 

FD&C Act and to be directed to 

additional information about the 

expanded access program. Therefore, we 

propose that responsible parties meet 

the requirements of section 

402(j)(2)(A)(ii)(II)(gg) by indicating in 

the clinical trial record whether 

expanded access is available for the 

drug under study (i.e., ‘‘yes’’ or ‘‘no’’) 

and, if so, submitting the additional 

information about the expanded access 

in the form of an expanded access 

record under proposed § 11.28(c) and 

including the NCT number for the 

expanded access record in the record of 

a clinical trial that studies the drug. 

We propose to require the submission 

of information to create an Expanded 

Access record using the statutory 

authority at section 402(j)(2)(A)(iii) of 

the PHS Act, which allows the Secretary 

by regulation to modify the 

requirements for clinical trial 

registration information if the Secretary 

provides a rationale for why such a 

modification ‘‘improves and does not 

reduce such clinical trial information.’’ 

Information about the availability of 

expanded access is a data element that 

a responsible party is required to submit 

under section 402(j)(2)(A)(ii)(II) and 

thus meets the definition of ‘‘clinical 

trial information’’ in section 

402(j)(1)(A)(iv). We believe the 

additional data elements describing 

expanded access would improve and 

not reduce this clinical trial information 

by providing users with more complete 

and consistent information about 

expanded access programs for drugs 

studied in applicable clinical trials than 

would be available pursuant to section 

402(j)(A)(ii)(II)(gg) of the PHS Act alone. 

We further conclude that we have 

authority to require that the clinical trial 

information required under proposed 

§ 11.28(c) be submitted by creating a 

separate expanded access record in 

ClinicalTrials.gov under section 

402(j)(2)(B)(iv) of the PHS Act, as the 

expanded access record will ensure that 

the public may more easily use the data 

bank to determine whether there is 

expanded access to a drug and to 

compare different expanded access 

programs. 

Prior to FDAAA, those submitting 

information to the ClinicalTrials.gov 

registry were requested to submit a 

description of whether and through 

what procedure, the manufacturer or 

sponsor will respond to requests for 

protocol exception, with appropriate 

safeguards, for single-patient and 

expanded access use of the 

investigational drug, particularly in 

children [Ref. 3]. The data bank also 

permitted submission of information 

about expanded access to devices. At 

that time, the data bank included a ‘‘Has 

Expanded Access?’’ data field, which 

asked data submitters to ‘‘indicate 

whether any non-protocol access is to be 

provided for the investigational drug or 

device.’’ If expanded access were 

available, data submitters were 

requested to create an expanded access 

record via ClinicalTrials.gov. These 

expanded access records provided 

information to users of 

ClinicalTrials.gov about treatment 

access to investigational drugs or 

devices for patients for whom there was 

no satisfactory therapy available for 

their condition or who were unable to 

participate in ongoing clinical trials. 

Expanded access records were used to 

register all types of non-protocol access 

to investigational treatments [Ref. 2]. 

We propose a similar approach in this 

rule. Proposed § 11.28(a)(2)(ix) would 

require the responsible party for an 

applicable clinical trial of a drug that is 

not approved under section 505 of the 

FD&C Act to submit the Availability of 

Expanded Access data element, which 

is defined in proposed § 11.10(b)(29) to 

include ‘‘[a]n indication of whether 

there is expanded access to the drug 

under section 561 of the Federal Food, 

Drug, and Cosmetic Act (21 U.S.C. 

360bbb) for those who do not qualify for 

enrollment in the applicable clinical 

trial,’’ and if expanded access is 

available, ‘‘the NCT number of the 

expanded access record.’’ The 

availability of expanded access would 

be indicated via a yes/no designation in 

ClinicalTrials.gov. If the NCT number is 

not available, because an expanded 

access record has not yet been created, 

the responsible party would enter 

‘‘pending’’ for the NCT number. 

In addition, if the drug studied in the 

clinical trial is available through 

expanded access under section 561 of 

the FD&C Act and an expanded access 

record has not been created, the 

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responsible party would be required to 

create an expanded access record, 

consisting of the information specified 

in proposed § 11.28(c). As was the case 

prior to FDAAA, the manner in which 

the responsible party would submit the 

data elements describing the expanded 

access program would be to create an 

expanded access record in 

ClinicalTrials.gov. Upon completion of 

the quality control process for the 

expanded access record, the expanded 

access record would be assigned its own 

NCT number and thus would be 

searchable and retrievable independent 

of the record(s) for the applicable 

clinical trial(s) of the investigational 

product for which expanded access is 

available. We would expect the sponsor 

of the expanded access program to be 

responsible for informing the 

responsible party(ies) of any applicable 

clinical trial that studies the drug 

available under expanded access that an 

expanded access record has been 

created and providing them with the 

NCT number for the expanded access 

record. The responsible party(ies) would 

be required to update the related 

clinical trial record under proposed 

§ 11.64(b) to include the NCT number 

for the expanded access record within 

30 days of receipt. Accordingly, a single 

expanded access record could be linked, 

via the expanded access record NCT 

number, to several applicable clinical 

trials that study the drug that is 

available via expanded access. 

If an expanded access record has 

already been completed at the time of 

registration of an applicable clinical 

trial (e.g., to fulfill the registration or 

updating requirements for a previously 

registered applicable clinical trial), the 

responsible party would be required to 

submit the NCT number for that 

expanded access record as part of the 

Availability of Expanded Access data 

element. If an expanded access program 

is in place but an expanded access 

record has not been created at the time 

an applicable clinical trial of a drug is 

registered, the responsible party would 

not be required to submit the expanded 

access data elements under proposed 

§ 11.28(c) prior to the date on which 

clinical trial registration information 

under proposed § 11.28(a) is due (i.e., in 

order to have the expanded access 

program NCT number available at the 

time of registration of the applicable 

clinical trial). Rather, the responsible 

party would be required at the time of 

registration to indicate that expanded 

access is available, to submit the data 

elements required by § 11.28(c), and to 

indicate that the NCT number for the 

expanded access record is ‘‘pending.’’ 

As described previously, within 30 days 

of receipt of the NCT number for the 

expanded access record, the responsible 

party would be required to update the 

applicable clinical trial record with the 

NCT number assigned to the Expanded 

Access record. 

We note that expanded access is 

available via treatment INDs, which 

provide widespread access, expanded 

access for intermediate-size patient 

populations, and expanded access for 

individual patients. Because requests for 

individual patient access generally are 

handled on a case-by-case basis, a 

responsible party likely would not be 

able to provide detailed information 

describing individual patient access at 

the time of registering an applicable 

clinical trial. In cases where expanded 

access is only available for individual 

patients on a case-by-case basis, we 

would not require the responsible party 

to submit the expanded access record, 

as described below, and we expect that 

users of ClinicalTrials.gov may direct 

inquiries regarding individual patient 

access to the facility contact. 

Finally, we note both that expanded 

access to a drug may not be available at 

the time an applicable clinical trial is 

registered and that an expanded access 

program may be discontinued on a date 

other than the completion date of an 

applicable clinical trial. We believe that 

information about changes in the 

availability of expanded access should 

be conveyed to users of 

ClinicalTrials.gov in a timely manner 

and thus that the availability of 

expanded access is a data element that 

should be updated more frequently than 

once every 12 months. Accordingly, as 

explained in further detail in section 

IV.D.3 of this preamble, we propose that 

the availability of expanded access data 

element be updated within 30 calendar 

days of either the initiation or 

termination of an expanded access 

program, consistent with proposed 

§ 11.64(b). 

(3) Location and Contact Information 

Name of the Sponsor. Section 

402(j)(2)(A)(ii)(III)(aa) of the PHS Act 

expressly requires responsible parties to 

submit the name of the sponsor as part 

of clinical trial information at the time 

of registration. Proposed § 11.28(a)(3)(i) 

implements this provision. In this part, 

the term ‘‘sponsor’’ is defined as ‘‘either 

a ‘sponsor’ or ‘sponsor-investigator,’ as 

each is defined in 21 CFR 50.3, or any 

successor regulation.’’ If the sponsor is 

a sponsor-investigator, we would expect 

the name of the sponsor to be the name 

of an individual; otherwise the name of 

the sponsor may be an organizational 

name. Hence, in proposed 

§ 11.10(b)(30), Name of the Sponsor is 

defined as ‘‘the name of the entity or the 

individual that is the sponsor of the 

clinical trial, as defined in § 11.10(a).’’ 

Responsible Party, by Official Title. 

Section 402(j)(2)(A)(ii)(III)(bb) of the 

PHS Act expressly requires the 

submission of the ‘‘responsible party, by 

official title’’ as part of clinical trial 

registration information. We recognize 

that the responsible party for an 

applicable clinical trial may be the 

sponsor of the clinical trial (a term 

defined by this regulation to include the 

sponsor or the sponsor-investigator, as 

each is defined in 21 CFR 50.3) or a 

designated principal investigator. A 

responsible party that is the sponsor 

will typically be an organizational entity 

(e.g., a drug or device manufacturer that 

is the sponsor of an applicable clinical 

trial). A responsible party that is a 

sponsor-investigator will be an 

individual. A responsible party that is a 

designated principal investigator will be 

an individual. When an organizational 

entity is the responsible party, we 

believe that the official name of the 

entity (e.g., company name, university 

name, name of government agency) 

should be included to satisfy the 

requirement for the Responsible Party, 

by Official Title. When the responsible 

party is an individual, we believe that 

the official job title and the 

organizational affiliation of the 

individual are necessary (e.g., ‘‘Director 

of Clinical Research, Institution X’’ or 

‘‘Professor of Medicine, Institution Y’’). 

In addition, we believe it is important 

to ask whether the responsible party is 

the sponsor, sponsor-investigator, or a 

principal investigator designated by the 

sponsor, grantee, contractor, or awardee. 

Collection of this information will help 

determine what information must be 

provided for the official title and will 

allow a principal investigator to provide 

an affirmative acknowledgement that he 

or she has been designated the 

responsible party. In light of these 

considerations, proposed § 11.10(b)(31) 

defines Responsible Party, by Official 

Title to mean an ‘‘[i]ndication of 

whether the responsible party is the 

sponsor of the clinical trial, as that term 

is defined in 21 CFR 50.3, the sponsorinvestigator, as that term is defined in 

21 CFR 50.3, or a principal investigator 

designated pursuant to this part’’ (this 

indication would be provided by 

selecting among these three options) 

and either ‘‘the official name of the 

entity’’ if the responsible party is an 

organizational entity, or ‘‘the official 

title and primary organizational 

affiliation of the individual’’ if the 

responsible party is an individual. An 

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individual who serves as a responsible 

party and has multiple affiliations (e.g., 

a research university and a teaching 

hospital, or a research institution and a 

private company), would be required to 

submit only one such affiliation; 

namely, the affiliation they consider 

their primary affiliation. We note that 

proposed § 11.10(b)(38) defines a related 

data element, Responsible Party Contact 

Information. 

Facility Information. Section 

402(j)(2)(A)(ii)(III)(cc) of the PHS Act 

expressly requires the submission of 

‘‘the facility name and facility contact 

information’’ as part of clinical trial 

information at the time of registration 

and describes facility contact 

information as ‘‘including the city, 

State, and zip code for each clinical trial 

location, or a toll-free number through 

which such location information may be 

accessed.’’ In considering how to 

implement this provision, we took into 

consideration section 402(j)(2)(B)(i) of 

the PHS Act, which requires the 

Director to ensure that the public may 

search the entries in ClinicalTrials.gov 

by one or more of several enumerated 

criterion, one of which is ‘‘location of 

the clinical trial.’’ We interpret 

‘‘location of the clinical trial’’ in this 

context as meaning each location of the 

clinical trial because section 

402(j)(2)(A)(ii)(III)(cc) of the PHS Act 

describes ‘‘facility contact information’’ 

as meaning contact information ‘‘for 

each clinical trial location.’’ In order for 

users of ClinicalTrials.gov to be able to 

search the data bank by each location of 

the clinical trial, the responsible party 

must submit to the data bank the 

location of each facility at which the 

applicable clinical trial is conducted. In 

our view, a toll-free telephone number 

is not a substitute for the location 

information for each facility or site but 

rather is a source of supplementary 

information about the clinical trial 

overall and an alternative to site-specific 

contact information for each location. 

For these reasons, we believe 

including this information improves 

and does not reduce the clinical trial 

registration information. Under our 

authority in section 402(j)(2)(A)(iii) of 

the PHS Act, we therefore propose in 

§ 11.28(a)(3)(iii) to modify the 

requirement in section 

402(j)(2)(A)(ii)(III)(cc) of the PHS Act for 

‘‘facility name and facility contact 

information’’ to require Facility 

Information for each participating 

facility in the clinical trial, which we 

define in proposed § 11.10(b)(32) as (1) 

‘‘Facility Name, meaning the full name 

of the organization where the clinical 

trial is being conducted’’; (2) ‘‘Facility 

Location, including city, state, country 

and zip code for U.S. locations 

(including territories of the United 

States) and city and country for 

locations in other countries,’’ and (3) 

either ‘‘[for each facility location 

submitted], a Facility Contact, including 

the name or title, telephone number, 

and email address of a person to whom 

questions concerning the trial and 

enrollment at that site can be 

addressed,’’ or a ‘‘Central Contact 

person, including the name or title, tollfree telephone number and email 

address of a person to whom questions 

concerning enrollment at any location of 

the trial can be addressed.’’ 

As noted above, the Agency intends to 

exercise its authority under section 

402(j)(2)(B)(i) to enable the public to 

search the data bank by the location of 

the clinical trial and, in our view, 

satisfactory searching by location can 

only be accomplished if responsible 

parties submit complete facility location 

information for each clinical trial 

location. In addition, our proposal to 

allow (but not require) responsible 

parties to submit the name or title of a 

person knowledgeable about the clinical 

trial at each site, along with the phone 

number and email address of that 

person, would help prospective human 

subjects obtain additional, specific 

information about a clinical trial at a 

particular location. Our proposal to 

permit responsible parties to submit a 

Central Contact in lieu of Facility 

Contact is intended to reduce the 

burden on responsible parties who must 

submit clinical trial registration 

information. However, the central 

contact person should be fully informed 

of, and able to respond to, requests for 

information concerning the clinical trial 

at all of its sites. This approach is 

similar to the one used prior to FDAAA, 

when those submitting information to 

the ClinicalTrials.gov registry were 

requested to include each facility name 

and facility contact information for the 

registered clinical trial and were 

permitted to include a ‘‘central contact’’ 

rather than contact information for each 

facility of the trial [Ref. 4]. At the time, 

the term ‘‘facility name’’ was defined to 

include the ‘‘full name of the 

organization where the protocol is being 

conducted’’ and central contact was 

defined as a ‘‘person providing 

centralized, coordinated recruitment 

information for the entire study’’ [Ref. 

2]. 

(4) Administrative Data 

Section 402(j)(2)(A)(ii)(IV) of the PHS 

Act provides for certain ‘‘administrative 

data’’ to be submitted by responsible 

parties as part of clinical trial 

registration information; however, 

unlike the other categories of clinical 

trial registration information, the statute 

specifies that the Secretary may make 

administrative data ‘‘publicly available 

as necessary.’’ Accordingly, in the 

descriptions below of each 

administrative data element, the Agency 

indicates whether it proposes to make 

the information publicly available 

through ClinicalTrials.gov. 

Unique Protocol Identification 

Number. Section 402(j)(2)(A)(ii)(IV)(aa) 

of the PHS Act expressly requires the 

submission of ‘‘the unique protocol 

identification number’’ as part of 

clinical trial information at the time of 

registration, but it does not define the 

term. We propose in § 11.10(b)(33) to 

define ‘‘unique protocol identification 

number’’ as ‘‘any unique identification 

number assigned to the protocol by the 

sponsor.’’ Once entered into 

ClinicalTrials.gov, that unique protocol 

identification number cannot be 

assigned to another protocol for another 

clinical trial in the sponsor’s 

ClinicalTrials.gov account. In cases in 

which multiple identification numbers 

may have been assigned to a clinical 

trial (e.g., a funding organization’s grant 

number, a unique identifier established 

by another clinical trial registry), we 

believe that interpreting this term as a 

number ‘‘assigned by the sponsor’’ will 

remove any ambiguity for responsible 

parties about which number to submit 

as the unique protocol identification 

number for purposes of registration on 

ClinicalTrials.gov. We also expect that 

the unique protocol identification 

number would be readily available to 

the responsible party, whether the 

sponsor or a designated PI, who would 

have access to the protocol itself and/or 

be able to obtain the unique protocol 

number from the sponsor. Further, these 

numbers often are used in other clinical 

trial documentation, which will enable 

cross-referencing of information 

submitted to different data systems. To 

enable such cross-referencing, we plan 

to make this data element publicly 

available in ClinicalTrials.gov. 

This approach is consistent with that 

used in ClinicalTrials.gov prior to 

FDAAA, when those submitting 

information to the registry were 

requested to include the unique 

protocol ID of the trial [Ref. 4]. This 

term was defined to mean any ‘‘unique 

identification assigned to the protocol 

by the sponsoring organization, usually 

an accession number or a variation of a 

grant number. Multiple studies 

conducted under the same grant must 

each have a unique number’’ [Ref. 2]. 

The wording of our proposed 

description modifies the previous one 

by, among other things, removing the 

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reference to ‘‘a variation of a grant 

number’’ because all grant-related 

information is proposed to be collected 

under the Secondary IDs data element. 

Secondary IDs. Section 

402(j)(2)(A)(ii)(IV)(bb) of the PHS Act 

expressly requires the submission of 

‘‘other protocol identification numbers, 

if any,’’ at the time of registration, but 

does not define this term. Prior to 

FDAAA, those submitting information 

to ClinicalTrials.gov were requested to 

include secondary IDs of the clinical 

trial. This term was defined as ‘‘other 

identification numbers assigned to the 

protocol, including ISRCTN . . . and 

NIH grant numbers, if applicable’’ [Ref. 

2]. This definition is consistent with 

‘‘secondary identification number(s)’’ 

(data item #3) of the WHO Trial 

Registration standard (version 1.0) and 

ICMJE registration policies [Ref. 13, 10]. 

To maintain consistency with these 

widely used terms and definitions, we 

propose in proposed § 11.10(b)(34) to 

define the term, in part, as ‘‘[a]ny 

identification number(s) other than the 

organization’s unique protocol 

identification number or NCT number 

that is assigned to the clinical trial . . .’’ 

We also propose that the Secondary IDs 

include ‘‘any unique clinical trial 

identification numbers assigned by 

other publicly available clinical trial 

registries,’’ such as EudraCT in the 

European Union. We intend to post 

publicly the Secondary IDs, as such 

information will enable users to locate 

additional information about the 

clinical trial that may be included in 

other registries; it also will enable users 

to determine if registration information 

listed in another registry refers to the 

same trial that is registered in 

ClinicalTrials.gov, thereby avoiding 

potential confusion. 

In addition, we propose that 

Secondary IDs include the complete 

grant or contract number for any clinical 

trial that is funded, in whole or in part, 

by a U.S. federal government agency. 

This requirement would enable users of 

ClinicalTrials.gov to identify 

government-funded clinical trials. It 

also would assist agencies of the 

Department (including NIH, FDA, CDC, 

and the Agency for Healthcare Research 

and Quality) to verify that clinical trial 

information for each applicable clinical 

trial for which a grantee is the 

responsible party has been submitted 

consistent with sections 402(j)(2) and (3) 

of the PHS Act and this proposed Part 

before they release any remaining 

funding for a grant or provide funding 

for a future grant to such grantee. Such 

verification procedures are required 

under section 402(j)(5)(A)(ii) of the PHS 

Act of any agency of the Department 

that funds applicable clinical trials. In 

addition, although the requirement of 

section 402(j)(5)(A)(ii) of the PHS Act 

applies only to the agencies of the 

Department, the inclusion of grant and 

contract numbers for awards from other 

federal agencies (e.g., Department of 

Veterans Affairs, Department of 

Defense) would facilitate efforts by the 

Secretary, as required under section 

402(j)(5)(A)(iv) of the PHS Act, to 

consult with such other agencies and to 

develop comparable procedures for 

verification of compliance with the 

requirements of sections 402(j)(2) and 

(3) of the PHS Act. 

Finally, in order that users can 

interpret the various Secondary IDs that 

might be provided in response to this 

requirement, we propose to require 

responsible parties to submit ‘‘[a] 

description of the type of Secondary ID’’ 

for each Secondary ID submitted. These 

descriptions should be brief, but should 

clearly indicate the source of the 

identifier, e.g., ‘‘U.S. NIH Grant 

Number’’ or ‘‘[XYZ] Registry Identifier.’’ 

To facilitate data entry and improve 

comparability across registered clinical 

trials, we will include a list of several 

common identifier types in 

ClinicalTrials.gov, while permitting 

free-text entries, as well. Currently, 

ClinicalTrials.gov allows responsible 

parties to select from the following 

options: ‘‘US NIH Grant/Contract Award 

Number,’’ ‘‘Other Grant/Funding 

Number,’’ ‘‘Registry Identifier,’’ 

‘‘EudraCT Number,’’ and ‘‘Other 

Identifier.’’ Responsible parties who 

select ‘‘Other Grant/Funding Number,’’ 

‘‘Registry Identifier,’’ or ‘‘Other 

Identifier’’ are required to enter the 

name of the granting organization or a 

brief description of the identifier. 

Food and Drug Administration IND or 

IDE number. Section 

402(j)(2)(A)(ii)(IV)(cc) of the PHS Act 

expressly requires the ‘‘Food and Drug 

Administration IND/IDE protocol 

number’’ to be submitted to 

ClinicalTrials.gov at the time of 

registration in ClinicalTrials.gov, but it 

does not define this term. FDA does not 

issue an ‘‘IND/IDE protocol number,’’ as 

referred to in section 

402(j)(2)(A)(ii)(IV)(cc) of the PHS Act; 

rather it issues an IND or IDE number. 

We therefore propose to use the term 

‘‘Food and Drug Administration IND or 

IDE number’’ to identify this data 

element in ClinicalTrials.gov. We also 

recognize that not all applicable clinical 

trials will be conducted under an IND 

or IDE (e.g., because they are exempt). 

Because CDER, CBER, and CDRH each 

issues IND or IDE numbers using a 

similar format, we believe that, for 

purposes of registration with 

ClinicalTrials.gov, a complete, 

unambiguous IND or IDE number must 

include the name of the FDA center that 

issued it. In addition, if several clinical 

trials are conducted under a single IND, 

for example, each such clinical trial may 

have a different serial number assigned 

to it. We believe that any such serial 

number must also be specified to avoid 

confusion. Moreover, if multiple serial 

numbers are assigned to a single IND 

(e.g., to reflect different clinical trials, 

protocols, or protocol amendments), the 

responsible party should submit only 

the first serial number that corresponds 

to the clinical trial being registered. 

Taking the foregoing into 

consideration, we propose in 

§ 11.10(b)(35) to define the Food and 

Drug Administration IND or IDE 

Number data element to include an 

indication whether or not there is an 

IND or IDE for the clinical trial (a yes/ 

no response) and, if so, each of the 

following elements: (1) ‘‘Name or 

abbreviation of the FDA center with 

whom the IND or IDE is filed;’’ (2) ‘‘IND 

or IDE number assigned by the FDA 

center;’’ and (3) for an IND, ‘‘the IND 

serial number (as defined in 21 CFR 

312.23(e), or any successor regulation), 

if any, assigned to the clinical trial.’’ In 

specifying the FDA center with which 

the IND or IDE is filed, responsible 

parties would select from the following 

limited set of options: CDER, CBER, or 

CDRH. These abbreviations correspond 

to the FDA Center for Drug Evaluation 

and Research, Center for Biologics 

Evaluation and Research, and Center for 

Devices and Radiological Health, 

respectively, which are the three FDA 

centers with which INDs and IDEs are 

filed. 

Our proposed approach for IND or 

IDE numbers is consistent with that 

used prior to FDAAA, when those 

submitting information to the 

ClinicalTrials.gov registry were 

requested to include ‘‘the IND number 

and serial number and designate 

whether the IND is located in the Center 

for Drug Evaluation and Research 

(CDER) or the Center for Biologics 

Evaluation and Research (CBER)’’ [Ref. 

4]. Also consistent with previous 

ClinicalTrials.gov practice, we do not 

intend to make the Food and Drug 

Administration IND or IDE number 

available to the public. Section 

402(j)(2)(A)(ii)(IV) of the PHS Act 

indicates that administrative data 

submitted as part of clinical trial 

information may be made publicly 

available ‘‘as necessary.’’ We do not 

consider public posting of information 

in this field to be necessary for the 

effective use of ClinicalTrials.gov or for 

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understanding of the information 

submitted. 

Human Subjects Protection Review 

Board Status. We propose to require the 

submission of information about human 

subjects protection review board status 

as part of clinical trial information. 

Submission of this information is not 

required by section 402(j) of the PHS 

Act, but we propose to add this 

requirement pursuant to the authority 

given by section 402(j)(2)(A)(iii) of the 

PHS Act to modify the requirements for 

clinical trial registration information if 

such modification ‘‘improves and does 

not reduce such clinical trial 

information.’’ We believe that 

submission of the Human Subjects 

Protection Review Board Status, as 

specified below, to ClinicalTrials.gov 

would improve and not reduce clinical 

trial information by indicating to users 

of the data bank whether a clinical trial 

registered in ClinicalTrials.gov is 

undergoing or has undergone human 

subjects protection review board review. 

We believe that the submission of 

Human Subjects Protection Review 

Board Status is consistent with the 

purpose of the data bank ‘‘to enhance 

patient enrollment,’’ as described in 

section 402(j)(2)(A)(i) of the PHS Act. 

While review and approval by a human 

subjects protection review board, such 

as an IRB, cannot guarantee the 

scientific merit of a clinical trial or the 

safety of human subjects enrolled in it, 

it may provide some assurance that such 

factors are considered by a group of 

individuals who are not directly 

involved in the conduct of the clinical 

trial and who are charged to consider 

the safety of human subjects. Inclusion 

of such information in 

ClinicalTrials.gov would demonstrate to 

potential human subjects whether the 

clinical trials they find in 

ClinicalTrials.gov have undergone at 

least one human subjects protection 

review board review, have received 

necessary approvals for human subjects 

research from at least one human 

subjects protection review board, or 

were exempt from such review. For 

clinical trials conducted in the United 

States or under an IND or IDE, human 

subjects review would be conducted by 

an IRB as described in 45 CFR 46 and 

21 CFR 50 and 56, as applicable, or any 

successor regulations. For clinical trials 

conducted outside the United States, we 

would expect the review to be 

conducted by a human subjects 

protection review board that is charged 

with providing independent ethics 

review that is aimed at ensuring the 

protection of the rights, safety, and wellbeing of human subjects involved in a 

clinical investigation by a group that is 

adequately constituted to provide 

assurance of that protection. 

Inclusion of this data element is 

consistent with longstanding Agency 

practice. Prior to FDAAA, those 

submitting information to 

ClinicalTrials.gov were requested to 

include information regarding human 

subjects review [Ref. 4]. Human subjects 

protection review board approval 

information was not required to be 

submitted if the data submitter 

indicated that the trial was conducted 

under an IND or IDE because IRB 

approval is a requirement for 

conducting a clinical trial under an IND 

or IDE. We therefore interpreted the 

presence of an IND or IDE number as an 

acceptable indication that the trial had 

received necessary human subjects 

protection review board review. For 

trials not conducted under an IND or 

IDE, data providers were requested to 

submit information for only one human 

subjects protection review board even if 

multiple boards had reviewed the trial. 

Although it did not provide information 

on the status of review by every human 

subjects protection review board with 

authority over a trial, we viewed 

submission of information about one 

human subjects protection review board 

as establishing a minimum floor for 

studies listed in ClinicalTrials.gov by 

indicating whether they had been 

approved by at least one human subjects 

protection review board, or were 

seeking approval from such a board, or 

were exempt from such review. 

Our current proposal requires 

submission of Human Subjects 

Protection Review Board Status for all 

applicable clinical trials and other 

clinical trials registered with 

ClinicalTrials.gov, but it does not 

require information about the specific 

review board. Under proposed 

§ 11.28(a)(4)(v), responsible parties 

would be required to submit Human 

Subjects Protection Review Board Status 

as part of clinical trial information at the 

time of registration. We define Human 

Subjects Protection Review Board Status 

in § 11.10(b)(36) as ‘‘information to 

indicate whether a clinical trial has 

been approved by a human subjects 

protection review board or is exempt 

from human subjects protection review 

board approval, . . .’’ Human Subjects 

Protection Review Board Status would 

be provided by the Responsible Party 

selecting from a limited set of options 

described in ClinicalTrials.gov that are 

intended to cover all of the possible 

types of status: ‘‘Request not yet 

submitted’’ (review board approval is 

required but has not yet been 

requested); ‘‘Submitted, pending’’ 

(review board approval has been 

requested but not yet granted); 

‘‘Submitted, approved’’ (review board 

approval has been requested and 

obtained); ‘‘Exempt’’ (an exemption in 

accord with applicable law and 

regulation has been granted); 

‘‘Submitted, denied’’ (review board has 

denied the approval request); and 

‘‘Submission not required’’ (review 

board approval is not required because 

the study is not subject to laws, 

regulations, or applicable institutional 

policies requiring human subjects 

review). No ‘‘other’’ option is proposed. 

We request comment on whether the 

above menu of options adequately 

captures all possible types of review 

status for applicable clinical trials and 

voluntarily registered trials that would 

be subject to this regulation. The status 

must be listed as ‘‘approved’’ if at least 

one human subjects protection review 

board has approved the clinical trial. An 

applicable clinical trial could be 

registered prior to human subjects 

protection review board approval by 

indicating that the status is, for 

example, pending, not yet submitted, or 

exempt. If the status subsequently 

changes, the responsible party would be 

required, consistent with proposed 

§ 11.64(b), to update the Human 

Subjects Protection Review Board Status 

not later than 30 calendar days after the 

change. 

Consistent with longstanding practice, 

responsible parties would be required to 

indicate that the clinical trial is 

approved when at least one human 

subjects protection review board has 

granted approval. To clarify for users 

that the human subjects protection 

review board status pertains to only one 

human subjects protection review 

board, we would indicate that fact in 

ClinicalTrials.gov and instruct potential 

human subjects to communicate with 

the site-specific point-of-contact or the 

central contact for the clinical trial 

(included as part of the Facility 

Information that is submitted as part of 

clinical trial information under 

proposed § 11.28(a)(3)(iii)) in order to 

determine the status of human subjects 

protection review board review at other 

sites of interest. We believe this 

approach will provide users with 

important information about human 

subjects review without burdening 

responsible parties with updating 

information on multiple sites. 

Our proposal deviates from current 

practice with regard to the information 

that would be necessary for clinical 

trials conducted under an IND or IDE. 

We considered maintaining the current 

requirement that human subjects 

protection review board information 

(which is currently more extensive than 

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the single status element) be submitted 

only for clinical trials that are not 

conducted under an IND or IDE. We 

believe, however, that there would be an 

advantage in applying a consistent 

requirement across all registered clinical 

trials. Doing so would reduce confusion 

among responsible parties who might 

otherwise face different information 

submission requirements for different 

clinical trials and among users who 

might not be sure why certain clinical 

trials contain human subjects review 

information but others do not (as 

indicated above, we do not propose to 

make information about IND or IDE 

numbers publicly available in the data 

bank). We do not expect the burden of 

providing the human subjects protection 

review board status for a particular 

clinical trial to be significant, especially 

as it would be limited to a single data 

element about one human subjects 

protection review board. 

Record Verification Date is a data 

element required by section 

402(j)(2)(A)(ii)(IV)(cc) of the PHS Act to 

be submitted as part of clinical trial 

information at the time of registration, 

but the statute does not define this term. 

The statutory provision calls for the 

submission of ‘‘the Food and Drug 

Administration IND/IDE protocol 

number and the record verification 

date.’’ We believe record verification 

date is intended to be submitted as a 

separate data element that indicates to 

users of the data bank how recently the 

information for a particular clinical trial 

was verified and, hence, whether or not 

it may be out of date. We therefore 

intend to collect and post publicly the 

Record Verification Date data element in 

ClinicalTrials.gov. Our interpretation of 

this term is consistent with that used 

prior to FDAAA when those submitting 

information to the registry were 

requested to list the ‘‘record verification 

date’’ of the trial, meaning the ‘‘date the 

protocol information was last verified’’ 

[Ref. 4]. 

We propose to require responsible 

parties to include the Record 

Verification Date data element as part of 

an initial submission of clinical trial 

registration information to 

ClinicalTrials.gov and to update it any 

time the responsible party reviews the 

complete clinical trial record for 

accuracy, such as when making a 

periodic review of an entire clinical trial 

record. For example, if a responsible 

party examines the entire record as part 

of a monthly or annual review and 

determines that no additional or 

updated information needs to be 

submitted, the responsible party would 

be required to update the Record 

Verification Date data element to 

indicate the date on which the review 

occurred. Or, if a responsible party 

updates a data element and also reviews 

the rest of the record for accuracy, the 

responsible party would also be 

required to update the Record 

Verification Date data element. 

However, if the responsible party 

submits updates to one or more data 

elements without reviewing the 

accuracy of the rest of the record, the 

Record Verification Date would not be 

updated. This proposal would not 

require a responsible party to review 

records more frequently or regularly 

than would be needed in order to 

update submitted information as 

specified in proposed § 11.64 (should 

the responsible party use this method to 

help ensure that updates are submitted 

on time), but it would require that the 

Record Verification Date be updated if 

the complete record were reviewed for 

accuracy during such an update. This 

proposal is consistent with current 

practice. Starting prior to FDAAA, those 

submitting data to ClinicalTrials.gov 

were requested to update the 

verification date when reviewing the 

record for accuracy and completeness, 

even if no other changes were made’’ 

[Ref. 2]. At the time, we also suggested 

that records be reviewed at least every 

six months to help ensure that 

information available to the public in 

the data bank was up-to-date. Under 

proposed § 11.10(b)(37), we define 

Record Verification Date as ‘‘the date 

upon which the responsible party last 

verified the clinical trial information in 

the entire ClinicalTrials.gov record for 

the clinical trial, even if no additional 

or updated information was submitted 

at that time.’’ 

Responsible Party Contact 

Information. Section 402(j)(1)(B) of the 

PHS Act requires the Secretary to 

develop a mechanism ‘‘by which the 

responsible party for each applicable 

clinical trial shall submit the identity 

and contact information of such 

responsible party to the Secretary at the 

time of submission of clinical trial 

information . . .’’ We propose that the 

mechanism whereby the responsible 

party communicates the identity and 

contact information to the Secretary 

shall be via submission of such 

information at the time clinical trial 

information is first submitted to Clinical 

Trials.gov. Using the authority in 

section 402(j)(2)(A)(iii) of the PHS Act, 

we propose to modify the requirements 

for clinical trial information submitted 

at the time of registration to require 

responsible parties to submit 

Responsible Party Contact Information. 

In proposed § 11.10(b)(38), we describe 

Responsible Party Contact Information 

as ‘‘[a]dministrative information to 

identify and allow communication with 

the responsible party by telephone, 

email, and regular mail or delivery 

service. Responsible Party Contact 

Information includes the name, official 

title, organizational affiliation, physical 

address, mailing address, phone 

number, and email address of the 

individual who is the responsible party 

or of a designated employee of the 

organization that is the responsible 

party.’’ We believe that the addition of 

this information will improve and not 

reduce clinical trial information by 

providing a mechanism for the Agency 

to communicate with the responsible 

party about submitted information, 

which can improve its quality, accuracy 

and completeness. We do not intend to 

post the physical address, mailing 

address, phone number or email address 

of the responsible party. The system 

will contain other information, such as 

central or site-specific contact 

information that interested parties can 

use to request additional information 

about a clinical trial or inquire about 

participation. In general, we do intend 

to post the name of the responsible 

party if the responsible party is an 

individual, e.g., a sponsor-investigator 

who holds the IND or IDE for a clinical 

trial or a designated principal 

investigator. We would post the name of 

the responsible party, along with the 

Responsible Party, By Official Title, 

which section 402(j)(2)(A)(ii)(III)(bb) of 

the PHS Act requires to be made 

publicly available. We believe that 

posting of the individual’s name is 

necessary to avoid ambiguity, e.g., if the 

responsible party is a university 

professor, there might be numerous 

individuals with the same title and 

affiliation (professor of medicine at ABC 

University). Posting the name of the 

individual when the individual is the 

responsible party would also be 

consistent with posting of the name of 

an entity when an entity is the 

responsible party of an applicable 

clinical trial. Responsible Party Contact 

Information would be required to be 

updated as specified in proposed 

§ 11.64. 

(b) Data elements required to register 

a pediatric postmarket surveillance of a 

device that is not a clinical trial. 

Proposed § 11.28(b) specifies the 

clinical trial information that must be 

submitted to ClinicalTrials.gov to 

register a pediatric postmarket 

surveillance of a device that is not a 

clinical trial as defined in this part, but 

is required to be registered under 

proposed § 11.22. Section 801(c) of 

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Federal Register / Vol. 79, No. 225 / Friday, November 21, 2014 / Proposed Rules 69629 

FDAAA recognizes that not all of the 

clinical trial information specified in 

section 402(j) of the PHS Act or 

proposed in this rule will apply to all 

pediatric postmarket surveillances of a 

device and directs the Secretary to issue 

guidance explaining how the 

registration and results submission 

provisions of section 402(j) of the PHS 

Act apply to a pediatric postmarket 

surveillance of a device that is not a 

clinical trial. The Agency intends this 

and the other discussions in this 

preamble related to pediatric postmarket 

surveillances of a device to serve as 

draft guidance that will be finalized 

when the final rule is issued. 

In 21 CFR 822.3, ‘‘postmarket 

surveillance’’ is defined as the ‘‘active, 

systematic, scientifically valid 

collection, analysis, and interpretation 

of data or other information about a 

marketed device.’’ The Agency 

interprets a pediatric postmarket 

surveillance of a device as a postmarket 

surveillance of a device used in a 

pediatric population (i.e., patients who 

are 21 years of age or younger at the 

time of diagnosis or treatment). (See 21 

U.S.C. 360j(m)(6)(E)). The clinical trial 

information specified in proposed 

§ 11.28(a) and defined in proposed 

§ 11.10(b), would apply to any pediatric 

postmarket surveillance of a device that 

is a clinical trial (i.e., Study Type would 

be ‘‘interventional’’). However, because 

not all pediatric postmarket 

surveillances under section 522 of the 

FD&C Act are clinical trials, as defined 

in this part, many of the data elements 

listed in proposed § 11.28(a) or the 

definitions proposed in § 11.10(b) might 

not apply to them. Therefore, proposed 

§ 11.28(b) specifies a more limited set of 

data elements required to register a 

pediatric postmarket surveillance of a 

device that is not a clinical trial; 

moreover, it also modifies the 

definitions of certain of the data 

elements that are defined in § 11.10(b). 

As set forth in proposed § 11.28(b), to 

register a pediatric postmarket 

surveillance of a device that is not a 

clinical trial, the responsible party must 

provide the following data elements: (1) 

Brief Title; (2) Official Title; (3) Brief 

Summary; (4) Study Type; (5) Whether 

the Study is a Pediatric Postmarket 

Surveillance of a Device; (6) Primary 

Disease or Condition Being Studied, or 

the Focus of the Study; (7) Intervention 

Name(s); (8) Other Intervention 

Name(s); (9) Intervention Description; 

(10) Intervention Type; (11) Study Start 

Date; (12) Completion Date; (13) Name 

of the Sponsor; (14) Responsible Party, 

by Official Title; (15) Contact 

Information; (16) Unique Protocol 

Identification Number, if any; (17) 

Secondary IDs; (18) Human Subjects 

Protection Review Board Status; (19) 

Record Verification Date; and (20) 

Responsible Party Contact Information. 

Consistent with the elaboration of these 

data elements in section IV.B.4 of this 

preamble, for a pediatric postmarket 

surveillance of a device that is not a 

clinical trial the Study Type must be 

designated as ‘‘observational’’ and 

Whether the Study is a Pediatric 

Postmarket Surveillance of a Device 

must indicate ‘‘yes.’’ 

In general, the definitions of these 

data elements are consistent with the 

definitions of the named data elements 

in proposed § 11.10(b); however, we 

have modified them, where appropriate, 

to better match the characteristics of 

pediatric postmarket surveillances of a 

device that are not clinical trials. For 

example, Study Start Date, which is 

defined in proposed § 11.10(b)(16) for a 

clinical trial as ‘‘the estimated date on 

which a clinical trial will be open to 

enrollment of human subjects, or the 

actual date on which the first human 

subject was enrolled, is defined in 

proposed § 11.28(b)(1)(xi) as the ‘‘date 

on which FDA approves the postmarket 

surveillance plan, as specified in 21 

CFR 822.19(a) (or any successor 

regulation).’’ Similarly, the definition of 

Completion Date in section 402(j)(1)(A) 

of the PHS Act and proposed 

§ 11.10(b)(17) generally would not apply 

to a pediatric postmarket surveillance of 

a device that is not a clinical trial; 

hence, in proposed § 11.28(b)(1)(xii), we 

propose to require submission of the 

Completion Date data element, which is 

defined as ‘‘[t]he estimated date on 

which the final report summarizing the 

results of the pediatric postmarket 

surveillance of a device is expected to 

be submitted to FDA. Once the final 

report has been submitted, the actual 

date on which the final report is 

submitted to FDA.’’ 

The Agency considers the proposed 

list of required data elements for a 

pediatric postmarket surveillance of a 

device that is not a clinical trial to be 

the most inclusive set of data elements 

that could be expected to apply to all 

pediatric postmarket surveillances of a 

device that are not clinical trials, 

regardless of the design of the 

surveillance. The proposed required 

information would allow users to access 

records of a pediatric postmarket 

surveillance of a device that is not a 

clinical trial by searching using a 

number of relevant criteria, retrieve 

basic descriptive information about the 

surveillance, and find a point-of-contact 

for additional surveillance information. 

We do not propose the submission of 

those data elements listed under section 

402(j)(2)(A)(ii) of the PHS Act that are 

not expected to apply to all pediatric 

postmarket surveillances of a device 

that are not clinical trials. For example, 

Study Phase is relevant only to clinical 

trials involving drugs. The specific 

elements of Study Design (e.g., 

Interventional Study Model, Allocation, 

Masking, Single Arm Controlled?) 

would not apply to most studies that are 

not interventional clinical studies (i.e., 

clinical trials). Eligibility Criteria, Age, 

and Gender might not be defined 

specifically for the study population in 

a pediatric postmarket surveillance of a 

device that is not a clinical trial. 

Enrollment would not be relevant to a 

pediatric postmarket surveillance of a 

device that takes the form of a literature 

review. We expect that some 

information about the study design and 

relevant study population would be 

included in the brief summary of the 

pediatric postmarket surveillance of a 

device. 

In addition, for pediatric postmarket 

surveillances of a device that are not 

clinical trials, we would recommend 

that the responsible party submit any 

other registration information data 

elements that are consistent with the 

surveillance design and are capable of 

being accepted by ClinicalTrials.gov. 

For example, for a pediatric postmarket 

surveillance of a device that takes the 

form of a prospective observational 

study, information such as the 

location(s) of the surveillance, its 

eligibility criteria, recruitment status, 

and outcome measures would also be 

relevant and should be submitted. We 

believe the public would be best served 

if additional descriptive information 

about these pediatric postmarket 

surveillances of devices were included 

in the data bank, but, given the lack of 

experience to date, we cannot at this 

time specify which additional 

information would be relevant to a 

particular type of pediatric postmarket 

surveillance of a device that is not a 

clinical trial. We invite public 

comments on alternative approaches to 

specifying the registration requirements 

for a pediatric postmarket surveillances 

of a device that is not a clinical trial, 

including specific information that 

should be required to be submitted for 

such a surveillance and approaches to 

help ensure that important information 

is not missing from the record when 

such information might not be relevant 

to all pediatric postmarket surveillances 

of a device that are not clinical trials. 

(c) Data elements required to create 

expanded access records. Proposed 

§ 11.28(c) describes the clinical trial 

information that must be submitted to 

ClinicalTrials.gov to register an 

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applicable drug clinical trial that studies 

an unapproved drug or unlicensed 

biological product that is available via 

an Expanded Access Program under 

section 561 of the FD&C Act to those 

who do not qualify for enrollment in a 

clinical trial. Under our proposal in 

§ 11.28(c), the following set of data 

elements would be required to be 

submitted to ClinicalTrials.gov at the 

time of registration of such clinical 

trials: (1) Brief Title; (2) Official Title; 

(3) Brief Summary; (4) Study Type 

(which would be ‘‘expanded access 

program’’ for this type of record); (5) 

Primary Disease or Condition; (6) 

Intervention Name(s); (7) Other 

Intervention Name(s); (8) Intervention 

Description; (9) Intervention Type 

(which would be a drug, including 

biological products, for applicable 

clinical trials that are required to submit 

such information under the proposed 

part, but could be a device if clinical 

trial information is submitted 

voluntarily for an expanded access 

program for a device); (10) Eligibility 

Criteria, (11) Gender, (12) Age Limits, 

(13) Expanded Access Status; (14) Name 

of the Sponsor; (15) Responsible Party, 

by Official Title; (16) Contact 

Information; (17) Unique Protocol 

Identification Number; (18) Secondary 

IDs; (19) Food and Drug Administration 

IND Number; (20) Record Verification 

Date; and (21) Responsible Party Contact 

Information. 

