256 Federal Register / Vol. 76, No. 2 / Tuesday, January 4, 2011 / Rules and Regulations 

3Based on Investment Adviser Registration 

Depository data as of December 1, 2010, 92% of 

SEC-registered investment advisers report a 

December fiscal year end. 

4Memorandum from Morgan Lewis on behalf of 

certain SIFMA member firms dated Dec. 16, 2010 

available at http://www.sec.gov/rules/proposed/ 

s71000.shtml. 

5The North American Securities Administrators 

Association has recommended that the State 

securities authorities provide the same extension 

for State-registered investment advisers. However, 

State-registered advisers should contact the States 

where they are registered to confirm compliance 

dates. 

6Advisers may choose to deliver brochure 

supplements earlier than the dates outlined in this 

release. 

7See Section 553(b)(3)(B) of the Administrative 

Procedure Act (5 U.S.C. 553(b)(3)(B)) (‘‘APA’’) (an 

agency may dispense with prior notice and 

comment when it finds, for good cause, that notice 

and comment are ‘‘impracticable, unnecessary, or 

contrary to the public interest’’). This finding also 

satisfies the requirements of 5 U.S.C. 808(2), 

allowing the rules to become effective 

notwithstanding the requirement of 5 U.S.C. 801 (if 

a Federal agency finds that notice and public 

comment are ‘‘impractical, unnecessary or contrary 

to the public interest,’’ a rule ‘‘shall take effect at 

such time as the Federal agency promulgating the 

rule determines’’). Also, because the Regulatory 

Flexibility Act (5 U.S.C. 601–612) only requires 

agencies to prepare analyses when the 

Administrative Procedures Act requires general 

notice of rulemaking, that Act does not apply to the 

actions that we are taking in this release. The 

change to the compliance date is effective upon 

publication in the Federal Register. This date is less 

than 30 days after publication in the Federal 

Register, in accordance with the APA, which allows 

effectiveness in less than 30 days after publication 

for ‘‘a substantive rule which grants or recognizes 

an exemption or relieves a restriction.’’ See 5 U.S.C. 

553(d)(1). 

Form ADV for fiscal year ends 

beginning on December 31, 2010, and to 

existing clients within 60 days of filing 

the annual updating amendment. Most 

registered advisers have fiscal years 

ending on December 31 and must, as a 

result, file an annual updating 

amendment by March 31, 2011.3 Absent 

an extension of the compliance date, 

these advisers would be required to 

deliver their first brochure supplements 

to new and prospective clients no later 

than March 31, 2011 and to existing 

clients no later than May 31, 2011. 

We have received correspondence 

from the Securities Industry and 

Financial Markets Association 

(‘‘SIFMA’’), requesting that we delay the 

compliance date for at least an 

additional four months, until July 31, 

2011, solely with respect to 

requirements regarding delivery of the 

brochure supplement.4 SIFMA asserts 

that preparing and disseminating 

brochures with respect to thousands of 

supervised persons to tens of thousands 

of clients presents its members with 

substantial logistical challenges in 

meeting the compliance date. It asserts 

that its members need additional time to 

design, test and implement systems and 

controls that will assure that each client 

receives an accurate brochure 

supplement with respect to the 

supervised person who provides advice 

to that client. 

Based on the concerns expressed in 

the correspondence, and in light of 

similar concerns that have been 

expressed by other investment advisers 

to our staff, we are persuaded that a 

limited extension of the compliance 

date for the delivery of brochure 

supplements for existing registered 

advisers is appropriate.5 We have based 

this decision on the information SIFMA 

has provided and our experience in 

overseeing the industry. In addition, to 

provide consistent treatment for newly 

registering advisers, we are also 

persuaded that the limited extension of 

the compliance date for the delivery of 

brochure supplements is appropriate for 

these advisers as well. We are not 

extending the compliance date for the 

filing and delivery of the brochure 

required by Part 2A of Form ADV and 

related rules under the Advisers Act, 

which is required for newly registering 

investment advisers beginning on 

January 1, 2011, and for existing 

registered advisers when they file their 

annual updating amendments for fiscal 

years ending on and after December 31, 

2010. 

Accordingly, the Commission believes 

it is appropriate to modify and extend 

the compliance date for brochure 

supplements for the following 

investment advisers: 6

Existing Registered Investment 

Advisers. All investment advisers 

registered with the Commission as of 

December 31, 2010, and having a fiscal 

year ending on December 31, 2010 

through April 30, 2011, have until July 

31, 2011, to begin delivering brochure 

supplements to new and prospective 

clients. These advisers have until 

September 30, 2011 to deliver brochure 

supplements to existing clients. The 

compliance dates for delivering 

brochure supplements for existing 

registered investment advisers with 

fiscal years ending after April 30, 2011 

remain unchanged. 

Newly-registered Investment Advisers. 

All newly registered investment 

advisers filing their applications for 

registration from January 1, 2011 

through April 30, 2011, have until May 

1, 2011 to begin delivering brochure 

supplements to new and prospective 

clients. These advisers have until July 1, 

2011 to deliver brochure supplements to 

existing clients. The compliance dates 

for delivering brochure supplements for 

newly-registered investment advisers 

filing applications for registration after 

April 30, 2011 remain unchanged. 

The Commission finds that, for good 

cause and the reasons cited above, 

including the brief length of the 

extension we are granting, notice and 

solicitation of comment regarding the 

extension of the compliance date for 

Part 2B of Form ADV and the provisions 

of rule 204–3 that relate to the delivery 

of brochure supplements are 

impracticable, unnecessary, or contrary 

to the public interest.7 In this regard, the 

Commission also notes that investment 

advisers need to be informed as soon as 

possible of the extension and its length 

in order to plan and adjust their 

implementation process accordingly. 

Dated: December 28, 2010. 

By the Commission. 

Elizabeth M. Murphy, 

Secretary. 

[FR Doc. 2010–33142 Filed 1–3–11; 8:45 am] 

BILLING CODE 8011–01–P 

DEPARTMENT OF HEALTH AND 

HUMAN SERVICES 

Food and