We consider the proposed set of data 

elements to be the most inclusive set of 

data elements that would be relevant to 

all expanded access programs (other 

than individual patient access), 

regardless of design, and would be 

helpful to users of ClinicalTrials.gov 

who wish to determine whether they 

might be eligible to receive treatment 

through the expanded access program 

and obtain additional information about 

such access. The proposed list is, in 

most part, a subset of the data elements 

that would be required to register an 

applicable clinical trial of a drug. The 

descriptions of the data elements 

generally parallel the definitions of the 

data elements in proposed § 11.10(b) 

that are required to be submitted when 

registering a clinical trial under 

proposed § 11.28(a) but have been 

modified to refer to expanded access 

programs rather than clinical trials and 

to be limited to expanded access 

programs for drugs and biologics. One 

data element that is not defined in 

proposed § 11.10(b) and would be 

required to be submitted only for 

expanded access records is the 

Expanded Access Status data element. It 

is defined in proposed § 11.28(c)(2)(iv) 

to mean ‘‘[t]he status of availability of 

the investigational drug through the 

expanded access program.’’ When 

submitting this data element, 

responsible parties would be required to 

select from the following limited set of 

options for describing the current status 

of availability of the investigational drug 

through the expanded access program: 

‘‘Available’’ (expanded access is 

currently available), ‘‘No longer 

available’’ (expanded access was 

available previously but is not currently 

available and is not expected to be 

available in the future), ‘‘Temporarily 

not available’’ (expanded access was 

previously available, is not currently 

available, but is expected to be available 

in the future), and ‘‘Approved for 

marketing’’ (expanded access was 

available previously but is not currently 

available because the drug or device has 

been approved, licensed, or cleared by 

the Food and Drug Administration). No 

‘‘other’’ option is proposed. These 

proposed options are consistent with 

those used in ClinicalTrials.gov prior to 

enactment of FDAAA [Ref. 2] and would 

provide patients and other users of 

ClinicalTrials.gov with what we believe 

is more valuable information about 

expanded access status than a simple 

‘‘yes’’ or ‘‘no’’ indication. We invite 

comment on whether this list of options 

is sufficient to describe the status of an 

expanded access program for which 

information would be submitted to 

ClinicalTrials.gov under this proposed 

rule. 

We note that, notwithstanding the 

foregoing, if some form of expanded 

access were offered to a medical device 

that is studied in an applicable clinical 

trial, such information could be 

submitted voluntarily under section 

402(j)(4)(A) of the PHS Act to create an 

expanded access record for the device. 

Accordingly, even though the expanded 

access data elements are intended for 

expanded access programs for drugs, a 

responsible party who voluntarily 

submits information about an expanded 

access program for a device would be 

able to submit the IDE number that 

CDRH assigns to the expanded access 

program. We would require that a 

responsible party who voluntarily 

creates an expanded access record for a 

device expanded access program submit 

all of the data elements that are required 

for a drug expanded access program. In 

other words, an expanded access record 

may be created voluntarily, but it must 

be complete. In addition, we would 

require that an expanded access record 

that is submitted voluntarily must be 

updated following the same 

requirements that would apply to an 

expanded access record that is required 

to be submitted under this part. See 

proposed 11.64(b)(1(iv). 

We propose to require the submission 

of information to create an Expanded 

Access record using the statutory 

authority in section 402(j)(2)(A)(iii) of 

the PHS Act, which allows the Secretary 

by regulation to modify the 

requirements for clinical trial 

registration information if the Secretary 

provides a rationale why such a 

modification ‘‘improves and does not 

reduce such clinical trial information.’’ 

Information about the availability of 

expanded access is a data element that 

a responsible party is required to submit 

under section 402(j)(2)(A)(ii)(II) of the 

PHS Act and thus meets the definition 

of ‘‘clinical trial information’’ as that 

term is used in section 402(j)(1)(A)(iv) of 

the PHS Act. We believe the additional 

data elements describing expanded 

access would improve and not reduce 

clinical trial information by providing 

users with more complete and 

consistent information about expanded 

access programs for drugs studied in 

applicable clinical trials than would be 

available pursuant to section 

402(j)(A)(ii)(II)(gg) of the PHS Act alone. 

We further conclude that we have 

authority to require that the clinical trial 

information required under proposed 

§ 11.28(c) be submitted by creating a 

separate expanded access record in 

ClinicalTrials.gov under section 

402(j)(2)(B)(iv) of the PHS Act, as the 

expanded access record will ensure that 

the public may more easily use the data 

bank to determine whether there is 

expanded access to a drug and to 

compare different expanded access 

programs. In addition, this approach is 

consistent with the practice followed 

prior to enactment of FDAAA when 

those registering trials in compliance 

with FDAMA submitted expanded 

access information in the form of 

expanded access records at 

ClinicalTrials.gov. As discussed above 

in section IV.A.5 of this preamble, in the 

rare instance in which an expanded 

access program for a drug is controlled 

and meets all of the elements of an 

applicable drug clinical trial, the 

expanded access program must be 

registered as an applicable drug clinical 

trial. 

We considered alternative 

approaches, such as requiring the 

responsible party to submit the name, 

phone number, and email address of a 

point-of-contact or Web site for 

information about the expanded access 

program for each clinical trial of a drug 

that has such a program. However, we 

believe that such an approach would 

not ensure that complete information is 

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available in a consistent form and 

would not allow users of 

ClinicalTrials.gov to as quickly and 

easily review eligibility criteria and the 

disease or condition for which 

expanded access is available. In 

addition, by including such information 

as part of clinical trial registration 

information, we can better ensure that 

the information is kept up-to-date 

because it would be subject to the 

updating requirements described in 

proposed § 11.64. We also believe that 

our proposal could reduce the burden a 

responsible party faces when providing 

information about expanded access. An 

alternative we considered was to require 

responsible parties to enter the 

additional data elements describing 

expanded access with every applicable 

clinical trial of a drug or biological 

product for which expanded access is 

available. Under our proposal, in 

situations in which multiple applicable 

clinical trials study the same drug that 

is available via the expanded access 

program, the expanded access record 

would be submitted only once, and 

thereafter, any responsible party could 

link the expanded access record to his 

or her clinical trial record(s) using the 

NCT number assigned to the expanded 

access record. As explained further in 

section IV.D.3 in this preamble, only 

that responsible party who registered 

the initial clinical trial that included the 

expanded access record would be 

responsible for updating the expanded 

access program information in the 

expanded access record. 

As explained in section IV.B.4, in the 

discussion of the Availability of 

Expanded Access data element, the 

expanded access record generated in 

ClinicalTrials.gov pursuant to the 

submission of the data elements at 

proposed § 11.28(c) would be assigned 

its own NCT number and would be 

searchable and retrievable independent 

of the record(s) for the clinical trial(s) 

that study(ies) the drug or biological 

product to which expanded access is 

offered. To establish the link between 

the expanded access record and the 

clinical trial record(s), the responsible 

party(ies) for any applicable clinical 

trials of the drug available via expanded 

access would be required to include the 

NCT number that is assigned to the 

expanded access record as part of the 

registration information submitted for 

that clinical trial. The expanded access 

record could be linked in this fashion to 

several applicable clinical trials that 

study the drug or biological product that 

is available via the expanded access 

program. 

We seek comment on the proposed 

approach. 

5. By when will NIH post clinical trial 

information submitted under § 11.28?— 

§ 11.35. 

Proposed § 11.35 describes the 

timelines by which NIH will post 

publicly on ClinicalTrials.gov the 

clinical trial information that is required 

to be submitted for registration of 

applicable drug clinical trials and 

applicable device clinical trials, 

respectively. Proposed § 11.35 takes into 

account the timelines described for 

posting registration information in 

section 402(j)(2)(D) of the PHS Act. 

The timelines in proposed § 11.35 

apply only to clinical trials that are 

required to register with 

ClinicalTrials.gov under 402(j)(2)(C) of 

the PHS Act. If a clinical trial is 

registered with ClinicalTrials.gov and 

appears to be a voluntary submission 

according to the approach specified in 

proposed § 11.22(b), we will post the 

registration information as soon as 

practicable after it has been submitted 

and reviewed as part of our quality 

review procedures. 

(a) Applicable drug clinical trials. For 

applicable drug clinical trials, section 

402(j)(2)(D)(i) of the PHS Act requires 

NIH to publicly post registration 

information not later than 30 days after 

it is submitted in accordance with 

section 402(j) of the PHS Act. Proposed 

§ 11.35(a) implements this provision, 

stating that NIH will post publicly the 

registration information ‘‘not later than 

30 calendar days after the responsible 

party has submitted such information in 

accordance with § 11.24 of this part.’’ 

(b) Applicable device clinical trials of 

devices that previously were approved 

or cleared. For applicable device 

clinical trials of devices that previously 

were approved or cleared by FDA for 

any indication, section 402(j)(2)(D)(ii)(II) 

of the PHS Act requires that registration 

information be posted ‘‘not later than 30 

days after’’ results information is 

required to be posted. The Agency 

interprets section 402(j)(2)(D)(ii)(II) of 

the PHS Act as providing a deadline by 

which such registration information 

must be posted. In other words, the 

Agency considers the requirement to 

post registration information ‘‘not later 

than 30 days after [results information] 

is required to be posted’’ to be the last 

possible date on which it may post 

registration information. 

The Agency believes that for 

applicable device clinical trials of 

devices that previously were approved 

or cleared it is permissible and 

appropriate to post registration 

information prior to the deadline. 

Posting this information prior to the 

deadline would be consistent with the 

objectives of expanding the registry and 

results data bank by rulemaking, 

facilitating enrollment in clinical trials 

and providing a mechanism to track 

subsequent progress of clinical trials. 

(See sections 402(j)(2)(A)(i) and (3)(D)(i) 

of the PHS Act.) Conversely, waiting to 

post registration information for 

applicable device clinical trials of 

devices that previously were approved 

or cleared until after results information 

is required to be posted would delay 

access to information about such 

clinical trials and would eliminate the 

possibility for the data bank to be used 

to facilitate enrollment in such trials 

and to allow the public to track such 

trials while they are ongoing. 

The Agency proposes in § 11.35(b)(1) 

to post registration information for an 

applicable device clinical trial of a 

device that previously was approved or 

cleared ‘‘not later than 30 calendar days 

after clinical trial results information is 

required to be posted in accordance 

with § 11.52 of this part.’’ However, in 

light of the objectives of the data bank 

discussed above we intend, in practice, 

to post registration information for such 

applicable device clinical trials as soon 

as practicable after submission, but not 

later than 30 calendar days after clinical 

trial results information is required to be 

posted. 

(c) Applicable device clinical trials of 

devices that have not been approved or 

cleared previously. Section 

402(j)(2)(D)(ii)(I) of the PHS Act 

provides that for applicable device 

clinical trials of devices that have not 

previously been approved or cleared 

(i.e., unapproved or uncleared devices), 

registration information must be posted 

publicly not earlier than the date of 

approval or clearance of the device and 

not later than 30 days after such date. 

Proposed § 11.35(b)(2) reflects this 

statutory provision. In order to help us 

meet the posting deadline and identify 

the set of applicable device trials for 

which registration information needs to 

be posted after approval or clearance of 

a device, we have included a 

requirement in proposed § 11.64(b)(2) 

for the responsible party to update the 

U.S. FDA Approval, Licensure, or 

Clearance Status data element not later 

than 15 calendar days after a change in 

status has occurred. The responsible 

party would be required to update that 

data element for all applicable clinical 

trials that study the device that was 

approved or cleared. 

(d) Exception to posted information. 

Section 402(j)(2)(A)(ii)(IV) of the PHS 

Act specifies that the Secretary ‘‘may 

make publicly available as necessary’’ 

(emphasis added) administrative data 

that are submitted as part of clinical 

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trial registration information. We 

interpret this provision as permitting 

the Secretary not to post certain 

administrative data in the data bank if 

the data are not considered necessary 

for understanding the clinical trial or for 

recruitment. As explained more fully in 

section IV.B.4(a) of this preamble, we do 

not believe it is necessary to make 

public the following administrative data 

and currently do not intend to post 

them publicly in ClinicalTrials.gov for 

any applicable clinical trials: (1) Food 

and Drug Administration IND or IDE 

Number and (2) Responsible Party 

Contact Information other than the 

name of the responsible party if the 

responsible party is an individual (as 

opposed to an entity). Note that 

Responsible Party, by Official Title, 

which is proposed in § 11.28(a)(3)(ii), is 

not considered an element of 

administrative data and will be publicly 

posted in the data bank as required by 

section 402(j)(2)(A)(ii)(III)(bb) of the 

PHS Act. 

C. Results Submission—Subpart C 

Proposed subpart C establishes 

requirements and procedures related to 

the submission of results information. In 

addressing what constitutes results 

information, proposed subpart C does 

not specify what results information 

must be collected during an applicable 

clinical trial or other clinical trial, but 

which elements of the collected data 

must be submitted and in what required 

format. Proposed Subpart C also 

specifies when NIH will post results 

information in ClinicalTrials.gov. 

Finally, proposed subpart C specifies 

the procedures that may be used to 

request a waiver of any applicable 

requirements for results submission. 

1. Who must submit results 

information?—§ 11.40 

Proposed § 11.40 requires that the 

responsible party for an applicable 

clinical trial specified in proposed 

§ 11.42 submit results information for 

that clinical trial. This approach is 

consistent with section 401(j)(3)(E)(i) of 

the PHS Act. 

2. For which applicable clinical trials 

must results information be 

submitted?—§ 11.42 

Proposed § 11.42 identifies the 

applicable clinical trials for which 

results information must be submitted 

to ClinicalTrials.gov, according to this 

proposed rule unless the requirement is 

waived under proposed § 11.54. 

Pursuant to section 402(j)(3)(D)(ii)(I)of 

the PHS Act, we propose to require the 

submission of results information for 

specified: (1) Applicable clinical trials 

of drugs that are approved under section 

505 of the FD&C Act or licensed under 

section 351 of the PHS Act; and (2) 

applicable clinical trials for devices that 

are cleared under section 510(k) of the 

FD&C Act or approved under section 

515 or 520(m) of the FD&C Act. For 

reasons described in section III.C.5 of 

this preamble, we also propose to 

require the submission of results 

information for specified applicable 

clinical trials of drugs or devices that 

are not approved, licensed, or cleared 

for any indication (regardless of whether 

the sponsor seeks approval, licensure, or 

clearance). This proposal is consistent 

with the requirement in section 

402(j)(3)(D)(ii)(II) of the PHS Act that 

the Secretary establish through 

regulation whether or not results 

information must be submitted for 

applicable clinical trials of drugs and 

devices that have not been approved, 

licensed, or cleared by FDA, whether or 

not approval, licensure, or clearance is 

sought. 

In order to maintain consistency with 

the registration requirements proposed 

in this rule, the proposed requirements 

for results submission would apply to 

those applicable clinical trials that are 

required to be registered with 

ClinicalTrials.gov under the 

requirements of proposed § 11.22 and 

that meet the criteria under proposed 

§ 11.42, unless a waiver were granted in 

accordance with proposed § 11.54. We 

note as described in section III.D of this 

preamble, responsible parties would not 

be required to submit results 

information under this proposed 

subpart if the completion date of the 

applicable clinical trial is prior to the 

effective date of this rule, except if any 

of the following situations applies: (1) 

The completion date is prior to the 

effective date of the rule, but results 

information is neither due under 

proposed § 11.44 nor submitted until on 

or after the effective date of the rule; or 

(2) the completion date is prior to the 

effective date of the rule, but secondary 

outcome measures are neither due 

under proposed § 11.44 nor submitted 

until on or after the effective date of the 

rule. 

3. When must results information be 

submitted for applicable clinical trials 

subject to § 11.42–§ 11.44? 

Proposed § 11.44 specifies the 

deadlines for submitting results 

information for applicable clinical trials. 

Subsection (a) specifies the standard 

submission deadlines for applicable 

clinical trials that are clinical trials. 

Subsections (b) and (c) specify 

procedures for delaying the standard 

submission deadlines when seeking 

initial approval or approval of a new use 

of a drug or device studied in an 

applicable clinical trial. Subsection (d) 

describes procedures for requesting a 

good-cause extension of the submission 

deadline. Subsection (e) establishes the 

timeline for submitting results of a 

pediatric postmarket surveillance of a 

device that is not a clinical trial. 

(a) Standard submission deadlines. 

Proposed § 11.44(a) prescribes the 

standard deadlines for submitting 

results information for applicable 

clinical trials that are clinical trials 

subject to proposed § 11.42. This 

proposed deadline would apply to all 

applicable clinical trials for which the 

responsible party does not submit a 

certification to delay results submission, 

as permitted under proposed § 11.44(b) 

or (c), or for which the Director has not 

granted a good-cause extension of the 

results submission deadline pursuant to 

proposed § 11.44(e). 

(1) In general. Proposed § 11.44(a)(1) 

specifies that, in general, the deadline 

for submitting results information for 

applicable clinical trial would be 1 year 

after the completion date of the clinical 

trial. Sections 402(j)(3)(E)(i)(I) and (II) of 

the PHS Act specify that results 

information is to be submitted not later 

than 1 year after the ‘‘earlier of’’ the 

estimated completion date or the actual 

completion date. Under proposed 

§ 11.64(b)(1), however, we would 

require responsible parties to update the 

completion date not later than 30 

calendar days after a change has 

occurred or after the clinical trial has 

reached its completion date. Therefore, 

the estimated completion date would be 

updated to reflect the actual completion 

date not later than 30 calendar days 

after the applicable clinical trial has 

reached its completion date and results 

would be due not later than 1 year after 

the actual completion date of the 

applicable clinical trial. 

The 1 year deadline would apply to 

applicable clinical trials of drugs and 

devices, whether or not approved, 

licensed, or cleared, except as described 

in (2) and (3) below. Section 

402(j)(3)(D)(iv)(III) of the PHS Act 

requires the Secretary to determine by 

regulation ‘‘the date by which . . . 

clinical trial [results] information [for 

applicable clinical trials of unapproved, 

unlicensed, or uncleared products] shall 

be required to be submitted . . .’’ As 

discussed further in section III.C.5 of 

this preamble, our proposal would 

apply the same general deadline for 

results submission to both applicable 

clinical trials of approved, licensed, or 

cleared products and applicable clinical 

trials of unapproved, unlicensed, or 

uncleared products in order to simplify 

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results submission procedures and 

provide consistency between the 

deadlines for applicable clinical trials, 

regardless of the approval status of the 

products under study. Applicable 

clinical trials of unapproved, 

unlicensed, or uncleared drugs and 

devices (and of approved, cleared, and 

licensed drugs and devices that are 

studied for a new use) may, however, 

qualify for delayed submission of 

results, as described in section IV.C.3(b) 

below. 

Section 402(j)(3)(D)(iv)(I) of the PHS 

Act requires the Secretary to determine 

whether to increase the general deadline 

for results submission from 1 year to ‘‘a 

period not to exceed 18 months’’ after 

the earlier of the estimated or actual 

completion date. We solicited comment 

on this topic as part of the public 

meeting held in April 2009 but received 

few comments on this issue. Comments 

that supported a longer deadline cited 

concerns about applicable clinical trials 

for which data collection for secondary 

outcome measures and adverse events 

would continue beyond the completion 

date of the clinical trial. During the time 

that we have been operating the data 

bank, we have seen only few clinical 

trials in which this situation occurs. 

Rather than extending the general 

results submission deadline to as long 

as 18 months in order to accommodate 

what we believe would be a small 

number of such trials, we propose 

instead alternative methods for 

addressing such trials in proposed 

§ 11.44(a)(2). 

(2) Submitting results information 

following initial product approval, 

licensure, or clearance. Proposed 

§ 11.44(a)(2) specifies the timeline for 

submitting results information for any 

applicable clinical trial of an FDAregulated drug (including biological 

product) or device that is unapproved, 

unlicensed, or uncleared as of its 

completion date. It would require that 

results information as specified in 

proposed § 11.48(a) must be submitted 

for such trials by the earlier of 1 year 

after the completion date, or 30 calendar 

days after FDA approves, licenses, or 

clears the drug or device for any 

indication studied in the applicable 

clinical trial. This proposal is consistent 

with section 402(j)(3)(E)(iv) of the PHS 

Act. 

(b) Delayed results submission with 

certification. Proposed §§ 11.44(b) and 

(c) establish procedures whereby 

responsible parties may delay 

submission of results information for a 

particular applicable clinical trial 

beyond the general deadline specified in 

proposed § 11.44(a)(1) (i.e., 1 year after 

the completion date). 

(1) Seeking approval, licensure, or 

clearance of a new use for the drug or 

device. Consistent with section 

402(j)(3)(E) (iii) and (v) of the PHS Act, 

we propose in § 11.44(b) to allow a 

delay in the submission of results 

information if the responsible party 

certifies that an applicable clinical trial 

meets the following criteria: (1) The 

drug (including biological product) or 

device studied in the applicable clinical 

trial previously has been approved, 

licensed, or cleared by FDA; (2) the 

sponsor of the applicable clinical trial is 

the manufacturer of the product; and (3) 

the manufacturer has filed, or will file 

within 1 year, an application seeking 

approval, licensure, or clearance of the 

use being studied in the applicable 

clinical trial (a use that is not included 

in the labeling of the approved, 

licensed, or cleared product). As 

proposed, this certification would be 

required to be submitted to 

ClinicalTrials.gov before the general 

results submission deadline specified in 

proposed § 11.44(a)(1), i.e., 1 year or less 

after the completion date. The record for 

the clinical trial would indicate that 

results submission has been delayed, 

but would not specify the particular 

reason for the delay. (See section IV.C.3 

of this preamble). 

In accordance with section 

402(j)(3)(E)(v) of the PHS Act, once a 

certification has been submitted, 

proposed § 11.44(b)(2) would permit a 

delay in the submission of results 

information of up to two years after the 

date on which the certification is 

submitted, unless one of the following 

events occurs: (1) FDA approves, 

licenses, or clears the drug or device 

studied in the applicable clinical trial 

for the use studied in the clinical trial; 

(2) FDA issues a letter that ends the 

regulatory review cycle for the 

application or submission (e.g., a 

complete response letter, a not 

substantially equivalent letter, or a not 

approvable letter) but does not approve, 

license, or clear the product studied in 

applicable clinical trial for the use 

studied in the clinical trial; or (3) the 

manufacturer, which is also the sponsor 

of the applicable clinical trial, 

withdraws the application or premarket 

notification and does not resubmit it 

within 210 calendar days. In the event 

that any one of these ‘‘triggering events’’ 

occurs, the responsible party would be 

required to submit results information 

for the applicable clinical trial for which 

a certification had been submitted under 

proposed § 11.44(b)(1) not later than 30 

calendar days after the earliest of the 

triggering events occurred, consistent 

with section 402(j)(3)(E)(v)(I). 

If the responsible party for an 

applicable trial for which a new-use 

certification has been submitted is not 

the sponsor/manufacturer of the drug 

(including biological product) or device 

studied in the clinical trial, the sponsor/ 

manufacturer may need to notify the 

responsible party of the occurrence of 

these triggering events in order to help 

ensure that the responsible party is 

aware that results submission is 

required. As discussed in section IV.A.2 

of this preamble, the sponsor may 

designate a principal investigator as 

responsible party under proposed § 11.4 

only if, among other things, the 

principal investigator ‘‘has the ability to 

meet all of the requirements for 

submitting and updating clinical trial 

information as specified in this part.’’ 

Accordingly, a responsible party who is 

not the sponsor will only be able to 

comply with the results submission 

requirements subsequent to a 

certification under sections 

402(j)(3)(E)(iii) and (v) of the PHS Act, 

if notified by the sponsor when one of 

these triggering events occurs. In a 

situation in which a sponsor is not 

willing or able to provide the principal 

investigator with this information, the 

conditions for designation under 

proposed § 11.4 cannot be met. 

In addition, consistent with section 

402(j)(3)(E)(v)(II) of the PHS Act, if a 

manufacturer makes a certification to 

delay submission of results information 

because the manufacturer is seeking or 

will seek within 1 year approval of a 

new use for a drug or device, the 

responsible party shall make such a 

certification ‘‘with respect to each 

applicable clinical trial that is required 

to be submitted in an application or 

report for licensure, approval, or 

clearance’’ of the use studied in the 

clinical trial. Proposed § 11.44(b)(3) 

implements this provision. For purposes 

of this requirement, we interpret 

‘‘manufacturer’’ to mean ‘‘manufacturer/ 

sponsor who is the responsible party’’ 

because section 402(j)(3)(E)(v) of PHS 

Act applies only when the manufacturer 

is the sponsor of the applicable clinical 

trial, and under section 402(j)(3)(E)(iii) 

of the PHS Act, it is the responsible 

party who must submit the certification 

for delayed submission of clinical trial 

results information. 

(2) Seeking initial approval, licensure, 

or clearance for the drug or device. 

Proposed requirements for delayed 

submission of results information with 

certification when seeking initial 

approval, licensure, or clearance of a 

drug or device are described in 

proposed § 11.44(c). As discussed above 

in section III.C.5 of this preamble, this 

proposal reflects our efforts to adhere to 

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the statutory requirement that, when 

proposing to require the submission of 

results information for trials of 

unapproved, unlicensed, or uncleared 

products, we take into account the 

certification process in section 

402(j)(3)(E)(iii) of the PHS Act ‘‘when 

approval, licensure, or clearance is 

sought,’’ and that we determine 

‘‘whether there should be a delay of 

submission when approval, licensure or 

clearance will not be sought.’’ See 

section 402(j)(3)(D)(iv)(III) of the PHS 

Act. 

We propose in § 11.44(c) that 

submission of results information may 

be delayed if the responsible party 

certifies that the following criteria 

apply: (1) The drug (including biological 

product) or device studied in the 

applicable clinical trial previously was 

not approved, licensed, or cleared by 

FDA for any use before the completion 

date of the clinical trial; and (2) the 

sponsor of the applicable clinical trial 

intends to continue with product 

development and is seeking, or may at 

a future date seek, FDA approval, 

licensure, or clearance of the product 

under study. As proposed, this 

certification would be required to be 

submitted to ClinicalTrials.gov before 

the general results submission deadline 

specified in proposed § 11.44(a)(1), i.e., 

1 year or less after the completion date. 

The intent of this certification is to 

permit delayed results submission only 

if the sponsor of the applicable clinical 

trial intends to continue with product 

development of the drug (including 

biological product) or device under 

study, such that there is an expectation 

that marketing approval or clearance 

will be sought. We do not believe that 

results submission should be delayed 

for applicable clinical trials of products 

that the sponsor has no intention of 

marketing or for which product 

development has been abandoned. 

Hence, our proposal would permit 

delayed submission of results 

information only if the responsible party 

certifies that the sponsor of the 

applicable clinical trial is continuing to 

study the product with an expectation 

of seeking future marketing approval, 

licensure, or clearance. We recognize 

that it may be difficult for the sponsor 

of the applicable clinical trial to know 

early on in the product development 

process whether it will seek approval, 

licensure, or clearance for a product 

studied in an applicable clinical trial, 

but we would, in general, view further 

development of a product through 

subsequent clinical trials as an 

indication that the product development 

process is continuing and may lead to 

seeking initial approval, licensure, or 

clearance. When the responsible party is 

not the sponsor of the applicable 

clinical trial and wishes to delay results 

submission, we would expect the 

responsible party to obtain such 

information from the sponsor before 

submitting a certification, in order to 

help ensure the truthfulness of the 

certification. 

Under our proposal, submission of a 

certification would delay the deadline 

for submitting results for the applicable 

clinical trial by up to two years from the 

date on which the certification is 

submitted to ClinicalTrials.gov. 

However, in the event that FDA 

approves, licenses, or clears the drug or 

device studied in the applicable clinical 

trial for any indication that is studied in 

the clinical trial within this two-year 

period, the responsible party would be 

required to submit results information 

not later than 30 calendar days after 

such approval, licensure, or clearance. 

Similarly, if the sponsor withdraws the 

application or premarket notification 

without resubmission for 210 calendar 

days during this two-year period, the 

responsible party would be required to 

submit results information not later than 

30 calendar days after such date. The 

agency believes that this latter situation 

represents a significant enough 

interruption to product development to 

trigger the submission of results 

information. 

We note that, unlike delayed results 

submission with certification that the 

sponsor of the applicable clinical trial is 

seeking approval, licensure, or clearance 

of a new use, we do not propose to 

require the submission of results 30 

days after FDA issues a letter not 

approving, licensing, or clearing the 

product under study because we do not 

think that the issuance of such a letter 

necessarily indicates abandonment of 

product development. For the reasons 

set forth above in ‘‘(1) ‘‘Seeking 

approval, licensure, or clearance of a 

new use for the drug or device[,]’’ a 

responsible party who is not the sponsor 

(i.e., a responsible party who is a 

principal investigator) will be able to 

comply with the results submission 

requirements subsequent to a 

certification under sections 

402(j)(3)(E)(iii) and (iv) of the PHS Act, 

only if notified by the sponsor when one 

of the triggering event occurs. In a 

situation where the sponsor is not 

willing or able to provide the principal 

investigator with this information, then 

the conditions for designation under 

proposed § 11.4 cannot be met, and/or 

the responsible party will not be eligible 

to delay results submission. 

(3) Two-Year Limitation of Delay. 

With regard to the maximum delay 

pursuant to a certification submitted 

under section 402(j)(3)(E)(iii) of the PHS 

Act, the agency expects that in most 

situations a delay of an additional two 

years beyond the date the certification is 

submitted (i.e., up to three years after 

the completion date of the clinical trial, 

if the certification is submitted 1 year 

after the completion date) provides 

sufficient time for the sponsor of the 

applicable clinical trial to protect its 

competitive advantage, a concern 

expressed in public comments. Within 

this time frame, a sponsor would likely 

make a decision about whether to halt 

product development, initiate another 

clinical trial (e.g., a phase 3 clinical trial 

to follow a phase 2 clinical trial), or 

submit a marketing application or 

premarket notification to FDA. 

Subsequent trials would most likely be 

required to register at ClinicalTrials.gov 

and, for applicable drug clinical trials, 

the clinical trial registration information 

for those subsequent trials would be 

posted publicly in the data bank, 

thereby providing some information to 

competitors about the outcome of 

previous trials and the objectives of 

future trials. As discussed further in 

Section III.C.5 of this preamble, we 

believe any competitive disadvantage 

caused by the disclosure of summary 

results information three years or more 

after the completion date of the trial 

would be limited and outweighed by the 

public health benefits of making such 

information publicly available. We 

invite public comment on this 

approach. 

For applicable clinical trials that meet 

the criteria for delayed results 

submission with certification—whether 

seeking initial approval, licensure, or 

clearance or seeking approval, licensure, 

or clearance of a new use—measuring 

the maximum delay of two years from 

the date on which the certification is 

submitted may result in responsible 

parties submitting certifications as close 

as possible to the general results 

submission deadline under proposed 

§ 11.44(a)(1) (i.e., 1 year after the 

completion date). Submitting a 

certification just before the general 

results submission deadline would 

postpone results submission until as 

late as three years after the completion 

date of the clinical trial, while 

submitting a certification on the 

completion date of the clinical trial 

would extend the results submission 

deadline only as long as two years 

beyond the completion date. We believe 

that users of ClinicalTrials.gov would 

benefit from knowing as early as 

possible that results submission for an 

applicable clinical trial of interest 

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would be delayed. Until a certification 

is submitted, users may expect that 

results will be submitted not later than 

1 year after the completion date. If a 

certification were submitted soon after 

the completion date, the clinical trial 

record could be updated at that time to 

indicate that results submission would 

be delayed, and users could adjust their 

expectations accordingly. 

The statute does not appear to permit 

us to change the timeline for results 

submission when a responsible party 

submits a certification when seeking 

approval of a new use for the drug or 

device under section 402(j)(3)(E)(v) of 

the PHS Act and proposed § 11.44(b). 

For delayed submission of results when 

seeking initial approval, licensure, or 

clearance, however, the statute offers 

greater flexibility in establishing the 

timeline: Section 402(j)(3)(D)(iv)(III) of 

the PHS Act expressly authorizes the 

Secretary to establish the date by which 

clinical trial information for applicable 

clinical trials of unapproved products 

must be submitted to ClinicalTrials.gov. 

We considered establishing the 

maximum available delay with 

certification when seeking initial 

approval, licensure, or clearance to be 

three years from the completion date of 

the applicable clinical trial, regardless 

of when during the one-year period 

following the completion date the 

certification is submitted. Such a 

provision would accomplish the same 

objective as the statutory provision for 

delayed submission when seeking 

approval, licensure, or clearance of a 

new use by allowing responsible parties 

to delay results submission by as long 

as three years beyond the completion 

date of a clinical trial, without creating 

a disincentive to submit the certification 

early. We did not include this provision 

in this proposed rule so that we could 

keep the same maximum delay for 

results submission whether seeking 

initial approval, licensure, or clearance 

or seeking approval, licensure, or 

clearance of a new use. We invite public 

comments on the advantages and 

disadvantages of establishing maximum 

different timelines for results 

submission under the two delayedresults-with- certification provisions. 

We also invite public comment on 

alternative approaches we could take to 

encourage early submission of 

certifications in a way that is consistent 

with the statutory requirement for 

seeking approval, licensure, or clearance 

of a new use, without causing a 

responsible party to have to submit 

results information earlier than the 

latest deadline they could have under 

the statute. 

We note that the maximum delay of 

two years pursuant to a certification 

submitted under section 402(j)(3)(E)(iii) 

of the PHS Act applies to all primary 

outcomes and any secondary outcomes 

for which the final subject was 

examined or received an intervention 

for the purposes of final data collection 

by the completion date. In the event that 

data collection for any secondary 

outcome measure(s) will not be 

completed as of the completion date, 

clinical trial results information for such 

secondary outcome measure(s) shall be 

due under proposed § 11.44(b) and (c) 

by the later of: (1) ‘‘1 year after the date 

on which the final subject is examined 

or receives an intervention for the 

purposes of final collection of data for 

such secondary outcome measure(s), 

whether the applicable clinical trial was 

concluded according to the prespecified protocol or was terminated;’’ 

or (2) ‘‘the date on which the primary 

outcomes are due pursuant to . . . 

[proposed §§ 11.44(b) or (c).’’ 

(c) Explanation of ‘‘initial approval,’’ 

‘‘initial clearance,’’ and approval or 

clearance of a ‘‘new use.’’ For purposes 

of proposed §§ 11.44(b) and (c), we 

interpret the term ‘‘drug’’ in sections 

402(j)(3)(E)(iv) and 402(j)(3)(E)(v) of the 

PHS Act to mean ‘‘drug product’’ or 

‘‘biological product,’’ referring to a 

finished product that is approved or 

licensed for marketing, and not to the 

active ingredient or active moiety in 

such a product. We conclude that this 

is the most appropriate interpretation of 

the statutory term and that this 

interpretation is consistent with the 

statutory intent to draw a distinction 

between applicable drug clinical trials 

that are ‘‘completed before the drug is 

initially approved’’ (See section 

402(j)(3)(E)(iv) of the PHS Act) and 

those pertaining to uses that are ‘‘not 

included in the labeling of the approved 

drug’’ (See section 402(j)(3)(E)(v) of the 

PHS Act). Accordingly, ‘‘initial 

approval’’ pertains to the approval or 

licensure of an original NDA, 

abbreviated new drug application 

(ANDA) or BLA, and ‘‘new use’’ 

pertains to the approval or licensure of 

a supplemental NDA, ANDA, or BLA for 

an additional indication for that 

particular drug product or biological 

product. Similarly, we interpret ‘‘initial 

approval’’ of a device under sections 

515 or 520(m) of the FD&C Act to 

pertain to the approval of an original 

premarket approval application (PMA) 

or humanitarian device exemption 

application (HDE) and ‘‘new use’’ to 

pertain to the approval of a 

supplemental PMA for an additional 

indication for that particular device. 

In addition, for purposes of proposed 

§ 11.44(c), the first 510(k) cleared for a 

particular device type would be 

considered ‘‘initial clearance’’ of the 

device. For example, when a device is 

reclassified from Class III to Class II, 

then the first 510(k) that is cleared as 

having demonstrated substantial 

equivalence to the reclassified device 

would be considered initial clearance of 

the device. Consequently, for purposes 

of proposed § 11.44(b), all other 510(k)s 

cleared for a device type other than the 

first one, would be considered clearance 

of a new use. 

We recognize that in some cases a 

responsible party may not know 

whether a particular applicable clinical 

trial will be used to support an original 

NDA, ANDA, BLA, PMA, or HDE as 

opposed to a supplemental NDA, 

ANDA, BLA, PMA, or HDE, or whether 

a clinical trial will be used to support 

a 510(k) seeking initial clearance of a 

device as opposed to a 510(k) seeking 

clearance of a new use. Responsible 

parties should use their best judgment 

based on information available at the 

time of certification in order to 

determine which type of certification is 

appropriate. We solicit comments on 

whether these are appropriate 

interpretations and distinctions for 

purposes of proposed §§ 11.44(b) and 

(c). 

(d) Submitting partial results. 

Proposed § 11.44(d) specifies 

procedures for submitting results when 

required results information, as 

specified in proposed § 11.48, has not 

been collected for all secondary 

outcome measures by the date on which 

results information is due. Under the 

definition of completion date in 

proposed § 11.10(a), whether or not a 

clinical trial is completed is determined 

by the status of data collection for solely 

the primary outcome measure(s). An 

applicable clinical trial may therefore 

still be collecting data for the secondary 

outcome measure(s) after it has reached 

its completion date. 

In this situation, the responsible party 

would be required to submit results 

information for the primary outcome 

measure(s) by the required due date 

specified in proposed § 11.44(a), (b), or 

(c), as applicable. Under proposed 

§ 11.44(d)(i). If a certification to delay 

results submission has not been 

submitted under proposed § 11.44(b) or 

(c), results for each remaining secondary 

outcome measure would be due not 

later than 1 year after the date on which 

the final subject is examined or receives 

an intervention for the purposes of final 

collection of data for that secondary 

outcome measure, whether the clinical 

trial was concluded according to the 

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pre-specified protocol or was 

terminated. If the responsible party has 

submitted a certification to delay results 

submission under proposed § 11.44(b) 

or (c), results of the secondary outcome 

measures could be submitted by the 

later of the date specified proposed 

§ 11.44(d)(i) or the date on which the 

primary outcome measures would be 

required to be submitted. We note that 

in either situation, if data collection for 

a secondary outcome measure is 

completed as of the completion date, 

results information for that secondary 

outcome measure would be required to 

be submitted on the same date as the 

primary outcome measure(s). 

With respect to adverse event 

information (which is considered to be 

part of clinical trial results information 

described under proposed § 11.48), a 

responsible party would be required to 

submit information summarizing 

serious and frequent adverse events 

recorded to-date each time results 

information for a secondary outcome is 

submitted, until all the adverse event 

information required by this part has 

been submitted. We believe that this 

approach provides a better mechanism 

for handling submission of adverse 

event information than extending the 

general results submission deadline for 

all applicable clinical trials up to 18 

months after the completion date. It 

would ensure that key results 

information for primary outcome 

measures is submitted to 

ClinicalTrials.gov within 1 year of the 

completion date, while allowing 

subsequent data collection to continue 

as planned. 

We recognize that this approach may 

not be suitable for all applicable clinical 

trials for which data collection for 

secondary outcome measures extends 

more than 1 year beyond the completion 

date. In some circumstances, submitting 

results information for the primary 

outcomes not later than 1 year after the 

completion date might compromise the 

scientific integrity of the applicable 

clinical trial, for example, by requiring 

the applicable clinical trial to be 

unblinded before all data for the 

secondary outcome measures are 

collected. In those circumstances, we 

would expect a responsible party to seek 

a good-cause extension of the results 

submission deadline in proposed 

§ 11.44(a)(1), following the procedures 

specified in proposed § 11.44(e). 

We clarify in proposed § 11.44(d)(2) 

the way to handle results submission if 

results related to the primary outcome(s) 

were submitted prior to the effective 

date of the rule, but results data for the 

secondary outcome(s) are required to be 

submitted after the effective date. In 

such cases the responsible party would 

be required to provide results 

information for all primary and 

secondary outcome(s) as specified in 

§ 11.48 of this proposed rule. We believe 

that consistent data must be provided 

for all outcome measures in a single 

clinical trial and therefore would apply 

the requirements of proposed § 11.48 to 

the clinical trial as a whole. 

(e) Requesting a good-cause extension 

of the results submission deadline. 

Proposed § 11.44(e) outlines procedures 

for requesting good-cause extensions of 

the deadline for submitting results 

information. Section 402(j)(3)(E)(vi) of 

the PHS Act authorizes the Director to 

‘‘provide an extension of the deadline 

for submission of clinical trial [results] 

information . . . if the responsible party 

for the trial submits to the Director a 

written request that demonstrates good 

cause for the extension and provides an 

estimate of the date on which the 

information will be submitted.’’ We 

interpret this authority as allowing the 

Director to grant an extension of any 

results submission deadline that may be 

in effect for a given applicable clinical 

trial, e.g., the general 12-month results 

submission deadline; a delayed 

submission deadline established by the 

submission of an appropriate 

certification under section 

402(j)(3)(E)(iii) of the PHS Act; or an 

extended deadline established by a 

previously-granted good-cause 

extension. As for the latter, section 

402(j)(3)(E)(vi) of the PHS Act explicitly 

allows the Director to ‘‘grant more than 

one [good-cause] extension for a clinical 

trial.’’ For a pediatric postmarket 

surveillance of a device that is not a 

clinical trial, the agency also proposes 

to allow more than one good-cause 

extension for such a surveillance. Goodcause extensions apply only in the 

context of applicable clinical trials 

subject to the results submission 

requirements of section 402(j)(3) of the 

PHS Act because the good-cause 

extension provision specifically refers to 

results submission under 402(j)(3)(E)(i) 

of the PHS Act. Accordingly, good-cause 

extensions do not apply to clinical trial 

results that are submitted under section 

402(j)(4)(A) of the PHS Act, i.e., 

voluntarily submitted trials (see 

proposed rule § 11.60(a)(2)(i)) and 

triggered trials (see § 11.60(a)(2)(iii) of 

this proposed rule). 

Section 402(j)(3)(E)(vi) of the PHS Act 

does not define ‘‘good cause.’’ Similarly, 

this proposed rule does not contain 

specific proposals for determining 

which situations will and will not be 

considered good cause for an extension. 

Instead we intend to develop guidance 

(which would be subject to public 

comment) as the agency gains more 

experience with extension requests and 

communicate with the regulated 

community via other channels, 

including the ClinicalTrials.gov Web 

site. In order to assist responsible 

parties who are considering submitting 

a good-cause extension request, we 

intend to prepare, update periodically, 

and post on ClinicalTrials.gov a list of 

reasons that the agency generally will 

consider to be ‘‘good cause’’ and not 

‘‘good cause’’ for granting an extension 

under section 402(j)(3)(E)(vi) of the PHS 

Act and proposed § 11.44(e). The list 

would not necessarily be an exhaustive 

list of reasons for which applicable 

clinical trials have or have not been 

granted an extension, but would contain 

those reasons that we believe would 

serve as useful examples for responsible 

parties of other applicable clinical trials. 

All good-cause extension requests 

would be considered on a case-by-case 

basis, and any generalizable conclusions 

that can be drawn from the granting or 

denial of a request may be added to the 

list of good causes and not-good causes 

for granting extensions. 

In general, we believe that there are 

likely to be only a few situations that 

would constitute good cause under 

section 402(j)(3)(E)(vi) of the PHS Act 

and proposed § 11.44(e). To-date, we 

have identified only two situations that 

we believe would constitute good cause, 

as follows: 

(1) The need to preserve the scientific 

integrity of an applicable clinical trial 

for which data collection is ongoing. 

This would include situations in which 

the submission of results information 

for the primary outcome(s) of an 

applicable clinical trial would impair or 

otherwise bias the ongoing collection, 

analysis, and/or interpretation of data 

for secondary outcome(s). We recognize 

that permitting an extension in such 

circumstances could provide an 

incentive for someone wishing to delay 

results submission to add to their 

applicable clinical trial a secondary 

outcome measure with a very long data 

collection time frame, even if the 

outcome measure has limited 

significance or relevance to the clinical 

trial. Because protocols are typically 

revised by outside entities (e.g., human 

subjects protection review boards), one 

way to protect against such behavior is 

to ensure that the secondary outcome 

measures are pre-specified in the 

protocol or statistical analysis plan. 

Accordingly, in order to demonstrate 

good cause, we believe that an extension 

should be granted only in those 

situations in which it can be 

demonstrated that the data collection for 

the secondary outcome(s) of interest 

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extends more than 1 year beyond the 

completion date, that the secondary 

outcome(s) is pre-specified in the 

protocol or statistical analysis plan 

(consistent with the definition of 

secondary outcomes in this proposed 

part), and the planned analysis of the 

outcome measure is also described in 

the protocol or statistical analysis plan. 

The responsible party could provide 

this information either by voluntarily 

submitting copies of the protocol or 

statistical analysis plan with the goodcause extension request or describing 

them in the extension request itself. 

(2) Emergencies that prevent timely 

submission of clinical trial results 

information. This would include 

situations in which one or more data 

collection sites are affected by natural 

disasters or other catastrophes outside 

the responsible party’s or sponsor’s 

control. In such cases we generally 

would expect to grant the responsible 

party an initial extension of up to 6 

months, after which time additional 

extensions could be granted, as 

necessary. We generally would not 

consider events that might reasonably 

have been avoided or anticipated 

through standard contingency planning, 

e.g., transition planning for key staff 

members who leave an organization, to 

constitute good cause for an extension 

under section 402(j)(3)(E)(vi) of the PHS 

Act or proposed § 11.44(e). 

The following non-exhaustive list 

enumerates scenarios that we generally 

do not believe ordinarily would 

constitute good cause: 

• Pending publication. The ICMJE has 

asserted that results submission to 

ClinicalTrials.gov in compliance with 

section 402(j) of the PHS Act will not be 

considered ‘‘prior publication’’ and 

would not preclude future publication 

[Ref. 10]. 

• Delay in data analysis for 

unspecified causes. A general statement 

that provides no specific reason for a 

delay in data analysis, e.g., ‘‘data could 

not be analyzed fully within 12 

months,’’ would not be considered to 

have demonstrated good cause. 

If the estimated completion date 

displayed in the applicable clinical trial 

record is earlier than the actual (or 

current estimated) completion date, a 

responsible party must update the 

estimated completion date in the 

clinical trial record to reflect the actual 

(or revised estimated) completion date 

within 30 calendar days, as required by 

11.64(b)(1)(viii) and should not request 

an extension based on the outdated 

completion date posted in the data 

bank. The fact that the responsible party 

has updated the completion date will be 

reflected in ClinicalTrials.gov, 

consistent with the handling of all 

updates under proposed § 11.64. 

We invite public comment on these 

specific situations and on more general 

criteria that could be used to determine 

what constitutes good cause for an 

extension. 

Proposed § 11.44(e)(1) outlines 

procedures for submitting a good-cause 

extension request. It indicates that 

extension requests must be submitted to 

NIH via ClinicalTrials.gov prior to the 

date on which results information 

would otherwise be due in accordance 

with the results submission deadlines 

established in proposed § 11.44(a), or 

§ 11.44(b), or § 11.44(c), if the relevant 

certification has been submitted. The 

proposed process for submission of 

extension requests calls for direct 

electronic submission to 

ClinicalTrials.gov at http://prsinfo.

clinicaltrials.gov/. Consistent with 

section 402(j)(3)(E)(vi) of the PHS Act, 

our proposal would require an 

extension request to include a 

description of the reason(s) why results 

information cannot be provided 

according to the applicable deadline 

and an estimated date on which results 

information will be submitted. Requests 

missing either piece of information 

would be considered incomplete and 

the responsible party would be notified 

that the request would not be 

considered by the agency until missing 

information is provided. The submitted 

extension request would be reviewed by 

an NIH official designated by the 

Director. 

Proposed § 11.44(e)(2) specifies that a 

response to the good-cause extension 

request would be communicated 

electronically to the responsible party, 

providing notice as to whether or not 

the requested extension has been 

granted. This communication would 

take place via ClinicalTrials.gov. As 

indicated, if a request were granted, a 

revised deadline for results submission 

would be communicated in the notice, 

taking into account the particulars of the 

request. We note that the agency may 

grant a deadline that is earlier than that 

requested by the responsible party in 

the good-cause extension request. If a 

request were denied, the deadline for 

submitting results would be the later of 

the original submission deadline (e.g., 1 

year after the completion date or the 

delayed submission deadline if a 

certification has been filed under 

subparts (b) or (c)) or 15 calendar days 

after the date the electronic notice of the 

denial of the request is sent to the 

responsible party. 

Proposed § 11.44(e)(3) establishes an 

appeals process that would permit a 

responsible party a single opportunity to 

appeal the decision of the agency to 

deny an extension request or the 

deadline specified in a granted 

extension request. An appeals process 

was a feature that was requested at the 

public meeting in April 2009 (see, Ref. 

1). Under proposed § 11.44(e)(3), a 

responsible party who appeals a denied 

extension request must submit the 

appeal in letter form to the Director not 

later than 15 calendar days after the date 

on which electronic notification of grant 

or denial of the request was sent to the 

responsible party.’’ The appeal must 

explain why, in the view of the 

responsible party, the initial decision to 

deny an extension request or to grant an 

extension request with a shorter 

deadline than requested by the 

responsible party should be overturned 

or revised, e.g., by providing further 

elaboration of the grounds for the 

request or by highlighting factors that 

justify an extension. Generally, new 

information should not be submitted 

upon appeal, unless such information 

was not available at the time of the 

initial request. The submitted appeal 

will be considered by the Director. 

If an appeal is granted, a revised 

deadline for results submission would 

be set by the Director, based on the 

particulars of the request, and provided 

to the responsible party in an electronic 

notification. If the appeal of a denied 

extension request is denied, the 

deadline for submitting results would be 

the later of the original submission 

deadline or 15 calendar days after the 

electronic notification of the denial of 

the appeal is sent to the responsible 

party. If the appeal of an extension 

request that was granted with a shorter 

deadline than was originally requested 

is denied, the deadline for submitting 

results would be the later of the 

deadline specified in the notification 

granting the extension request or 15 

calendar days after the electronic 

notification of the denial of the appeal 

is sent to the responsible party. 

(f) Posting of information about 

certifications for delayed submission 

and about good-cause extensions. We 

believe that ClinicalTrials.gov should 

indicate when the results submission 

deadline for a particular applicable 

clinical trial has been postponed 

because an extension request has been 

granted or the responsible party has 

submitted a certification for delayed 

submission. Without such an indication, 

users who view a clinical trial record 

that contains no results information 

more than 1 year after the completion 

date might be led to believe, incorrectly, 

that the responsible party has not 

complied with the results submission 

requirements of section 402(j)(3)(E) of 

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the PHS Act or this proposed rule, or 

that the agency has failed to post such 

information. 

We believe that there would be value 

in posting information about the 

specific mechanism that has been used 

to delay the submission of clinical trial 

results information, i.e., a certification 

under proposed § 11.44(c) seeking 

initial approval, licensure, or clearance; 

a certification under proposed § 11.44(b) 

seeking approval, licensure, or clearance 

of a new use; or a good-cause extension 

under proposed § 11.44(e). Doing so 

would provide a mechanism to track the 

progress of clinical trials by informing 

users why clinical trial results 

information is not yet publicly 

available. 

However, we recognize that the public 

posting of information about the specific 

mechanism used to delay results 

submission could result in the posting 

of information that might in some 

circumstances be considered 

confidential. For example, the fact that 

a responsible party had submitted a 

certification under proposed § 11.44(b) 

would indicate that the sponsor or 

manufacturer had submitted or was 

planning to submit within 1 year a 

marketing application or premarket 

notification to FDA for a new use of a 

drug or device that was studied in the 

applicable clinical trial. Such 

certification could be submitted to 

ClinicalTrials.gov prior to any public 

statement by the sponsor or 

manufacturer about its plans to apply 

for a new use. Similarly, the reasons 

underlying a request for a good-cause 

extension might contain details about 

the applicable clinical trial that 

previously have not been made public. 

Our proposed approach attempts to 

balance the desire to indicate that the 

submission of clinical trial results 

information has been postponed for 

reasons that are permitted by statute and 

the need to avoid disclosure of 

confidential information. In order to 

avoid putting responsible parties in a 

position where they must agree to the 

release of information that would 

otherwise be considered confidential in 

order to delay results submission in 

accordance with a mechanism specified 

in section 402(j) of the PHS Act and this 

proposed part, we would post only 

minimal information about delayed 

results submissions in these 

circumstances. If a responsible party 

delays results submission via 

certification or is granted a good-cause 

extension of the deadline for submitting 

clinical trial results information, we 

propose to indicate in the clinical trial 

record only that results submission has 

been delayed. We would not indicate 

which mechanism was used to delay 

submission or the reason for which an 

extension may have been granted for a 

particular applicable clinical trial. In 

order to provide responsible parties 

with insight into the general types of 

reasons that have and have not been 

considered to constitute good cause for 

an extension, we propose to post and 

update periodically on the 

ClinicalTrials.gov Web site a 

generalized list of reasons for which 

extensions have and have not been 

granted. The listing would not indicate 

which applicable clinical trials have 

been granted or denied extensions based 

on the listed reason(s), and we would 

attempt to remove from the list any 

information that might allow a user to 

identify a specific applicable clinical 

trial. 

We invite public comments on our 

proposed approach and whether more 

specific information could be provided 

about extensions and certifications for 

an individual applicable clinical trial 

(e.g., whether submission was delayed 

via extension or certification, and, if so, 

which type of certification) without 

releasing confidential information, what 

types of certification and extension 

information responsible parties would 

consider confidential, and alternative 

approaches that we could take that 

would provide more information to the 

public about the reasons for delayed 

submissions of clinical trial results 

information. We specifically invite 

comments on the advantages and 

disadvantages of providing more 

specific information about extension 

requests, e.g., that a request has been 

submitted for a clinical trial, the specific 

reason for the extension request, the 

responsible party’s estimate of the date 

on which clinical trial results 

information could be submitted, 

whether or not the request was 

subsequently granted or denied, 

whether a denial has been appealed, 

and whether the appeal was granted or 

denied. Making such information 

available in ClinicalTrials.gov would 

further increase transparency into 

agency decisions and would provide an 

alternative means of informing 

interested parties about the types of 

situations that we consider good cause 

for an extension. We additionally invite 

public comment on whether extension 

requests could be submitted without 

containing any information that would 

be considered confidential and thus not 

suitable for release to the public. 

(g) Results submission deadline for a 

pediatric postmarket surveillance of a 

device that is not a clinical trial. We 

recognize that the proposed deadlines 

for submitting clinical trial results 

information under proposed 

§§ 11.44(a)–(d) are not well adapted to 

a pediatric postmarket surveillance of a 

device that is not a clinical trial. Such 

surveillances generally do not have a 

completion date that can be easily 

measured by the date that the final 

subject was examined or received an 

intervention for the purposes of final 

collection of data for the primary 

outcome. However, these surveillances 

will have a date on which a final report 

must be sent to FDA, as specified in the 

approved postmarket surveillance plan. 

Hence for a pediatric postmarket 

surveillance of a device that is not a 

clinical trial, we propose in § 11.44(e) 

that results information be submitted 

not later than 30 calendar days after the 

date that the final report is submitted to 

FDA. We believe that 30 days is 

sufficient additional time to allow the 

responsible party to format data as 

required by this part and submit it to 

ClinicalTrials.gov. 

4. What constitutes results 

information?—§ 11.48 

Proposed § 11.48 specifies procedures 

for submitting results information for an 

applicable clinical trial. Proposed 

§ 11.48(a) specifies the general 

requirements that would apply to an 

applicable clinical trial other than a 

pediatric postmarket surveillance of a 

device that is not a clinical trial. 

Proposed § 11.48(b) describes the 

requirements for a pediatric postmarket 

surveillance of a device that is not a 

clinical trial. 

In specifying the results information 

that must be submitted for a clinical 

trial proposed § 11.48(a) separates the 

data elements into the following general 

categories of information: (1) Participant 

flow, (2) demographic and baseline 

characteristics of the study population; 

(3) outcomes and statistical analyses; (4) 

adverse event information; (5) 

administrative information; and (6) 

additional results information for 

applicable device clinical trials of 

unapproved or uncleared devices. Note 

that whenever possible 

ClinicalTrials.gov will use information 

that was submitted during registration 

to pre-populate column and row names 

of the tables of information that required 

as part of results submission. Doing so 

would reduce the data entry burden on 

responsible parties and minimize the 

possibility of clerical errors. However, 

in all cases, the responsible party would 

be required to revise the information, as 

needed, so that the results information 

appropriately and accurately reflects the 

way data were collected and analyzed in 

the clinical trial. Each of the categories 

of results information that is required to 

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be submitted is addressed, in turn, 

below. 

(a) Participant flow: As part of the 

requirements related to the demographic 

and baseline characteristics of the 

patient sample, section 402(j)(3)(C)(i) of 

the PHS Act specifies that a responsible 

party must submit ‘‘[a] table of . . . data 

collected overall and for each arm of the 

clinical trial to describe the patients 

who participated in the clinical trial, 

including the number of patients who 

dropped out of the clinical trial and the 

number of patients excluded from the 

analysis, if any.’’ We consider this 

information to be part of what we call 

‘‘participant flow.’’ Participant flow 

refers to information, organized by arm 

of the clinical trial that documents the 

progression of human subjects through 

the clinical trial. 

Consistent with section 402(j)(3)(C)(i) 

of the PHS Act and pursuant to our 

authority under section 

402(j)(3)(D)(iii)(IV) of the PHS Act, we 

propose in § 11.48(a)(1) to require the 

submission of the following participant 

flow information: (1) Participant Flow 

Arm Information, consisting of ‘‘[a] brief 

description of each arm used for 

describing the flow of participants 

through the clinical trial, including a 

descriptive title used to identify each 

arm[;]’’ (2) Pre-assignment Information, 

which consists of ‘‘[a] description of any 

significant events affecting the number 

of human subjects enrolled in the 

clinical trial but not assigned to an arm, 

if any[,]’’ and (3) Participant Data, 

which is ‘‘[t]he number of human 

subjects that started, and completed the 

clinical trial, by arm.’’ This information 

permits the construction of a table that 

shows the flow of participants through 

the clinical trial. 

In our proposed approach, 

information about the number of 

participants excluded from the analysis 

is not contained within participant flow, 

but would be submitted as part of the 

information about outcome measures, 

described below. We propose this 

approach because the number of 

participants excluded from analysis 

generally depends on the particular 

outcome measure being analyzed. A 

participant who drops out midway 

through a clinical trial, for example, 

may be included in the analysis of one 

outcome measure for which data 

collection was completed early in the 

study, but excluded from the analysis of 

another outcome measure for which 

data collection occurred (or continued) 

after the drop out. Hence, the aggregate 

number of participants excluded from 

the analysis could not generally be 

calculated by arm and the information 

by outcome measure would give a more 

accurate representation of the flow of 

human subjects through the clinical 

trial. 

We intend to continue to provide 

responsible parties with a means of 

providing, on a voluntary basis, 

additional details about participant flow 

in a manner consistent with CONSORT 

guidelines [Ref. 24]. This information 

would consist of details about the flow 

of participants through different periods 

or milestones that might have been 

defined for a clinical trial and the 

reason(s) why participants did not 

complete the clinical trial or reach a 

particular milestone. Clinical trials often 

proceed through multiple periods (e.g., 

wash-out, consecutive cycles of the 

intervention), and having information 

about the participant flow in each 

period and reasons why participants did 

not complete the clinical trial or reach 

a particular milestone, if applicable, 

could improve users’ understanding of 

the clinical trial data. Because clinical 

trials vary considerably in their design 

and may or may not include specific 

periods or milestones, there are no 

generally accepted approaches for 

submitting such information; nor is 

there consensus on how best to classify 

reasons for non-completion using 

categories that are comprehensive and 

not overlapping. Therefore, we do not 

propose a requirement to submit such 

information in this proposed rule; 

instead, we would allow such 

information to be submitted voluntarily 

by the responsible party. We have built 

into ClinicalTrials.gov the capability to 

accept such information, and we expect 

that continued experience with the 

voluntary submission of such 

information and continued efforts by the 

clinical trial research community may, 

over time, lead to the development of 

more widely accepted approaches to 

organize such information. We welcome 

public comment on the value of 

providing such additional information 

in ClinicalTrials.gov and on approaches 

for collecting it. 

(b) Demographic and baseline 

characteristics: Section 402(j)(3)(C)(i) of 

the PHS Act requires submission of the 

following results information: ‘‘A table 

of the demographic and baseline data 

collected overall and for each arm of the 

clinical trial to describe the patients 

who participated in the clinical 

trial . . .’’ 

ClinicalTrials.gov provides preformatted rows that enable responsible 

parties to submit common demographic 

characteristics, including age, gender, 

race, ethnicity, and region of enrollment 

(with countries and geographic regions, 

such as Europe, Middle East, South 

America, listed on a pull-down menu), 

by arm or comparison group and overall 

for the clinical trial. Race and ethnicity 

data are submitted in accordance with 

the classification system of the Office of 

Management and Budget (OMB) (See 62 

FR 58782, Oct. 30, 1997). We do not 

propose to require the submission of 

information describing all of these 

demographic characteristics because 

they may not all be collected as part of 

a particular clinical trial, and we do not 

wish to impose requirements on the 

data that must be collected during a 

clinical trial. Instead, in 

§ 11.48(a)(2)(iii), we propose as a 

minimum requirement that responsible 

parties submit information describing 

the age and gender of the human 

subjects enrolled in the clinical trial. 

Age information can be provided as 

either a continuous variable (e.g., 

average age is 52 years) along with a 

measure of dispersion (e.g., standard 

deviation is 4.5 years) or a categorical 

variable (e.g., pediatrics, adults, 

seniors). Such information is generally 

collected in clinical trials and can be 

expected to be available for applicable 

clinical trials. 

In addition, ClinicalTrials.gov 

accommodates the submission of 

information to describe an unlimited 

number of customized demographic and 

baseline characteristics. In general, we 

cannot specify in advance which other 

demographic and baseline 

characteristics must be provided for a 

particular clinical trial. Only those 

conducting the clinical trial will know 

which characteristics are important for 

their clinical trial and which actually 

were collected. We do believe it is 

important, however, that demographic 

and baseline measures be provided for 

any characteristic that is used in 

assessing outcome measures. For 

example, if an outcome measure 

compares a subject’s blood pressure 

after 6 weeks of treatment with a 

particular intervention, we believe the 

baseline measure of blood pressure must 

be submitted. Similarly, if a clinical trial 

includes a statistical analysis that uses 

baseline data as part of the calculation 

(e.g., a regression analysis) we believe it 

is necessary to submit the relevant 

baseline data. The use of this baseline 

data in analyzing the outcome measure 

indicates that it would have been 

collected during the clinical trial and 

thus would be important to the 

interpretation of results. 

We specify this requirement in 

proposed § 11.48(a)(2)(iii) which 

requires, in addition to age and gender, 

the submission of information for each 

baseline or demographic characteristic 

measured in the clinical trial that is 

used in the analysis of any of the 

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outcome measures (See section IV.C.4.c 

of this preamble for a discussion of 

outcome measures). In order for 

submitted demographic and baseline 

characteristic information to be 

meaningful to users, we specify that the 

responsible party must submit the 

following information for each 

demographic or baseline measure 

submitted to ClinicalTrials.gov: the 

Name of the measure (e.g., gender) and 

Description of the measure (e.g., ‘‘male’’ 

and ‘‘female’’); the type of measure 

(Measure Type) and an associated 

Measure of Dispersion; and the unit of 

measure (e.g., milligrams). When 

specifying the Measure Type, the 

responsible party would have to select 

from the following limited list of 

options: ‘‘number,’’ ‘‘mean,’’ ‘‘median,’’ 

‘‘least squares mean,’’ ‘‘geometric 

mean,’’ or ‘‘log mean.’’ When specifying 

the associated Measure of Dispersion, 

the responsible party would have to 

select from the following limited list of 

options: ‘‘standard deviation,’’ ‘‘interquartile range,’’ ‘‘full range,’’ or ‘‘not 

applicable’’ (which would be permitted 

only if the specified measure type is 

‘‘number’’). No ‘‘other’’ option is 

proposed for either the Measure Type or 

Measure of Dispersion, but responsible 

parties would have the option of 

providing voluntarily additional 

information about the baseline measures 

as part of a free-text Baseline Measure 

Description. We believe that this 

approach would allow a responsible 

party to accurately describe the baseline 

characteristics of an applicable clinical 

trial or other clinical trial that is subject 

to this proposed rule. We invite public 

comment on the sufficiency of the 

proposed approach for submitting 

baseline characteristics. 

Collecting the information in the 

structured manner proposed is intended 

to improve the comparability of 

information across clinical trials and to 

ensure complete data collection. For 

example, if a responsible party indicates 

that the measure of dispersion for a 

measure is interquartile range, for 

example, ClinicalTrials.gov could 

prompt the submission of the two data 

elements needed to specify the upper 

and lower bounds of the interquartile 

range; if a responsible party indicates 

that the measure of dispersion is a 

standard deviation, ClinicalTrials.gov 

could prompt the submission of that 

single value. Note that baseline 

characteristic information may also be 

submitted as a number instead of a 

central tendency (e.g. number of 

participants), in which case the measure 

of dispersion must be indicated as ‘‘Not 

Applicable.’’ 

We invite comments on whether or 

not we should require the submission of 

additional demographic or baseline 

characteristics that were collected 

during the clinical trial, the advantages 

and disadvantages of requiring the 

submission of such information, and, if 

so, how such information can be 

specified in the rule. We also invite 

comments on other types of 

demographic information that could be 

required for all clinical trials, for 

example, country-of-origin or countryof-residence, which are collected in 

many clinical trials. We invite comment 

on whether the fixed list of proposed 

choices for measures of central tendency 

and of dispersion is adequate to provide 

an accurate description of the measures 

used in any clinical trial. 

Our proposal for demographic and 

baseline characteristics indicates that 

responsible parties should submit such 

information by ‘‘arm or comparison 

group.’’ The reference to comparison 

group recognizes that when analyzing 

data collected during clinical trials, data 

are often aggregated into groupings of 

human subjects (i.e., comparison 

groups) other than the arms into which 

they were assigned for the study. This 

is often the case in clinical trials that 

use a cross-over study design in which 

human subjects in different arms of the 

clinical trial receive the same 

interventions in a different order; the 

results are often analyzed not by arm 

but by intervention (See the discussion 

of comparison group in section IV.A.5). 

We believe it is appropriate when 

submitting demographic and baseline 

characteristics, as well as other results 

information, that the information to be 

submitted according to the same 

groupings by which it was analyzed, 

whether the arm of the clinical trial or 

a different comparison group. So that 

users of ClinicalTrials.gov can 

understand how information about 

human subjects was aggregated for 

analysis, proposed § 11.48(a)(2)(i) 

requires submission of a Baseline 

Characteristic Arm/Group Information 

data element, which consists of ‘‘[a] 

brief description of each arm or 

comparison group used for describing 

the demographic and baseline 

characteristics of the human subjects in 

the clinical trial, including a descriptive 

title used to identify each arm or 

comparison group.’’ 

We also propose in § 11.48(a)(2)(ii) to 

require submission of Overall Number 

of Baseline Participants, ‘‘[t]he total 

number of human subjects for whom 

baseline characteristics were measured, 

by arm or comparison group and 

overall.’’ This information is necessary 

to indicate whether some subjects 

enrolled in the clinical trial were not 

measured at baseline (e.g., because they 

dropped out of the clinical trial before 

that point in time) and to help ensure 

that results information is submitted for 

all subjects who were measured at 

baseline. 

(c) Outcomes and statistical analyses: 

Section 402(j)(3)(C)(ii) of the PHS Act 

requires the following as results 

information: ‘‘The primary and 

secondary outcome measures as 

submitted under paragraph 

(2)(A)(ii)(I)(ll), and a table of values for 

each of the primary and secondary 

outcome measures for each arm of the 

clinical trial, including the results of 

scientifically appropriate tests of the 

statistical significance of such outcome 

measures.’’ As discussed in section 

IV.B.4 of this preamble, primary and 

secondary outcome measures are 

submitted as part of the registration 

process. ClinicalTrials.gov was designed 

to display the results of each prespecified outcome measure (primary or 

secondary) in separate tables organized 

by arm or comparison group. The 

responsible party determines the rows 

and columns of each outcome measure 

table: The columns represent arms or 

comparison groups, and the rows 

represent data categories (e.g., for 

categorical data types) and data 

attributes (e.g., mean and standard 

deviation). The responsible party 

populates the table cells with data from 

the clinical trial. In this way, the system 

can accommodate either continuous or 

categorical data, as desired by the 

responsible party based upon the design 

of the clinical trial as specified in the 

protocol and statistical analysis plan. 

For example, time-to-event data could 

be provided as either a continuous 

measure (e.g., median time to response) 

or as categorical data (e.g., number of 

participants with response at five-years). 

In order to enhance the ability of 

users to understand and interpret the 

submitted clinical trial results 

information and to help ensure that 

submitted information is complete, we 

propose in §§ 11.48(a)(3)(i)–(v) that the 

responsible party submit the following 

information to create and populate the 

outcome data tables: 

(1) Outcome Measure Arm/Group 

Information, which is described as ‘‘[a] 

brief description of each arm or 

comparison group used for submitting 

an outcome measure for the clinical 

trial, including a descriptive title to 

identify each arm or comparison 

group.’’ As discussed in the section 

IV.C.4(b) on demographic and baseline 

characteristics, this information would 

describe the grouping of human subjects 

for purposes of analysis, whether by arm 

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of the clinical trial or other comparison 

group. 

(2) Analysis Population Information, 

which must include the Number of 

Participants Analyzed, meaning ‘‘[t]he 

number of human subjects for which an 

outcome was measured and analyzed, 

by arm or comparison group.’’ If the 

analysis is based on a unit other than 

human subjects (e.g., lesions, eyes, 

implants), the responsible party would 

also be required to provide the Number 

of Units Analyzed, which is defined as 

‘‘. . . a description of the unit of 

analysis and the number of units for 

which an outcome was measured and 

analyzed, by arm or comparison group.’’ 

In addition, if the Number of 

Participants Analyzed in an arm or 

comparison group differs from the 

number of human subjects assigned to 

the arm or comparison group, the 

responsible party would also be 

required to provide an Analysis 

Population Description, which would 

briefly describe the reason(s) for the 

difference (e.g., if a clinical trial is 

terminated after participants are 

assigned to arms but before one of the 

outcome measures is assessed, the 

responsible party would include a 

statement in the Analysis Population 

Description indicating that the clinical 

trial was terminated before the outcome 

measure was collected). This entry 

would explain why the total Number of 

Participants Analyzed is zero even 

though participants had been assigned 

to the relevant arm or comparison 

group. 

(3) Outcome Measure Information, 

which includes the following 

components: (A) Name of the specific 

outcome measure, including the titles of 

any categories into which outcome 

measure data are aggregated; (B) 

Description of the metric used to 

characterize the specific outcome 

measure; (C) Time point(s) at which the 

measurement was assessed for the 

specific metric; (D) Outcome Measure 

Type, which indicates whether the 

outcome measure is one of the following 

types of outcome measure: Primary 

outcome measure, secondary outcome 

measure, other pre-specified outcome 

measure, or post-hoc outcome measure; 

(E) Outcome Measure Reporting Status, 

which indicates whether the data for the 

outcome measure are included in the 

present submission and, if not, the 

anticipated submission date; (F) 

Measure Type, which indicates whether 

the outcome is measured as a number 

(e.g., number of subjects with a 

measured value of hemoglobin 5% 

above the baseline value) or a measure 

of central tendency, and the associated 

Measure of Dispersion or precision; and 

(G) Unit of Measure (e.g., blood pressure 

in ‘‘millimeters of mercury’’ or ‘‘percent 

change’’). In specifying a Measure Type, 

the responsible party would be required 

to select from the following limited list 

options: ‘‘number,’’ ‘‘mean,’’ ‘‘median,’’ 

‘‘least squares mean,’’ ‘‘geometric 

mean,’’ or ‘‘log mean.’’ In specifying the 

associated Measure of Dispersion, the 

responsible party would be required to 

select from the following limited set of 

options: ‘‘standard deviation,’’ ‘‘interquartile range,’’ ‘‘full range,’’ ‘‘standard 

error,’’ ‘‘95% confidence interval,’’ 

‘‘90% confidence interval,’’ ‘‘geometric 

coefficient of variation’’ (which would 

be permitted only if the specified 

Measure Type is ‘‘geometric mean’’), or 

‘‘not applicable’’ (which would be 

permitted only if the specified Measure 

Type is ‘‘number’’). No ‘‘other’’ option 

is proposed for either the Measure Type 

or Measure of Dispersion entries, but 

responsible parties would have the 

option of voluntarily providing 

additional descriptive information about 

the outcome measure type and measure 

of dispersion as part of a free-text 

Outcome Measure Description. We 

propose to collect Measure Type and 

Measure of Dispersion in this manner to 

improve the ability to compare 

submitted information across clinical 

trials and to ensure complete data 

submission, e.g., if the responsible party 

indicates that the Measure of Dispersion 

is interquartile range, ClinicalTrials.gov 

can prompt the submission of two 

values corresponding to the upper and 

lower bounds of the interquartile range, 

instead of just the single value needed 

to submit a standard deviation. We 

invite public comment on this proposal 

and whether the proposed options for 

Measure Type and Measure of 

Dispersion are sufficient for collecting 

data from the full range of applicable 

clinical trials or voluntarily submitted 

trials that would be subject to this 

proposed rule. 

In most cases, items (A), (B), and (C) 

above would have been submitted at the 

time of clinical trial registration and 

updated during the course of the 

clinical trial, as specified in proposed 

§ 11.64. Proposed § 11.64(c) specifically 

requires that responsible parties update 

information submitted during 

registration at the time they submit 

results. To ensure consistent data entry 

and reduce the data entry burden on 

responsible parties, ClinicalTrials.gov 

would automatically pre-populate the 

results data tables with the previously 

submitted (and updated) values and 

allow the responsible party to make 

further updates, as necessary or desired 

(e.g., to provide further clarification that 

would enable a user to better interpret 

the submitted results values). If data 

were not collected for an outcome 

measure in a clinical trial, i.e., the 

Number of Participants Analyzed in all 

arms or comparison groups is zero for 

that outcome measure, the responsible 

party would not be required to submit 

items (F) and (G) for that outcome 

measure, as no Outcome Measure Data 

would be submitted. This situation 

might occur, for example, if a clinical 

trial is terminated before data are 

collected for all pre-specified outcome 

measures. 

(4) Outcome Measure Data, which 

consists of the measurement values for 

each outcome measure for which data 

were collected, by arm or comparison 

group. The information provided under 

Outcome Measure Data must use the 

Unit of Measure and correspond to the 

Outcome Measure Type submitted 

under (3) above, i.e., be a number or a 

central tendency plus a measure of 

dispersion or precision. 

(5) Statistical analyses, which are 

specified in proposed § 11.48(a)(v) as 

the ‘‘[r]esults of scientifically 

appropriate statistical analyses, if 

any . . .’’ performed on the primary or 

secondary outcome measure(s). In 

implementing this requirement we 

clarify the meaning of ‘‘scientifically 

appropriate’’ as it relates to statistical 

analyses. We believe that the scientific 

appropriateness of a statistical analysis 

in a clinical trial is inherently 

subjective. For purposes of this rule, we 

propose that a statistical analysis that 

meets any of the following criteria be 

considered scientifically appropriate in 

the context of a particular applicable 

clinical trial: (1) The statistical analysis 

is pre-specified in the protocol or 

statistical analysis plan; (2) the 

statistical analysis is made public by the 

sponsor or responsible party in written 

form (e.g., in a journal publication) prior 

to the date on which results submission 

is otherwise completed for all primary 

and secondary outcome measures 

studied in the clinical trial; or (3) the 

statistical analysis is conducted in 

response to a specific request from the 

FDA that is made before complete 

results information is submitted for all 

of the primary outcome measures 

studied in the clinical trial. We limit the 

requirement to submit FDA-requested 

statistical analyses to those analyses that 

are requested prior to the submission of 

results information for primary outcome 

measures only, so as to avoid causing a 

responsible party to have to submit 

analyses that are requested on data that 

were previously submitted to 

ClinicalTrials.gov. We propose that 

statistical analyses that meet any of 

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these criteria be submitted to 

ClinicalTrials.gov at the time of results 

submission. We clarify that a 

responsible party would not be required 

to submit a statistical analysis that is not 

pre-specified in the protocol or 

statistical analysis plan, is published 

after complete results information is 

submitted to ClinicalTrials.gov, or is 

requested by the FDA after the date on 

which complete results information is 

submitted for all of the primary outcome 

measures studied in the clinical trial. 

We further clarify that the requirement 

to submit results of any scientifically 

appropriate statistical analyses would 

not cause a responsible party to conduct 

a statistical analysis that was not 

otherwise planned or required. We 

invite public comments on these 

proposals and on other criteria the 

agency should consider determining 

what constitutes a ‘‘scientifically 

appropriate’’ statistical analysis. 

We specify in proposed 

§ 11.48(a)(3)(v) the information that a 

responsible party must submit for any 

scientifically appropriate analysis: 

(A) Statistical Analysis Overview: The 

responsible party would identify the 

arms or comparison groups compared in 

the statistical analysis (by selecting the 

arms or comparison groups already 

defined for the outcome measures) and 

specify the type of analysis conducted. 

The type of analysis conducted would 

be selected from the following limited 

set of options: ‘‘superiority,’’ ‘‘noninferiority,’’ ‘‘equivalence,’’ or ‘‘not 

applicable,’’ where ‘‘not applicable’’ 

would be appropriate for a single group 

analysis, for example. No ‘‘other’’ option 

is proposed. If the type of analysis 

selected is ‘‘non-inferiority’’ or 

‘‘equivalence,’’ the responsible party 

would be required to also provide a freetext description of key parameters of the 

statistical analysis to include, at 

minimum, information about the power 

calculation and the non-inferiority or 

equivalence margin. An additional 

comment field would be offered to 

allow the responsible party to 

voluntarily submit additional 

information about the statistical 

analysis. We invite comment on 

whether the list of proposed options is 

sufficient for all applicable clinical 

trials or voluntarily submitted clinical 

trials for which statistical analysis 

information might be submitted to 

ClinicalTrials.gov under this proposed 

rule. 

(B) Statistical Test of Hypothesis: The 

responsible party would submit the pvalue and specify the procedure used 

for statistical analysis of the outcome 

data. For convenience in specifying the 

procedure used for the statistical 

analysis, ClinicalTrials.gov includes a 

list of commonly used statistical tests 

for calculating p-values from which 

responsible parties may select: 

ANCOVA; ANOVA; Chi-squared; Chisquared, Corrected; Cochran-MantelHaenszel; Fisher Exact; Kruskal-Wallis; 

Log Rank; Mantel Haenszel; McNemar; 

Mixed Models Analysis; Regression, 

Cox; Regression, Linear; Regression, 

Logistic; Sign Test; t-Test, 1-sided; tTest, 2-sided; and Wilcoxon (MannWhitney). Responsible parties may also 

select ‘‘other’’ and submit the name of 

another method that was used. 

Additional comment fields would be 

available in ClinicalTrials.gov to allow 

the responsible party to submit 

voluntarily additional information about 

the statistical test of hypothesis, such as 

a description of the null hypothesis, 

adjustments for multiple comparisons, a 

priori thresholds for statistical 

significance, and degrees of freedom. 

(C) Method of Estimation: The 

responsible party would provide a 

description of the method of estimation 

that specifies: The estimation parameter, 

the estimated value, and a confidence 

interval. For convenience in describing 

the method of estimation, 

ClinicalTrials.gov includes a list of more 

than a dozen commonly used estimation 

parameters from which responsible 

parties may select: Cox Proportional 

Hazard; Hazard Ratio (HR); Hazard 

Ratio, log; Mean Difference (Final 

Values); Mean Difference (Net); Median 

Difference (Final Values); Median 

Difference (Net); Odds Ratio (OR); Odds 

Ratio, log; Risk Difference (RD); Risk 

Ratio (RR); Risk Ratio, log; and Slope. 

Responsible parties may also specify 

‘‘other’’ and provide the name of 

another estimation parameter using free 

text. In specifying a confidence interval, 

the responsible party would submit the 

confidence level, indicate whether the 

confidence interval is one-sided or twosided, and provide the upper and/or 

lower limits of the confidence interval. 

A responsible party could specify that 

the confidence interval is one-sided and 

provide only the upper or lower limit. 

If one of the limits of a two-sided 

confidence interval cannot be 

calculated, the responsible party would 

be required to specify that limit as ‘‘Not 

Available’’ and provide a brief narrative 

explanation (e.g., because an 

insufficient number of clinical trial 

participants reached the event at the 

final time point for assessment). A 

responsible party would also have the 

option of submitting voluntarily a 

dispersion value for the confidence 

interval. If a dispersion value is 

submitted, the responsible party would 

be required to specify the parameter of 

dispersion by selecting one of the 

following options: ‘‘Standard deviation’’ 

or ‘‘standard error of the mean.’’ No 

‘‘other’’ option is proposed. An 

additional comment field would be 

available to allow the responsible party 

to submit voluntarily additional 

information about the method of 

estimation, such as the direction of the 

comparison (e.g., for a relative risk). 

These proposed requirements for 

submitting statistical analysis 

information attempt to balance the 

benefits of structured data with minimal 

narrative text against the need to 

describe what was evaluated in the 

statistical analysis. In addition to the 

information specified above, responsible 

parties also would have the option of 

voluntarily submitting additional freetext information in order to provide a 

more complete description of the 

statistical analyses. This free-text 

information would not include 

interpretation of results or conclusions, 

just a description of the statistical test(s) 

conducted. Submitted statistical 

analyses would be linked to each 

submitted outcome measure. Although a 

responsible party would not be limited 

in the number of statistical analyses that 

could be submitted for each outcome 

measure, only statistical analyses that 

are related to a submitted outcome 

measure could be described. 

In specifying requirements for 

outcome measures and statistical 

analyses under proposed § 11.48(a)(3), 

two situations merit further 

clarification. The first is a clinical trial 

that is terminated before data are 

collected for one or more of the prespecified outcome measures. Certain 

information would still be required to 

be submitted for outcome measures for 

which data were not collected. Under 

proposed § 11.48(a)(3)(ii) the 

responsible party would be required to 

submit the Number of Participants 

Analyzed, which would be zero (‘‘0’’) 

for an outcome measure for which no 

data were collected. As noted in (3) 

above and specified in proposed 

§ 11.48(a)(3)(iii)(F) and (G), the 

responsible party would not be required 

to submit the Measure Type and Unit of 

Measure data elements for any outcome 

measure for which data were not 

collected but would be required to 

provide the other elements of Outcome 

Measure Information specified in 

proposed § 11.48(a)(3)(iii). As specified 

in proposed § 11.48(a)(3)(iv), the 

responsible party would not be required 

to submit Outcome Measure Data for the 

outcome measure(s) for which no data 

were collected, but would be required to 

submit Outcome Measure Data for any 

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other outcomes for which data were 

collected. The responsible party would 

nevertheless still be required to meet the 

requirements specified in proposed 

§§ 11.48(a)(1), (2), and (4) for the 

submission of information for the 

Participant Flow, Baseline 

Characteristics, and Adverse Events 

modules. Note, that if a clinical trial 

enrolls no participants, the information 

to be submitted for the Actual 

Enrollment data elements under 

proposed § 11.64(b)(1)(v)(B) would be 

zero (‘‘0’’) and no results information 

would be required to be submitted for 

that clinical trial. 

The second situation consists of a 

clinical trial in which outcome 

measures are collected but the actual 

enrollment falls well below the target 

enrollment. This could occur, for 

example, if a clinical trial is terminated 

due to poor enrollment after some 

participants are enrolled and outcomes 

are measured. We believe that even in 

such situations collected results 

information must be submitted to 

ClinicalTrials.gov as specified in this 

proposed rule (taking into consideration 

the privacy considerations discussed in 

section III.C.16 of this preamble if actual 

enrollment is very small). Submission 

and posting of results information for 

such a clinical trial would be consistent 

with section 402(j) of the PHS Act and 

provide a means of tracking the progress 

of the clinical trial and demonstrating 

what happened to the human subjects 

who were enrolled. If the clinical trial 

was terminated because of safety 

concerns or efficacy, the results 

information would be of considerable 

interest to human health and safety. In 

order to reduce the chance that users of 

ClinicalTrials.gov might misinterpret 

submitted results information, we 

would encourage the responsible party 

to voluntarily submit additional 

information about the clinical trial in 

the Analysis Population Description 

data element and/or in the Limitations 

and Caveats module of 

ClinicalTrials.gov. The submitted 

information would highlight that 

enrollment in the clinical trial was 

insufficient to produce statistically 

reliable results. We would also take 

steps to highlight in the public display 

the fact that actual enrollment fell far 

short of expected enrollment. We would 

expect that in these situations, no 

statistical analysis information would be 

submitted for the affected outcome 

measure(s) because none would have 

been conducted or would be considered 

scientifically valid. We invite public 

comments on other ways in which the 

limitations of the submitted data could 

be highlighted. 

(d) Adverse event information. 

Proposed § 11.48(a)(4) requires the 

submission of summary information on 

adverse events that occurred during an 

applicable clinical trial. Such 

information is considered part of results 

information. Our proposal derives from 

the default provisions in sections 

402(j)(3)(I)(ii)–(iii) of the PHS Act, 

which require the submission of 

information necessary to complete two 

tables: (1) A table of all anticipated and 

unanticipated serious adverse events, 

and (2) a table of all anticipated and 

unanticipated adverse events other than 

serious adverse events with a frequency 

of more than 5 percent in any arm of the 

clinical trial (i.e., ‘‘other frequent 

adverse events’’). Sections 

402(j)(3)(I)(ii)–(iii) of the PHS Act 

further specify that the information 

submitted for each table be grouped by 

organ system and include the number 

and frequency of events in each arm of 

the clinical trial. As explained in greater 

detail in section III.C.15 of this 

preamble, our proposal for the 

submission of adverse event information 

derives from the default provisions in 

sections 402(j)(3)(I)(ii)–(iii) of the PHS 

Act, but includes additional 

requirements intended to assist users in 

understanding and interpreting the 

submitted adverse event information. 

In implementing the statutory default 

provisions, we propose in § 11.48(a)(4) 

that responsible parties submit the 

following information for all serious 

adverse events and for other adverse 

events with a frequency of more than 5 

percent in any arm or comparison group 

of the clinical trial: (1) A description of 

each arm or comparison group from 

which adverse event information was 

collected (see proposed 

§ 11.48(a)(4)(ii)(A)); (2) for each arm or 

comparison group, a description of each 

serious adverse event or other adverse 

event with a frequency of more than 5 

percent in any arm of the clinical trial, 

along with the organ system that is 

associated with the adverse event (see 

proposed § 11.48(a)(4)(ii)(F)); (3) the 

number of participants experiencing the 

adverse event (see proposed 

§ 11.48(a)(4)(ii)(G)(1)), and (4) the 

number of participants at risk for the 

adverse event (see proposed 

§ 11.48(a)(4)(ii)(G)(2)). In most cases, the 

number of participants at risk will equal 

the number of participants who started 

that arm of the clinical trial, but the two 

numbers could differ if participants 

were assigned to an arm but did not 

receive the intervention (e.g., because 

they dropped out of the clinical trial) or 

because a comparison group combines 

participants from multiple arms of the 

trial. Using the data submitted for 

number of participants experiencing the 

adverse event and the number of 

participants at risk, ClinicalTrials.gov 

will automatically calculate the 

percentage of participants who 

experienced the event. We believe that 

this approach will help reduce 

calculation errors and help users 

interpret the frequency information in 

those cases in which the full study 

population may not have been at-risk. 

To assist users of ClinicalTrials.gov in 

better understanding the number of 

participants affected by adverse events, 

we also propose in § 11.48(a)(4) that 

responsible parties be required to 

submit the following information both 

for all serious adverse events and for 

other adverse events with a frequency of 

more than 5 percent in any arm or 

comparison group of the clinical trial: 

(1) The overall number of human 

subjects affected, by arm or comparison 

group, by one or more serious adverse 

events or other adverse events above the 

specified threshold (see proposed 

§ 11.48(a)(4)(ii)(B)), (2) the overall 

number of participants at risk for any 

adverse event, by arm or comparison 

group (see proposed § 11.48(a)(4)(ii)(C)), 

(3) for each organ system class that has 

one or more adverse events listed in 

either table, the overall number of 

participants affected, by arm or 

comparison group, by any adverse event 

in that organ system class (see proposed 

§ 11.48(a)(4)(ii)(D)), and (4) for each 

organ system class that has one or more 

adverse events listed in either table, the 

number of participants at risk, by arm or 

comparison group, for any adverse event 

in that organ system class (see proposed 

§ 11.48(a)(4)(ii)(E)). ClinicalTrials.gov 

will automatically calculate the 

percentage of those at risk that 

experienced any adverse event and the 

percentage of those at risk that 

experienced any adverse event in each 

organ system class. We believe that this 

approach will help reduce calculation 

errors and help users interpret the 

frequency information in those cases in 

which the full study population may not 

have been at-risk for any adverse event 

or for adverse events affecting particular 

organ systems. 

As explained in section III.C.5 of this 

preamble, we propose to require 

responsible parties to submit adverse 

event information classified according 

to the scheme specified in 

ClinicalTrials.gov, which includes the 

following 26 categories adapted from 

the Medical Dictionary for Regulatory 

Affairs (MedDRA) system (http://

www.meddramsso.com/): Blood and 

lymphatic system disorders; Cardiac 

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disorders; Congenital, familial and 

genetic disorders; Ear and labyrinth 

disorders; Endocrine disorders; Eye 

disorders; Gastrointestinal disorders; 

General disorders; Hepatobiliary 

disorders; Immune system disorders; 

Infections and infestations; Injury, 

poisoning and procedural 

complications; Investigations; 

Metabolism and nutrition disorders; 

Musculoskeletal and connective tissue 

disorders; Neoplasms benign, malignant 

and unspecified (including cysts and 

polyps); Nervous system disorders; 

Pregnancy, puerperium and perinatal 

conditions; Psychiatric disorders; Renal 

and urinary disorders; Reproductive 

system and breast disorders; 

Respiratory, thoracic and mediastinal 

disorders; Skin and subcutaneous tissue 

disorders; Social circumstances; 

Surgical and medical procedures; and 

Vascular disorders organ classes. No 

‘‘other’’ option is proposed. ‘‘Social 

circumstances’’ is a not an organ class 

(like most of the other categories) but is 

used in MedDRA to accommodate the 

classification of some types of adverse 

events that are not specific to an organ 

system, such as ‘‘automobile accident,’’ 

‘‘homicide,’’ or ‘‘fall’’. Adverse events 

that affect multiple systems should be 

reported only once (to avoid overcounting), preferably under the organ 

system class that is considered primary. 

If there is no primary organ system 

class, the event should be listed under 

‘‘General disorders,’’ and additional 

explanation may be provided in the 

optional free-text field, Adverse Event 

Term Additional Description. Our 

experience with submission of adverse 

event information since September 2008 

indicates that responsible parties are 

able to use these classes effectively to 

classify the adverse event information 

submitted to ClinicalTrials.gov. We 

request comment on whether this organ 

system classification is sufficient for 

submitting adverse event information 

for all applicable clinical trials and 

voluntarily registered trials that are 

subject to this rule, or whether 

additional categories or an ‘‘other’’ 

option are necessary. 

As specified in the statutory default 

provisions, the adverse event 

information submitted under proposed 

§ 11.48(a)(4)(ii)(G)(1) and (2) would be 

required to include information on 

anticipated and unanticipated adverse 

events. We understand that protocols 

sometimes specify the collection of only 

a more limited set of adverse events in 

a clinical trial, e.g. only unanticipated 

events, or only events associated with a 

particular organ system. We do not 

intend this proposed rule to cause 

investigators or responsible parties to 

collect information that is not specified 

in the clinical trial protocol. Therefore, 

in those situations in which the protocol 

specifies a more limited collection of 

adverse events, we would require the 

responsible party to submit the 

specified information about serious and 

other adverse events with a frequency 

greater than 5 percent in any arm of the 

trial for those adverse events that were 

collected during the trial. To help 

ensure that users of ClinicalTrials.gov 

know when adverse event collection 

was limited, the responsible party 

would be further required, as indicated 

in proposed § 11.48(a)(4)(ii)(H), to 

submit an Additional Description that 

briefly describes how the scope of 

adverse events for which information 

was submitted differs from the broader 

definitions of adverse event and serious 

adverse event proposed in this rule. 

Finally, we note that the agency 

interprets section 402(j)(3)(I)(v) of the 

PHS Act to deem the adverse event 

information required under section 

402(j)(3)(I) of the PHS Act as clinical 

trial information for all clinical trials, 

including applicable clinical trials and 

voluntarily-submitted clinical trials. 

(e) Administrative information: 

Proposed § 11.48(a)(5) describes certain 

administrative information that we 

propose to require to be submitted as 

results information data elements. 

Section 402(j)(3)(C)(iii) of the PHS Act 

requires that ‘‘a point of contact for 

scientific information about the clinical 

trial results’’ be submitted as part of 

clinical trial results information. 

Proposed § 11.48(a)(5)(i) implements 

this provision by requiring the following 

information: (1) Name or official title of 

the point of contact; (2) name of 

affiliated organization; and (3) 

telephone number and email address of 

the point of contact. We believe that this 

is the information is needed in order to 

allow a user to inquire about the results 

of the clinical trial. This information 

would be required to be submitted, even 

if the point of contact is the same as the 

responsible party because we do not 

otherwise plan to make public the 

responsible party contact information. 

Section 402(j)(3)(C)(iv) of the PHS Act 

requires responsible parties to indicate 

‘‘whether there exists an agreement . . . 

between the sponsor or its agent and the 

principal investigator . . . that restricts 

in any manner the ability of the 

principal investigator, after the 

completion date of the trial, to discuss 

the results of the trial at a scientific 

meeting or any other public or private 

forum, or to publish in a scientific or 

academic journal information 

concerning the results of the trial.’’ The 

statutory provision also provides that 

this requirement does not apply to an 

agreement between a sponsor or its 

agent and the principal investigator 

solely to comply with applicable 

provisions of law protecting the privacy 

of participants in the clinical trial. 

Consistent with the definition of PI 

proposed in this part, we interpret this 

provision as applying to a PI who has 

oversight over the entire applicable 

clinical trial, not to site-specific 

investigators or other investigators (such 

as those on grant-funded studies) who 

might be referred to as principal 

investigators in other contexts but who 

do not meet the definition of ‘‘principal 

investigator’’ under this part. 

In implementing the requirement 

under section 402(j)(3)(C)(iv) of the PHS 

Act, we propose in § 11.48(a)(5)(ii) to 

require responsible parties to indicate 

(yes/no) whether the PI is an employee 

of the sponsor. If the PI is an employee 

of the sponsor, then no further 

information must be provided, although 

it may be provided voluntarily. If the 

responsible party indicates that the PI is 

not an employee of the sponsor, then 

the responsible party would be required 

to indicate (yes/no) whether or not an 

agreement (other than one solely to 

comply with applicable provisions of 

law protecting the privacy of human 

subjects participating in the clinical 

trial) exists between the sponsor or its 

agent and the PI that restricts in any 

manner the ability of the PI, after the 

completion date of the clinical trial, to 

discuss the results of the clinical trial at 

a scientific meeting or any other public 

or private forum, or to publish in a 

scientific or academic journal 

information concerning the results of 

the clinical trial. 

Although we are only requiring, 

consistent with section 402(j)(3)(C)(iv) 

of the PHS Act, that the responsible 

party indicate whether such an 

agreement exists, we also propose to 

permit responsible parties to provide 

voluntary additional information about 

existing agreements. In our interactions 

with responsible parties and 

consultations with stakeholders, we 

have learned that certain agreements of 

the nature described in section 

402(j)(3)(C)(iv) of the PHS Act exist 

routinely in the clinical trials 

community, although they may vary in 

their terms and the duration of their 

limitations on the PI. Such agreements 

typically permit the sponsor or its agent 

to review results communications prior 

to public release and to impose a shortterm embargo of 60 days or less, from 

the date the communication is 

submitted to the sponsor for review, but 

other agreements can impose 

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restrictions that have much longer 

durations or are broader in scope. In 

order to provide responsible parties 

with an opportunity to provide 

additional information about the 

agreements that are in place between the 

sponsor or its agent and the PI, we 

propose to permit the voluntary 

submission of additional, structured 

information about the agreement. 

Currently in ClinicalTrials.gov, a 

responsible party who wishes to provide 

this additional information may select 

among the following choices: 

(1) The only disclosure restriction on 

the PI is that the sponsor can review 

results communications prior to public 

release and can embargo 

communications regarding clinical trial 

results for a period that is less than or 

equal to 60 days from the date the 

communication is submitted to the 

sponsor for review. The sponsor cannot 

require changes to the communication 

and cannot extend the embargo. 

(2) The only disclosure restriction on 

the PI is that the sponsor can review 

results communications prior to public 

release and can embargo 

communications regarding clinical trial 

results for a period that is more than 60 

days but less than or equal to 180 days 

from the date the communication is 

submitted to the sponsor for review. The 

sponsor cannot require changes to the 

communication and cannot extend the 

embargo. 

(3) Other disclosure agreement that 

restricts the right of the PI to discuss or 

publish clinical trial results after the 

trial is completed. The responsible party 

may provide additional description of 

the disclosure agreement. 

Based on our experience to-date in 

operating ClinicalTrials.gov and on 

feedback we have received from 

responsible parties, these categories 

appear to provide an acceptable way to 

describe these agreements in a 

consistent form and manner that can 

help identify those that deviate from 

standard practice. These categories 

could be modified over time in order to 

reflect changes in clinical trials practice 

or provide other information of interest 

to users. We invite public comment on 

the proposed approach, experience to 

date with the current approach, and 

other information that might be 

collected on a voluntary basis. 

(f) Additional results information for 

applicable device clinical trials of 

unapproved or uncleared devices. For 

applicable device clinical trials of 

unapproved or uncleared devices, the 

results information specified in (a) 

through (e) above would be submitted to 

ClinicalTrials.gov and publicly posted 

prior to the date on which clinical trial 

information submitted at the time of 

registration would have been publicly 

posted. As a result, users of 

ClinicalTrials.gov would lack access to 

certain descriptive information that is 

necessary to enhance access to and 

understanding of the submitted results 

information and to determine whether 

complete results information has been 

submitted (e.g., for all arms of the 

study). 

Section 402(j)(3)(D)(iii)(IV) of the PHS 

Act grants the Secretary wide discretion 

in determining what information can be 

required through rulemaking to be 

submitted as part of results information, 

stating that the regulations ‘‘shall 

require, in addition to the elements 

described in [section 402(j)(3)(C)] . . . 

[s]uch other categories as the Secretary 

determines appropriate.’’ Thus, the 

Secretary can require, through 

rulemaking, submission of not only that 

results information that is required 

under section 402(j)(3)(C) of the PHS 

Act, but also ‘‘such other categories’’ of 

information as the Secretary determines 

appropriate. We interpret ‘‘such other 

categories’’ of results information for 

applicable device clinical trials of 

unapproved or uncleared devices to 

include, among other things, certain 

descriptive information that is the same 

type of information that was required to 

be submitted under section 

402(j)(2)(A)(ii) of the PHS Act. 

In order ‘‘to enhance patient access to 

and understanding of the results of 

clinical trials’’ (See section 

402(j)(3)(D)(i) of the PHS Act), we 

propose to exercise the authority under 

sections 402(j)(3)(D)(ii)(II) and 

402(j)(3)(D)(iii) of the PHS Act to require 

responsible parties of applicable device 

clinical trials of unapproved or 

uncleared devices to submit, as part of 

results information, certain additional, 

descriptive information that is the same 

type of information that is submitted at 

the time of registration. This descriptive 

information, defined as part of results 

information, would be posted not later 

than 30 calendar days after submission, 

pursuant to section 402(j)(3)(G) of the 

PHS Act. A more detailed discussion of 

how the specified data elements would 

enhance access to and understanding of 

clinical trial results information is 

contained in section III.C.5 of this 

preamble. 

Proposed § 11.48(a)(6)(i) lists the 

descriptive information we propose that 

responsible parties must submit as part 

of the clinical trial results information 

submitted for applicable device clinical 

trials of unapproved or uncleared 

devices. We believe that the listed data 

elements are necessary to enhance 

access to and understanding of the 

results of applicable clinical trials of 

unapproved or uncleared devices for 

which information submitted at 

registration would not have been posted 

publicly in ClinicalTrials.gov. We 

interpret this necessary standard 

broadly to enhance access to and 

understanding of study results by the 

lay public, as well as users of the data 

bank who have high levels of expertise 

in evaluating the results of clinical 

trials. Moreover, we interpret this 

necessary standard broadly to enhance 

access to and the understanding of 

results of clinical trials that are posted 

in ClinicalTrials.gov as well as those 

that are not posted in ClinicalTrials.gov; 

for example: the comparison of the 

results of multiple clinical trials of the 

same or similar devices may be 

necessary to understand the results of a 

clinical trial. We further believe that 

information indicating the status of any 

necessary human subjects protection 

review board approval must be 

submitted so that users can understand 

whether results information voluntarily 

submitted to ClinicalTrials.gov and 

available in the data bank derives from 

clinical trials that were reviewed and 

approved for ethical and scientific 

considerations, or were exempt from 

such review. 

Because responsible parties for 

applicable device clinical trials of 

unapproved or uncleared devices will 

already have provided this descriptive 

information to the data bank when 

submitting (and updating, as necessary) 

registration information, the agency 

believes that it would be an unnecessary 

burden on these responsible parties to 

require them to resubmit descriptive 

information as part of clinical trial 

results information. Instead, we propose 

under § 11.48(a)(6)(ii) to require 

responsible parties to affirm that they 

have verified and updated as necessary 

the descriptive information that is the 

same type of information that is 

submitted when the trial is registered 

and that this descriptive information is 

ready to be posted along with the results 

information. Doing so would allow 

information that previously had been 

submitted to the data bank to 

automatically populate the data 

elements for these clinical trial results. 

This approach would also reduce 

inconsistencies between information 

that previously had been submitted at 

registration and information that would 

be submitted with results, and increase 

administrative efficiency by reducing 

the need for the agency to conduct a 

quality review of this information. In 

this manner, we can help ensure that 

the results information necessary ‘‘to 

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enhance patient access to and 

understanding of the results of clinical 

trials,’’ section 402(j)(3)(D)(i) of the PHS 

Act, is submitted and made available 

publicly, but can reduce the burden 

placed on responsible parties. 

(g) Results information for a pediatric 

postmarket surveillance of a device that 

is not a clinical trial. Subsection (b) of 

proposed § 11.48 specifies the results 

information that must be submitted to 

ClinicalTrials.gov for a pediatric 

postmarket surveillance of a device that 

is not a clinical trial. We recognize that 

a pediatric postmarket surveillance of a 

device may take any of several forms, 

including prospective surveillance 

studies and historical reviews of the 

health records of those who have 

received a device as an intervention, 

and may not meet the definition of a 

‘‘clinical trial’’ under this part. For this 

reason, we do not believe that it is 

possible to specify particular data 

elements or tables of data, similar to 

those for applicable clinical trials that 

are clinical trials, that could be required 

as results information for all types of 

pediatric postmarket surveillances of a 

device that are not clinical trials. We are 

aware, however, that for each pediatric 

postmarket surveillance of a device that 

is required by FDA, a final report must 

be submitted to FDA according to 21 

CFR 822.38 (or any successor 

regulation). Thus, for each pediatric 

postmarket surveillance of a device that 

is not a clinical trial, we believe that the 

final report would contain a suitable 

summary of the surveillance results, and 

we propose that it be submitted to 

ClinicalTrials.gov in a form that can be 

made available to the public, e.g., after 

redacting: (a) Any personally 

identifiable information (other than that 

required to be submitted under this 

part), and (b) information that is not 

required to be submitted under this part 

and that is commercial confidential 

information. Any information not 

redacted would be included in the 

public data bank. The final report would 

be required to be submitted in a 

common electronic document format, 

such as Portable Document Format 

(PDF) or Microsoft Word, specified in 

ClinicalTrials.gov at http://prsinfo.

clinicaltrials.gov/. The set of acceptable 

formats may be updated periodically to 

include new formats that become 

commonly used in the regulated 

community. This proposed requirement 

is included in section 11.48(b). We 

invite public comment on this 

approach. 

5. When will NIH post submitted results 

information?—§ 11.52 

Proposed § 11.52 provides that the 

Director will post results information 

not later than 30 days after the date on 

which the information is submitted to 

the agency for an applicable clinical 

trial. This proposal corresponds to the 

posting deadline established in section 

402(j)(3)(G) of the PHS Act. Proposed 

§ 11.52 does not apply to clinical trials 

that are not required to register under 

402(j)(2)(C) of the PHS Act. For such 

trials that voluntarily register with 

ClinicalTrials.gov, regardless of whether 

they are subject to the requirements for 

voluntary submission under proposed 

§ 11.60 or are subject to the 

requirements in § 11.60(a)(2)(ii), we 

intend to post results information as 

soon as practicable after clinical trial 

results information has been submitted 

and reviewed as part of our quality 

review procedures. 

6. Under what circumstances will the 

Secretary grant a waiver of the 

requirements of this subpart?—§ 11.54 

Section 402(j)(3)(H) of the PHS Act 

provides that ‘‘[t]he Secretary may 

waive any applicable requirements of 

this paragraph for an applicable clinical 

trial, upon written request from the 

responsible party, if the Secretary 

determines that extraordinary 

circumstances justify the waiver and 

that providing the waiver is consistent 

with the protection of public health or 

in the interest of national security . . .’’ 

Proposed § 11.54, implements this 

provision by outlining procedures by 

which a responsible party may submit a 

written request for a waiver from the 

requirements of subpart C for an 

applicable clinical trial in extraordinary 

circumstances where provision of the 

waiver is consistent with protecting 

public health or in the interest of 

national security. 

We expect that waivers would be 

requested and granted in only a very 

limited number of situations. As 

described in section III.C.16 of this 

preamble, one example of a situation in 

which a waiver might be granted is if 

results information could be submitted 

only in a manner that would be likely 

to enable the re-identification of clinical 

trial participants. We invite public 

comments on other situations in which 

a waiver might be granted and would be 

consistent with the protection of public 

health or in the interest of national 

security. 

The proposal specifies that waiver 

requests must be submitted in the form 

of a written letter to the Secretary or a 

delegated official and indicate the NCT 

Number, Brief Title, and Sponsor of the 

trial. This information is necessary to 

identify positively the specific trial for 

which the waiver is requested (the 

combination of NCT Number and Brief 

Title will assist in identifying mistyped 

NCT numbers) and the key parties 

involved (i.e., sponsor and responsible 

party). Because the statute grants the 

Secretary the authority to waive ‘‘any 

applicable requirements’’ of this subpart 

if justified by ‘‘extraordinary 

circumstances’’, we also propose that 

the responsible party identify the 

specific provisions(s) for which a waiver 

is requested and provide a description 

of the circumstances that are believed to 

justify the waiver. 

The responsible party would not be 

required to comply with those 

provisions of subpart C for which the 

waiver was granted. Such provisions 

could include all or just some of the 

provisions for which the waiver was 

requested. The responsible party would 

be expected to comply with any 

remaining provisions of subpart C for 

which the waiver was not requested or 

not granted. The deadline for submitting 

results information to ClinicalTrials.gov 

would be the later of the original 

submission deadline or 15 calendar 

days after the notification denying the 

waiver is sent to the responsible party. 

In subsection (b), we propose an 

appeals process that would permit a 

responsible party to appeal a denied 

waiver request by writing to the 

Secretary or delegated official. The 

delegated official for deciding upon 

waiver appeals would, as a matter of 

practice, differ from the delegated 

official for reviewing the initial waiver 

request. As with the original request, the 

responsible party would not be required 

to comply with specific provisions of 

subpart C for which the waiver is 

granted upon appeal; for those 

provisions for which a waiver is not 

granted upon appeal, the responsible 

party would be required to submit 

results information by the later of the 

original results submission deadline or 

15 calendar days after the notification 

denying the appeal is sent to the 

responsible party. 

As required by section 402(j)(3)(H) of 

the PHS Act, if such a waiver is granted, 

the Secretary will notify the appropriate 

Congressional committees that the 

waiver has been granted and explain 

why it has been granted, not later than 

30 calendar days after any part of the 

waiver is granted. A notation would be 

made in the record for the applicable 

clinical trial in ClinicalTrials.gov to 

indicate that certain requirements for 

results submission have been waived, 

pursuant to section 402(j)(3)(H) of the 

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PHS Act. This notation is intended to 

inform users of ClinicalTrials.gov that 

the absence of certain results 

information does not constitute a failure 

to comply with the statute and 

implementing regulation. Because the 

waiver would be based on extraordinary 

circumstances that could include 

considerations of public health and/or 

national security, the agency proposes 

not to post publicly information 

describing the reason for the waiver. We 

invite public comment on this proposal. 

D. Additional Submissions of Clinical 

Trial Information—Subpart D 

Proposed subpart D describes 

requirements for additional submissions 

of clinical trial information to 

ClinicalTrials.gov, including: (1) 

Voluntary submission of clinical trial 

information for certain clinical trials 

that are not otherwise subject to the 

registration and results submission 

requirements of this proposed rule; (2) 

submission of clinical trial information 

when it is determined that posting of 

such information is necessary to protect 

public health; and (3) timelines for 

updating clinical trial information. 

1. What requirements apply to the 

voluntary submission of clinical trial 

information for clinical trials of FDAregulated drugs and devices?—§ 11.60 

Proposed § 11.60 describes 

requirements that would apply to 

certain voluntary submissions of 

clinical trial information to 

ClinicalTrials.gov, specifically, 

submissions of information for clinical 

trials that are not otherwise subject to 

the registration and results submission 

requirements of section 402(j) of the 

PHS Act. This proposed section 

implements section 402(j)(4)(A) of the 

PHS Act which specifies certain 

requirements that apply to voluntary 

submissions of clinical trial information 

for two types of clinical trials for which 

submission of information is not 

otherwise required, as follows: (1) 

Clinical trials that do not meet the 

definition of an applicable clinical trial; 

and (2) clinical trials that are applicable 

clinical trials but are not required to 

register under section 402(j)(2)(C) of the 

PHS Act or proposed § 11.22(a) (i.e., 

clinical trials that are applicable clinical 

trials that were initiated on or before 

September 27, 2007, and that reached 

their completion dates before December 

26, 2007). 

If a responsible party wishes to 

submit clinical trial information 

voluntarily for one of these two types of 

clinical trials, the responsible party 

must: (1) Submit complete registration 

information as specified in proposed 

§ 11.60(a)(2)(i)(A) or complete results 

information as specified in proposed 

§ 11.60(a)(2)(i)(B) for the voluntarilysubmitted clinical trial; and (2) submit 

clinical trial information for ‘‘each 

applicable clinical trial that is required 

to be submitted under section 351 [of 

the PHS Act] or under section 505, 

510(k), 515, or 520(m) of the [FD&C] Act 

in an application or report for licensure, 

approval, or clearance of the drug or 

device for the use studied in the clinical 

trial.’’ (See section 402(j)(4)(A) of the 

PHS Act.) While the Agency encourages 

submissions of complete registration 

information and complete results 

information for all types of clinical 

trials, regardless of whether they are 

subject to section 402(j) of the PHS Act, 

responsible parties should consider the 

above conditions before deciding 

whether to register a clinical trial or 

submit results information voluntarily. 

In considering which clinical trials 

fall under this provision, we believe that 

section 402(j)(4)(A) of the PHS Act 

should be interpreted in a way that is 

consistent with the scope of FDA’s 

regulatory authorities and the scope of 

this proposed regulation. Hence, we 

interpret the phrase ‘‘a clinical trial that 

is not an applicable clinical trial,’’ in 

section 402(j)(4)(A) of the PHS Act, to be 

limited to a clinical trial of an FDAregulated drug (including biological 

product) or device that is not an 

applicable clinical trial. We do not 

interpret this phrase to include clinical 

trials of other types of interventions, 

whether regulated by FDA or not, that 

would not meet the definition of an 

applicable clinical trial. Thus, proposed 

§ 11.60 would apply, for example, to a 

phase 1 trial of an FDA-regulated drug, 

or to a clinical trial that evaluates the 

feasibility of an FDA-regulated device, 

but not to a clinical trial that studies 

only behavioral interventions that are 

not drugs, biological products, or 

devices. In addition, we interpret the 

phrase ‘‘applicable clinical trial that is 

not subject to [the mandatory 

registration requirement of] paragraph 

(2)(C),’’ in section 402(j)(4)(A) of the 

PHS Act, to mean a clinical trial that 

meets the definition of an applicable 

clinical trial, as specified in section 

402(j)(1)(A) of the PHS Act and this 

part, but that was initiated on or before 

September 27, 2007, and that reached its 

completion date prior to December 26, 

2007. This would mean that proposed 

§ 11.60, and not proposed subparts B 

and/or C, would apply to submissions of 

clinical trial information for such 

applicable clinical trials. 

In considering the information that 

must be submitted to ClinicalTrials.gov 

for a voluntarily-submitted clinical trial 

under section 402(j)(4)(A) of the PHS 

Act, we interpret section 402(j)(4)(A) of 

the PHS Act as permitting a responsible 

party to submit voluntarily registration 

information for a clinical trial without 

having to submit results information. 

Section 402(j)(4)(A) of the PHS Act uses 

the term ‘‘or’’ when referring to the 

submission of ‘‘clinical trial registration 

information described in paragraph (2) 

[clinical trial registration information] 

or (3) [clinical trial results information]’’ 

[emphasis added]. While we encourage 

those who register clinical trials 

voluntarily to also submit results 

information voluntarily, we see value in 

having voluntarily submitted 

registration information in 

ClinicalTrials.gov even if associated 

results information is not submitted. 

Clinical trial registration information 

can, for example, assist with 

recruitment and indicate the existence 

of a clinical trial. Similarly, we believe 

section 402(j)(4)(A) of the PHS Act 

permits a responsible party to submit 

voluntarily results information without 

having to have previously submitted 

registration information. Hence, 

proposed § 11.60(a)(2)(i) expressly 

permits the submission of registration 

information, results information, or 

both. 

In specifying requirements for the 

voluntary submission of results 

information, proposed § 11.60(a)(2)(i)(B) 

requires the submission of the results 

information set forth at proposed 

§ 11.48(a). However, we believe that 

certain descriptive information 

ordinarily submitted at the time of 

registration would be necessary to 

enhance access to results information, 

render it meaningful to the public, and 

demonstrate that the clinical trial is not 

an applicable clinical trial subject to 

proposed §§ 11.22 and 11.42. Thus, we 

propose that a responsible party who 

voluntarily submits only results 

information for a clinical trial under 

proposed § 11.60(a)(2)(i)(B), must 

submit the data elements set forth at 

proposed § 11.60(a)(2)(i)(B), in addition 

to the data elements set forth at 

proposed § 11.48(a), as clinical trial 

results information. 

Sections III.C.5(b) and IV.C.4(f) of this 

preamble describe our rationale for 

requiring much of the descriptive 

information set forth at proposed 

§ 11.60(a)(2)(i)(B). Those sections of the 

preamble, however, address only those 

data elements that we believe are 

necessary to enhance access to and 

understanding the results of a clinical 

trial of a device for which complete 

registration information has been 

previously submitted to 

ClinicalTrials.gov. We believe that 

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additional descriptive information is 

necessary to enhance access to and 

understanding of the results of a clinical 

trial of a drug (or a biological product): 

‘‘Study Phase’’ is necessary to enable a 

user to understand the relative stage of 

development of an experimental drug 

(including biological product) studied 

in a clinical trial; and ‘‘Availability of 

Expanded Access’’ is necessary to 

provide patients with access to 

information about the availability of the 

drug to those who do not qualify for 

enrollment in the clinical trial. 

In addition, we believe that several 

other data elements must be submitted 

with voluntarily submitted results 

information in order for users of the 

data bank and/or the Agency to confirm 

that a clinical trial for which 

information is submitted voluntarily is 

not an applicable clinical trial subject to 

mandatory registration or results 

submission under this part. Specifically, 

we believe that the following data 

elements are necessary: ‘‘Single Arm 

Control?,’’ ‘‘Whether the Study is a 

Pediatric Postmarket Surveillance of a 

Device,’’ ‘‘Product Manufactured in the 

U.S.?,’’ and ‘‘U.S. Food and Drug 

Administration IND or IDE Number.’’ 

For situations in which a responsible 

party submits voluntarily only clinical 

trial results information under section 

402(j)(4)(A) of the PHS Act, we propose 

to use our authority under section 

402(j)(3)(D)(iii)(IV) of the PHS Act to 

interpret results information to include 

the data elements under proposed 

§ 11.60(a)(2)(i)(B) in addition to the data 

elements set forth at proposed 

§ 11.48(a). 

As stated, section 402(j)(4)(A) of the 

PHS Act specifies that voluntary 

submissions of information must consist 

of ‘‘complete’’ clinical trial registration 

or results information. We interpret the 

reference to ‘‘complete’’ in section 

402(j)(4)(A) to mean that as a condition 

of voluntary submission under section 

402(j)(4)(A) and proposed § 11.60, 

responsible parties must submit all 

registration information or results 

information data elements specified in 

proposed §§ 11.60(a)(2)(i)(A) or (B), as 

applicable. We note, however, that we 

propose in § 11.60(a)(2)(iv)(A) that a 

responsible party may submit results 

information for a voluntarily-submitted 

clinical trial once results information is 

available for the primary outcome 

measure(s). If data collection for the 

secondary outcome measure(s) for such 

clinical trials is not completed by the 

completion date of the voluntarilysubmitted clinical trial, then results 

information for the secondary outcome 

measure(s) must be submitted by the 

later of the date that the results 

information is voluntarily submitted for 

the primary outcome measure(s) or 1 

year after the date on which the final 

subject was examined or received an 

intervention for the purposes of final 

collection of data for the secondary 

outcome measure(s), whether the 

clinical trial was concluded according 

to the pre-specified protocol or was 

terminated. 

Section 402(j)(4)(A) of the PHS Act 

also specifies that a responsible party 

who voluntarily registers or submits 

results information for a clinical trial 

must also submit clinical trial 

information for ‘‘each applicable 

clinical trial that is required to be 

submitted under section 351 [of the PHS 

Act] or under section 505, 510(k), 515, 

or 520(m) of the Federal Food, Drug, 

and Cosmetic Act in an application or 

report for licensure, approval, or 

clearance of the drug or device for the 

use studied in the clinical trial.’’ We 

believe this condition of section 

402(j)(4)(A) of the PHS Act may be 

intended to help prevent selective 

voluntary submissions, for example, if a 

responsible party voluntarily submitted 

clinical trial information only from 

clinical trials that showed positive 

results for a particular product, but not 

from clinical trials that showed negative 

or uncertain results for the same 

product. Voluntary submissions under 

section 402(j)(4)(A) of the PHS Act only 

trigger the required submission of 

clinical trial information for clinical 

trials that are applicable clinical trials 

(e.g., not phase 1 trials of a drug or small 

feasibility studies of a device) that were 

not required to be submitted to 

ClinicalTrials.gov under sections 402(i) 

or 402(j) of the PHS Act (e.g., those 

applicable clinical trials that were 

initiated on or before September 27, 

2007, and reached their completion date 

prior to December 26, 2007). 

One challenge in implementing this 

provision of section 402(j)(4)(A) of the 

PHS Act is that a responsible party who 

voluntarily submits clinical trial 

information about a clinical trial may 

not know at the time the voluntary 

submission is made which applicable 

clinical trials subsequently will be 

required to be included in a marketing 

application or premarket notification to 

FDA for the product for the use studied 

in the voluntarily-submitted clinical 

trial. Such a marketing application 

could be submitted many years after the 

completion date of the voluntarilysubmitted clinical trial. Another 

challenge is that the responsible party 

for the voluntarily-submitted clinical 

trial might not be the responsible party 

for some or any of the applicable 

clinical trial(s) for which the submission 

of clinical trial information is triggered 

by the voluntary submission. As such, 

the responsible party voluntarily 

submitting clinical trial information for 

a clinical trial under section 402(j)(4)(A) 

of the PHS Act may not be aware of the 

triggered applicable clinical trial(s) and/ 

or may not have access to the clinical 

trial information required to be 

submitted for such trials. In addition, a 

manufacturer who ultimately submits a 

marketing application or premarket 

notification may not be the responsible 

party for all of the applicable clinical 

trials that are required to be included in 

the marketing application or premarket 

notification, and might not have access 

to clinical trial information for those 

clinical trials. 

To address these concerns, we 

propose in § 11.60(a)(2)(ii) to require a 

submission of clinical trial information 

for any triggered trials (i.e., for 

applicable clinical trials required to be 

included in a marketing application or 

premarket notification to FDA for 

approval, licensure, or clearance of the 

drug or device and that study the same 

use studied in the voluntarily-submitted 

clinical trial) only when the responsible 

party for the voluntarily-submitted 

clinical trial is also the manufacturer 

submitting the marketing application or 

premarket notification. This approach 

would reduce the likelihood of a 

responsible party making selective 

voluntarily submissions, consistent with 

our understanding of the intent of 

section 402(j)(4)(A) of the PHS Act, 

while ensuring that a responsible party 

would not be required to submit clinical 

trial information for a triggered 

applicable clinical trial for which he or 

she is not also the responsible party and 

does not have access to the relevant 

data. This approach also would avoid a 

situation in which one responsible party 

would be unaware that its clinical trials 

are subject to the requirements of 

section 402(j)(4)(A) of the PHS Act by 

virtue of a previous voluntary 

submission of clinical trial information 

made by another responsible party. We 

request public comment on our 

proposed approach in § 11.60(a)(2)(ii). 

Section 402(j)(4)(A) of the PHS Act 

does not specify when information from 

each triggered applicable clinical trial 

must be submitted to ClinicalTrials.gov. 

At the time clinical trial information is 

submitted for a voluntarily-submitted 

clinical trial, a marketing application or 

premarket notification that includes 

such triggered trials may or may not 

have been submitted to FDA; thus, it 

may not be apparent at the time the 

voluntarily-submitted clinical trial is 

submitted to ClinicalTrials.gov which 

applicable clinical trials are triggered 

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under section 402(j)(4)(A) of the PHS 

Act. Therefore, rather than requiring 

information on the triggered applicable 

clinical trials to be submitted at the time 

the clinical trial information is 

submitted for the voluntarily-submitted 

clinical trial, we propose in 

§ 11.60(a)(2)(iv)(B), that the information 

be submitted not later than the date on 

which the application or premarket 

notification is submitted to FDA or the 

date on which clinical trial information 

is submitted for the voluntarilysubmitted clinical trial to 

ClinicalTrials.gov, whichever is later. 

This approach would prevent a 

responsible party from having to submit 

information for a clinical trial that is not 

subsequently included in the marketing 

application or premarket notification. 

We note that, in many cases, we expect 

that a triggered applicable clinical trial 

will have reached its completion date by 

the time clinical trial information for the 

voluntarily-submitted clinical trial is 

submitted because, given the scope of 

applicable clinical trials subject to 402(j) 

or the PHS Act, generally, most or all 

applicable clinical trials for which 

submission would be triggered by a 

voluntary submission would have been 

initiated on or before September 27, 

2007, and reached their completion 

dates prior to December 26, 2007. 

Proposed § 11.60(a)(2)(iii) specifies 

which clinical trial information must be 

submitted for a triggered applicable 

clinical trial. Section 402(j)(4)(A) 

requires that the responsible party 

submit ‘‘clinical trial information’’ for 

all triggered applicable clinical trials. 

Because section 402(j)(1)(A)(iv) of the 

PHS Act defines ‘‘clinical trial 

information’’ to mean ‘‘. . . those data 

elements that the responsible party is 

required to submit under paragraph (2) 

[clinical trial registration information] 

or under paragraph (3) [clinical trial 

results information],’’ the information 

required to be submitted for a triggered 

applicable clinical trial could include 

registration information, results 

information, or both. The construction 

of this requirement mirrors that in 

section 402(j)(4)(A) of the PHS Act, 

which specifies that clinical trial 

information that is voluntarily 

submitted to ClinicalTrials.gov may 

consist of registration information or 

results information. Hence, we propose 

that the type(s) of clinical trial 

information required to be submitted for 

a triggered applicable clinical trial be, at 

minimum, the same as that for the 

voluntarily-submitted clinical trial. In 

other words, if a responsible party 

voluntarily submits registration 

information for a clinical trial pursuant 

to section 402(j)(4)(A) of the PHS Act 

and proposed § 11.60(a), the responsible 

party must submit complete registration 

information specified under proposed 

§ 11.28(a) for any triggered applicable 

clinical trial(s). Likewise, if a 

responsible party voluntarily submits 

results information for a clinical trial 

pursuant to section 402(j)(4)(A) of the 

PHS Act and proposed § 11.60(a), then 

the responsible party must submit 

complete results information specified 

under proposed §§ 11.60(a)(2)(i)(B) for 

any triggered applicable clinical trial(s). 

Because the submission of clinical trial 

information for a triggered applicable 

clinical trial is a condition of voluntary 

registration under section 402(j)(4)(A) of 

the PHS Act, the Agency does not 

propose to treat the submission of such 

information as a voluntary submission 

under section 402(j)(4)(A) or proposed 

§ 11.60(a)(2)(ii) that itself could trigger 

the submission of clinical trial 

information for other applicable clinical 

trials. However, as indicated in 

proposed § 11.60(a)(2)(v), responsible 

parties who voluntarily submit clinical 

trial information to ClinicalTrials.gov 

would be required to update submitted 

information, including information 

submitted for triggered trials, in 

accordance with proposed § 11.64. As 

noted in section IV.C.5 of this preamble, 

clinical trial information submitted 

under proposed § 11.60 will be posted 

on ClinicalTrials.gov as soon as 

practicable after it has been submitted 

and reviewed as part of our quality 

review procedures. Corrections would 

be required, in accordance with 

proposed § 11.66. 

We clarify that because section 

402(j)(4)(A) of the PHS Act has been in 

effect since September 27, 2007, any 

voluntarily-submitted clinical trial 

submitted on or after September 27, 

2007, is subject to the requirements of 

section 402(j)(4)(A) of the PHS Act. We 

interpret the relevant marketing 

application or premarket notification 

under section 402(j)(4)(A) of the PHS 

Act to be any marketing application or 

premarket notification submitted to 

FDA on or after September 27, 2007. 

However, we propose that the 

requirements of proposed § 11.60 apply 

only to clinical trial information 

submitted to ClinicalTrials.gov on or 

after the effective date of this rule. We 

do not propose to impose the 

requirements of proposed § 11.60 with 

respect to any voluntarily-submitted 

clinical trial or any triggered applicable 

clinical trial that was submitted under 

section 402(j)(4)(A) of the PHS Act, 

prior to the effective date. The Agency 

is aware that many clinical trials were 

registered on a voluntary basis at 

ClinicalTrials.gov before publication of 

this proposed rule in an effort to comply 

with other policies (e.g., the policy of 

the ICMJE), to enhance recruitment, or 

to enhance transparency related to such 

clinical trials. To the extent that a 

responsible party complied with section 

402(j)(4)(A) of the PHS Act prior to the 

effective date of the final rule, we do not 

believe it is reasonable to require the 

responsible party to comply with the 

requirements of proposed § 11.60. 

Proposed § 11.60(b) specifies the text 

of ‘‘a statement to accompany the entry 

for an applicable clinical trial when the 

primary and secondary outcome 

measures for such clinical trial are 

submitted under [section 402(j)(4)(A) of 

the PHS Act] after the date specified for 

the submission of such information in 

paragraph (2)(C) [clinical trial 

registration information submission].’’ 

(See section 402(j)(3)(D)(v)(V) of the 

PHS Act.) Because primary and 

secondary outcome measures are data 

elements under both clinical trial 

registration and results information (See 

sections 402(j)(2)(A)(ii)(I)(ll) and 

(3)(C)(ii).), we interpret section 

402(j)(3)(D)(v)(V) of the PHS Act to 

require submissions of registration 

information or results information 

under section 402(j)(4)(A) of the PHS 

Act and/or proposed § 11.60(a) for 

applicable clinical trials to be 

accompanied by a statement to clarify 

that the submission was not subject to 

the deadlines imposed by section 402(j) 

of the PHS Act for registration and 

results information. The required 

statement would apply to any 

applicable clinical trial, including any 

triggered applicable clinical trial, 

submitted under section 402(j)(4)(A) of 

the PHS Act and proposed § 11.60(a). 

Accordingly, the proposed statement is 

as follows: ‘‘Clinical trial information 

for this applicable clinical trial was 

submitted under section 402(j)(4)(A) of 

the PHS Act and 42 CFR 11.60 and is 

not subject to the deadlines established 

by sections 402(j)(2) or (3) of the Public 

Health Service Act or 42 CFR 11.24 or 

11.44.’’ 

2. What requirements apply to 

applicable clinical trials for which 

submission of clinical trial information 

has been determined by the Director to 

be necessary to protect the public 

health—§ 11.62 

Proposed § 11.62 implements the 

requirement in section 402(j)(4)(B) of 

the PHS Act for submission of clinical 

trial information if the Director 

determines that the posting of such 

information on ClinicalTrials.gov is 

necessary to protect the public health. 

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Section 402(j)(4)(B)(i) of the PHS Act 

specifically authorizes the Secretary to 

‘‘require by notification’’ the submission 

of clinical trial information ‘‘in any case 

in which the Secretary determines for a 

specific clinical trial [. . .] that posting 

in the registry and results data bank of 

clinical trial information for such 

clinical trial is necessary to protect the 

public health.’’ This authority has been 

delegated to the Director of NIH (74 FR 

19973, Apr. 30, 2009). If the Director so 

determines, clinical trial information 

must be submitted for that clinical trial 

in accordance with sections 402(j)(2) 

and (3) of the PHS Act, except with 

regard to timing requirements. With 

respect to timing, such clinical trial 

information must be submitted to 

ClinicalTrials.gov ‘‘not later than 30 

days after the date specified by the 

[Director] in the notification,’’ unless 

the responsible party submits a 

certification for delayed results 

submission under section 

402(j)(3)(E)(iii) of the PHS Act. (See 

section 402(j)(4)(B)(i)(II) of the PHS 

Act.) Proposed § 11.62(a) implements 

this provision by requiring the 

responsible party for an applicable 

clinical trial who receives notification 

pursuant to section 402(j)(4)(B) of the 

PHS Act that the Director has 

determined that posting of clinical trial 

information is necessary to protect the 

public health to submit such 

information to ClinicalTrials.gov in 

accordance with proposed § 11.62(c). 

We invite public comment on the types 

of situations in which the posting of 

clinical trial information might be 

necessary to protect the public health 

and on the criteria that the Director 

should consider when making such a 

determination. 

Proposed § 11.62(b) implements 

section 402(j)(4)(B)(ii) of the PHS Act, 

which specifies that the types of clinical 

trials subject to this provision are 

limited to those that are: (1) ‘‘an 

applicable clinical trial for a drug that 

is approved under section 505 of the 

Federal Food, Drug, and Cosmetic Act 

or licensed under section 351 of this Act 

or for a device that is cleared under 

section 510(k) of the Federal Food, 

Drug, and Cosmetic Act or approved 

under section 515 or section 520(m) of 

such Act, whose completion date is on 

or after the date 10 years before the date 

of the enactment of the Food and Drug 

Administration Amendments Act of 

2007;’’ or (2) ‘‘an applicable clinical trial 

that is described by both by paragraph 

(2)(C) and paragraph (3)(D)(ii)(II)) [sic].’’ 

As explained in section III.D of this 

preamble, we interpret the approval 

status of a product studied in an 

applicable clinical trial (i.e., either 

‘‘unapproved, unlicensed, or uncleared’’ 

or ‘‘approved, licensed, or cleared’’) to 

be the approval status of the product on 

any given date. In this context, we 

interpret the approval status of the 

product to be the approval status on the 

date that the Director notifies the 

responsible party that clinical trial 

information must be submitted to 

ClinicalTrials.gov for an applicable 

clinical trial under proposed § 11.62. 

The clinical trials specified in (1) would 

consist of applicable clinical trials of 

approved, licensed, or cleared drugs 

(including biological products) or 

devices that reached their completion 

dates on or after September 27, 1997. 

We note that this set of clinical trials 

would include applicable clinical trials 

that reach their completion dates on or 

after the date of enactment of FDAAA, 

many of which already would be subject 

to the registration and results 

submission requirements of section 

402(j) of the PHS Act, with the 

exception of applicable clinical trials 

that were initiated prior to the date of 

enactment of FDAAA (i.e., September 

27, 2007) and were not ongoing as of 

December 26, 2007. The clinical trials 

specified in (2) would consist of 

applicable clinical trials that are 

required to register at ClinicalTrials.gov 

pursuant to section 402(j)(2)(C) of the 

PHS Act and proposed § 11.22(a) of this 

part and that study drugs (including 

biological products) or devices that are 

unapproved, unlicensed, or uncleared 

by FDA (regardless of whether or not 

approval, licensure, or clearance was 

sought). This set of clinical trials would 

consist of registered applicable clinical 

trials that are not required to submit 

clinical trial results information to 

ClinicalTrials.gov under section 402(j) 

of the PHS Act because they are not 

subject to the results provision in 

section 402(j)(3)(C) of the PHS Act. 

However, many of these applicable 

clinical trials would be required to 

submit results information under this 

proposed rule. (See, e.g., proposed 

§ 11.42 and the discussion of effective 

date implementation in section III.D of 

this preamble.) 

Proposed § 11.62(c) specifies which 

information must be submitted to 

ClinicalTrials.gov and the timelines for 

submitting such information pursuant to 

a notification from the Director under 

section 402(j)(4)(B)(i) of the PHS Act. In 

general, we interpret the references to 

‘‘clinical trial information’’ in section 

402(j)(4)(B)(i) of the PHS Act and 

submission ‘‘in accordance with 

paragraphs (2) and (3)’’ in section 

402(j)(4)(B)(i)(I) of the PHS Act to mean 

registration information and results 

information as enumerated in proposed 

§§ 11.28(a) and 11.48(a). Consistent with 

section 402(j)(4)(B)(i)(II) of the PHS Act, 

such information generally must be 

submitted ‘‘not later than 30 days after 

the date specified by the [Director] in 

the notification.’’ We are interpreting 

‘‘the date specified . . . in the 

notification’’ to mean the date 

established by the Director for 

submission of clinical trial information 

under proposed § 11.62. We note that 

section 402(j)(4)(B)(i)(II) of the PHS Act 

permits an exception to the submission 

deadline if a certification for delayed 

results submission is submitted not later 

than 30 days after the submission date 

specified by the Director in the 

notification and in accordance with 

section 402(j)(3)(E)(iii) of the PHS Act. 

Because a certification under section 

402(j)(3)(E)(iii) of the PHS Act would 

delay only the submission of results 

information, we propose that if the 

responsible party has submitted such a 

certification, only the submission of 

results information may be delayed. 

Accordingly, if a responsible party for 

an applicable clinical trial subject to 

proposed § 11.62 submits a certification 

under section 402(j)(3)(E)(iii) of the PHS 

Act not later than 30 calendar days after 

the submission date specified in the 

Director’s notification, the responsible 

party still would be required to submit 

registration information not later than 

30 calendar days after the submission 

date specified in the notification, 

although results information would be 

required to be submitted by the 

applicable deadline established under 

proposed §§ 11.44(b) or (c). 

To clarify the submission requirement 

in those situations in which registration 

information was submitted to 

ClinicalTrials.gov before a notification 

under section 402(j)(4)(B)(i)(I) of the 

PHS Act was sent to the responsible 

party, we indicate in proposed 

§ 11.62(c)(3) that the registration 

information must be updated, if 

necessary, not later than 30 calendar 

days after the submission date specified 

in the notification. Notwithstanding this 

initial update, we propose that the 

requirements of proposed § 11.64 would 

apply to clinical trial information 

submitted pursuant to proposed § 11.62. 

All clinical trial information 

submitted to ClinicalTrials.gov under 

proposed § 11.62 would be subject to 

the quality review procedures described 

in section III.C.12 of this preamble. We 

would intend to post such information 

as soon as practicable after it has 

completed quality review. This timeline 

for posting would apply to all clinical 

trial information submitted under 

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proposed § 11.62, including registration 

information for an applicable clinical 

trial of a device that has not previously 

been approved or cleared by FDA. 

Section 402(j)(4)(B) of the PHS Act 

applies equally to applicable clinical 

trials of drugs and devices that are 

approved, licensed, or cleared or are 

unapproved, unlicensed, or uncleared. 

It applies to ‘‘any case’’ in which the 

Director, as delegated by the Secretary, 

determines that posting of clinical trial 

information in ClinicalTrials.gov—not 

just submission of the information to 

ClinicalTrials.gov—is necessary to 

protect public health. Although section 

402(j)(4)(B) of the PHS Act specifically 

allows for a delay in submission of 

results information if the responsible 

party submits a certification for delayed 

results submission under section 

402(j)(3)(E)(iii) of the PHS Act, it does 

not specifically delay or prohibit 

posting submitted registration 

information until a device is cleared or 

approved. We therefore believe that 

registration information for all 

applicable clinical trials subject to 

section 402(j)(4)(B) of the PHS Act may 

be posted as soon as practicable after it 

has completed quality review, 

regardless of the approval, licensure, or 

clearance status of the devices studied. 

We do not interpret the waiver 

provisions in section 402(j)(3)(H) of the 

PHS Act or proposed § 11.54 to permit 

a responsible party to request a waiver 

of the requirement to submit clinical 

trial information pursuant to a 

notification from the Director under 

section 402(j)(4)(B) of the PHS Act or 

proposed § 11.62. The waiver provisions 

in section 402(j)(3)(H) of the PHS Act 

and proposed § 11.54 apply only to 

submissions of results information that 

would be required by section 402(j)(3) of 

the PHS Act or proposed subpart C. We 

invite public comment on this proposed 

interpretation. 

3. When must clinical trial information 

submitted to ClinicalTrials.gov be 

updated?—§ 11.64 

Proposed § 11.64 establishes 

requirements for updating clinical trial 

information that has been submitted to 

ClinicalTrials.gov. Section 402(j)(4)(C)(i) 

of the PHS Act requires responsible 

parties for applicable clinical trials to 

submit updates to ClinicalTrials.gov to 

reflect changes to previously submitted 

registration information. Section 

402(j)(4)(C)(i)(I) of the PHS Act provides 

that, in general, updates must be made 

‘‘not less than once every 12 months, 

unless there were no changes to the 

clinical trial information during the 

preceding 12-month period.’’ Section 

402(j)(4)(C)(i)(III) of the PHS Act 

specifies that the responsible party must 

update recruitment status not later than 

30 days after a change in the 

recruitment status of a registered 

applicable clinical trial, and section 

402(j)(4)(C)(i)(IV) of the PHS Act 

specifies that the responsible party must 

update the completion date not later 

than 30 days after the completion date 

of the applicable clinical trial. We 

believe the shorter update time frames 

specified for these two elements of 

registration information in section 

402(j)(4)(C) of the PHS Act are intended 

to help ensure that information in 

ClinicalTrials.gov of particular 

importance to prospective human 

subjects is updated in a timely fashion. 

Section 402(j)(4)(C)(i)(II) of the PHS Act 

indicates updates to submitted clinical 

trial information ‘‘shall include 

identification of the dates of any such 

changes.’’ 

In addition, section 402(j)(3)(D)(v)(IV) 

of the PHS Act requires the Secretary to 

establish, by regulation, ‘‘the 

appropriate timing and requirements for 

updates of clinical trial information.’’ 

Pursuant to this authority, we propose 

to modify the updating requirements 

under section 402(j)(4)(C)(i) of the PHS 

Act. First, we propose to require 

updates for all clinical trials that are 

subject to section 402(j) of the PHS Act 

and/or this proposed rule with a record 

in ClinicalTrials.gov, not just the 

applicable clinical trials that are 

specified in section 402(j)(4)(C)(i) of the 

PHS Act. This would include those 

clinical trials for which clinical trial 

information was voluntarily submitted 

under section 402(j)(4)(A) of the PHS 

Act and/or proposed § 11.60 and those 

for which clinical trial information was 

required to be submitted to protect the 

public health under section 402(j)(4)(B) 

of the PHS Act and/or proposed § 11.62. 

Second, we propose to require updates 

for all clinical trial information 

submitted to ClinicalTrials.gov. This 

would include the registration 

information that is referenced in section 

402(j)(4)(C)(i) of the PHS Act, the 

additional registration data elements, 

and expanded access record information 

proposed in § 11.28, and results 

information. 

Proposed § 11.64(a)(1) establishes a 

general requirement for responsible 

parties to update clinical trial 

information not less than once every 12 

months if there are changes to any of the 

data elements previously submitted. We 

emphasize that this requirement to 

update clinical trial information not less 

than once every 12 months includes a 

requirement to update the estimated 

Completion Date data element, unless 

there have been no changes in the 

preceding 12 months. The public should 

be able to rely upon the accuracy of this 

date to assist them in determining when 

results information may be available on 

ClinicalTrials.gov. In general, we 

recommend that the complete clinical 

trial record in ClinicalTrials.gov be 

reviewed not less than once every 12 

months to help ensure that the clinical 

trial information it contains remains 

accurate. Proposed § 11.64(a)(2) 

specifies that updates to clinical trial 

information must be submitted until the 

date on which all required clinical trial 

results information has been submitted 

to ClinicalTrials.gov, meaning results 

for all primary and secondary outcome 

measures and all adverse events 

collected in accordance with the 

protocol. After that time, submitted 

clinical trial information would 

continue to be subject to the corrections 

provisions in proposed § 11.66, and 

responsible parties would be required to 

submit corrected information when the 

responsible party becomes aware of any 

errors or needed corrections in the 

clinical trial information. 

Proposed § 11.64(b) establishes 

requirements for a responsible party to 

update certain clinical trial information 

more rapidly after a change in the status 

or conduct of a clinical trial or pediatric 

postmarket surveillance of a device. We 

recognize that it would be impractical 

and potentially burdensome to 

responsible parties to require rapid 

updates to all clinical trial information 

data elements each time a change 

occurs, but section 402(j) of the PHS Act 

requires more rapid changes of some 

elements, and we believe that changes 

to other data elements are sufficiently 

time-sensitive to require updates more 

rapidly than once every 12 months. 

Proposed § 11.64(b)(1) would require 

that the following data elements be 

updated not less than 30 days after a 

change has occurred: 

(1) Study Start Date. We propose that 

the Study Start Date data element be 

updated not later than 30 calendar days 

after the first human subject is enrolled 

in the clinical trial. This requirement 

would apply to clinical trials for which 

an estimated study start date was 

provided at the time of registration, 

rather than an actual study start date, 

i.e., clinical trials that were registered 

prior to enrollment of the first human 

subject. The update would ensure that 

potential human subjects know in a 

timely fashion that recruitment has 

begun. It also would ensure that the 

record reflects the actual start date, as 

opposed to an estimated start date, and 

it would provide a mechanism to 

demonstrate whether a clinical trial had 

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been registered not later than 21 days 

after enrollment of the first subject. 

(2) Intervention Name(s). We propose 

that the Intervention Name(s) data 

element be updated to a non-proprietary 

name not later than 30 calendar days 

after a non-proprietary name is 

established for an intervention studied 

in a clinical trial. Intervention Name is 

frequently used as a search term to 

identify and retrieve clinical trials of 

interest. If it is not updated for as long 

as a year, users of ClinicalTrials.gov 

would not be able to accurately retrieve 

trials of interest during that time or to 

easily compare information among 

multiple trials of the same intervention. 

(3) Availability of Expanded Access. 

We propose that the clinical trial 

information submitted under the 

Availability of Expanded Access data 

element in proposed § 11.10(b)(29) be 

updated not later than 30 calendar days 

after an expanded access program is 

initiated or terminated, or an NCT 

number is assigned to an expanded 

access record. This data element 

informs patients whether access to a 

drug to treat serious or life-threatening 

diseases or conditions is available 

outside of the clinical trial. Expanded 

access may not be available at the time 

a clinical trial is registered, and an 

expanded access program may be 

terminated on a date other than the 

completion date of the clinical trial. We 

therefore propose three specific update 

requirements: 

First, for clinical trials registered on 

or after the effective date of this 

regulation, we propose that when an 

expanded access program for a 

particular drug is implemented after the 

clinical trial(s) of that drug is (are) 

registered, the responsible party must 

change the indication in proposed 

§ 11.10(b)(29)(i) of whether there is 

expanded access to the drug not later 

than 30 calendar days after expanded 

access becomes available. 

Second, we propose that not later 

than 30 calendar days after the initiation 

of the expanded access program, the 

responsible party must create an 

expanded access record by submitting 

the data elements required under 

proposed § 11.28(c), unless an expanded 

access record for the drug already was 

already created by another responsible 

party. The responsible party would be 

required to enter the NCT number of the 

expanded access record in the relevant 

clinical trial record(s) not later than 30 

calendar days after the date on which 

the responsible party receives such NCT 

number. In the event that there are 

multiple clinical trials of the same drug 

that is available through an expanded 

access program, the responsible party 

who first changes the Availability of 

Expanded Access data element from 

‘‘yes’’ to ‘‘no’’ would be required to 

create the expanded access record under 

proposed § 11.28(c); once the NCT 

number is assigned, responsible parties 

for other clinical trials of that drug 

would be required to update their 

clinical trial records by changing the 

Availability of Expanded Access data 

element and providing the NCT number. 

We would expect the sponsor to inform 

these relevant responsible parties that 

an expanded access record has been 

created and provide them with the NCT 

number. 

Third, we propose that if expanded 

access is terminated, a responsible party 

must update the Availability of 

Expanded Access data element not later 

than 30 calendar days after termination 

of the program. We note that the 

expanded access record, including the 

NCT number, would remain available in 

ClinicalTrials.gov as archived 

information. We would expect the 

sponsor to inform relevant responsible 

parties that the drug is no longer 

available through an expanded access 

program so that the responsible parties 

may update their clinical trial records 

accordingly. To help sponsors and 

responsible parties in this process, we 

could consider developing procedures 

to send electronic notification to 

responsible parties of all applicable 

clinical trials that list the NCT number 

of the expanded access record of the 

discontinued terminated expanded 

access program. 

Consistent with the discussion in the 

Effective Date/Compliance Date in 

section III.D of this preamble, the 

responsible party for an applicable 

clinical trial that is registered under 

section 402(j) of the PHS Act and 

reaches its completion date prior to the 

effective date of this regulation would 

be required to update the expanded 

access program information required 

under section 402(j)(2)(A)(ii)(II)(gg) of 

the PHS Act not later than 12 months 

after a change in the availability of 

expanded access, as specified in the 

updating requirement in section 

402(j)(4)(C) of the PHS Act. The 

responsible party of such a clinical trial 

would not be subject to the requirement 

to submit the expanded access record 

data elements listed in proposed 

§ 11.28(c) or to update them as specified 

in proposed § 11.64. If a responsible 

party registers an applicable drug 

clinical trial prior to the effective date 

of the regulation, however, and such 

trial is ongoing after the effective date of 

the regulation, the responsible party 

would need to submit the necessary 

expanded access program information 

by the compliance date for the clinical 

trial registration information in the 

databank to comply with proposed 

§ 11.28(c). In addition, the responsible 

party would be subject to the 

requirement to provide updates to 

expanded access program information 

within 30 calendar days of any change, 

consistent with proposed § 11.64(b). 

(4) Expanded Access Status. We 

propose that Expanded Access Status, 

under § 11.28(c)(2)(iv), must be updated 

not later than 30 calendar days after a 

change in the status of an expanded 

access program, whether or not access to 

the investigational drug or device is 

currently available. This data element 

plays a role in expanded access 

programs that is similar to the role of 

Overall Recruitment Status in 

applicable clinical trials, indicating 

whether a particular expanded access 

program is still open to participants. We 

believe that a timely update of any 

change in status is important to have 

reflected in the data bank and is 

consistent with the requirement in 

section 402(j)(4)(C)(III). Note that we 

propose to apply this update 

requirement to expanded access records 

that are submitted voluntarily (e.g., for 

an expanded access record submitted 

for an applicable device clinical trial) as 

well as to those that are required to be 

submitted under this part. 

(5) Overall Recruitment Status. We 

propose that the Overall Recruitment 

Status data element be updated not later 

than 30 days after a change in the 

overall recruitment status of the clinical 

trial. This proposal is consistent with 

section 402(j)(4)(C)(i)(III) of the PHS 

Act. We believe that changes in 

recruitment status should be 

communicated promptly so that 

potential human subjects can know 

whether or not a clinical trial is 

currently recruiting subjects. 

In addition, we propose that if Overall 

Recruitment Status is updated to 

‘‘suspended,’’ ‘‘terminated,’’ or 

‘‘withdrawn,’’ the responsible party 

must at the same time provide 

information for the Why Study Stopped 

data element. We believe that 

suspension, termination, and 

withdrawal of a clinical trial are 

significant changes that should be 

communicated promptly to prospective 

human subjects, along with the reason 

for the change. We propose to allow a 

responsible party to enter this 

information as free-text so that he or she 

has flexibility to explain the reason(s) 

why a clinical trial stopped 

prematurely. We believe such 

information is consistent with the 

statutory objective in section 

402(j)(2)(A)(i) of the PHS Act to enable 

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users ‘‘to track subsequent progress of 

clinical trials.’’ 

Similarly, we propose that if Overall 

Recruitment Status is updated to 

‘‘terminated’’ or ‘‘active, not recruiting,’’ 

the responsible party also must update 

the Actual Enrollment data element. In 

either of these situations, recruitment of 

human subjects is complete. As 

explained in more detail in section 

IV.B.4 of this preamble, submission of 

actual enrollment information will 

provide users of ClinicalTrials.gov with 

a mechanism for tracking the progress of 

registered clinical trials by enabling 

comparison of the actual enrollment 

information with the target or estimated 

enrollment information. More rapid 

updating is expected to contribute to 

more accurate reporting of the Actual 

Enrollment information and to permit 

users of ClinicalTrials.gov to know more 

quickly whether the clinical trial 

achieved its target enrollment. 

(6) Individual Site Status. We propose 

that Individual Site Status be updated 

not later than 30 calendar days after a 

change in status of any individual site. 

We believe this proposal is consistent 

with the requirement in section 

402(j)(4)(C)(III) of the PHS Act. It also 

supports the purpose of 

ClinicalTrials.gov to ‘‘enhance patient 

enrollment’’ (See section 402(j)(2)(A)(I) 

of the PHS Act) by assisting potential 

human subjects who search for clinical 

trials by location and wish to retrieve 

information about only those trials that 

are open to recruitment in specified 

locations. 

(7) Human Subjects Protection Review 

Board Status. We propose that Human 

Subjects Protection Review Board Status 

be updated not later than 30 calendar 

days after a change in Human Subjects 

Protection Review Board Status. 

Because such information is intended to 

demonstrate to potential human subjects 

whether a registered applicable clinical 

trial or other clinical trial has undergone 

necessary human subjects protection 

review board review, has received 

necessary approvals for human subjects 

research, or was exempt from such 

review, we believe it must be updated 

in a timely fashion. 

(8) Completion Date. Pursuant to 

section 402(j)(4)(C)(i)(IV) of the PHS 

Act, proposed § 11.64(b) specifies that 

the Completion Date data element must 

be updated not later than 30 calendar 

days after a clinical trial reaches its 

actual completion date. 

(9) Responsible Party, by Official 

Title. We propose the Responsible Party, 

by Official Title data element be 

updated not later than 30 calendar days 

after a change in either the name of the 

responsible party of in the responsible 

party’s official title. We believe this 

update is necessary to enable NIH and 

other users of the data bank to 

accurately identify the responsible party 

for the clinical trial. 

(10) Responsible Party Contact 

Information. Consistent with (9) above, 

we propose that Responsible Party 

Contact Information be updated not 

later than 30 days after a change in the 

responsible party or the responsible 

party’s contact information. Given that 

the responsible party must make 

updates to clinical trial information and, 

in general, must submit clinical trial 

results information, we consider it 

essential to know of changes to the 

responsible party and to responsible 

party contact information in a timely 

manner. Up-to-date information about 

the responsible party would ensure that 

the Agency has contact information for 

the appropriate person responsible for 

submitting clinical trial information 

about the applicable clinical trial or 

clinical trial. 

In addition, we propose in 

§ 11.64(b)(2) that responsible parties be 

required to update the U.S. FDA 

Approval, Licensure, or Clearance 

Status data element not later than 15 

calendar days after a change in the 

approval, licensure, or clearance status 

of the product under study. Products 

may appear in the market place or 

manufacturers may announce the 

pending availability of a product soon 

after they receive FDA approval, 

licensure, or clearance. We believe that 

a prompt update to the information in 

ClinicalTrials.gov is necessary to help 

avoid confusing users who seek 

information about a drug or device in 

ClinicalTrials.gov after finding the 

product in the market place (e.g., after 

being prescribed a new drug) or finding 

other public information about it (e.g., a 

news release announcing a new 

product). In addition, a shorter update 

period for this data element would 

enable users to better anticipate when 

clinical trial results information would 

be due for an applicable clinical trial. 

Furthermore, a change in the approval 

or clearance status of a device can 

trigger a requirement for the Agency to 

post previously-submitted clinical trial 

registration information within 30 days 

of the change in status. Updating the 

U.S. FDA Approval, Licensure, or 

Clearance Status data element not later 

than 15 calendar days would provide 

the Agency timely notice that it must 

post publicly clinical trial registration 

information. 

In § 11.64(b)(3) we propose that 

relevant clinical trial registration 

information be updated not later than 30 

calendar days after a protocol 

amendment is approved by a human 

subjects protection review board, if the 

protocol is amended in such a manner 

that changes are communicated to 

participants in the applicable clinical 

trial or other clinical trial. We believe 

that protocol amendments that are 

communicated to enrolled participants 

could be important to those considering 

enrollment and should be 

communicated quickly through an 

update to the record in 

ClinicalTrials.gov. Rapid updating of 

this information would be consistent 

with the stated purpose of 

ClinicalTrials.gov to ‘‘enhance patient 

enrollment and provide a mechanism to 

track subsequent progress of clinical 

trials.’’ (See section 402(j)(2)(A) of the 

PHS Act.) If such key changes were not 

reflected in the record in 

ClinicalTrials.gov for as long as 12 

months after the change, the value of 

ClinicalTrials.gov as a source of reliable, 

accurate information for the public and 

potential participants in clinical trials 

would be compromised. We recognize 

that other thresholds could be used to 

determine which protocol changes are 

significant enough to warrant 30-day 

updating of affected clinical trial 

information. For example, updating of 

relevant data elements could also be 

required any time a protocol 

amendment is reported to a human 

subjects protection review board. We 

invite public comments on our 

proposed approach and alternatives. 

In § 11.64(b)(4), we propose that the 

Record Verification Date must be 

updated any time the responsible party 

reviews the complete set of submitted 

clinical trial information for accuracy, 

even if no other updated information is 

submitted at that time. The record 

verification date is intended to 

demonstrate when the information in 

ClinicalTrials.gov for a particular 

clinical trial was last checked for 

accuracy. As noted in section IV.B.4 of 

this preamble, a responsible party 

would be required to update the Record 

Verification Date if he or she examines 

the complete set of submitted clinical 

trial information as part of a monthly or 

annual review, even if he or she 

determines that no additional or 

updated information needs to be 

submitted. Similarly, the responsible 

party would be required to update the 

Record Verification Date data element if 

he or she updates a data element and 

reviews the rest of the record for 

accuracy. However, the responsible 

party would not be required to update 

the Record Verification date if he or she 

submits updates to one or more data 

elements without reviewing the 

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accuracy of the rest of the record. This 

proposal would not require a 

responsible party to review records 

more frequently or regularly than would 

be needed in order to update submitted 

information as otherwise required by 

proposed § 11.64, but it would require 

that the Record Verification Date be 

updated if the complete record were 

reviewed for accuracy during such an 

update. Doing so would indicate to 

users of ClinicalTrials.gov the currency 

of the information and provide an 

additional assurance that it is not outof-date. 

In addition, we propose in § 11.64(c) 

that responsible parties update clinical 

trial registration information at the time 

they submit clinical trial results 

information to ClinicalTrials.gov (unless 

there are no changes to the clinical trial 

registration information). This 

requirement is intended to help ensure 

the consistency and accuracy of 

information in the registry and results 

portions of the data bank. Updated 

registration information would then be 

used to pre-populate certain data 

elements in the clinical trial record so 

that responsible parties do not have to 

enter them again. Because the 

submission and subsequent posting of 

clinical trial results information is often 

a reason for users to retrieve the record 

for a particular clinical trial, the 

additional update requirement will also 

ensure that users have access to 

complete registration and results 

information that is up-to-date and 

internally consistent. 

We note that the updating 

requirements under proposed § 11.64 

would be prompted by changes in the 

clinical trial and not by changes in the 

information submission requirements 

for ClinicalTrials.gov or the form and 

manner in which data must be 

submitted to ClinicalTrials.gov. For 

example, if clinical trial results 

information were submitted prior to the 

effective date of the rule consistent with 

the requirements of section 402(j)(3)(C) 

of the PHS Act, the responsible party 

would not be required as a result of the 

updating requirements to submit 

clinical trial results information for the 

expanded results data elements required 

under proposed § 11.48. Similarly, if the 

Agency were to make administrative 

changes to the manner in which clinical 

trial information is submitted to 

ClinicalTrials.gov after the responsible 

party has submitted clinical trial 

information in accordance with section 

402(j) of this PHS Act and this proposed 

part, the Agency’s revisions to 

ClinicalTrials.gov would not themselves 

give rise to a requirement that the 

responsible party update the applicable 

clinical trial information. For example, 

if the Agency added additional options 

to a drop-down menu for a particular 

data element, even if one of the 

additional options would be more 

appropriate with respect to an 

applicable clinical trial, the responsible 

party would not be required to update 

its previously-submitted clinical trial 

information, although they could do so 

voluntarily. However, if a responsible 

party makes a required update to 

previously submitted clinical trial 

information, e.g., to reflect a change in 

the conduct or progress of a clinical 

trial, he or she would be required to 

submit the updated information in the 

form and manner required by 

ClinicalTrials.gov at the time the update 

is submitted. For example, if the set of 

options in a drop-down menu had 

changed since the information had 

previously been submitted, the 

responsible party would be required to 

select from the new set of options. 

Updates to clinical trial registration 

information and clinical trial results 

information will be posted in 

accordance with proposed §§ 11.35 and 

11.52, respectively. Previously 

submitted clinical trial information will 

remain publicly available through the 

ClinicalTrials.gov archive. See proposed 

§ 11.64(d)(1) and (2). 

4. What are the requirements for 

corrections of clinical trial 

information?—§ 11.66 

Proposed § 11.66 sets out 

requirements for responsible parties to 

correct clinical trial information 

submitted to ClinicalTrials.gov. This 

would include clinical trial information 

voluntarily submitted under section 

402(j)(4)(A) of the PHS Act and/or 

proposed § 11.60 as well as clinical trial 

information necessary to protect the 

public health and submitted under 

section 402(j)(4)(B) of the PHS Act and/ 

or proposed § 11.62. We consider 

corrections of information to be 

different from updates to information, as 

described in proposed § 11.64. In our 

view, updates modify clinical trial 

information to reflect changes in the 

status or conduct of an ongoing clinical 

trial or the associated analysis. 

Corrections revise submitted clinical 

trial information that is found to be 

false, invalid, incorrect, inconsistent, or 

incomplete. 

Proposed § 11.66 addresses several 

types of corrections. First, § 11.66(a) 

addresses corrections of errors, or 

misstatement of facts that are found to 

be incorrect. Errors include, but are not 

limited to: Inadvertent, typographical 

errors, such as transpositions of 

numbers or characters; or inadvertent 

omissions of data, such as omission of 

one component of set of participant 

exclusion criteria. They also include 

submitted values that are demonstrably 

wrong, such as an outcome measure 

indicating more than 24 hours per day 

of a given value. We expect to detect 

some such errors during the quality 

review procedures described in section 

III.C.12 of this preamble and may 

identify others in the course of 

operating the data bank. We intend to 

inform responsible parties of errors we 

identify so that they may be corrected. 

Responsible parties may also detect 

errors when reviewing submitted 

information, or they may be alerted to 

potential errors by other parties. As 

indicated in proposed § 11.66(a), we 

would require responsible parties to 

correct identified errors not later than 

15 calendar days after becoming aware 

of them, whether they identify the errors 

themselves, or whether we inform them 

of errors we have detected, such as 

through our quality assurance 

procedures, whichever is earlier. 

Second, § 11.66(b) addresses 

corrections to information that is 

falsified or based on falsified 

information. Consistent with FDA’s 

proposed use of the term ‘‘falsification 

of data’’, we consider ‘‘information that 

is falsified or based on falsified 

information’’ to mean information that 

was created, altered, recorded, or 

omitted in such a way that the data do 

not represent what actually occurred in 

the clinical trial. (See 75 FR 7414, Feb. 

19, 2010.) Examples of information that 

are falsified or based on falsified 

information include, but are not limited 

to, the following (based on examples in 

75 FR 7414, Feb. 19, 2010): 

(1) Created information that was never 

obtained (e.g., the values submitted for 

a primary outcome measure were made 

up or based on participant-level data 

that were made up; the actual 

enrollment value submitted includes 

subjects who did not exist or were not 

actually enrolled in the clinical trial). 

(2) Information that was altered by 

replacing original information with 

something different that does not 

accurately reflect study conduct or 

results (e.g., the value submitted for a 

baseline characteristic is changed to a 

less extreme deviation from normal or is 

based on individual measures of the 

baseline characteristic that were 

changed be less extreme deviations from 

normal). 

(3) Information that was recorded or 

obtained from a human subject in a way 

that does not accurately reflect the study 

protocol (e.g., a submitted outcome 

measure is based on measurements from 

subjects who were given a different dose 

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of an experimental drug than that 

specified in the protocol and the 

ClinicalTrials.gov record). 

(4) Omitted information that was 

obtained and would be appropriate for 

submission based on study design and 

conduct (e.g., values are not submitted 

for a secondary outcome measure for 

which data were collected during the 

clinical trial or the values submitted for 

the secondary outcome measure do not 

include outcomes that were measured 

on some subjects so the analysis yields 

a result that would not have been 

obtained had all data been analyzed). 

As specified in proposed § 11.66(b), 

we would require a responsible party to 

inform the Director when a sponsor 

determines that information submitted 

to ClinicalTrials.gov was falsified or 

based on falsified information. The 

responsible party would be required to 

inform the Director about falsification at 

the same time as he or she submits 

corrected information or informs the 

Director that either correct information 

cannot be generated or previously 

submitted information is correct (i.e., 

the falsification did not result in 

incorrect information being submitted to 

ClinicalTrials.gov). If corrected 

information can be generated, we would 

require the responsible party to submit 

corrected information not later than 15 

calendar days after it becomes available. 

If it is determined that submitted 

information cannot be corrected or is 

correct as previously submitted we 

would require the responsible party to 

notify the Director not later than 15 days 

after such a determination is made. For 

a clinical trial for which corrected data 

cannot be generated, we would indicate 

in ClinicalTrials.gov that data for such 

clinical trial were determined to be 

falsified or based on falsified 

information and that corrected 

information is not available. Such an 

indication would inform users of 

ClinicalTrials.gov of the status of the 

information in the record for that 

clinical trial. For a clinical trial for 

which the falsification of data does not 

affect the information submitted to 

ClinicalTrials.gov (e.g., because 

underlying falsified data did not 

contribute to the analysis of outcomes), 

we would not include an indication of 

falsification on the ClinicalTrials.gov 

record. Information about findings of 

falsification might be included in 

published journal articles for which 

Medline citations are linked from the 

record, in FDA information that is 

linked from the record, or in other 

publicly available information. 

We recognize that, in some cases, after 

determining that submitted information 

was falsified or based on falsified 

information, it may take time for a 

responsible party to assess whether or 

not the information submitted to 

ClinicalTrials.gov was affected, 

determine whether any affected 

information can be corrected, and 

generate corrected information, as 

needed. For example, the results of the 

clinical trial may need to be reanalyzed 

after excluding data that have been 

falsified and the results of such 

reanalysis compared with previously 

submitted data. Under our proposal, a 

responsible party would be required to 

notify the Director of falsification only 

after he or she had assessed whether or 

not the falsification resulted in incorrect 

data being submitted to 

ClinicalTrials.gov, determined whether 

corrected information could be 

generated, and generated any needed 

corrections to the data. We considered, 

but do not include in this proposed rule, 

a requirement for a responsible party to 

provide earlier notification to the 

Director of a determination that 

information submitted to 

ClinicalTrials.gov had been falsified or 

was based on falsified information (e.g., 

such notification could be provided not 

later than 15 days after the 

determination is made). Following such 

a proposal, the responsible party would 

then have been required either to make 

a second notification stating whether 

the submitted information was correct 

as submitted or unable to be corrected 

or to submit corrected information. We 

invite public comment on the 

advantages and disadvantages of this 

alternative approach, including on the 

amount of time that might typically pass 

between determining that data have 

been falsified and determining whether 

submitted clinical trial information can 

be corrected or does not need 

correction. We specifically invite 

comment on the implications of the 

proposed approach in cases when that 

time period may be lengthy. We also 

invite comment on what, if any, 

information might be made make 

publicly available in ClinicalTrials.gov 

in these situations. We invite comments 

on all other aspects of our proposal, as 

well. 

Third, § 11.66(c) addresses corrections 

necessary to address various other 

deficiencies in submitted information. 

Such deficiencies include but are not 

limited to inconsistencies in submitted 

data, for example, a mismatch between 

the reported number of subjects enrolled 

in a clinical trial and the sum of 

reported number of subjects assigned to 

different arms, and incomplete entries 

that are insufficient to convey their 

intended meaning, such as a description 

of an outcome measure that does not 

describe the measurement scale being 

used. We believe that requiring 

corrections of such information is 

necessary step in ensuring that the 

information contained in 

ClinicalTrials.gov is not false or 

misleading. We expect to identify some 

needed corrections during the quality 

review procedures described in section 

III.C.12 of this preamble and in the 

course of operating the data bank. As 

with errors, we plan to inform 

responsible parties of these needed 

corrections. We expect that responsible 

parties may also become aware of 

needed corrections through their own 

reviews of submitted data or from other 

parties. Proposed § 11.66(c) provides 

that responsible parties who become 

aware of needed corrections or are 

informed by NIH of needed corrections 

to clinical trial information submitted 

under §§ 11.28, 11.48, or 11.60 must 

submit corrected information as soon as 

possible, but not later than 15 calendar 

days after the date that they become 

aware of the need for correction or that 

NIH informs them of the needed 

correction, whichever is earlier. 

Compliance with our quality control 

process, including the requirements set 

forth in § 11.66, does not necessarily 

constitute a legal defense to 

enforcement pursuant to section 301(jj) 

of the FD&C Act (21 U.S.C. 331) and 

303(f) of the FD&C Act (21 U.S.C. 

333(f)). 

V. Response to Comments 

Because of the large number of public 

comments we normally receive on 

Federal Register documents, we are not 

able to acknowledge or respond to them 

individually. We will consider all 

comments we receive by the date and 

time specified in the Dates section of 

this preamble, and will respond 

generally to the comments in the 

preamble to any subsequent rulemaking 

document. 

VI. Regulatory Impact Statement 

The Agency has examined the 

impacts of this proposed rule under 

Executive Order 12866, Regulatory 

Planning and Review, Executive Order 

13563, Improving Regulation and 

Regulatory Review, the Regulatory 

Flexibility Act (5 U.S.C. 601–612) 

(RFA), the Unfunded Mandates Reform 

Act of 1995 (Public Law 104–4), and 

Executive Order 13132, Federalism. 

Executive Order 12866, as amended by 

Executive Order 13563, directs agencies 

to assess all costs and benefits of 

available regulatory alternatives and, 

when regulation is necessary, to select 

regulatory approaches that maximize 

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net benefits (including potential 

economic, environmental, public health 

and safety, and other advantages; 

distributive impacts; and equity). A 

regulatory impact analysis (RIA) must 

be prepared for major rules with 

economically significant effects ($100 

million or more in any single year). The 

Agency estimates that the total cost of 

the proposed requirements to regulated 

entities is approximately $49.7 million 

annually. We believe there are 

intangible benefits, in the form of 

increased public trust in clinical 

research and improvements in human 

subjects protection, clinical care, 

clinical research, and product 

development that may result from 

enhanced access to clinical trial results. 

We believe that this proposed rule is not 

an economically significant regulatory 

action as defined by Executive Order 

12866. Because of the interest in this 

proposed rule among regulated entities 

and others involved in conducting or 

using the results of clinical trials, we 

have nevertheless prepared an analysis 

that, to the best of our ability, estimates 

the costs and benefits of this proposed 

rule. We request comments on the 

economic analyses provided in this 

proposed rule. 

The RFA requires agencies to analyze 

regulatory options that would minimize 

any significant impact of a rule on a 

substantial number of small entities. 

Because the rule is likely to impose 

estimated costs of approximately $6,700 

per applicable clinical trial on 

organizations that conduct applicable 

clinical trials, the Agency proposes to 

certify that the final rule will not have 

a significant economic impact on a 

substantial number of small entities. 

Section 202 of the Unfunded 

Mandates Reform Act of 1995 requires, 

among other things, that agencies 

prepare a written statement, which 

includes an assessment of anticipated 

costs and benefits, before proposing 

‘‘any rule that includes any Federal 

mandate that may result in the 

expenditure by State, local, and tribal 

governments, in the aggregate, or by the 

private sector, of $100,000,000 or more 

(adjusted annually for inflation) in any 

one year.’’ (See 2 U.S.C. 1352(a)) The 

current threshold after adjustment for 

inflation is $141 million, based on the 

Gross Domestic Price deflator for 2012. 

The Agency does not expect this 

proposed rule to result in any 1-year 

expenditure that would meet or exceed 

this amount. As explained above, 

however, the Agency has conducted an 

analysis of the costs that could result 

from this proposed rule. 

Executive Order 13132 (Federalism) 

establishes certain requirements that an 

Agency must meet when it promulgates 

a proposed rule (and subsequent final 

rule) that imposes substantial direct 

requirement costs on State and local 

governments, preempts State law, or 

otherwise has Federalism implications. 

A. The Proposed Rule 

This proposed rule would implement 

the provisions for the mandatory 

registration and submission of results 

information for applicable clinical trials 

at ClinicalTrials.gov, as required by 

section 402(j) of the PHS Act (42 U.S.C. 

282(j)), added by section 801 of FDAAA. 

This proposed rule would both clarify 

the statutory requirements for 

submission of registration and results 

information, including adverse events 

information, and implement the 

expansion of the registry and results 

data bank by rulemaking as required by 

section 402(j)(3)(D) of the PHS Act. 

B. Need for the Proposed Rule 

The Agency is promulgating this 

proposed rule to fulfill the requirements 

of section 402(j) of PHS Act in a manner 

that will provide broad public access to 

pertinent clinical trial registration and 

results information. Section 

402(j)(2)(A)(i) of the PHS Act requires 

the Secretary to expand the clinical 

trials registry data bank with respect to 

clinical trial information to ‘‘enhance 

patient enrollment and provide a 

mechanism to track subsequent 

progress’’ of the clinical trials. Sections 

402(j)(3)(B) and 402(j)(3)(C) of the PHS 

Act instruct the Secretary to expand the 

clinical registry data bank not later than 

1 year after enactment of FDAAA to 

include the results information 

specified in section 402(j)(3)(C) for 

certain applicable clinical trials. Section 

402(j) of the PHS Act also requires 

responsible parties to submit to the 

expanded data bank specified 

registration information (i.e., descriptive 

information, recruitment information, 

location information, and administrative 

information) summarizing key aspects 

of applicable clinical trials that are 

subject to the law and specified results 

information describing the outcomes of 

applicable clinical trials for which the 

drugs or devices under study have been 

approved, cleared, or licensed by FDA. 

Section 402(j) of the PHS Act further 

establishes deadlines by which such 

information must be submitted and 

establishes penalties for noncompliance. This proposed rule is 

intended, in part, to implement the 

statutory requirements and clarify the 

Agency’s interpretation of them. It 

clarifies the meaning of terms defined in 

the PHS Act (e.g., responsible party and 

applicable clinical trial) and of several 

data elements that are required to be 

submitted to the data bank (e.g., study 

design, eligibility criteria). It also 

exercises the authority given to the 

Secretary in section 402(j)(2)(iii) of the 

PHS Act to modify by regulation the 

requirements for clinical trial 

registration information. This proposed 

rule specifies several modifications to 

the clinical trial registration information 

that the Agency believes meet the 

statutory criteria of improving and not 

reducing the statutorily specified 

clinical trial registration information. 

In addition, this proposed rule is 

necessary to implement provisions of 

section 402(j) of the PHS Act that are 

specifically required to be addressed by 

regulation. Section 402(j)(3)(I) of the 

PHS Act, requires the Secretary to 

determine by regulation the ‘‘best 

method’’ for including in the registry 

and results data bank appropriate 

results information on serious adverse 

and other adverse events collected for 

certain applicable clinical trials. Section 

402(j)(3)(D) of the PHS Act requires, 

among other things, the Secretary to 

further expand the registry and results 

data bank through rulemaking to 

‘‘provide more complete results 

information and to enhance patient 

access to and understanding of the 

results of clinical trials.’’ That section of 

the PHS Act specifies several topics that 

the rule is to address, including: 

Whether to require the submission of 

results information for applicable 

clinical trials of drugs and devices that 

previously have not been approved, 

licensed, or cleared by FDA; whether 

technical or lay summaries of a clinical 

trial can be included in the data bank 

without being misleading or 

promotional; and whether to require 

responsible parties to submit the full 

protocol or ‘‘such information on the 

protocol . . . as may be necessary to 

help evaluate the results of the trial.’’ 

This proposed rule addresses each of 

these topics and others specified in 

section 402(j) of the PHS Act. 

C. Benefits of the Proposed Rule 

As discussed in this preamble, the 

overarching aim of this proposed rule is 

to provide public access to a 

standardized set of non-technical and 

technical information describing the 

conduct and results of certain clinical 

trials of FDA-regulated drugs (including 

biological products) and devices. Access 

to this information will benefit not only 

the general public, but also other groups 

of people involved in improving public 

health. These groups of people include 

potential and enrolled clinical trial 

participants, clinical researchers, 

systematic reviewers, disease and 

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patient advocacy groups, regulators, 

drug and device manufacturers, health 

care providers, patients and their family 

members. Access to information 

contained in the data bank is intended 

to enhance patient enrollment in 

clinical trials and improve the evidencebase that informs clinical care, enhance 

public health and safety, increase the 

efficiency of drug and device 

development processes, and improve 

clinical research practice, among other 

uses. It is also intended to build public 

trust in clinical research by providing 

public access to the results of such 

research. These benefits are intangible. 

D. Costs Associated With the Proposed 

Rule 

The costs associated with this 

proposed rule consist of the time and 

effort necessary for responsible parties 

to comply with the proposed 

requirements to register applicable 

clinical trials; submit specified results 

information (including adverse event 

information); update and correct 

submitted registration and results 

information, as needed; submit 

certifications and/or extension requests 

to delay the deadline for submitting 

results information; submit information 

describing expanded access programs 

for drugs studied in an applicable 

clinical trial, and request waivers to any 

of the requirements for results 

submission. We do not intend this 

proposed rule to cause responsible 

parties to collect any information that 

was not already intended to be collected 

during the clinical trial (as described by 

the study protocol), nor do we intend 

this proposed rule to cause responsible 

parties to analyze such information in 

ways that were not intended, as 

described in the protocol or the 

associated statistical analysis plan. 

Rather, the rule specifies those elements 

of the collected results information and 

statistical analyses that must be 

submitted to the data bank and the 

format in which they must be 

submitted. 

The calculations below present our 

estimates of the time and cost associated 

with meeting the information 

submission requirements of this 

proposed rule, including the burden 

associated with assembling the required 

information, formatting the information 

for submission, submitting it to the data 

bank, and correcting or updating it over 

time. The calculations break out the 

estimated annual costs associated with: 

(1) registering a trial, (2) submitting 

results information (including adverse 

event information), (3) submitting 

certifications, extension requests and 

appeals to delay the results submission 

deadline, (4) submitting clinical trial 

information that is triggered by a 

voluntary submission; and (5) creating 

expanded access records for drugs 

studied in an applicable clinical trial. 

The estimates include the costs 

associated with updating submitted 

information and with correcting errors 

detected by NIH. We estimate the total 

annual cost to be $49,713,753. As 

explained below, we expect that during 

the first year after the effective date of 

this proposed rule, responsible parties 

will incur some additional time and cost 

to update clinical trial information that 

previously was submitted to the data 

bank for trials that were initiated prior 

to the effective date and ongoing as of 

that date. We estimate this additional, 

non-recurring cost to be $2,457,080. 

We expect that over time the cost of 

complying with this proposed rule will 

decline notably once a final rule is 

published and responsible parties 

become more familiar with the 

registration and results submission 

requirements as well as the data 

submission and review processes. Many 

data providers have developed standard 

operating procedures for data entry 

personnel and refined their data 

management systems to facilitate data 

submission. A number of clinical trial 

data management software tools 

currently allow users to output 

registration information for automatic 

uploading of files in bulk to 

ClinicalTrials.gov. We expect that once 

the requirements for submission of 

clinical trial information are clarified, 

responsible parties will automate 

portions of the data extraction and 

formatting processes for required results 

information, significantly reducing the 

burden of compliance with this 

proposed rule. 

TABLE 2—ESTIMATED ANNUAL COST OF PROPOSED RULE

Provision Proposed section(s) 

Estimated annual 

cost prior to 

rulemaking 

Estimated annual 

cost under the 

proposed rule 

Incremental cost 

above pre-rule 

data collection 

Registration of applicable clinical trials, including updates .. 11.28(a),(b), 11.64 ........ $11,005,132 $11,483,616 $478,484 

Results submission for applicable clinical trials, including 

updates.

11.48, 11.64 ................. 6,444,954 37,828,800 31,383,846 

Submission of certifications, extension requests, and appeals to delay results submission.11.44(b), (c), (e) ........... 189,783 261,990 72,207 

Triggered registration and results submission following voluntary submissions.11.60 ............................. 0 129,260 129,260 

Submission of expanded access records ............................. 11.28(c). ....................... 0 10,087 10,087 

Total ............................................................................... ....................................... 17,639,869 49,713,753 32,073,884 

1. Registration of Applicable Clinical 

Trials 

To estimate the costs of trial 

registration, we first estimated the 

number of applicable clinical trials that 

would be initiated in a given year and 

be subject to the provisions of this 

proposed rule. Using the approach 

described below, we estimate that a total 

of 7,400 applicable clinical trials of 

drugs (including biological products) 

and devices per year would be subject 

to the registration requirement of this 

proposed rule. This estimate is based on 

information from FDA indicating that it 

receives approximately 5,150 clinical 

trial protocol submissions annually for 

applicable clinical trials (76 FR 256, Jan. 

4, 2011). This figure includes protocol 

submissions to CDER, CBER, and CDRH; 

it does not include clinical trials that 

were not conducted under an IND or 

IDE. To estimate the number of such 

clinical trials, we examined the number 

of clinical trials registered with 

ClinicalTrials.gov that appear to meet 

the criteria of an applicable clinical trial 

but do not appear to have been 

conducted under an IND or IDE, e.g., 

because they are exempt. We found 

approximately 1,700 and 2,000 such 

clinical trials in 2012 and 2013, 

respectively. We increased this figure to 

2,250 to accommodate further growth in 

the number of such clinical trials that 

would be registered following 

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publication of the final rule. The sum of 

these figures (i.e., 5,150 plus 2,250 

equals 7,400) provides an estimate of 

the number of applicable clinical trials 

that would be subject to the registration 

requirement of this proposed rule each 

year. 

To calculate the burden associated 

with registering these clinical trials, we 

estimated the time required to submit 

complete clinical trial registration 

information for an applicable clinical 

trial. We estimate this time to be 8 

hours, including time to extract 

information from the study protocol, 

reformat it, and submit it to 

ClinicalTrials.gov. This figure is one 

hour more than the estimate used in the 

existing OMB Paperwork Reduction Act 

clearance for the ClinicalTrials.gov data 

collection (77 FR 22579, Apr. 16, 2012) 

to account for the additional data 

elements that would be required by this 

proposed rule. Applying this time 

estimate to the estimated number of 

applicable clinical trials yields a burden 

of 59,200 hours per year for registering 

applicable clinical trials. Based on our 

previous experience, we estimate that 

each registration record would be 

updated an average of 8 times during 

the course of the study (e.g., to reflect 

changes in the conduct of the clinical 

trial, additions of investigational sites, 

recruitment status updates). Although 

clinical trials of long duration and with 

multiple sites would likely submit more 

updates during the course of the trial, 

we have found that many applicable 

clinical trials have a relatively short 

duration and a limited number of study 

sites, which lowers the average per 

clinical trial. The time required for 

subsequent updates of clinical trial 

registration information is expected to 

be significantly less than for the original 

registration (as less information must be 

provided) and is estimated to be 2 hours 

per update. Using these figures, we 

calculated the annual hour burden for 

updates to clinical trial registration 

information to be 118,400 hours. 

Combining this figure with the 

estimated time for initial registrations 

(59,200 hours) yields an estimate of the 

total hour burden associated with the 

submission and updating of clinical trial 

registration information of 177,600 

hours per year. 

To calculate the cost of registration, 

we examined May 2011 data from the 

U.S. Bureau of Labor Statistics on the 

average wages of workers in the 

pharmaceuticals and medical 

equipment industries who are involved 

typically in submitting registration 

information. During the time we have 

operated ClinicalTrials.gov, we have 

found that this task is generally 

performed by junior-level researchers or 

administrative staff. For purposes of this 

estimate we used an average hourly 

wage rate of $32.33, which is equivalent 

to the weighted 25th percentile wage of 

a medical scientist in the 

pharmaceutical and medical equipment 

industries and is significantly higher 

than the median wage of other 

administrative staff in those sectors who 

sometimes submitting registration 

information to ClinicalTrials.gov. We 

doubled these wage figures (to $64.66 

per hour) to account for benefits and 

overhead. Using this adjusted wage 

figure, we calculated an estimated total 

annual cost of registration under the 

proposed rule, including updates over 

the course of a clinical trial, of 

$11,483,616 (Table 2). This figure 

represents an incremental increase of 

$478,484 per year above the estimated 

cost of registration under the existing 

OMB Paperwork Reduction Act 

clearance for the ClinicalTrials.gov data 

collection. 

2. Results Submission 

To estimate the burden associated 

with submission of clinical trial results 

information, we start from the premise 

that every clinical trial required to 

register in a given year would be 

required subsequently to submit results 

information. The statute requires results 

submission for all applicable clinical 

trials that study drugs (including 

biological products) or devices that are 

approved, cleared, or licensed by FDA; 

the proposed regulation would require, 

in addition, the submission of clinical 

results information for applicable 

clinical trials of drugs (including 

biological products) and devices that are 

not approved, cleared, or licensed by 

FDA. We therefore estimate the burden 

associated with results submission for a 

total of 7,400 applicable clinical trials of 

drugs (including biological products) 

and devices per year, recognizing that in 

most cases, such clinical trial results 

information would not be submitted in 

the same year as the associated clinical 

trial registration information but in 

accordance with the deadlines specified 

in proposed § 11.44. We expect, 

however, that on average the number of 

clinical trials for which clinical trial 

results information is submitted in any 

given year would approximate the 

number of new trials for which clinical 

trial registration information is 

submitted. 

To estimate an average amount of 

time required to submit clinical trial 

results information, we reviewed a 

variety of data sources, including 

publicly available information from 

various organizations about results 

submission times [Ref. 45], comments 

made at the April 2009 public meeting 

(Ref. 1), responses to the burden 

estimates included in the current and 

previous OMB clearance documents (77 

FR 22579, Apr. 16, 2012; 73 FR 58972, 

Oct. 8, 2008), feedback from 

respondents who tested preliminary 

versions of the data entry system during 

the summer of 2008, and feedback from 

those submitting data to the existing 

ClinicalTrials.gov system. These sources 

contain a wide-range of estimates, from 

as little as 6 hours to as long as 60 

hours. We believe the differences in 

these estimates reflect a number of 

factors, including the significant 

variation in the complexity of 

applicable clinical trials, in terms of 

their study design, number of outcome 

measures (primary and secondary), 

statistical analyses, and adverse event 

information. They also reflect 

differences in the responsible party’s 

familiarity with the clinical trial results 

information and the ClinicalTrials.gov 

submission process and the time they 

attribute to assembling the information 

for submission. Shorter estimates may 

be indicative of situations in which the 

responsible party already has assembled 

(and analyzed) the clinical trial results 

information for purposes of preparing a 

journal article or other summary report, 

while longer estimates may assume the 

clinical trial results information needs 

to be compiled. We expect that in most 

situations, the responsible party would 

have ready access to the necessary 

information because it is information 

that the clinical trial is conducted to 

collect and analyze (i.e., the information 

we propose for submission would have 

been collected during the trial, as 

specified in the protocol). Nevertheless, 

for purposes of this analysis, we 

selected an average time of 40 hours for 

initial submission of clinical trial results 

information, which corresponds to the 

higher range of estimates contained in 

several industry surveys and in other 

comments the Agency received. This 

figure represents an increase of 15 hours 

over the 25-hour estimate that was 

included in the most recent OMB 

Paperwork Reduction Act clearance for 

the ClinicalTrials.gov data collection 

and reflects the additional information 

that would be required to be submitted 

under this proposed rule. We expect the 

hour burden would decline as 

responsible parties become more 

familiar with ClinicalTrials.gov and 

implement procedures for streamlining 

data collection, analysis, and formatting. 

In the most recent OMB Paperwork 

Reduction Act clearance for the current 

ClinicalTrials.gov data collection, we 

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estimated that results information 

would be submitted for 1,845 applicable 

clinical trials per year, which is the 

estimated number of clinical trials that 

would have been included in marketing 

applications for drugs, biological 

products, and devices that were initially 

approved, licensed, or cleared by the 

FDA and subject to the basic results 

reporting provisions of FDAAA. Under 

this proposed rule, results information 

would be required for all applicable 

clinical trials that were subject to the 

registration requirement (i.e., an 

estimated 7,400 clinical trials per year). 

Applying the 40-hour figure to 7,400 

applicable clinical trials per year 

produces a total estimated burden of 

296,000 hours per year for submitting 

clinical trial results information. This 

figure compares to an estimated 46,125 

hours under the current information 

collection. 

We also estimate that, on average, 

each results record would be updated 

twice after the initial submission to 

reflect changes in data analysis or the 

submission of additional results from 

other pre-specified outcome measures. 

We estimate that each such update 

would take 10 hours, on average. This 

figure is 2 hours higher than the 8-hour 

estimate used in the OMB Paperwork 

Reduction Act clearance for the current 

ClinicalTrials.gov data collection and 

reflects ongoing experience with data 

submission to ClinicalTrials.gov. 

Applying these estimates to 7,400 

applicable clinical trials per year 

produces an estimate of 148,000 hours 

per year for updates to clinical trial 

results information (two updates per 

trial), compared to 29,520 hours for the 

1,845 applicable clinical trials estimated 

under the existing information 

collection. Combining the figure for 

updates with the estimate of the initial 

burden of submitting clinical trial 

results information, produces a total 

estimated annual hour burden for 

results submission under the proposed 

rule of 444,000 hours, compared with 

75,645 hours under the existing 

information collection. 

To calculate the economic cost of 

clinical trial results submission, we 

examined the average wages of workers 

in the pharmaceuticals and medical 

equipment industries who typically are 

involved in submitting clinical trial 

results information. Based on our 

experience in operating the results 

database and our consultations with 

data submitters, we believe that this task 

is performed generally by clinical 

researchers who are more experienced 

than those involved in registration. 

Based on May 2011 data from the U.S. 

Bureau of Labor Statistics, we use an 

average hourly wage rate of $42.60, 

which corresponds to the weighted 

median hourly wage of a medical 

scientist in the pharmaceutical and 

medical equipment manufacturing 

industries. We doubled this wage rate 

(to $85.20 per hour) to account for 

benefits and overhead. Using this 

adjusted wage rate, we estimate a total 

annual cost of results submission under 

this proposed rule, including updates, 

of $37,828,800 (Table 2). This represents 

an increase of $31,383,846 per year 

above the estimated $6,444,954 cost of 

results submission under the current 

information collection. 

3. Delayed Submission of Results via 

Certification or Extension Request 

We also have estimated the average 

time and cost associated with the 

submission of certifications and 

extension requests to delay results 

submission, consistent with proposed 

§§ 11.44(b), (c), and (e). Responsible 

parties for applicable clinical trials may 

submit a certification to delay results 

submission provided that initial 

approval or approval of a new use is 

sought. We estimate that the number of 

clinical trials that would qualify for 

delayed submission of results in a given 

year would not exceed the estimated 

number of newly initiated applicable 

clinical trials per year that are 

conducted under an IND or IDE. Such 

clinical trials would study drugs and 

devices that are unapproved, 

unlicensed, or uncleared or that are 

approved, licensed, or cleared but are 

studied for possible new uses. While 

some responsible parties might elect to 

submit clinical trial results information 

1 year after the completion date instead 

of delaying submission via a 

certification, for purposes of this 

estimate, we assume that they all will 

elect to submit a certification to delay 

results submission. (Note that the 

subsequent burden of submitting 

clinical trial results information is 

captured by the calculations in section 

2 above). Using the same FDA data as 

was used to estimate the number of 

applicable clinical trials subject to the 

registration requirements of this 

proposed rule, we estimate that 

certifications would be submitted for 

5,150 trials per year. We estimate that it 

would take no more than 30 minutes for 

a responsible party to determine that a 

clinical trial is eligible for a certification 

(and to verify the eligibility with a 

sponsor or manufacturer, if necessary) 

and to submit the necessary information 

through ClinicalTrials.gov. Using this 

figure produces an estimated annual 

hour burden of 2,575 hours for 

certifications. We estimate that the 

hourly wage of personnel who would 

submit the certification is the same as 

that for submitting clinical trial results 

information, or $42.60. Doubling this 

wage rate to account for benefits and 

overhead produces an annual estimated 

cost of $219,390 per year. 

For good-cause extension requests, we 

estimate that approximately 200 

requests will be submitted each year. 

This estimate is based on several 

considerations, including the rate of 

submission of requests between 

September 2008 and September 2010, 

when some 70 extension requests were 

submitted to ClinicalTrials.gov. In many 

cases, responsible parties did not need 

to submit an extension request in order 

to delay results submission; many of the 

submitted extension requests indicated 

that the estimated completion date of 

the applicable clinical trial had changed 

or that the clinical trial was not an 

applicable clinical trial subject to 

section 402(j) of the PHS Act. We would 

not expect an extension request to be 

submitted in these situations; rather, we 

would expect responsible parties to 

update their estimated completion date 

to reflect changes in the progress of the 

trial or to use the approach described in 

proposed § 11.22(b) and section 

IV.B.2(b) of this preamble to determine 

that the clinical trial is not an applicable 

clinical trial that is subject to this 

proposed rule. Excluding such 

unnecessary requests and considering 

only those submitted for applicable 

clinical trials for which the actual 

completion date had passed, we 

received approximately 20 requests per 

year. We expect that the number of 

extension requests will increase once a 

final rule is published and responsible 

parties have more clarity about the 

deadlines for submitting clinical trial 

results information. The estimated 200 

extension requests per year represent a 

10-fold increase over the annual rate of 

submissions to date and would be 

equivalent to four percent of all 

applicable clinical trials for which 

clinical trial results information is to be 

submitted in a given year (i.e., 200 out 

of 5,500). It would also represent more 

than 10 percent of the applicable 

clinical trials that do not delay results 

submission via certification. While 

responsible parties may request an 

extension request even after they have 

filed a certification, we expect this 

would happen infrequently. Moreover, 

as explained in section IV.C.3(d) of this 

preamble, we expect that extensions 

will be granted in only a limited set of 

circumstances where ‘‘good cause’’ has 

been demonstrated. In those cases in 

which an extension request is denied, 

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the responsible party would have the 

opportunity to appeal the denial. If we 

estimate that 50 percent of extension 

requests are denied and that 50 percent 

of denials result in an appeal, the 

number of appeals per year would total 

50. 

We estimate that the time required 

gathering the information required for a 

good-cause extension request or appeal 

and submitting it to ClinicalTrials.gov 

would be no more than 2 hours. Using 

this figure, we estimate that the 

annualized hourly burden for extension 

requests and appeals would be 500 

hours. We expect that requests will be 

submitted by those familiar with the 

results submission requirements and 

therefore use an hourly wage of $42.60. 

Doubling this wage rate (to $85.20) to 

account for benefits and overhead brings 

the annualized cost of extension 

requests to $42,600. Combining the 

estimated costs for certification and 

extension requests produces a total cost 

of $261,990 per year (Table 2). The most 

recent OMB Paperwork Reduction Act 

clearance for the ClinicalTrials.gov data 

collection estimated that 3,655 

certifications would be submitted by 

responsible parties seeking initial 

approval or approval of a new-use of a 

drug, biological product, or device 

studied in an applicable clinical trial 

and that 200 extension requests would 

be submitted per year. These figures 

would yield an estimated annual cost of 

$189,783, meaning that the incremental 

cost attributable to this rule would be 

$72,207 per year. 

4. Triggered Submission of Clinical 

Trial Information Following a Voluntary 

Submission 

Proposed § 11.60 implements section 

(402(j)(4)(A) of the PHS Act and 

indicates that if a responsible party 

voluntarily registers or submits results 

information for a clinical trial of an 

FDA-regulated drug or device that is not 

an applicable clinical trial subject to the 

mandatory clinical trial information 

submission requirements under the 

proposed part, that responsible party 

must, under specified circumstances, 

also submit information for other 

applicable clinical trials that are 

included in a marketing application or 

premarket notification that is submitted 

to FDA and for which clinical trial 

information has not already been 

submitted to ClinicalTrials.gov. The 

types of trials for which the voluntary 

submission of clinical trial information 

would invoke this requirement would 

include, e.g., phase 1 trials of drugs, 

small feasibility studies of devices 

(neither of which are considered to be 

applicable clinical trials), or applicable 

clinical trials that are not otherwise 

subject to section 402(j) of the PHS Act 

because they were initiated prior to the 

date of enactment of FDAAA and were 

no longer ongoing as of December 26, 

2007. The voluntary submission of 

clinical trial information for such trials 

would trigger a requirement to submit 

clinical trial information for other 

applicable clinical trials that are 

included in the marketing application 

for a drug or device, as long as the entity 

submitting the marketing application or 

premarket notification is the same as the 

responsible party for those other trial 

and still has access to and control over 

the necessary data. 

In practice, we expect that the 

requirement under section 402(j)(4)(A) 

of the PHS Act to submit clinical trial 

information for applicable clinical trials 

not otherwise registered in 

ClinicalTrials.gov would be triggered 

infrequently. In most cases, when 

clinical trial information is submitted 

voluntarily, we expect that the 

applicable clinical trials required to be 

submitted in a marketing application 

that includes the voluntarily-submitted 

clinical trial would have been required 

to be registered in ClinicalTrials.gov 

under section 402(j)(2)(C) of the PHS 

Act and this proposed part. For 

example, the voluntary submission of 

information for a phase 1 trial of an 

unapproved drug would trigger the 

submission of information for an 

applicable clinical trial only if that 

phase 1 trial were included in a 

marketing application that also included 

an applicable clinical trial (e.g., a phase 

2 clinical trial) that was not otherwise 

required to submit clinical trial 

information to ClinicalTrials.gov (e.g., 

because it completed before September 

27, 2007), and if the responsible party 

of the voluntarily-submitted trial were 

the same as the entity submitting the 

marketing application. For these 

reasons, we do not anticipate many 

clinical trials that are submitted 

voluntarily after the date of enactment 

of FDAAA to be associated—through an 

FDA marketing application—with 

applicable clinical trials that pre-date 

FDAAA. For purposes of this analysis, 

we estimate that 1 percent of the clinical 

trials registered voluntarily with 

ClinicalTrials.gov each year could 

trigger the submission of clinical trial 

information for an applicable clinical 

trial for which clinical trial information 

was not otherwise required to be 

submitted to ClinicalTrials.gov. Of the 

17,000 clinical trials that are registered 

every year, on average, with 

ClinicalTrials.gov, we estimate that 

9,600 are voluntary submissions (all but 

the 7,400 that are applicable clinical 

trials). Using this figure, voluntary 

registrations would trigger the required 

submission of clinical trials information 

for an estimated 96 clinical trials per 

year. Based on our experience to-date 

with voluntary submissions, we expect 

that for at least three-quarters of those 

triggered trials (72), registration 

information only would need to be 

submitted; for the other quarter, results 

information would need to be 

submitted. For those clinical trials for 

which only registration information is 

required, we estimate that it would take 

8 hours to register the clinical trial by 

a data submitter with an average hourly 

wage rate of $32.33 (consistent with the 

figures used for registration of 

applicable clinical trials). Doubling the 

wage rate to account for benefits and 

overhead produces an estimated cost of 

$37,244 per year. Submitted information 

would not generally need to be updated 

because the clinical trial would, in 

general, have reached its completion 

date by the time the requirement to 

submit clinical trial information is 

triggered and there would be few, if any, 

updates to report. For the remaining 

quarter of the triggered clinical trials 

(24) we estimate that the hourly burden 

would equal the 40 hours estimated for 

results submission for other applicable 

clinical trials plus 5 hours to account for 

the additional data elements that are 

specified in proposed § 11.60(a)(2)(i)(B). 

Using these figures and doubling the 

estimated average hourly rate of $42.60, 

we estimate the annual cost of 

submission as $92,016. Combining this 

figure with the $37,244 figure for 

triggered clinical trials that submit only 

registration information, produces a 

total annual estimated cost for the 

submission of clinical trial information 

triggered by the voluntary submission of 

information under proposed § 11.60 of 

$129,260 (Table 2). Because the 

submission of clinical trial information 

triggered by the voluntary submission of 

information was not included in the 

most recent OMB Paperwork Reduction 

Act clearance for the ClinicalTrials.gov 

data collection, the incremental cost 

attributable to this rule would be the 

full estimated cost of $129,260 per year. 

We note that a number of voluntary 

submissions of clinical trial information 

would likely be made to 

ClinicalTrials.gov each year. 

Responsible parties often register 

clinical trials voluntarily in order to 

assist in the recruitment of subjects or 

so that they may publish any resulting 

scientific papers in leading peerreviewed scientific journals. Because 

such clinical trials are not required to be 

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registered or to submit results 

information under section 402(j) of the 

PHS Act, we do not include them in this 

cost estimate. Because such information 

is submitted voluntarily to 

ClinicalTrials.gov, we do account for 

voluntary submissions in the estimates 

for Paperwork Reduction Act clearance. 

See section VII below. 

5. Expanded Access Records 

As specified in proposed § 11.28(a), if 

expanded access is available under 

section 561 of the Federal Food, Drug, 

and Cosmetic Act to a drug that is 

studied in an applicable drug clinical 

trial, the responsible party must include 

the NCT number of an expanded access 

record with the clinical trial information 

submitted at the time of registration. If 

an expanded access record for the drug 

has not yet been submitted to 

ClinicalTrials.gov, the responsible party 

must create an expanded access record 

by submitting the data elements listed 

§ 11.28(c). To determine the cost and 

burden associated with the creation of 

this record, we relied on information 

from the FDA that estimates that 10 

treatment INDs or treatment protocols 

and 68 expanded access programs for 

treatment of an intermediate size patient 

population are initiated annually. These 

are the two types of expanded access 

programs for which the information 

listed in § 11.28(c) must be submitted to 

ClinicalTrials.gov under this proposed 

rule (i.e., as explained in section IV.an 

expanded access record is not required 

if expanded access is available for 

treatment of an individual). We estimate 

the time required to submit the required 

information for an expanded access 

record to be 2 hours, which is onequarter of the estimated time to register 

an applicable clinical trial. An 

expanded access record requires only 

about one-half of the data elements 

required for an applicable clinical trial 

(22 versus 39) and does not require 

some of the more detailed data 

elements, such as Primary Outcome 

Measure, Secondary Outcome Measure, 

Individual Site Status, and Facility 

Location information. We therefore 

estimate the total hour burden 

associated with expanded access 

records to be 156 hours per year. We 

expect that expanded access records are 

submitted by staff with the same 

qualifications as those registering 

applicable clinical trials and, hence use 

an estimated hourly wage of $32.33. 

Doubling this wage rate (to $64.66) to 

account for benefits and overhead 

results in a total estimated annual cost 

of $10,087 (Table 1). Because the 

submission of expanded access records 

was not included in the most recent 

OMB Paperwork Reduction Act 

clearance for the ClinicalTrials.gov data 

collection, the incremental cost 

attributable to this rule is the full 

estimated cost of $10,087 per year. 

6. Non-Recurring Cost of Bringing 

Previously Submitted Registration 

Information Into Compliance With This 

Proposed Rule 

As discussed in section III.D of this 

preamble (‘‘Effective Date’’), we expect 

that a responsible party for any 

applicable clinical trial for which 

results information would be required to 

be submitted to ClinicalTrials.gov after 

the effective date of this rule would 

have to update any previously 

submitted clinical trial registration 

information by the compliance date to 

meet the requirements of proposed 

§ 11.28. The responsible party would 

need to submit any data elements 

specified in proposed § 11.28(a)) that 

were not submitted at the time the trial 

was registered and make sure the entries 

for all required data elements include 

the complete set of information defined 

in proposed § 11.10(b) (e.g., include all 

the specified elements of Study Design). 

To estimate the number of clinical 

trials that might require such updates, 

we searched ClinicalTrials.gov for 

clinical trials that were registered after 

the enactment of FDAAA (i.e., 

September 27, 2007) and appeared to 

meet the definition of an applicable 

clinical trial. We found nearly 3,700 

such clinical trials registered each year. 

Of those clinical trials, approximately 

1,800 per year had results information 

submitted to ClinicalTrials.gov and 

would therefore not require further 

submissions of results or updating of 

previously submitted registration 

information. Subtracting these 1,800 

clinical trials from the 3,700 trials that 

were registered each year results in an 

estimated 1,900 clinical trials per year 

that would be subject to this one-time 

updating. We estimate that if the final 

rule were to go into effect 5 years after 

enactment of FDAAA (e.g., December 

2013), there could be as many as 9,500 

registered applicable clinical trials for 

which results have not been submitted 

(i.e., 1,900 clinical trials per year 

multiplied by 5 years), although the 

actual number would probably be 

smaller because clinical trials that had 

been initiated earlier would be more 

likely to have reached their completion 

date prior to the effective date of the 

rule and to have submitted complete 

clinical trial results information. We 

estimate that the time required to 

update the registration information 

would be, on average, 4 hours, which is 

half the estimated time required to 

submit the full set of clinical trial 

registration information and reflects that 

fact that many registration data elements 

would already have been submitted and 

would not need updating. Applying this 

figure to the estimated 9,500 clinical 

trials produces an annual hour burden 

of 38,000 hours. Using an average wage 

of $32.33 (as for the registration 

calculation in 1 above) and doubling it 

to account for benefits and overhead 

yields an additional cost of $2,457,080. 

Note that this would be a one-time cost 

associated with updating registration 

information previously submitted to 

ClinicalTrials.gov, not a recurring 

annual cost. 

E. Alternatives to the Proposed Rule 

Section 402(j)(3)(D)(v)(VI) of the PHS 

Act requires the Secretary to promulgate 

regulations to expand the registry and 

results data bank and to address specific 

issues that are enumerated in the 

statute. Section 402(j)(2)(A)(iii) of the 

PHS Act also authorizes the Secretary to 

make additions or modifications to the 

statutory enumerated clinical trial 

information required for registration. 

This proposed rule implements and 

expands the basic provisions mandated 

by section 402(j) of the PHS Act that 

became effective prior to rulemaking on 

the schedule established by the statute. 

The preamble describes various 

alternatives considered by the Agency 

in exercising its authority to add or 

modify the statutory provisions and in 

addressing the topics it was required to 

address via regulation. It also describes 

alternatives it considered in 

implementing statutory provisions of 

the law that were not required 

specifically to be addressed by 

regulation. It also invites comments on 

alternative approaches. 

F. Regulatory Flexibility Act 

The RFA (5 U.S.C. 601–612) requires 

agencies to analyze regulatory options 

that would minimize any significant 

impact of a rule on small entities. This 

proposed rule would affect a number of 

small entities that conduct clinical trials 

of drugs and devices, but the Agency 

estimates that the costs incurred by 

small entities would be limited, 

especially in relation to the other costs 

associated with conducting a clinical 

trial. As explained below, the Agency 

believes that the final rule is not likely 

to have a significant economic impact 

on a substantial number of small 

entities. 

The companies that would be affected 

by this proposed rule are classified in 

seven separate North American 

Industrial Classification System 

(NAICS) categories by the Census 

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Bureau. The affected industries are 

NAICS 325412—Pharmaceutical 

Preparation; NAICS 325414—Biological 

Products (except diagnostic); NAICS 

334510—Electromedical and 

Electrotherapeutic Apparatus; NAICS 

339112—Surgical and Medical 

Instrument; NAICS 339113—Surgical 

Appliance and Supplies; NAICS 

339114—Dental Equipment and 

Supplies; NAICS 339115—Ophthalmic 

Goods. The Small Business 

Administration (SBA) size standards for 

all these industries define small entities 

as those companies with less than 500 

employees, except for pharmaceutical 

preparation, for which it defines a small 

entity as one with less than 750 

employees. The most recent data from 

the U.S. Census of Manufacturers that 

offers the level of detail for 

establishments at or near the employee 

size limits as defined by SBA is from 

2007. In each of these establishment size 

categories, large majorities of the 

establishments meet the criteria as small 

entities. Even taking into account that 

many of these establishments are parts 

of multi-establishment corporations, 

significant numbers of companies 

would still qualify as small entities and 

have fewer than 100 employees across 

all of these categories. Although the 

Agency expects that most companies 

sponsoring applicable clinical trials 

would be larger than the average-sized 

company in their industry, the Agency 

concludes that a substantial number of 

companies would still qualify as small 

entities. 

The cost analysis presented above 

indicates an estimated cost of 

compliance with this proposed rule of 

$6,718 per applicable clinical trial 

($49,713,753 for 7,400 clinical trials per 

year). While some larger firms could be 

the responsible party for multiple 

applicable clinical trials in the same 

year, we expect most small firms would 

be responsible for no more than one 

applicable clinical trial per year. Using 

data from the 2007 Census of 

Manufacturers, the average value of 

shipments for establishments in these 

industries with one to four employees 

ranged from $353,000 to $844,000. 

Assuming that such small operations 

had one applicable clinical trial that 

was required to submit registration or 

results information each year, the costs 

of this proposed rule would represent, 

at most, 1.9 percent of the annual value 

of shipments. For establishments with 

50 to 99 employees, the costs of this 

proposed rule would represent at most 

0.6 percent of the value of shipments, 

even if they were responsible for 10 

applicable clinical trials administered 

annually. For establishments with 100 

or more employees, the costs of this 

proposed rule would represent at most 

0.24 percent of the value of shipments 

even with 10 applicable clinical trials 

administered annually. These figures 

are well below the threshold of 3 to 5 

percent of the total revenue for small 

entities needed to consider that this 

proposed rule would have a significant 

economic impact on a substantial 

number of small entities. The Agency 

concludes that this proposed rule would 

not have a significant economic impact 

on a substantial number of small 

entities. 

In practice, we expect the burden on 

small firms would be significantly lower 

than this estimate. In general the 

applicable clinical trials initiated by 

small firms would be less complex than 

the applicable clinical trials initiated by 

large firms, including, for example, 

fewer trial locations (sites), shorter 

duration, and fewer outcome measures. 

As a result, the amount of results 

information to be submitted—and the 

time and cost associated with such 

submissions—would be less than for 

larger entities and represent a smaller 

share of shipments. In addition, these 

costs would affect only a fraction of 

small firms in any given year. For 

example, by our estimates registration 

information would be required to be 

submitted (and results information 

subsequently submitted) for 

approximately 500 applicable device 

clinical trials in any given year. 

Information from the 2007 Census of 

Manufacturers indicates that there are 

approximately 5,600 companies in the 

United States that are involved in the 

manufacture of medical devices and that 

almost 4,900 of them have fewer than 

100 employees. Even if no company 

engaged in more than one applicable 

clinical trial at the same time, then on 

average, less than 10 percent of all 

medical device manufacturers would 

initiate a trial subject to the registration 

and results submission requirements of 

this proposed rule in any given year 

(500 applicable device clinical trials per 

year divided by 5,600 firms equals 0.089 

or 8.9 percent). 

G. Unfunded Mandates Reform Act of 

1995 

Section 1352(a) of the Unfunded 

Mandates Reform Act of 1995 requires 

that the agency prepare, among other 

things, a written statement which 

includes an assessment of anticipated 

costs and benefits before proposing ‘‘any 

rule that includes any Federal mandate 

that may result in the expenditure by 

State, local, and Tribal governments, in 

the aggregate, or by the private sector, of 

$100,000,000 or more (adjusted 

annually for inflation) in any 1 year.’’ 2 

U.S.C. 1532(a). The current threshold, 

adjusted for inflation using the 2012 

Implicit Price Deflator for the Gross 

Domestic Product, is $141 million. As 

indicated above, we do not expect the 

direct burden of this proposed rule, 

including the cost of compiling, 

submitting, and updating clinical trial 

registration and results information for 

applicable clinical trials, to result in any 

1-year expenditure that would meet or 

exceed this amount. Nor do we expect 

that State or local governments would 

bear a significant fraction of this cost, as 

most of the entities affected by the 

proposed regulation would be private 

entities. As a result, we conclude that 

this rule will have no consequential 

effect on State, local, or tribal 

governments or on the private sector. 

We have determined that this proposed 

rule would not constitute a significant 

rule under the Unfunded Mandates 

Reform Act of 1995, because it would 

impose no mandates with costs 

exceeding the current threshold. 

H. Federalism 

Executive Order 13132, Federalism, 

establishes certain requirements that an 

Agency must meet when it promulgates 

a proposed rule (and subsequent final 

rule) ‘‘that imposes substantial direct 

compliance costs on State and local 

governments,’’ preempts State law, or 

otherwise has federalism implications. 

The Agency has analyzed this proposed 

rule in accordance with the principles 

set forth in Executive Order 13132 and 

has determined that this proposed rule 

does not contain policies that would 

impose any ‘‘substantial direct 

compliance costs on State or local 

governments[.]’’ This proposed rule, 

does, however, have federalism 

implications. 

Section 801(d)(1) of FDAAA expressly 

provides a preemption provision as 

follows: ‘‘Upon the expansion of the 

registry and results data bank under 

section 402(j)(3)(D) of the Public Health 

Service Act . . . no State or political 

subdivision of a State may establish or 

continue in effect any requirement for 

the registration of clinical trials or for 

the inclusion of information relating to 

the results of Clinical trials in a 

database.’’ We interpret this language to 

prohibit a State or political subdivision 

of a State from establishing any 

requirement for the inclusion of 

information in a database that is: (1) 

Clinical trial registration information, as 

that term is defined in § 11.10, i.e., the 

actual registration data elements; (2) 

clinical trial results information 

required to be submitted under section 

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402(j)(3) of the PHS Act and this part; 

or (3) information that is otherwise 

collected through any data element in 

ClinicalTrials.gov, such as information 

relating to voluntary submissions and 

other information whether or not 

required to be submitted under section 

402(j) of the PHS Act and this part. We 

do not interpret section 801(d)(1) of 

FDAAA to preempt other types of 

reporting and/or data collection that 

States may require related to public 

health, disease surveillance, clinical 

care, or the practice of medicine such as 

patient and disease registries or public 

health surveillance registries. 

Following publication of this 

proposed rule, the Agency will further 

consult with appropriate State officials 

and organizations to review the scope of 

this proposed rule and to seek input on 

federalism issues. We specifically solicit 

comments on this proposed rule from 

representatives of State and local 

governments. 

VII. Paperwork Reduction Act of 1995 

This proposed rule contains 

requirements that are subject to review 

by OMB under the Paperwork 

Reduction Act of 1995 (44 U.S.C. 3501– 

3520) (PRA). Sections 11.28, 11.48, 

11.60, 11.62, and 11.64 of this proposed 

rule contain information collection 

requirements that are subject to OMB 

approval. A revision of the existing PRA 

clearance for clinical trial registration 

and results submission (OMB 0925– 

0586) to meet the requirements of this 

proposed Part will be submitted to OMB 

for review. 

A description of the information 

collection requirements included in this 

proposed rule is provided in the 

Regulatory Impact Statement (section V) 

and is summarized in this section of the 

preamble with an estimate of the 

annualized burden hours. Included in 

this estimate is the time for reviewing 

instructions, searching existing data 

sources, gathering and maintaining the 

data needed, and completing, reviewing, 

updating, and correcting each collection 

of information. The Agency invites 

comments on: (1) Whether the proposed 

collection of information is necessary 

for the proper performance of the 

functions of NIH, including whether the 

information will have practical utility; 

(2) the accuracy of the estimate of the 

burden of the proposed collection of 

information by NIH, including the 

validity of the methodology and 

assumptions used; (3) ways to enhance 

the quality, utility, and clarity of the 

information to be collected; and (4) 

ways to minimize the burden of the 

collection of information on 

respondents, including through the use 

of automated collection techniques, 

when appropriate, and other forms of 

information technology . 

The information collection provisions 

of this proposed rule will be submitted 

to OMB for review. Other organizations 

and individuals desiring to submit 

comments on the information collection 

and submission requirements should 

send their comments by February 19, 

2015 to (1) Ms. Seleda Perryman, Project 

Clearance Officer, National Institutes of 

Health, Rockledge Centre 1, 6705 

Rockledge Drive, Room 3509, Bethesda, 

Maryland 20817, telephone 301–594– 

7949 (not a toll-free number); and (2) the 

Office of Information and Regulatory 

Affairs, OMB, OIRA_submission@

omb.eop.gov, or by fax to 202–395– 

6974, and mark ‘‘Attention: Desk Officer 

for the National Institutes of Health, 

Department of Health and Human 

Services.’’ After we obtain OMB 

approval, we will publish the OMB 

control number in the Federal Register. 

The estimate includes the annual 

hourly burden for submission, updating, 

and correction of information both for 

applicable clinical trials that are subject 

to this proposed rule and for the larger 

number of clinical trials for which 

information is submitted to 

ClinicalTrials.gov on a voluntarily basis 

in order to recruit subjects, remain 

eligible to publish summary articles in 

scientific journals that follow the 

guidelines of the ICMJE, to comply with 

company or other organizational 

policies regarding public disclosure of 

clinical trial information, or for other 

purposes. 

The burden for trials that are subject 

to this regulation follows the estimates 

presented in section V of this preamble. 

They differ from the burden estimates 

contained in the current OMB 

Paperwork Reduction Act clearance in 

several ways. For registration, we have 

increased from 5,500 to 7,400 the 

estimate of the number of clinical trials 

that would be subject to mandatory 

registration under the rule. This 

increase reflects the revised estimate of 

the number of protocols for applicable 

clinical trials that are submitted to the 

FDA for under and IND or IDE. We also 

increased the estimated hour burden of 

registration from 7 hours to 8 hours to 

reflect the additional data elements that 

would be required under this proposed 

rule. For results submission we have 

increased from 1,845 to 7,400 our 

estimate of the number of clinical trials 

that would be subject to mandatory 

results submission under this proposed 

rule. This proposed rule would require 

the submission of results information 

for all registered applicable clinical 

trials, regardless of whether or not the 

drug (including biological product) or 

device under study in the trial is 

approved, licensed, or cleared. We have 

made commensurate increases in the 

estimated number of clinical trials for 

which a certification to delay results 

submission would be submitted. We 

have also increased the estimated hour 

burden for submitting results 

information from 25 hours to 40 hours 

to account for the additional results 

information that would be required to 

be submitted under this proposed rule. 

In addition, we have added estimates of 

the burden associated with the 

submission of registration and results 

information that could be triggered by 

some voluntary submissions of clinical 

trial information under proposed 

§ 11.60. Finally, we have included a 

separate estimate of the burden 

associated with the creation of an 

expanded access record if a drug that is 

studied in an applicable clinical trial is 

available via an expanded access 

program. 

TABLE 3—ESTIMATED BURDEN FOR REGISTRATION AND RESULTS SUBMISSION AT CLINICALTRIALS.GOV

Type of respondents Number of 

respondents Frequency of response 

Average time 

per response 

(hours) 

Annual hour 

burden 

Regulated submissions [Subject to this proposed rule]: 

Registration ............................................. 7,400 1 Initial ...........................................................

8 Subsequent Updates .................................

8 

2 

59,200 

118,400 

Results Information ................................. 7,400 1 Initial ...........................................................

2 Subsequent Updates .................................

40 

10 

296,000 

148,000 

Certifications to delay results ................. 5,150 1 .................................................................... 0 .5 2,575 

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TABLE 3—ESTIMATED BURDEN FOR REGISTRATION AND RESULTS SUBMISSION AT CLINICALTRIALS.GOV—Continued 

Type of respondents Number of 

respondents Frequency of response 

Average time 

per response 

(hours) 

Annual hour 

burden 

Extension requests and appeals ............ 250 1 .................................................................... 2 500 

Registration triggered by voluntary submission.72 1 .................................................................... 8 576 

Results triggered by voluntary submission.24 1 .................................................................... 45 1,080 

Expanded access records ...................... 78 1 .................................................................... 2 156 

SUBTOTAL ...................................... ........................ ........................................................................ .......................... 626,487 

Non-regulated submissions [Not subject to 

this Proposed Rule]: 

Registration ............................................. 9,600 1 Initial ...........................................................

8 Subsequent Updates .................................

8 

2 

76,800 

153,600 

Results Information ................................. 350 1 Initial ...........................................................

2 Subsequent Updates .................................

40 

10 

14,000 

7,000 

SUBTOTAL ...................................... ........................ ........................................................................ .......................... 251,400 

TOTAL ...................................... ........................ ........................................................................ .......................... 877,887 

In order to estimate the burden for 

clinical trials that are not subject to this 

proposed rule, we examined 

ClinicalTrials.gov to determine how 

many clinical trials were registered 

during calendar years 2008 through 

2011. We found that there were, on 

average, some 17,000 studies registered 

per year, and that the number was 

consistent across the 3-year period. We 

therefore believe it is a reasonable 

estimate of total registrations in future 

years. We subtracted from this total 

7,400 clinical trials to account for those 

applicable clinical trials that would be 

subject to mandatory submissions under 

this proposed rule. The remaining 9,600 

clinical trials registered would not be 

subject to section 402(j) of the PHS Act, 

e.g., because they are studies of 

interventions not regulated by FDA, are 

phase 1 studies of drugs or feasibility 

studies of devices, are observational 

studies, or otherwise fail to meet the 

definition of an applicable clinical trial. 

This figure represents a reduction (from 

11,500) in the number of non-regulated 

submissions to ClinicalTrials.gov that 

was contained in our previous OMB 

Paperwork Reduction Act clearance. 

These clinical trials would be expected 

to have the same clinical trial 

registration information submitted for 

them as is submitted for applicable 

clinical trials that are subject to this 

proposed rule. We expect that 

information submitted for such clinical 

trials will be updated as frequently as 

for clinical trials that are subject to the 

rule. Therefore, for calculating the 

registration burden associated with 

voluntarily submitted clinical trials, we 

use the same assumptions as for 

applicable clinical trials required to 

register under section 402(j)(2)(C) of the 

PHS Act: initial submission of 

registration information will take an 

average of 8 hours, updates of 2 hours 

apiece will take place 8 times during the 

course of the study. Applying these 

figures yields an estimated annual 

burden of 230,400 hours, of which 

76,800 derives from the initial 

registration and 153,600 derives from 

updates (Table 3). 

As for results submission, we do not 

expect that clinical trial results 

information will be submitted for most 

of the clinical trials for which 

registration information is submitted 

voluntarily (non-regulated). To estimate 

of the number of clinical trials for which 

results information would be submitted 

voluntarily, we reviewed the more than 

7,000 results records that have been 

posted publicly at ClinicalTrials.gov 

since late 2008. Of these, about 1,050, or 

350 per year, appear to be for studies 

that are unambiguously not applicable 

clinical trials, e.g., observational 

studies, clinical trials of interventions 

other than drugs (including biological 

products) and devices, and phase 1 

clinical trials of drugs. We expect that 

this number of results submissions 

would continue to be made in future 

years. We estimate that the time 

required to submit clinical trial results 

information for such clinical trials 

would be equivalent to that for 

applicable clinical trials required to 

register under section 402(j)(2)(C) of the 

PHS Act. Using those figures, we 

estimate that the total annual hour 

burden for submitting clinical trial 

results information for voluntarily 

submitted clinical trials would be 

14,000 hours, plus 7,000 hours for 

updates (Table 3). Thus the total burden 

associated with the voluntary 

submission of clinical trial information 

is 251,400 hours, and the total annual 

burden for regulated and unregulated 

submissions of information would be 

877,887 hours. 

VIII. Congressional Review Act 

The U.S. Department of Health and 

Human Services has determined that 

this proposed rule is not a major rule as 

defined in 5 U.S.C. 804, and, thus, does 

not require review by Congress. The 

Congressional Review Act (5 U.S.C. 

801–808) defines a major rule as one 

that the Administrator of the Office of 

Information and Regulatory Affairs of 

the Office of Management and Budget 

finds has resulted in or is likely to result 

in (A) an annual effect on the economy 

of $100,000,000 or more; (B) a major 

increase in costs or prices for 

consumers, individual industries, 

Federal, State, or local government 

agencies, or geographic regions; or ‘(C) 

significant adverse effects on 

competition, employment, investment, 

productivity, innovation, or on the 

ability of United States-based 

enterprises to compete with foreignbased enterprises in domestic and 

export markets. (5 U.S.C. 804). 

As described in section V of this 

preamble (Regulatory Impact 

Statement), we estimate that the rule 

will impose annual costs on responsible 

parties (i.e., sponsors of clinical trials or 

designated principal investigators) of 

less than $50 million. We do not believe 

such costs are significant enough to 

affect prices of the drugs (including 

biological products) or medical devices 

that eventually may be approved, 

cleared, or licensed for marketing by 

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FDA. Nor do we believe that the 

submission and public availability of 

clinical trial information, as required by 

this proposed rule, will have significant 

adverse effects on competition, 

employment, investment, productivity, 

or innovation in organizations that are 

subject to this proposed rule. This 

proposed rule contains provisions to 

delay the public posting of information 

that might be considered commercially 

relevant, including registration 

information for trials of previously 

unapproved or uncleared devices and 

results information for trials of 

unapproved products. In addition, this 

proposed rule would apply to all 

organizations, domestic and 

international, that are subject to FDA 

regulation (i.e., because they are 

conducting a trial under an IND or IDE 

or are seeking marketing approval from 

FDA). Thousands of organizations have 

submitted information similar to the 

clinical trial registration information 

proposed in this rule to publicly 

available registries, including 

ClinicalTrials.gov, for more than a 

decade on a voluntary basis. Many have 

also made results information publicly 

available, though not in a consistent 

manner. 

In accordance with the provisions of 

Executive Order 12866, this proposed 

rule was reviewed by the Office of 

Management and Budget. 

IX. Legal Authority 

These proposed regulations are issued 

under the authorities contained in 42 

U.S.C. 282(i); 42 U.S.C. 282(j); 5 U.S.C. 

301; 42 U.S.C. 286(a); 42 U.S.C. 241(a); 

42 U.S.C. 216(b); and sections 801(c)– 

(d), Pub. L. 110–85, 121 Stat. 921–922 

(42 U.S.C. 282(note)). 

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Services; April 27, 2006, available at http:// 

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from the Commission—Guidance on the 

information concerning paediatric clinical 

trials to be entered into the EU Database on 

Clinical Trials (EudraCT) and on the 

information to be made public by the 

European Medicines Agency (EMEA), in 

accordance with Article 41 of Regulation (EC) 

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regarding the guideline on the data fields 

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provided for in Article 11 of Directive 2001/ 

20/EC to be included in the database on 

medicinal products provided for in Article 57 

of Regulation (EC) No 726/2004,’’ Official 

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7, 2008, available at http://ec.europa.eu/

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to be made public from EudraCT for 

Paediatric Clinical Trials in accordance with 

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and its implementing guideline 2009/C28/

01,’’ February 4, 2009, available at http://ec.

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02_04_guidelines_paed_en.pdf. 

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CONSORT statement for reporting 

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elaboration,’’ Annals of Internal Medicine. 

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ReviewItems.pdf. 

34. Tse, T., et al., ‘‘Reporting ‘‘basic 

results’’ in ClinicalTrials.gov,’’ Chest. 136(1): 

295–303, 2009. 

35. Bent, S., et al., ‘‘Brief communication: 

Better ways to question patients about 

adverse medical events: a randomized, 

controlled trial,’’ Annals of Internal 

Medicine. 144(4): 257–61, 2006. 

36. Rief, W., et al., ‘‘Medication-attributed 

adverse effects in placebo groups: 

implications for assessment of adverse 

effects,’’ Archives of Internal Medicine. 

166(2): 155–60, 2006. 

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effect reporting in placebo groups in SSRI 

and tricyclic antidepressant trials: a 

systematic review and meta-analysis,’’ Drug 

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of harms in randomized trials: an extension 

of the CONSORT statement,’’ Annals of 

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39. Office of Human Research Protections, 

‘‘Guidance on Reviewing and Reporting 

Unanticipated Problems Involving Risks to 

Subjects or Others and Adverse Events,’’ U.S. 

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available at http://www.hhs.gov/ohrp/policy/ 

advevntguid.html. 

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Harmonisation of Technical Requirements for 

Registration of Pharmaceuticals for Human 

Use (ICH), ‘‘ICH E6(R1): Guideline for Good 

Clinical Practice,’’ June 10, 1996, available at 

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41. Food and Drug Administration, 

‘‘Guidance for Sponsors, Institutional Review 

Boards, Clinical Investigators and FDA Staff: 

Guidance on Informed Consent for In Vitro 

Diagnostic Device Studies Using Leftover 

Human Specimens that are Not Individually 

Identifiable,’’ U.S. Department of Health and 

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policy/clin_trials.html. 

43. Office of Extramural Research, National 

Institutes of Health, ‘‘Clarification of 

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44. National Library Medicine. National 

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List of Subjects in 42 CFR Part 11 

Biologics, Clinical trial, Data bank, 

Drugs, Human subjects research, 

Medical devices, Medical research, 

Registry, Reporting and recordkeeping 

requirements, Results information. 

For the reasons stated in this 

preamble, the Department of Health and 

Human Services proposes to amend 

Title 42, Chapter I of the Code of 

Federal Regulations by adding a Part 11 

to read as follows. 

PART 11—CLINICAL TRIAL 

REGISTRATION AND RESULTS 

SUBMISSION 

Subpart A—General Provisions 

Sec. 

11.2 What is the purpose of this part? 

11.4 To whom does this part apply? 

11.6 What are the requirements for the 

submission of truthful information? 

11.8 In what form and manner must clinical 

trial information be submitted? 

11.10 What definitions apply to this part? 

Subpart B—Registration 

Sec. 

11.20 Who must submit clinical trial 

registration information? 

11.22 Which applicable clinical trials must 

be registered? 

11.24 When must clinical trial registration 

information be submitted? 

11.28 What constitutes clinical trial 

registration information? 

11.35 By when will NIH post clinical trial 

registration information submitted under 

§ 11.28? 

Subpart C—Results Submission 

Sec. 

11.40 Who must submit clinical trial results 

information? 

11.42 For which applicable clinical trials 

must clinical trial results information be 

submitted in accordance with subpart C 

of this regulation? 

11.44 When must clinical trial results 

information be submitted for applicable 

clinical trials subject to § 11.42? 

11.48 What constitutes clinical trial results 

information? 

11.52 When will NIH post submitted 

clinical trial results information? 

11.54 What are the procedures for waiving 

of the requirements of this subpart? 

Subpart D—Additional Submissions of 

Clinical Trial Information 

Sec. 

11.60 What requirements apply to the 

voluntary submission of clinical trial 

information for clinical trials of FDAregulated drugs and devices? 

11.62 What requirements apply to 

applicable clinical trials for which 

submission of clinical trial information 

has been determined by the Director to 

be necessary to protect the public health? 

11.64 When must clinical trial information 

submitted to ClinicalTrials.gov be 

updated? 

11.66 What are the requirements for 

corrections of clinical trial information? 

Authority: 42 U.S.C. 282(i); 42 U.S.C. 

282(j); 5 U.S.C. 301; 42 U.S.C. 286(a); 42 

U.S.C. 241(a); 42 U.S.C. 216(b) 

Subpart A—General Provisions 

§ 11.2 What is the purpose of this part? 

This part implements section 402(j) of 

the Public Health Service Act [42 U.S.C. 

282(j)] by providing requirements and 

procedures for the submission of 

clinical trial information for certain 

applicable clinical trials and other 

clinical trials to the Director of the 

National Institutes of Health (NIH) to be 

made publicly available via 

ClinicalTrials.gov, the Internetaccessible clinical trial registry and 

results data bank established by the 

National Library of Medicine (NLM) at 

http://www.clinicaltrials.gov. 

§ 11.4 To whom does this part apply? 

(a) This part applies to the responsible 

party for an applicable clinical trial that 

is required to be registered under 

§ 11.22 or a clinical trial for which 

clinical trial registration information or 

clinical trial results information is 

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submitted voluntarily in accordance 

with § 11.60. 

(b) The responsible party must 

communicate the identity and contact 

information of the responsible party to 

the Director by submitting the 

Responsible Party Contact Information 

data element under § 11.28(a)(4)(vii) as 

part of the clinical trial information 

submitted at the time of registration. 

Changes to Responsible Party Contact 

Information must be communicated to 

the Director by updating this 

information not later than 30 calendar 

days after the change has occurred, as 

specified in § 11.64(b)(1)(ix) and 

§ 11.64(b)(1)(x). 

(c) Determination of responsible 

party. For purposes of this part, each 

applicable clinical trial or other clinical 

trial must have one responsible party. 

With respect to a clinical trial, the 

sponsor of the clinical trial will be 

considered the responsible party unless 

and until a principal investigator has 

been designated the responsible party, 

in accordance with paragraph (c)(2) of 

this section. With respect to a pediatric 

postmarket surveillance of a device that 

is not a clinical trial, the responsible 

party is the entity whom FDA orders to 

conduct the pediatric postmarket 

surveillance of a device. 

(1) Determination of sponsor. For 

purposes of this part, each applicable 

clinical trial or other clinical trial must 

have one sponsor. 

(i) When an applicable clinical trial or 

other clinical trial is conducted under 

an investigational new drug application 

(IND) or investigational device 

exemption (IDE), the IND or IDE holder 

will be considered the sponsor. 

(ii) When an applicable clinical trial 

or other clinical trial is not conducted 

under an IND or IDE, the single person 

or entity who initiates the trial, by 

preparing and/or planning the trial, and 

who has authority and control over the 

trial, will be considered the sponsor. 

(2) Designation of a principal 

investigator as the responsible party. (i) 

The sponsor may designate a principal 

investigator as the responsible party if 

such principal investigator meets all of 

the following: 

(A) Is responsible for conducting the 

trial; 

(B) Has access to and control over the 

data from the trial; 

(C) Has the right to publish the results 

of the trial; and 

(D) Has the ability to meet all of the 

requirements for submitting and 

updating clinical trial information as 

specified in this part. 

(ii) With regard to an applicable 

clinical trial or other clinical trial, a 

designation by the sponsor under 

paragraph (c)(2)(i) of this section shall 

consist of the sponsor providing notice 

of the designation to the principal 

investigator and obtaining from the 

principal investigator an 

acknowledgement of the principal 

investigator’s responsibilities under this 

part as responsible party, and the 

principal investigator acknowledging 

the designation as responsible party to 

the Director in the form and manner 

specified at http://

prsinfo.clinicaltrials.gov. 

(3) Withdrawal of the designation of a 

principal investigator as the responsible 

party. (i) In the event a principal 

investigator who has been designated 

the responsible party becomes unable to 

meet all the requirements for being so 

designated under paragraph (c)(2)(i) of 

this section, the principal investigator 

must withdraw the designation in the 

form and manner specified at http://

prsinfo.clinicaltrials.gov, at which time 

the sponsor will be considered the 

responsible party unless and until the 

sponsor makes a new designation in 

accordance with paragraph (c)(2) of this 

section. 

(ii) In the event a principal 

investigator who has been designated 

the responsible party is unable because 

of death or incapacity to withdraw his 

or her designation, the sponsor will be 

considered the responsible party unless 

and until the sponsor makes a new 

designation in accordance with 

paragraph (c)(2) of this section. 

§ 11.6 What are the requirements for the 

submission of truthful information? 

(a) General. The clinical trial 

information submitted by a responsible 

party under this part shall not be false 

or misleading in any particular. 

Submission of false and/or misleading 

information would subject the 

responsible party to civil, criminal, and/ 

or administrative liability under U.S. 

law. 

(b) Certification. The responsible 

party must certify that, to the best of his 

or her knowledge, the information 

submitted is truthful and not misleading 

and that he or she is aware that the 

submission of false and/or misleading 

information would subject the 

responsible party to civil, criminal, and/ 

or administrative liability under U.S. 

law. 

§ 11.8 In what form and manner must 

clinical trial information be submitted? 

Information submitted under this part 

must be submitted electronically to 

ClinicalTrials.gov, the Internetaccessible clinical trial registry and 

results data bank established by the 

National Library of Medicine, in the 

form and manner specified at http://

prsinfo.clinicaltrials.gov. 

§ 11.10 What definitions apply to this part? 

(a) The following definitions apply to 

terms used in this part: Adverse event 

means any untoward or unfavorable 

medical occurrence in a human subject, 

including any abnormal sign (for 

example, abnormal physical exam or 

laboratory finding), symptom, or 

disease, temporally associated with the 

subject’s participation in the research, 

whether or not considered related to the 

subject’s participation in the research. 

See also serious adverse event. 

Applicable clinical trial means an 

applicable device clinical trial or an 

applicable drug clinical trial. 

Applicable device clinical trial means: 

(1) A prospective clinical study of 

health outcomes comparing an 

intervention with a device subject to 

section 510(k), 515, or 520(m) of the 

Federal Food, Drug, and Cosmetic Act 

against a control in human subjects 

(other than a small clinical trial to 

determine the feasibility of a device, or 

a clinical trial to test prototype devices 

where the primary outcome measure 

relates to feasibility and not to health 

outcomes); and (2) a pediatric 

postmarket surveillance as required 

under section 522 of the Federal Food, 

Drug, and Cosmetic Act. 

Applicable drug clinical trial means a 

controlled clinical investigation, other 

than a phase 1 clinical investigation, of 

a drug subject to section 505 of the 

Federal Food, Drug, and Cosmetic Act 

or to section 351 of the Public Health 

Service Act, where ‘‘clinical 

investigation’’ has the meaning given in 

21 CFR 312.3 (or any successor 

regulation) and ‘‘phase 1’’ has the 

meaning given in 21 CFR 312.21 (or any 

successor regulation). In addition, a 

clinical trial of a combination product, 

where such combination product meets 

the definition in 21 CFR 3.2(e), shall be 

considered an applicable drug clinical 

trial, so long as the clinical trial of the 

combination product is a controlled 

clinical investigation, other than a phase 

1 clinical investigation, and the 

combination product is subject to 

section 505 of the Federal Food, Drug, 

and Cosmetic Act and/or section 351 of 

the Public Health Service Act and/or 

sections 510(k), 515, or 520(m) of the 

Federal Food, Drug, and Cosmetic Act. 

Approved drug means a drug that is 

approved for any indication under 

section 505 of the Federal Food, Drug, 

and Cosmetic Act or a biological 

product licensed for any indication 

under section 351 of the Public Health 

Service Act. 

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Approved or cleared device means a 

device that is cleared for any indication 

under section 510(k) of the Federal 

Food, Drug, and Cosmetic Act or 

approved for any indication under 

sections 515 or 520(m) of that Act. 

Arm means a pre-specified group or 

subgroup of human subjects in a clinical 

trial assigned to receive specific 

intervention(s) (or no intervention) 

according to a protocol. 

Clinical trial means a clinical 

investigation or a clinical study in 

which human subjects are prospectively 

assigned, according to a protocol, to one 

or more interventions (or no 

intervention) to evaluate the effect(s) of 

the intervention(s) on biomedical or 

health related outcomes. 

Clinical trial information means the 

data elements, including clinical trial 

registration information and clinical 

trial results information, the responsible 

party is required to submit to 

ClinicalTrials.gov under this part. 

Clinical trial registration information 

means the data elements that the 

responsible party is required to submit 

to ClinicalTrials.gov, as listed under 

§ 11.28. 

Clinical trial results information 

means the data elements that the 

responsible party is required to submit 

to ClinicalTrials.gov under § 11.48 or, if 

applicable, § 11.60(a)(2)(i)(B). 

Comparison group means a grouping 

of human subjects in a clinical trial that 

is used in analyzing the results data 

collected during the clinical trial. 

Completion date means, for a clinical 

trial, the date that the final subject was 

examined or received an intervention 

for the purposes of final collection of 

data for the primary outcome, whether 

the clinical trial concluded according to 

the pre-specified protocol or was 

terminated. In the case of clinical trials 

with more than one primary outcome 

measure with different completion 

dates, this term refers to the date upon 

which data collection is completed for 

all of the primary outcomes. For a 

pediatric postmarket surveillance of a 

device that is not a clinical trial, 

completion date means the date on 

which the final report summarizing the 

results of the pediatric postmarket 

surveillance is submitted to FDA. 

Control or controlled means, with 

respect to a clinical trial, that data 

collected on human subjects in the 

clinical trial will be compared to 

concurrently collected data or to nonconcurrently collected data (e.g., 

historical controls, including a human 

subject’s baseline data), as reflected in 

the pre-specified primary or secondary 

outcome measures. 

Device means a device as defined in 

section 201(h) of the Federal Food, 

Drug, and Cosmetic Act (21 U.S.C. 

321(h)). 

Director means the NIH Director or 

any official of the NIH to whom the NIH 

Director delegates authorities granted in 

42 U.S.C. 282(j). 

Drug means a drug as defined in 

section 201(g) of the Federal Food, Drug, 

and Cosmetic Act (21 U.S.C. 321(g)) or 

a biological product as defined in 

section 351 of the Public Health Service 

Act (42 U.S.C. 262). 

Enroll or enrolled means a human 

subject’s agreement to participate in a 

clinical trial, as indicated by the signing 

of the informed consent document(s). 

FDA-regulated device means, for 

purposes of this part, a device subject to 

section 510(k), 515, 520(m), or 522 of 

the Federal Food, Drug, and Cosmetic 

Act. 

FDA-regulated drug means, for 

purposes of this part, a drug subject to 

section 505 of the Federal Food, Drug, 

and Cosmetic Act or a biological 

product subject to section 351 of the 

Public Health Service Act. 

Human subjects protection review 

board means an institutional review 

board (IRB) as defined in 21 CFR 50.3 

or 45 CFR 46.102 (or any successor 

regulation), as applicable, or equivalent 

independent ethics committee that is 

responsible for ensuring the protection 

of the rights, safety, and well-being of 

human subjects involved in a clinical 

investigation and is adequately 

constituted to provide assurance of that 

protection. 

Interventional means, with respect to 

a clinical study or a clinical 

investigation, that participants are 

assigned prospectively to an 

intervention or interventions according 

to a protocol to evaluate the effect of the 

intervention(s) on biomedical or other 

health related outcomes. 

Investigational Device Exemption 

(IDE) has the meaning given in 21 CFR 

812, or any successor regulation. 

Investigational New Drug Application 

(IND) has the meaning given in 21 CFR 

312.3, or any successor regulation. 

NCT number means the unique 

identification code assigned to each 

record in ClinicalTrials.gov, including a 

record for an applicable clinical trial, a 

clinical trial, or an expanded access 

program. 

Ongoing means, with respect to a 

clinical trial of a drug or a device and 

to a date, that one or more human 

subjects is enrolled in the clinical trial, 

and the date is before the completion 

date of the clinical trial. With respect to 

a pediatric postmarket surveillance of a 

device, ongoing means a date between 

the date on which FDA approves the 

plan for conducting the surveillance and 

the date on which the final report is 

submitted to FDA. 

Outcome measure means a prespecified measurement that will be used 

to determine the effect of experimental 

variables on the human subjects in a 

clinical trial. See also primary outcome 

measure and secondary outcome 

measure. 

Pediatric postmarket surveillance of a 

device means the active, systematic, 

scientifically valid collection, analysis, 

and interpretation of data or other 

information conducted under section 

522 of the Federal Food, Drug, and 

Cosmetic Act about a marketed device 

that is expected to have significant use 

in patients who are 21 years of age or 

younger at the time of diagnosis or 

treatment. A pediatric postmarket 

surveillance of a device may be, but is 

not always, a clinical trial. 

Primary outcome measure means the 

outcome measure(s) of greatest 

importance specified in the protocol, 

usually the one(s) used in the power 

calculation. Most clinical trials have one 

primary outcome measure, but a clinical 

trial may have more than one. ‘‘Primary 

outcome’’ has the same meaning as 

primary outcome measure. 

Principal Investigator (PI) means the 

individual who is responsible for the 

scientific and technical direction of the 

study. 

Protocol means the written 

description of the clinical trial, 

including objective(s), design, and 

methods. It may also include relevant 

scientific background and statistical 

considerations. 

Responsible party means, with respect 

to a clinical trial, (i) the sponsor of the 

clinical trial, as defined in 21 CFR 50.3 

(or any successor regulation); or (ii) the 

principal investigator of such clinical 

trial if so designated by a sponsor, 

grantee, contractor, or awardee, so long 

as the principal investigator is 

responsible for conducting the trial, has 

access to and control over the data from 

the clinical trial, has the right to publish 

the results of the trial, and has the 

ability to meet all of the requirements 

under this part for the submission of 

clinical trial information. For a pediatric 

postmarket surveillance of a device that 

is not a clinical trial, the responsible 

party is the entity whom FDA orders to 

conduct the pediatric postmarket 

surveillance of the device. 

Secondary outcome measure means 

an outcome measure that is of lesser 

importance than a primary outcome 

measure, but is part of a pre-specified 

plan for evaluating the effects of the 

intervention or interventions under 

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investigation in a clinical trial. A 

clinical trial may have more than one 

secondary outcome measure. 

‘‘Secondary outcome’’ has the same 

meaning as secondary outcome 

measure. 

Secretary means the Secretary of 

Health and Human Services or any other 

official(s) to whom the Secretary 

delegates the authority contained in 42 

U.S.C. 282(j). 

Serious adverse event means an 

adverse event that results in any of the 

following outcomes: Death, a lifethreatening adverse event as defined in 

21 CFR 312.32 (or any successor 

regulation), inpatient hospitalization or 

prolongation of existing hospitalization, 

a persistent or significant incapacity or 

substantial disruption of the ability to 

conduct normal life functions, or a 

congenital anomaly/birth defect. 

Important medical events that may not 

result in death, be life-threatening, or 

require hospitalization may be 

considered serious when, based upon 

appropriate medical judgment, they may 

jeopardize the human subject and may 

require medical or surgical intervention 

to prevent one of the outcomes listed in 

this definition. Examples of such 

medical events include allergic 

bronchospasm requiring intensive 

treatment in an emergency room or at 

home, blood dyscrasias or convulsions 

that do not result in inpatient 

hospitalization, or the development of a 

substance use disorder. 

Sponsor means either a ‘‘sponsor’’ or 

‘‘sponsor-investigator’’, as each is 

defined in 21 CFR 50.3, or any successor 

regulation. 

(b) The following definitions apply to 

data elements of clinical trial 

information referenced in this part, 

unless otherwise specified. 

(1) Brief Title means a short title of the 

clinical trial written in language 

intended for the lay public, including 

any acronym or abbreviation used 

publicly to identify the clinical trial. 

(2) Official Title means the title of the 

clinical trial, corresponding to the title 

of the protocol. 

(3) Brief Summary means a short 

description of the clinical trial, 

including a brief statement of the 

clinical trial’s hypothesis, written in 

language intended for the lay public. 

(4) Primary Purpose means the main 

objective of the intervention(s) being 

evaluated by the clinical trial. 

(5) Study Design means a description 

of the manner in which the clinical trial 

will be conducted, including the 

following information: 

(i) Interventional Study Model. The 

strategy for assigning interventions to 

human subjects. 

(ii) Number of Arms. The number of 

arms in the clinical trial. For a trial with 

multiple periods or phases that have 

different numbers of arms, the 

maximum number of arms during any 

period or phase. 

(iii) Arm Information. A description 

of each arm of the clinical trial that 

indicates its role in the clinical trial, 

provides an informative title, and, if 

necessary, additional descriptive 

information to differentiate each arm 

from other arms in the clinical trial. 

(iv) Allocation. The method by which 

human subjects are assigned to arms in 

a clinical trial. 

(v) Masking. The party or parties, if 

any, involved in the clinical trial who 

are prevented from having knowledge of 

the interventions assigned to individual 

human subjects. 

(vi) Single Arm Controlled. For a 

single-armed clinical trial only, whether 

or not the clinical trial is controlled, as 

specified by the protocol or statistical 

analysis plan. 

(6) Study Phase means, for a clinical 

trial of a drug, the numerical phase of 

such clinical trial, consistent with 

terminology in 21 CFR 312.21, or any 

successor regulation, such as phase 2 or 

phase 3, and in 21 CFR 312.85, or any 

successor regulation, for phase 4 

studies. 

(7) Study Type means the type of 

study for which clinical trial 

information is being submitted. 

(8) Whether the Study is a Pediatric 

Postmarket Surveillance of a Device 

means, for a study that includes a 

device as an intervention and is a 

pediatric postmarket surveillance of a 

device, an affirmation that the study is 

a pediatric postmarket surveillance of a 

device. 

(9) Primary Disease or Condition 

Being Studied in the Trial, or the Focus 

of the Study means the name(s) of the 

disease(s) or condition(s) studied in the 

clinical trial, or the focus of the clinical 

trial, using, if available, appropriate 

descriptors from the National Library of 

Medicine’s Medical Subject Headings 

(MeSH) controlled vocabulary thesaurus 

http://www.nlm.nih.gov/mesh/, or terms 

from another vocabulary, such as the 

Systematized Nomenclature of 

Medicine—Clinical Terms (SNOMED 

CT), that has been mapped to MeSH 

within the Unified Medical Language 

System (UMLS) Metathesaurus, https:// 

uts.nlm.nih.gov. 

(10) Intervention Name means a brief 

descriptive name used to refer to the 

intervention(s) studied in each arm of 

the clinical trial. A non-proprietary 

name of the intervention must be used, 

if available. If a non-proprietary name is 

not available, a brief descriptive name 

or identifier must be used. 

(11) Other Intervention Name(s) 

means other current and former name(s) 

or alias(es), if any, different from the 

Intervention Name(s), that the sponsor 

has used publicly to identify the 

intervention(s), including, but not 

limited to, past or present names such 

as brand name(s), serial numbers, or 

chemical descriptions. 

(12) Intervention Description means, 

details that can be made public about 

the intervention, other than the 

Intervention Name and Other 

Intervention Name(s), sufficient to 

distinguish it from other, similar 

interventions studied in the same or 

another clinical trial. 

(13) Intervention Type means, for each 

intervention studied in the clinical trial, 

the general type of intervention. 

(14) U.S. FDA Approval, Licensure, or 

Clearance Status means, for each drug 

or device studied in the clinical trial, 

whether that drug or device is approved, 

licensed, or cleared by the U.S. Food 

and Drug Administration for any use. 

(15) Product Manufactured in the U.S. 

means, for a drug or device studied in 

a clinical trial, whether or not the drug 

or device is manufactured in the U.S. or 

one of its territories. 

(16) Study Start Date means the 

estimated date on which the clinical 

trial will be open to enrollment of 

human subjects. If the clinical trial has 

enrolled the first human subject, the 

actual date on which the first human 

subject was enrolled. 

(17) Completion Date means the 

estimated completion date. Once the 

clinical trial has reached the completion 

date, the responsible party must update 

the Completion Date data element to 

reflect the actual completion date. 

(18) Enrollment means the estimated 

total number of human subjects to be 

enrolled or target number of human 

subjects in the clinical trial. 

(19) Primary Outcome Measure 

Information means a description of each 

primary outcome measure, to include 

the following information: 

(i) Name of the specific primary 

outcome measure; 

(ii) Description of the metric used to 

characterize the specific primary 

outcome measure; and 

(iii) Time point(s) at which the 

measurement is assessed for the specific 

metric used. 

(20) Secondary Outcome Measure 

Information means a description of each 

secondary outcome measure, to include 

the following information: 

(i) Name of the specific secondary 

outcome measure; 

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(ii) Description of the metric used to 

characterize the specific secondary 

outcome measure; and 

(iii) Time point(s) at which the 

measurement is assessed for the specific 

metric used. 

(21) Eligibility Criteria means a 

limited list of criteria for selection of 

human subjects to participate in the 

clinical trial, provided in terms of 

inclusion and exclusion criteria and 

suitable for assisting potential human 

subjects in identifying clinical trials of 

interest. 

(22) Gender means the biological sex 

of the human subjects who may 

participate in the clinical trial. 

(23) Age Limits means the minimum 

and maximum age of human subjects 

who may participate in the clinical trial, 

provided in relevant units of time. 

(24) Accepts Healthy Volunteers 

means whether human subjects who do 

not have a disease or condition, or 

related conditions or symptoms, under 

study in the clinical trial are permitted 

to participate in the clinical trial. 

(25) Overall Recruitment Status 

means the recruitment status for the 

clinical trial as a whole, based upon the 

status of the individual sites. If at least 

one facility in a multi-site clinical trial 

has an individual site status of 

‘‘recruiting,’’ then the overall 

recruitment status for the trial must be 

‘‘recruiting.’’ 

(26) Why Study Stopped means, for a 

clinical trial that is suspended or 

terminated or withdrawn prior to its 

completion as anticipated by the 

protocol, a brief explanation of the 

reason(s) why such clinical trial was 

stopped. 

(27) Actual Enrollment means, for a 

clinical trial for which recruitment of 

human subjects has terminated or 

completed, the actual number of human 

subjects enrolled in the clinical trial. 

(28) Individual Site Status means the 

recruitment status of each participating 

facility in a clinical trial. 

(29) Availability of Expanded Access 

means, for an applicable drug clinical 

trial of a drug that is not an approved 

drug: 

(i) An indication of whether there is 

expanded access to the drug under 

section 561 of the Federal Food, Drug, 

and Cosmetic Act (21 U.S.C. 360bbb) for 

those who do not qualify for enrollment 

in the applicable clinical trial. 

(ii) If expanded access is available 

under section 561 of the Federal Food, 

Drug, and Cosmetic Act, the NCT 

number of the expanded access record. 

(30) Name of the Sponsor means the 

name of the entity or the individual that 

is the sponsor of the clinical trial, as 

defined in § 11.10(a). 

(31) Responsible Party, by Official 

Title means: 

(i) Indication of whether the 

responsible party is the sponsor of the 

clinical trial, as that term is defined in 

21 CFR 50.3, the sponsor-investigator, as 

that term is defined in 21 CFR 50.3, or 

a principal investigator designated 

pursuant to this part; and 

(ii) Either: 

(A) The official name of the entity, if 

the responsible party is an entity; or 

(B) The official title and primary 

organizational affiliation of the 

individual, if the responsible party is an 

individual. 

(32) Facility Information means, for 

each participating facility in a clinical 

trial, the following information: 

(i) Facility Name, meaning the full 

name of the organization where the 

clinical trial is being conducted; 

(ii) Facility Location, including city, 

state, country and zip code for U.S. 

locations (including territories of the 

United States) and city and country for 

locations in other countries; and 

(iii) Either: 

(A) For each facility participating in a 

clinical trial, Facility Contact, including 

the name or title, telephone number, 

and email address of a person to whom 

questions concerning the trial and 

enrollment at that site can be addressed; 

or 

(B) Central Contact Person, including 

the name or title, toll-free telephone 

number and email address of a person 

to whom questions concerning 

enrollment at any location of the trial 

can be addressed. 

(33) Unique Protocol Identification 

Number means any unique 

identification number assigned to the 

protocol by the sponsor. 

(34) Secondary ID means: 

(i) Any identification number(s) other 

than the organization’s unique protocol 

identification number or NCT number 

that is assigned to the clinical trial, 

including any unique clinical trial 

identification numbers assigned by 

other publicly available clinical trial 

registries. If the clinical trial is funded 

in whole or part by a U.S. federal 

government agency, the complete grant 

or contract number must be submitted 

as a Secondary ID. 

(ii) A description of the type of 

Secondary ID. 

(35) Food and Drug Administration 

IND or IDE Number means whether or 

not there is an IND or IDE for the 

clinical trial and, if so, each of the 

following elements: 

(i) Name or abbreviation of the FDA 

center with whom the IND or IDE is 

filed; 

(ii) IND or IDE number assigned by 

the FDA center; and 

(iii) For an IND, the IND serial 

number (as defined in 21 CFR 312.23(e), 

or any successor regulation), if any, 

assigned to the clinical trial. 

(36) Human Subjects Protection 

Review Board Status means information 

to indicate whether a clinical trial has 

been approved by a human subjects 

protection review board or is exempt 

from human subjects protection review 

board approval. Human Subjects 

Protection Review Board Status must be 

listed as ‘‘approved’’ if at least one 

human subjects protection review board 

has approved the clinical trial; 

(37) Record Verification Date means 

the date upon which the responsible 

party last verified the clinical trial 

information in the entire 

ClinicalTrials.gov record for the clinical 

trial, even if no additional or updated 

information was submitted at that time. 

(38) Responsible Party Contact 

Information means administrative 

information to identify and allow 

communication with the responsible 

party by telephone, email, and regular 

mail or delivery service. Responsible 

Party Contact Information includes the 

name, official title, organizational 

affiliation, physical address, mailing 

address, phone number, and email 

address of the individual who is the 

responsible party or of a designated 

employee of the organization that is the 

responsible party. 

(39) Studies an FDA-regulated Device 

means a clinical trial studies a device 

subject to section 510(k), 515, or 520(m) 

of the Federal Food, Drug, and Cosmetic 

Act. 

(40) Studies an FDA-regulated Drug 

means a clinical trial studies a drug 

subject to section 505 of the Federal 

Food, Drug, and Cosmetic Act or to 

section 351 of the Public Health 

Services Act 

Subpart B—Registration 

§ 11.20 Who must submit clinical trial 

registration information? 

The responsible party for an 

applicable clinical trial specified in 

§ 11.22 must register the applicable 

clinical trial by submitting clinical trial 

registration information specified in 

§ 11.28 for that clinical trial. 

§ 11.22 Which applicable clinical trials 

must be registered? 

(a) General specification. (1) Any 

applicable clinical trial that is initiated 

after September 27, 2007, must be 

registered. 

(2) Any applicable clinical trial that is 

initiated on or before September 27, 

2007, and is ongoing on December 26, 

2007, must be registered. 

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(3) Determining the date of initiation 

for an applicable clinical trial. An 

applicable clinical trial, other than a 

pediatric postmarket surveillance of a 

device that is not a clinical trial, is 

considered to be initiated on the date on 

which the first human subject is 

enrolled. A pediatric postmarket 

surveillance of a device that is not a 

clinical trial is considered to be initiated 

on the date on which U.S. Food and 

Drug Administration (FDA) approves 

the plan for conducting the surveillance. 

(b) Determination of applicable 

clinical trial. For purposes of this part, 

any clinical trial or study that, at any 

point in time, is described accurately by 

the data elements listed in paragraph 

(b)(1) or (2) of this section will be 

considered to meet the definition of an 

applicable clinical trial. 

(1) Applicable device clinical trial. A 

clinical trial or study that is described 

accurately by the data elements listed in 

either paragraph (b)(1)(i) or (ii) of this 

section meets the definition of an 

applicable device clinical trial: 

(i) The study is a pediatric postmarket 

surveillance of a device as required by 

FDA under section 522 of the Federal 

Food, Drug, and Cosmetic Act. 

(ii) The study is a clinical trial that 

meets all of the following criteria: 

(A) Study Type is interventional; 

(B) Primary Purpose of the clinical 

trial is other than a feasibility study; 

(C) Either: 

(1) Number of Arms is two or more; 

or 

(2) Number of Arms is one, and the 

clinical trial is Single Arm Controlled; 

(D) The Intervention Type is other 

than a combination product; 

(E) The clinical trial Studies an FDAregulated Device; and 

(F) One or more of the following 

applies: 

(1) At least one Facility Location is 

within the U.S. or one of its territories, 

(2) A device under investigation is a 

Product Manufactured in the U.S. or one 

of its territories and exported for study 

in another country, or 

(3) The clinical trial has a U.S. Food 

and Drug Administration IDE Number. 

(2) Applicable drug clinical trial. A 

clinical trial that is described accurately 

by the following data elements meets 

the definition of an applicable drug 

clinical trial: 

(i) Study Type is interventional; 

(ii) Study Phase is other than phase 1; 

(iii) Either: 

(A) Number of Arms is two or more, 

or 

(B) Number of Arms is one, and the 

clinical trial is Single Arm Controlled; 

(iv) The clinical trial Studies an FDAregulated Drug; and 

(v) One or more of the following 

applies: 

(A) At least one Facility Location for 

the clinical trial is within the U.S. or 

one of its territories, 

(B) A drug under investigation is a 

Product Manufactured in the U.S. or one 

of its territories and exported for study 

in another country, or 

(C) The clinical trial has a U.S. Food 

and Drug Administration IND Number. 

§ 11.24 When must clinical trial 

registration information be submitted? 

(a) General. Except as provided in 

paragraph (b) of this section, the 

responsible party for an applicable 

clinical trial subject to § 11.22 must 

submit clinical trial registration 

information, as specified in § 11.28(a), 

not later than December 26, 2007, or 21 

calendar days after the first human 

subject is enrolled, whichever date is 

later. 

(b) Exceptions. (1) The responsible 

party for an applicable clinical trial 

subject to § 11.22 that is not for a serious 

or life-threatening disease or condition 

must submit clinical trial registration 

information not later than September 

27, 2008, or 21 calendar days after the 

first human subject is enrolled, 

whichever date is later. 

(2) The responsible party for an 

applicable device clinical trial that is a 

pediatric postmarket surveillance of a 

device and is not a clinical trial must 

submit clinical trial registration 

information, as specified in § 11.28(b), 

not later than December 26, 2007, or 21 

calendar days after the U.S. Food and 

Drug Administration approves the 

postmarket surveillance plan, 

whichever date is later. 

§ 11.28 What constitutes clinical trial 

registration information? 

(a) For each applicable clinical trial 

that must be registered with 

ClinicalTrials.gov as required by 

§ 11.22, other than a pediatric 

postmarket surveillance of a device that 

is not a clinical trial, the responsible 

party must provide the data elements 

listed below in (1) through (4), as they 

are defined in § 11.10(b): 

(1) Descriptive information: 

(i) Brief Title; 

(ii) Official Title; 

(iii) Brief Summary; 

(iv) Primary Purpose; 

(v) Study Design; 

(vi) Study Phase, for an applicable 

drug clinical trial; 

(vii) Study Type; 

(viii) Whether the Study is a Pediatric 

Postmarket Surveillance of a Device; for 

an applicable device clinical trial that is 

a Pediatric Postmarket Surveillance of a 

Device; 

(ix) Primary Disease or Condition 

Being Studied in the Trial, or the Focus 

of the Study; 

(x) Intervention Name, for each 

intervention studied; 

(xi) Other Intervention Name(s), for 

each intervention studied; 

(xii) Intervention Description, for each 

intervention studied; 

(xiii) Intervention Type, for each 

intervention studied; 

(xiv) Studies an FDA-Regulated 

Device; 

(xv) Studies an FDA-Regulated Drug; 

(xvi) U.S. FDA Approval, Licensure, 

or Clearance Status, for each 

intervention studied; 

(xvii) Product Manufactured in the 

U.S., for each intervention studied, if 

the entry for U.S. Food and Drug 

Administration IND or IDE number in 

§ 11.28(a)(4)(iii) indicates that there is 

no IND or IDE for the clinical trial, and 

the entry(ies) for Facility Information in 

§ 11.28(a)(3)(iii) include no facility 

locations in the United States or its 

territories. 

(xviii) Study Start Date; 

(xiv) Completion Date. 

(xx) Enrollment; 

(xxi) Primary Outcome Measure 

Information, for each primary outcome 

measure. 

(xxii) Secondary Outcome Measure 

Information, for each secondary 

outcome measure. 

(2) Recruitment information: 

(i) Eligibility Criteria; 

(ii) Gender; 

(iii) Age Limits; 

(iv) Accepts Healthy Volunteers; 

(v) Overall Recruitment Status. 

(vi) Why Study Stopped? 

(vii) Actual Enrollment. 

(viii) Individual Site Status; 

(ix) Availability of Expanded Access, 

for an applicable drug clinical trial of a 

drug that is not an approved drug. If 

expanded access is available under 

section 561 of the Federal Food, Drug, 

and Cosmetic Act, and the expanded 

access record for the drug has not been 

submitted in accordance with § 11.28(c), 

the data elements listed § 11.28(c) must 

also be submitted. 

(3) Location and contact information: 

(i) Name of the Sponsor; 

(ii) Responsible Party, by Official 

Title; 

(iii) Facility information. 

(4) Administrative data: 

(i) Unique Protocol Identification 

Number. 

(ii) Secondary IDs. 

(iii) Food and Drug Administration 

IND or IDE number. 

(iv) Human Subjects Protection 

Review Board Status. 

(v) Record Verification Date. 

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(vii) Responsible Party Contact 

Information. 

(b) Pediatric postmarket surveillance 

of a device that is not a clinical trial. For 

each pediatric postmarket surveillance 

of a device that is not a clinical trial, 

that must be registered with 

ClinicalTrials.gov as required by 

§ 11.22, the responsible party must 

provide the information listed below in 

paragraphs (b)(1) through (3) of this 

section. 

(1) Descriptive information: 

(i) Brief Title. A short title of the 

pediatric postmarket surveillance of a 

device in language intended for the lay 

public. If an acronym or abbreviation is 

used to publicly identify the 

surveillance, it must be provided. 

(ii) Official Title. The title of the 

pediatric postmarket surveillance of a 

device, corresponding to the title of the 

protocol or the FDA-approved plan for 

conducting the surveillance. 

(iii) Brief Summary. A short 

description of the pediatric postmarket 

surveillance of a device, including a 

brief statement of the hypothesis or 

objective, written in language intended 

for the lay public, and a general 

description of the surveillance design 

including relevant population 

information. 

(iv) Study Type. The type of study 

being registered. In the case of a 

pediatric postmarket surveillance of a 

device that is not a clinical trial, a study 

type of ‘‘observational’’ is required. 

(v) Whether the Study is a Pediatric 

Postmarket Surveillance of a Device. For 

a study that includes a device as an 

intervention and is a pediatric 

postmarket surveillance of a device, an 

affirmation that the study is a pediatric 

postmarket surveillance of a device. 

(vi) Primary Disease or Condition 

Being Studied, or the Focus of the 

Study. The name(s) of the disease(s) or 

condition(s) being studied in the 

pediatric postmarket surveillance of a 

device, or the focus of the study, using, 

if available, appropriate descriptors 

from the National Library of Medicine’s 

Medical Subject Headings (MeSH) 

controlled vocabulary thesaurus, http:// 

www.nlm.nih.gov/mesh/, or terms from 

another vocabulary, such as the 

Systematized Nomenclature of 

Medicine—Clinical Terms (SNOMED 

CT), that has been mapped to MeSH 

within the Unified Medical Language 

System (UMLS) Metathesaurus, https:// 

uts.nlm.nih.gov. 

(vii) Intervention Name(s). A brief 

descriptive name used to refer to each 

intervention studied in the pediatric 

postmarket surveillance of a device. A 

non-proprietary name of the 

intervention must be used, if available. 

If a non-proprietary name is not 

available, a brief descriptive name or 

identifier must be used. 

(viii) Other Intervention Name(s). Any 

other current and former name(s) or 

alias(es), different from the Intervention 

Name(s), that the sponsor has used 

publicly to identify the intervention(s), 

including, but not limited to, past or 

present names such as brand name(s), 

serial numbers, or chemical 

descriptions. 

(ix) Intervention Description. Details 

that can be made public about each 

intervention, other than the Intervention 

Name and Other Intervention Name, 

sufficient to distinguish it from other, 

similar interventions studied in the 

same or another clinical trial or 

pediatric postmarket surveillance of a 

device that is not a clinical trial. 

(x) Intervention Type. For each 

intervention studied in the pediatric 

postmarket surveillance of a device, the 

general type of intervention. 

(xi) Study Start Date. The date on 

which FDA approves the pediatric 

postmarket surveillance plan, as 

specified in 21 CFR 822.19(a) (or any 

successor regulation). 

(xii) Completion Date. The estimated 

date on which the final report 

summarizing the results of the pediatric 

postmarket surveillance of a device is 

expected to be submitted to FDA. Once 

the final report has been submitted, the 

actual date on which the final report is 

submitted to FDA. 

(2) Location and contact information: 

(i) Name of the Sponsor. 

(ii) Responsible Party, by Official 

Title. 

(A) If the responsible party is an 

entity, the official name of the entity; or 

(B) If the responsible party is an 

individual, the official title and primary 

organizational affiliation of the 

individual. 

(iii) Contact Information. The name or 

official title, toll-free telephone number 

and email address of a person to whom 

questions concerning the pediatric 

postmarket surveillance of a device can 

be addressed. 

(3) Administrative data: 

(i) Unique Protocol Identification 

Number. The unique identification 

number assigned to the pediatric 

postmarket surveillance of a device by 

the sponsor, if any. 

(ii) Secondary IDs. (A) Identification 

number(s) other than the organization’s 

unique protocol identification number 

or NCT number that is assigned to the 

pediatric postmarket surveillance of a 

device, if any, including any unique 

identification numbers assigned by 

other publicly available registries. If the 

pediatric postmarket surveillance of a 

device is funded in whole or part by a 

U.S. Federal Government agency, the 

complete grant or contract number must 

be submitted as a Secondary ID. 

(B) For each secondary ID listed, a 

description of the type of secondary ID. 

(iii) Human Subjects Protection 

Review Board Status. Information to 

indicate whether a pediatric postmarket 

surveillance of a device has been 

approved by a human subjects 

protection review board or is exempt 

from (or otherwise not required to 

receive) human subjects protection 

review board approval. Human Subjects 

Protection Review Board Status must be 

listed as ‘‘approved’’ if at least one 

human subjects protection review board 

has approved the pediatric postmarket 

surveillance. 

(iv) Record Verification Date. The 

date upon which the responsible party 

last verified the clinical trial 

information in the entire 

ClinicalTrials.gov record for the 

pediatric postmarket surveillance of a 

device, even if no additional or updated 

information was submitted at that time. 

(v) Responsible Party Contact 

Information. Administrative 

information sufficient to identify and 

allow communication with the 

responsible party by telephone, email, 

and regular mail or delivery service. 

Responsible Party Contact Information 

includes the name, official title, 

organizational affiliation, physical 

address, mailing address, phone 

number, and email address of the 

individual who is the responsible party 

or of a designated employee of the 

organization that is the responsible 

party. 

(c) Expanded access record. If 

expanded access is available under 

section 561 of the Federal Food, Drug, 

and Cosmetic Act to a drug studied in 

an applicable drug clinical trial and the 

data elements set forth in paragraphs 

(b)(1) through (4) of this section have 

not been submitted via an expanded 

access record for a previously-registered 

applicable clinical trial of that drug, the 

responsible party must submit the 

clinical trial information specified in 

paragraphs (b)(1) through (4) of this 

section to ClinicalTrials.gov in the form 

of an expanded access record. If a 

responsible party voluntarily submits an 

expanded access record for a device, 

then the responsible party must submit 

the clinical trial information specified 

in paragraphs (b)(1) through (4) of this 

section. 

(1) Descriptive information: 

(i) Brief Title. A short title of the 

expanded access program written in 

language intended for the lay public. If 

an acronym or abbreviation is used 

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publicly to identify the program, it must 

be provided. 

(ii) Official Title. The title of the 

expanded access program, 

corresponding to the title of the program 

permitted by FDA. 

(iii) Brief Summary. A short 

description of the expanded access 

program, including the procedure for 

requesting the treatment. 

(iv) Study Type. The type of study 

that is being registered, in this case an 

‘‘expanded access program.’’ 

(v) Primary Disease or Condition. The 

name(s) of the disease(s) or condition(s) 

for which expanded access to the drug 

is offered, using, if available, 

appropriate descriptors from the 

National Library of Medicine’s Medical 

Subject Headings (MeSH) controlled 

vocabulary thesaurus http://

www.nlm.nih.gov/mesh/, or terms from 

another vocabulary, such as the 

Systematized Nomenclature of 

Medicine—Clinical Terms (SNOMED 

CT), that has been mapped to MeSH 

within the Unified Medical Language 

System (UMLS) Metathesaurus, https:// 

uts.nlm.nih.gov. 

(vi) Intervention Name(s). A brief 

descriptive name used to refer to the 

drug that is available through the 

expanded access program. A nonproprietary name of the intervention 

must be used, if available. If a nonproprietary name is not available, a brief 

descriptive name or identifier must be 

used. 

(vii) Other Intervention Name(s). Any 

other current and former name(s) or 

alias(es), different from the Intervention 

Name(s), that the sponsor has used 

publicly to identify the intervention, 

including, but not limited to, past or 

present names such as brand name(s), 

serial numbers, or chemical 

descriptions. 

(viii) Intervention Description. Details 

that can be made public about each 

intervention, other than the Intervention 

Name or Other Intervention Name, 

sufficient to distinguish it from other, 

similar interventions available through 

other expanded access programs or 

clinical trials. 

(ix) Intervention Type. For each 

intervention available through the 

expanded access program, the general 

type of intervention. 

(2) Recruitment information: 

(i) Eligibility Criteria. A limited list of 

criteria for determining who is eligible 

to receive treatment in the expanded 

access program, provided in terms of 

inclusion and exclusion criteria and 

suitable for assisting potential patients 

in identifying expanded access 

programs of interest. 

(ii) Gender. The biological sex of the 

patients who may receive treatment in 

the expanded access program. 

(iii) Age Limits. The minimum and 

maximum age of patients who may 

receive treatment in the expanded 

access program, provided in relevant 

units of time. 

(iv) Expanded Access Status. The 

status of availability of the 

investigational drug through the 

expanded access program. 

(3) Location and Contact Information: 

(i) Name of the Sponsor. 

(ii) Responsible Party, by Official 

Title. 

(A) If the responsible party entering 

the clinical trial information into the 

expanded access record is an entity, the 

official name of the entity; or 

(B) If the responsible party entering 

the clinical trial information into the 

expanded access record is an 

individual, the official title and primary 

organizational affiliation of the 

individual. 

(iii) Contact Information. The name or 

official title, toll-free telephone number, 

and email address of a person to whom 

questions concerning the expanded 

access program can be addressed. 

(4) Administrative data. (i) Unique 

Protocol Identification Number. Any 

unique identification number assigned 

to the expanded access program by the 

sponsor. 

(ii) Secondary IDs.(A) Any 

identification number(s) other than the 

organization’s unique protocol 

identification number or the NCT 

number that is assigned to the expanded 

access program, including any unique 

identification numbers assigned by 

other publicly available clinical trial or 

expanded access registries. 

(B) For each Secondary ID listed, a 

description of the type of Secondary ID. 

(iii) Food and Drug Administration 

IND Number. The IND number for the 

expanded access program, which must 

include each of the following elements: 

(A) Name or abbreviation of the FDA 

center with whom the IND is filed (i.e., 

CDER, CBER); 

(B) IND number assigned by the FDA 

center; and 

(C) IND serial number (as defined in 

21 CFR 312.23(e), or any successor 

regulation), if any, assigned to the 

expanded access program. 

(iv) Record Verification Date. The 

date upon which the responsible party 

last verified the clinical trial 

information in the entire 

ClinicalTrials.gov record for the 

expanded access program, even if no 

additional or updated information was 

submitted at that time. 

(v) Responsible Party Contact 

Information. Administrative 

information sufficient to identify and 

allow communication with the 

responsible party entering the clinical 

trial information into the expanded 

access record by telephone, email, and 

regular mail or delivery service. 

Responsible Party Contact Information 

includes the name, official title, 

organizational affiliation, physical 

address, mailing address, phone 

number, and -email address of the 

individual who is the responsible party 

or of a designated employee of the 

organization that is the responsible 

party. 

§ 11.35 By when will NIH post clinical trial 

registration information submitted under 

§ 11.28? 

(a) Applicable drug clinical trial. NIH 

will post publicly at ClinicalTrials.gov 

the clinical trial registration 

information, except for certain 

administrative data, for an applicable 

drug clinical trial not later than 30 

calendar days after the responsible party 

has submitted such information in 

accordance with § 11.24 of this part. 

(b) Applicable device clinical trial. (1) 

For an applicable device clinical trial of 

a device that previously was approved 

or cleared, NIH will post publicly at 

ClinicalTrials.gov the clinical trial 

registration information, except for 

certain administrative data, not later 

than 30 calendar days after clinical trial 

results information is required to be 

posted in accordance with § 11.52 of 

this part. 

(2) For an applicable device clinical 

trial of a device that has not been 

previously approved or cleared, NIH 

will post publicly at ClinicalTrials.gov 

the clinical trial registration 

information, except for certain 

administrative data, not earlier than the 

date of FDA approval or clearance of the 

device, and not later than 30 calendar 

days after the date of such approval or 

clearance. 

Subpart C—Results Submission 

§ 11.40 Who must submit clinical trial 

results information? 

The responsible party for an 

applicable clinical trial specified in 

§ 11.42 must submit clinical trial results 

information for that clinical trial. 

§ 11.42 For which applicable clinical trials 

must clinical trial results information be 

submitted in accordance with subpart C of 

this regulation? 

Unless a waiver of the requirement to 

submit clinical trial results information 

is granted in accordance with § 11.54, 

clinical trial results information must be 

submitted for any applicable clinical 

trial for which submission of clinical 

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trial registration information is required 

under § 11.22 and that meets one of the 

following criteria: 

(a) The completion date of the clinical 

trial is on or after the effective date of 

this rule; or 

(b) The completion date of the clinical 

trial is prior to the effective date of this 

rule, the applicable deadline established 

by § 11.44 is on or after the effective 

date of the rule, and clinical trial results 

information is submitted on or after the 

effective date of the rule, consistent 

with the applicable deadline established 

by § 11.44. 

§ 11.44 When must clinical trial results 

information be submitted for applicable 

clinical trials subject to § 11.42? 

(a) Standard submission deadlines (1) 

In general, clinical trial results 

information specified in § 11.48 must be 

submitted no later than 1 year after the 

completion date, except as otherwise 

provided in this section. 

(2) Submitting clinical trial results 

information following initial approval, 

licensure, or clearance. Except as 

otherwise provided in §§ 11.44(b), (c), 

(d) or (e), for any applicable clinical trial 

of an FDA-regulated drug or device that 

is not approved, licensed, or cleared as 

of the completion date and that receives 

initial FDA approval, licensure, or 

clearance thereafter, clinical trial results 

information specified in § 11.48(a) must 

be submitted by the earlier of the 

following: 

(i) The submission deadline specified 

in § 11.44(a)(1); or 

(ii) The date that is 30 calendar days 

after FDA approves, licenses, or clears 

the drug or device for any indication 

studied in the applicable clinical trial. 

(b) Delayed submission of results with 

certification if seeking approval, 

licensure, or clearance of a new use. (1) 

If, prior to the results submission 

deadline specified under paragraph 

(a)(1) of this section, the responsible 

party submits to ClinicalTrials.gov a 

certification that an applicable clinical 

trial involves an FDA-regulated drug or 

device that previously has been 

approved, licensed, or cleared, for 

which the manufacturer is the sponsor 

of the applicable clinical trial, and for 

which an application or premarket 

notification seeking approval, licensure, 

or clearance of the use being studied 

(which is not included in the labeling of 

the approved, licensed, or cleared drug 

or device) has been filed or will be filed 

within 1 year with FDA, the deadline 

for submitting complete clinical trial 

results information will be 30 calendar 

days after the earliest of the following 

events: 

(i) FDA approves, licenses, or clears 

the drug or device for the use studied in 

the applicable clinical trial; 

(ii) FDA issues a letter that ends the 

regulatory review cycle for the 

application or submission but does not 

approve, license, or clear the drug or 

device for the use studied in the 

applicable clinical trial; or 

(iii) The application or premarket 

notification seeking approval, licensure, 

or clearance of the new use is 

withdrawn without resubmission for not 

less than 210 calendar days. 

(2) Two-year limitation. 

Notwithstanding the deadlines specified 

in paragraph (b)(1) of this section, the 

responsible party must submit complete 

clinical trial results information not 

later than the date that is 2 years after 

the date that the certification was 

submitted, except to the extent that 

paragraph (d) of this section applies. 

(3) Additional Requirements. If a 

responsible party who is both the 

manufacturer of the drug or device 

studied in an applicable clinical trial 

and the sponsor of the applicable 

clinical trial submits a certification in 

accordance with paragraph (b)(1) of this 

section, that responsible party must 

submit such a certification for each 

applicable clinical trial that meets the 

following criteria: 

(i) The applicable clinical trial is 

required to be submitted in an 

application or premarket notification for 

seeking approval, licensure, or clearance 

of a new use; and 

(ii) The applicable clinical trial 

studies the same drug or device for the 

same use as studied in the applicable 

clinical trial for which the initial 

certification was submitted. 

(c) Delayed submission of results with 

certification if seeking initial approval, 

licensure or clearance of a drug or 

device. (1) If, prior to the submission 

deadline specified under paragraph 

(a)(1) of this section, a responsible party 

submits to ClinicalTrials.gov a 

certification that an applicable clinical 

trial studies an FDA-regulated drug or 

device that was not approved, licensed, 

or cleared by FDA for any use before the 

completion date of the trial, and that the 

sponsor intends to continue with 

product development and is either 

seeking, or may at a future date seek 

FDA approval, licensure, or clearance of 

the drug or device under study, the 

deadline for submitting complete 

clinical trial results information will be 

30 calendar days after the earlier of the 

date on which: 

(i) FDA approves, licenses, or clears 

the drug or device for any indication 

that is studied in the applicable clinical 

trial; 

(ii) The marketing application or 

premarket notification is withdrawn 

without resubmission for not less than 

210 calendar days. 

(2) Two-year limitation. 

Notwithstanding the deadlines 

established in paragraph (c)(1) of this 

section, the responsible party must 

submit complete clinical trial results 

information not later than 2 years after 

the date on which the certification was 

submitted, except to the extent that 

paragraph (d) of this section applies. 

(d) Submitting partial results. (1) If 

required clinical trial results 

information specified in § 11.48 has not 

been collected for a secondary outcome 

measure by the completion date, the 

responsible party must submit clinical 

trial results information for that 

secondary outcome measure by the later 

of: 

(i) 1 year after the date on which the 

final subject is examined or receives an 

intervention for the purposes of final 

collection of data for that secondary 

outcome measure, whether the clinical 

trial was concluded according to the 

pre-specified protocol or was 

terminated, or 

(ii) If a certification to delay results 

submission has been submitted under 

paragraph (b) or (c) of this section, the 

date on which results information for 

the primary outcome measures are due 

pursuant to paragraph (b) or (c) of this 

section. 

(2) If clinical trial results information 

was submitted for the primary outcome 

measure(s) prior to the effective date of 

the rule but data collection for all of the 

secondary outcome measure(s) is not 

completed until on or after the effective 

date of the rule, clinical trial results 

information for all primary and 

secondary outcome measures must be 

submitted in accordance with § 11.48 

not later than 1 year after the date on 

which the final subject is examined or 

receives an intervention for the 

purposes of final collection of data for 

such secondary outcome measure(s), 

whether the clinical trial was concluded 

according to the pre-specified protocol 

or was terminated. 

(e) Extensions. (1) Requesting a goodcause extension of the results 

submission deadline. A responsible 

party may request a good-cause 

extension of the deadline for submitting 

clinical trial results information to 

ClinicalTrials.gov subject to paragraphs 

(e)(1)(i) and (ii) of this section. A 

responsible party may request more 

than one good-cause extension for the 

same applicable clinical trial and may 

request a good-cause extension of a 

delayed results submission deadline 

established by the submission of a 

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certification as described in paragraph 

(b) or (c) of this section. 

(i) The responsible party must submit 

a request for a good-cause extension to 

ClinicalTrials.gov prior to the date on 

which clinical trial results information 

would otherwise be due in accordance 

with paragraph (a), (b), (c), (d), or (f) of 

this section. 

(ii) A request for a good-cause 

extension must contain the following 

elements: 

(A) Description of the reason(s) why 

clinical trial results information cannot 

be provided according to the deadline, 

with sufficient detail to allow 

evaluation of the request; and 

(B) Estimate of the date on which the 

clinical trial results information will be 

submitted. 

(2) Decision and submission deadline. 

The NIH will provide a written response 

electronically to the responsible party 

indicating whether or not the requested 

extension has been granted, and the 

responsible party must either submit 

clinical trial results information not 

later than the deadline established by 

paragraphs (e)(2)(i) or (ii) of this section, 

as applicable, or appeal the denial in 

accordance with paragraph (e)(3) of this 

section. 

(i) If the good-cause extension request 

is granted, the responsible party must 

submit clinical trial results information 

not later than the date of the deadline 

specified in the electronic response. 

(ii) If the good-cause extension 

request is denied, the responsible party 

must either appeal in accordance with 

paragraph (e)(3) of this section or submit 

complete clinical trial results 

information by the later of the original 

submission deadline specified in 

paragraph (a), (b), (c), (d), or (f) of this 

section, as applicable, or 15 calendar 

days after the date on which the 

electronic notice of the denial is sent to 

the responsible party. 

(3) Appealing a denied extension 

request. (i) A responsible party who 

seeks to appeal a denied extension 

request or the deadline specified in a 

granted extension must submit an 

appeal in the form of a written letter to 

the Director not later than 15 calendar 

days after the date on which the 

electronic notification of grant or denial 

of the request is sent to the responsible 

party. 

(ii) An appeal letter must contain an 

explanation of the reason(s) why the 

initial decision to deny an extension 

request or to grant an extension request 

with a shorter deadline than requested 

should be overturned or revised. 

(iii) The Director will provide an 

electronic notification to the responsible 

party indicating whether or not the 

requested extension has been granted 

upon appeal. 

(iv) If the Director grants the 

extension request upon appeal, the 

responsible party must submit clinical 

trial results information not later than 

the deadline specified in the electronic 

notification specified in paragraph 

(e)(3)(iii) of this section. 

(v) If the Director denies an appeal of 

a denied extension request, the 

responsible party must submit clinical 

trial results information by the later of 

the original submission deadline 

specified in paragraph (a), (b), (c), (d) or 

(f) of this section, or 15 calendar days 

after the electronic notification of the 

denial upon appeal specified in 

paragraph (e)(3)(iii) of this section, is 

sent to the responsible party. 

(vi) If the Director denies an appeal of 

a deadline specified in a granted 

extension request, the responsible party 

must submit clinical trial results 

information by the later of the deadline 

specified in the notification granting the 

extension request, specified in 

paragraph (e)(2)(i) of this section or 15 

calendar days after the electronic 

notification denying the appeal, 

specified in paragraph (e)(3)(iii) of this 

section, is sent to the responsible party. 

(f) Pediatric postmarket surveillance 

of a device that is not a clinical trial. For 

each pediatric postmarket surveillance 

of a device that is not a clinical trial as 

defined in this part, the responsible 

party must submit clinical trial results 

information as specified in § 11.48(b) 

not later than 30 calendar days after the 

date on which the final report of the 

approved pediatric postmarket 

surveillance of a device as specified in 

21 CFR 822.38 (or any successor 

regulation) is submitted to FDA. 

§ 11.48 What constitutes clinical trial 

results information? 

(a) For each applicable clinical trial 

other than a pediatric postmarket 

surveillance of a device that is not a 

clinical trial for which clinical trial 

results information must be submitted 

under § 11.42, the responsible party 

must provide the following: 

(1) Participant flow. Information for 

completing a table documenting the 

progress of human subjects through a 

clinical trial by arm, including the 

number who started and completed the 

clinical trial. This information must 

include the following elements: 

(i) Participant Flow Arm Information. 

A brief description of each arm used for 

describing the flow of human subjects 

through the clinical trial, including a 

descriptive title used to identify each 

arm. 

(ii) Pre-assignment Information. A 

description of significant events 

affecting the number of human subjects 

enrolled in the clinical trial but not 

assigned to an arm, if any. 

(iii) Participant Data. The number of 

human subjects that started and 

completed the clinical trial, by arm. 

(2) Demographic and baseline 

characteristics. Information for 

completing a table of demographic and 

baseline measures and data collected by 

arm or comparison group and for the 

entire population of human subjects 

who participated in the clinical trial. 

This information must include the 

following elements: 

(i) Baseline Characteristics Arm/

Group Information. A brief description 

of each arm or comparison group used 

for describing the demographic and 

baseline characteristics of the human 

subjects in the clinical trial, including a 

descriptive title used to identify each 

arm or comparison group. 

(ii) Overall Number of Baseline 

Participants. The total number of 

human subjects for whom baseline 

characteristics were measured, by arm 

or comparison group, and overall. 

(iii) Baseline Measure Information. A 

description of each baseline or 

demographic characteristic measured in 

the clinical trial, including age, gender, 

and any other measure(s) that were 

assessed at baseline and are used in the 

analysis of outcome measures in 

accordance with § 11.48(a)(3). The 

description of each measure must 

include the following elements: 

(A) Name and Description of the 

measure, including any categories that 

are used in submitting the results; 

(B) Measure Type and Measure of 

Dispersion: For each baseline measure 

submitted, an indication of the type of 

data to be submitted and, the associated 

measure of dispersion; 

(C) Unit of measure. 

(iv) Baseline Measure Data. The 

value(s) for each submitted baseline 

measure, by arm or comparison group 

and for the entire population of human 

subjects who participated in the clinical 

trial. 

(3) Outcomes and statistical analyses. 

Information for completing a table of 

data for each primary and secondary 

outcome measure by arm or comparison 

group, including the result(s) of 

scientifically appropriate statistical 

analyses that were performed on the 

outcome measure data, if any. This 

information must include the following 

elements: 

(i) Outcome Measure Arm/Group 

Information. A brief description of each 

arm or comparison group used for 

submitting an outcome measure for the 

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clinical trial, including a descriptive 

title to identify each arm or comparison 

group. 

(ii) Analysis Population Information 

(A) Number of Participants Analyzed. 

The number of human subjects for 

which an outcome was measured and 

analyzed, by arm or comparison group. 

(B) Number of Units Analyzed. If the 

analysis is based on a unit other than 

participants, a description of the unit of 

analysis and the number of units for 

which an outcome was measured and 

analyzed, by arm or comparison group. 

(C) Analysis Population Description. 

If the Number of Participants Analyzed 

differs from the number of human 

subjects assigned to the arm or 

comparison group, a brief description of 

the reason(s) for the difference. 

(iii) Outcome Measure Information. A 

description of each outcome measure, to 

include the following elements: 

(A) Name of the specific outcome 

measure, including the titles of any 

categories in which Outcome Measure 

Data are aggregated; 

(B) Description of the metric used to 

characterize the specific outcome 

measure; 

(C) Time point(s) at which the 

measurement was assessed for the 

specific metric; 

(D) Outcome Measure Type. The type 

of outcome measure, whether primary, 

secondary, other pre-specified, or posthoc; 

(E) Outcome Measure Reporting 

Status. Whether data for the outcome 

measure are included in the present 

submission and, if not, the anticipated 

submission date; 

(F) Measure Type. For each outcome 

measure for which data are collected, 

the type of data to be submitted (number 

or measure of central tendency) and, if 

a measure of central tendency, the 

related measure of dispersion or 

precision; 

(G) Unit of Measure. For each 

outcome measure for which data are 

collected, the unit of measure. 

(iv) Outcome Measure Data. The 

measurement value(s) for each outcome 

measure for which data are collected, by 

arm or comparison group, and by 

category (if specified). 

(v) Statistical Analyses. Result(s) of 

scientifically appropriate statistical 

analyses, if any, including any statistical 

analysis that is: 

(A) Pre-specified in the protocol and/ 

or statistical analysis plan that was 

performed on the outcome measure 

data, 

(B) Made public by the sponsor or 

responsible party prior to the date on 

which results information is submitted 

for all primary and secondary outcome 

measures studied in the clinical trial, or 

(C) Conducted in response to a 

request made by the U.S. Food and Drug 

Administration prior to the date on 

which complete clinical trial results 

information is submitted for all of the 

primary outcome measures studied in 

the clinical trial. Submitted Statistical 

Analysis information must include: 

(1) Statistical Analysis Overview: 

Identification of the arms or comparison 

groups compared in the statistical 

analysis, the type of statistical test 

conducted; and, for a non-inferiority 

test, a description of the analysis that 

includes, at minimum, the power 

calculation and non-inferiority margin; 

(2) Statistical Test of Hypothesis: The 

p-value and the procedure used for the 

statistical analysis; 

(3) Method of Estimation: The 

estimation parameter, estimated value, 

and confidence interval. 

(4) Adverse event information. (i) 

Information for completing two tables 

summarizing adverse events collected 

during an applicable clinical trial: 

(A) Table of all serious adverse events 

grouped by organ system, with the 

number and frequency of each event by 

arm or comparison group; and 

(B) Table of all adverse events, other 

than serious adverse events, that exceed 

a frequency of 5 percent within any arm 

of the clinical trial, grouped by organ 

system, with the number and frequency 

of each event by arm or comparison 

group. 

(ii) Information for each table 

specified in paragraph (a)(4)(i) of this 

section must include the following 

elements: 

(A) Adverse Event Arm/Comparison 

Group Information. A brief description 

of each arm or comparison group used 

for submitting adverse event 

information from the clinical trial, 

including a descriptive title used to 

identify each arm or comparison group. 

(B) Total Number Affected, by Arm or 

Comparison Group. The overall number 

of human subjects affected, by arm or 

comparison group, by one or more 

(1) Serious adverse event(s), or 

(2) Adverse event(s) other than 

serious adverse events that exceed a 

frequency of 5 percent within any arm 

of the clinical trial. 

(C) Total Number at Risk, by Arm or 

Comparison Group. The overall number 

of human subjects included in the 

assessment, by arm or comparison 

group, for 

(1) Serious adverse events, or 

(2) Adverse event(s) other than 

serious adverse events that exceed a 

frequency of 5 percent within any arm 

of the clinical trial. 

(D) Total Number Affected, by Organ 

System. For each organ system that has 

one or more adverse events listed in 

either the table of serious adverse events 

or the table of adverse events other than 

serious adverse events that exceed a 

frequency of 5 percent within any arm 

of the clinical trial, the overall number 

of human subjects affected, by arm or 

comparison group, within each table. 

(E) Total Number at Risk, by Organ 

System. For each organ system that has 

one or more adverse events listed in 

either the table of serious adverse events 

or the table of adverse events other than 

serious adverse events that exceed a 

frequency of 5 percent within any arm 

of the clinical trial, the overall number 

of human subjects at risk for the adverse 

event, by arm or comparison group. 

(F) Adverse Event Information. A 

description of each type of serious 

adverse event and other adverse event 

that is not a serious adverse event and 

exceeds a frequency of 5 percent within 

any arm of the clinical trial, consisting 

of the following attributes: 

(1) Descriptive term for the adverse 

event; and 

(2) Organ system associated with the 

adverse event. 

(G) Adverse Event Data. For each type 

of adverse event listed in accordance 

with paragraph (a)(4)(ii)(F) of this 

section: 

(1) Number of human subjects 

affected by such adverse event; 

(2) Number of human subjects at risk 

for such adverse event; 

(H) Additional Adverse Event 

Description. If the adverse event 

information collected in the applicable 

clinical trial is collected based on a 

different definition of adverse event 

and/or serious adverse event than 

defined in this part, a brief description 

of how those definitions differ. 

(iii) Information submitted by organ 

system must be grouped according to 

the organ system classification 

established in ClinicalTrials.gov. 

(5) Administrative information. (i) 

Results Point of Contact. Point of 

contact for scientific information about 

the clinical trial results information, 

including the following: 

(A) Name or official title of the point 

of contact; 

(B) Name of affiliated organization; 

and 

(C) Telephone number and email 

address of the point of contact. 

(ii) Certain Agreements. An indication 

of whether the principal investigator is 

an employee of the sponsor and, if not, 

whether there exists any agreement 

(other than an agreement solely to 

comply with applicable provisions of 

law protecting the privacy of human 

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subjects participating in the clinical 

trial) between the sponsor or its agent 

and the principal investigator that 

restricts in any manner the ability of the 

principal investigator, after the 

completion date of the clinical trial, to 

discuss the results of the clinical trial at 

a scientific meeting or any other public 

or private forum, or to publish in a 

scientific or academic journal 

information concerning the results of 

the clinical trial. 

(6) Additional clinical trial results 

information for applicable device 

clinical trials of unapproved or 

uncleared devices. (i) For an applicable 

device clinical trial of an unapproved or 

uncleared device, the responsible party 

must provide the following data 

elements, as the data elements are 

defined in § 11.10(b): Brief Title; Official 

Title; Brief Summary; Primary Purpose; 

Study Design; Study Type; Primary 

Disease or Condition Being Studied in 

the Trial, or the Focus of the Study; 

Intervention Name; Other Intervention 

Name; Intervention Description; 

Intervention Type; U.S. FDA Approval, 

Licensure, or Clearance Status; Study 

Start Date; Completion Date; 

Enrollment; Primary Outcome Measure 

Information, as previously submitted to 

ClinicalTrials.gov; Secondary Outcome 

Measure Information as previously 

submitted to ClinicalTrials.gov; 

Eligibility Criteria; Gender; Age Limits; 

Accepts Healthy Volunteers; Overall 

Recruitment Status; Why Study 

Stopped; Actual Enrollment; Name of 

the Sponsor; Responsible Party by 

Official Title; Facility Name and Facility 

Location, for each participating facility 

in a clinical trial; Unique Protocol 

Identification Number; Secondary IDs; 

Human Subjects Protection Review 

Board Status; and Record Verification 

Date. 

(ii) The responsible party shall submit 

the results information specified in 

paragraph (a)(6)(i) of this section by 

submitting an affirmation that the 

information previously submitted to 

ClinicalTrials.gov for the data elements 

listed in paragraph (a)(6)(i) of this 

section have been updated in 

accordance with § 11.64(c) and are to be 

included as clinical trial results 

information. 

(b) Pediatric postmarket surveillance 

of a device that is not a clinical trial. For 

each pediatric postmarket surveillance 

of a device that is not a clinical trial, the 

responsible party must submit a copy of 

any written final report that is 

submitted to FDA as specified in 21 CFR 

822.38 (or any successor regulation). 

The final written report must be in a 

common electronic document format 

specified at http://

prsinfo.clinicaltrials.gov. The 

responsible party must redact names, 

addresses, and other personally 

identifiable information or commercial 

confidential information contained in 

the final written report prior to 

submission to NIH. Redacted 

information may not include any 

information specified in §§ 11.28(a) or 

11.48(a) of this part. 

§ 11.52 When will NIH post submitted 

clinical trial results information? 

The Director will post publicly 

clinical trial results information 

submitted under this subpart at 

ClinicalTrials.gov not later than 30 

calendar days after the date of 

submission. 

§ 11.54 What are the procedures for 

waiving of the requirements of this 

subpart? 

(a) Waiver request. 

(1) A responsible party may request a 

waiver from any applicable 

requirement(s) of this subpart by 

submitting a waiver request in the form 

of a written letter to the Secretary or 

delegate prior to the deadline specified 

in § 11.42(a) for submitting clinical trial 

results information. 

(2) The waiver request must contain: 

(i) The NCT number, Brief Title, and 

Name of the Sponsor of the applicable 

clinical trial for which the waiver is 

requested; 

(ii) The specific requirement(s) of this 

subpart for which the waiver is 

requested; and 

(iii) A description of the extraordinary 

circumstances that the responsible party 

believes justify the waiver and an 

explanation of why granting the request 

would be consistent with the protection 

of public health or in the interest of 

national security. 

(3) The responsible party will not be 

required to comply with the specified 

requirements of this subpart for which 

a waiver is granted. 

(4) The responsible party must 

comply with any requirements of this 

subpart for which a waiver is not 

granted or must submit an appeal as set 

forth in paragraph (b) of this section. 

The deadline for submitting any 

required clinical trial results 

information will be the later of the 

original submission deadline or 15 

calendar days after the notification of 

the denial is sent to the responsible 

party. 

(b) Appealing a denied waiver request 

(1) A responsible party may appeal a 

denied waiver request by submitting a 

letter in writing to the Secretary or 

delegate not later than 15 calendar days 

after the date on which the letter in 

paragraph (a)(iii) of this section denying 

the request is transmitted. 

(2) The responsible party is not 

required to comply with any 

requirements of this subpart for which 

the waiver is granted upon appeal. 

(3) The responsible party must submit 

clinical trial results information to 

comply with any requirements of this 

subpart that are not waived upon appeal 

by the later of the original submission 

deadline or 15 calendar days after the 

written notice of the denial upon appeal 

is sent by the Secretary. 

(c) If a waiver is granted under 

paragraph (a) or (b) of this section, 

(1) The Director will include a 

notation in the clinical trial record that 

specified elements of the requirements 

of this part have been waived. 

(2) The Secretary will notify, in 

writing, the appropriate committees of 

Congress and provide an explanation for 

why the waiver was granted, not later 

than 30 calendar days after any part of 

a waiver is granted. 

Subpart D—Additional Submissions of 

Clinical Trial Information 

§ 11.60 What requirements apply to the 

voluntary submission of clinical trial 

information for clinical trials of FDAregulated drugs and devices? 

(a) If a responsible party voluntarily 

submits clinical trial information for a 

clinical trial described in paragraph 

(a)(1) of this section, the responsible 

party must meet the conditions 

specified in paragraph (a)(2) of this 

section. 

(1) Clinical trials to which this section 

applies. The requirements of this 

section apply to the following types of 

clinical trials: 

(i) A clinical trial of an FDA-regulated 

drug or device that is not an applicable 

clinical trial, and 

(ii) An applicable clinical trial that is 

not required to submit clinical trial 

registration information under 

§ 11.22(a). 

(2) Conditions for voluntary 

submission of certain clinical trials. The 

following conditions must be met by a 

responsible party who voluntarily 

submits clinical trial information for a 

clinical trial that is described in 

paragraph (a)(1) of this section. 

(i) The responsible party must submit 

the information in (A) or (B) for the 

clinical trial being submitted 

voluntarily. 

(A) If the responsible party 

voluntarily registers a clinical trial, the 

responsible party must submit complete 

clinical trial registration information 

specified in § 11.28(a). The responsible 

party may, but is not required to, submit 

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complete clinical trial results 

information in § 11.48(a). 

(B) If the responsible party voluntarily 

submits clinical trial results information 

for a clinical trial for which the clinical 

trial registration information specified 

in § 11.28(a) has not been submitted, the 

responsible party must submit the data 

elements specified in § 11.48(a), as well 

as the data elements listed below, as 

those the data elements are defined in 

§ 11.10(b) and apply to the clinical trial 

and the interventions studied: Brief 

Title; Official Title; Brief Summary; 

Primary Purpose; Study Design; Study 

Phase, for a clinical trial of a drug; 

Study Type; Whether the Study is a 

Pediatric Postmarket Surveillance of a 

Device; Primary Disease or Condition 

Being Studied in the Trial; or the Focus 

of the Study; Intervention Name, for 

each intervention studied; Other 

Intervention Name, for each 

intervention studied; Intervention 

Description, for each intervention 

studied; Intervention Type, for each 

intervention studied; U.S. FDA 

Approval, Licensure, or Clearance 

Status, for each intervention studied; 

Product Manufactured in the U.S., for 

each intervention studied; Studies an 

FDA-regulated Device; Studies an FDAregulated Drug; Study Start Date; 

Completion Date; Enrollment; Eligibility 

Criteria; Gender; Age Limits; Accepts 

Healthy Volunteers; Overall 

Recruitment Status; Why Study 

Stopped; Actual Enrollment; 

Availability of Expanded Access; Name 

of the Sponsor; Responsible Party by 

Official Title; Facility Name and Facility 

Location, for each participating facility; 

Unique Protocol Identification Number; 

Secondary IDs; Food and Drug 

Administration IND or IDE Number; 

Human Subjects Protection Review 

Board Status; Record Verification Date; 

and Responsible Party Contact 

Information. 

(ii) If, on or after September 27, 2007, 

a manufacturer submits an application 

or premarket notification to FDA for 

approval, licensure, or clearance of a 

drug or device under sections 505, 

510(k), 515, or 520(m) of the Federal 

Food, Drug, and Cosmetic Act or section 

351 of the Public Health Service Act for 

the use studied in the clinical trial 

submitted under paragraph (a)(1) of this 

section, the Responsible Party specified 

in paragraph (a)(1) of this section must 

also submit the information specified in 

paragraph (a)(2)(iii) of this section by 

the deadline specified in paragraph 

(a)(2)(iv)(B) of this section for any 

applicable clinical trial that has not 

been submitted to ClinicalTrials.gov and 

that meets the following criteria: 

(A) The applicable clinical trial is 

required to be submitted to FDA under 

sections 505, 510(k), 515, or 520(m) of 

the Federal Food, Drug, and Cosmetic 

Act or section 351 of the Public Health 

Service Act in an application or 

premarket notification for approval, 

licensure, or clearance to market the 

drug or device for the use studied in the 

clinical trial specified in paragraph 

(a)(1) of this section; and 

(B) The manufacturer of the drug or 

device studied in the applicable clinical 

trial is also the responsible party for the 

clinical trial specified in paragraph 

(a)(1) of this section. 

(iii) Information to be submitted for 

clinical trials described in paragraph 

(a)(2)(ii) of this section: 

(A) If the clinical trial information 

voluntarily submitted for a clinical trial 

described in paragraph (a)(1) of this 

section consists only of the clinical trial 

registration information specified in 

§ 11.28(a), then the information to be 

submitted in accordance with paragraph 

(a)(2)(ii) of this section must consist, at 

minimum, of the clinical trial 

registration information specified in 

§ 11.28(a). 

(B) If the clinical trial information 

voluntarily submitted for a clinical trial 

described by paragraph (a)(1) of this 

section consists of the clinical trial 

results information specified in 

§ 11.60(a)(2)(i)(B), then the information 

to be submitted in accordance with 

paragraph (a)(2)(ii) of this section must 

consist of the clinical trial results 

information specified in 

§ 11.60(a)(2)(i)(B). 

(C) If the clinical trial information 

voluntarily submitted for a clinical trial 

described by paragraph (a)(1) of this 

section consists of both the clinical trial 

registration information specified in 

§ 11.28(a) and the clinical trial results 

information specified in § 11.48(a), then 

the information to be submitted in 

accordance with paragraph (a)(2)(ii) of 

this section must consist of the clinical 

trial registration information specified 

in § 11.28(a) and the clinical trial results 

information specified in § 11.48(a). 

(iv) Submission deadlines: 

(A) Secondary outcome measure(s) for 

voluntarily-submitted clinical trials 

under paragraph (a) of this section. If 

data collection for the secondary 

outcome measure(s) for a voluntarilysubmitted clinical trial under paragraph 

(a) of this section, which submission 

consists of clinical trial results 

information, is not completed by the 

completion date of the voluntarilysubmitted clinical trial, then clinical 

trial results information for the 

secondary outcome measure(s) must be 

submitted by the later of the date that 

the clinical trial results information is 

voluntarily submitted for the primary 

outcome measure(s) or 1 year after the 

date on which the final subject was 

examined or received an intervention 

for the purposes of final collection of 

data for the secondary outcome(s), 

whether the clinical trial was concluded 

according to the pre-specified protocol 

or was terminated. 

(B) The clinical trial information 

specified in paragraph (a)(2)(iii) of this 

section must be submitted not later than 

the later of the date on which the 

application or premarket notification to 

FDA for approval, licensure, or 

clearance to market a drug or device 

under section 351 of the Public Health 

Service Act or sections 505, 510(k), 515, 

or 520(m) of the Federal Food, Drug, 

and Cosmetic Act for the use studied in 

the clinical trial specified under 

paragraph (a)(1) of this section is 

submitted to FDA; or, the date on which 

the clinical trial information specified 

in paragraph (a)(2)(i) of this section for 

the clinical trial specified under 

paragraph (a)(1) of this section is 

submitted to ClinicalTrials.gov. 

(v) All submissions of clinical trial 

information under paragraph (a) of this 

section are subject to the update 

requirements specified in § 11.64 and 

the corrections requirements specified 

in § 11.66. 

(b) Statement to accompany 

applicable clinical trials submitted 

under paragraph (a) of this section. Each 

applicable clinical trial for which 

clinical trial information is submitted 

under paragraph (a) of this section and 

posted at ClinicalTrials.gov will include 

the statement ‘‘Clinical trial information 

for this applicable clinical trial was 

submitted under section 402(j)(4)(A) of 

the Public Health Service Act and 42 

CFR 11.60 and is not subject to the 

deadlines established by sections 

402(j)(2) and (3) of the Public Health 

Service Act or 42 CFR 11.24 and 11.44.’’ 

§ 11.62 What requirements apply to 

applicable clinical trials for which 

submission of clinical trial information has 

been determined by the Director to be 

necessary to protect the public health? 

(a) A responsible party who receives 

notification that the Director has 

determined that posting of clinical trial 

information for an applicable clinical 

trial described in paragraph (b) of this 

section is necessary to protect the public 

health must submit clinical trial 

information as specified in paragraph (c) 

of this section. 

(b) An applicable clinical trial subject 

to this section must be either: 

(1) An applicable clinical trial of an 

approved, licensed, or cleared drug or 

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device that has a completion date on or 

after September 27, 1997; or 

(2) An applicable clinical trial that is 

subject to registration under § 11.22(a) 

and studies a drug or device that is 

unapproved, unlicensed, or uncleared. 

(c) Deadline for submission of clinical 

trial information. 

(1) General. Except as provided in 

paragraphs (c)(2) and (c)(3) of this 

section, a responsible party for an 

applicable clinical trial that is subject to 

this section must submit clinical trial 

registration information specified in 

§ 11.28(a) and clinical trial results 

information specified in § 11.48(a) to 

ClinicalTrials.gov not later than 30 

calendar days after the submission date 

specified in the notification described in 

paragraph (a) of this section. 

(2) Exception. If a responsible party 

submits a certification consistent with 

§ 11.44(b) or (c) not later than 30 

calendar days after the submission date 

specified in the notification described in 

paragraph (a) of this section, the 

responsible party must submit clinical 

trial results information specified in 

§ 11.48(a) not later than the deadline 

specified in § 11.44(b) or (c), as 

applicable. 

(3) If a responsible party submitted 

clinical trial registration information 

describing the applicable clinical trial 

specified in the notification described in 

paragraph (a) of this section prior to the 

date on which the notification is sent to 

the responsible party, the responsible 

party must update such clinical trial 

information to reflect changes, if any, in 

the applicable clinical trial not later 

than 30 calendar days after the 

submission date specified in the 

notification described in paragraph (a) 

of this section, irrespective of the 

deadline for updates specified in 

§ 11.64. 

§ 11.64 When must clinical trial 

information submitted to ClinicalTrials.gov 

be updated? 

(a) General. (1) Except as provided in 

paragraphs (b) and (c) of this section, 

the responsible party for an applicable 

clinical trial or other clinical trial must 

submit updates to reflect changes to 

previously-submitted clinical trial 

information not less than once every 12 

months, unless there are no changes to 

the clinical trial information during the 

preceding 12-month period. 

(2) Updates to the estimated 

Completion Date must be submitted not 

less than once every 12 months, unless 

there is no change to the estimated date 

during the preceding 12-month period. 

(3) A responsible party must continue 

to submit updates as specified in this 

section until the date on which 

complete clinical trial results 

information specified in § 11.48 has 

been submitted for all primary and 

secondary outcomes and all adverse 

events that were collected in accordance 

with the protocol. 

(b) Items Requiring More Rapid 

Updates. (1) A responsible party must 

submit updates to reflect changes to the 

following clinical trial information data 

elements not later than 30 calendar days 

after the change has occurred: 

(i) If the first human subject was not 

enrolled in the clinical trial at the time 

of registration, the Study Start Date data 

element must be updated not later than 

30 calendar days after the first human 

subject is enrolled. 

(ii) Intervention Name(s) must be 

updated to a non-proprietary name not 

later than 30 calendar days after a nonproprietary name is established for any 

intervention included in the 

Intervention Name(s) data element. 

(iii) Availability of Expanded Access. 

(A) If expanded access to a drug 

becomes available after a clinical trial of 

that drug has been registered, the 

responsible party must, not later than 30 

calendar days after expanded access 

becomes available, update the 

Availability of Expanded Access data 

element for that clinical trial and, unless 

an expanded access record has already 

been created as required by 

§ 11.28(a)(2)(ix), submit the data 

elements listed in § 11.28(c) to create an 

expanded access record. 

(B) Upon receipt of an NCT number 

for an expanded access record created 

for a clinical trial under § 11.28(a)(2)(ix), 

the responsible party must update the 

Availability of Expanded Access data 

element by entering in the clinical trial 

record the NCT number of the expanded 

access record no later than 30 calendar 

days after the date on which the 

responsible party receives such NCT 

number. 

(C) Upon termination of an expanded 

access program, the responsible party 

must, not later than 30 calendar days 

after the date of termination, update the 

Availability of Expanded Access data 

element to indicate that expanded 

access is no longer available. 

(iv) Expanded Access Status, under 

§ 11.28(c)(2)(iv), must be updated not 

later than 30 calendar days after a 

change in the availability of access to an 

investigational drug or investigational 

device under section 561 of the Federal 

Food, Drug, and Cosmetic Act (21 U.S.C. 

360bbb). 

(v) Overall Recruitment Status must 

be updated not later than 30 calendar 

days after any change in overall 

recruitment status. At the time Overall 

Recruitment Status is changed, the 

responsible party must also make the 

following updates, as applicable: 

(A) If Overall Recruitment Status is 

changed to ‘‘suspended,’’ ‘‘terminated,’’ 

or ‘‘withdrawn,’’ the Why Study 

Stopped data element must be 

submitted. 

(B) If Overall Recruitment Status is 

changed to ‘‘terminated’’ or ‘‘active, not 

recruiting,’’ the Actual Enrollment data 

element must be submitted. 

(vi) Individual Site Status must be 

updated not later than 30 calendar days 

after a change in status of any 

individual site. 

(vii) Human Subjects Protection 

Review Board Status must be updated 

not later than 30 calendar days after a 

change in status. 

(viii) Completion Date must be 

updated not later than 30 calendar days 

after the clinical trial reaches its actual 

completion date; 

(ix) Responsible Party, by Official 

Title must be updated not later than 30 

calendar days after a change in the 

responsible party or the official title of 

the responsible party; 

(x) Responsible Party Contact 

Information must be updated not later 

than 30 calendar days after a change in 

the responsible party or the contact 

information of the responsible party; 

(2) Updates to the U.S. FDA Approval, 

Licensure, or Clearance Status data 

element must be submitted not later 

than 15 calendar days after a change in 

status has occurred. 

(3) If a protocol is amended in such 

a manner that changes are 

communicated to human subjects in the 

clinical trial, updates to relevant clinical 

trial information data elements must be 

submitted no later than 30 calendar 

days after the protocol amendment is 

approved by a human subjects 

protection review board. 

(4) Record Verification Date must be 

updated any time the responsible party 

reviews the complete set of submitted 

clinical trial information for accuracy, 

even if no other updated information is 

submitted at that time. 

(c) Irrespective of update 

requirements established in paragraphs 

(a) and (b) of this section, upon 

submission of clinical trial results 

information for an applicable clinical 

trial or other clinical trial, a responsible 

party must submit updates to the 

clinical trial registration information 

submitted previously to 

ClinicalTrials.gov for that applicable 

clinical trial or other clinical trial, 

unless there are no changes to the 

clinical trial registration information. 

(d) Public availability of updates. 

(1) Updates to clinical trial 

registration information and clinical 

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69680 Federal Register / Vol. 79, No. 225 / Friday, November 21, 2014 / Proposed Rules 

trial results information will be posted 

in accordance with § 11.35 and § 11.52, 

respectively. 

(2) The Director will retain prior 

clinical trial registration information 

and clinical trial results information and 

make it publicly available in accordance 

with § 11.35 and § 11.52, respectively, 

through ClinicalTrials.gov so that the 

updates do not result in the removal of 

any information from the original 

submission or any preceding update. 

§ 11.66 What are the requirements for 

corrections of clinical trial information? 

(a) Correction of errors. A responsible 

party who becomes aware of errors in 

any clinical trial information submitted 

under this part or is informed by NIH 

that such clinical trial information 

contains errors shall correct such errors 

not later than 15 calendar days after the 

date on which the responsible party 

becomes aware of the errors or on which 

NIH informs the responsible party of the 

errors, whichever is earlier. 

(b) Correction of falsified data. A 

responsible party who becomes aware 

that clinical trial information submitted 

under this part was falsified or based on 

falsified information, shall notify the 

Director that such information was 

determined to be falsified or based on 

falsified information and either: 

(1) Submit corrected clinical trial 

information not later than 15 calendar 

days after corrected information 

becomes available; or 

(2) Notify the Director not later than 

15 calendar days after determining that 

such information cannot be corrected or 

is correct as submitted. 

(c) Other corrections of clinical trial 

information. A responsible party who 

becomes aware or is informed by NIH 

that corrections other than those 

specified in paragraphs (a) or (b) of this 

section are needed to any clinical trial 

information submitted under this part, 

shall correct such clinical trial 

information as soon as possible, but not 

later than 15 calendar days after the date 

on which the responsible party becomes 

aware, or is informed by NIH that such 

clinical trial information is in need of 

correction, whichever is earlier. 

Dated: October 7, 2014. 

Francis S. Collins, 

Director, National Institutes of Health. 

Approved: October 28, 2014. 

Sylvia Mathews Burwell, 

Secretary. 

[FR Doc. 2014–26197 Filed 11–19–14; 11:15 am] 

BILLING CODE 4140–01–P 

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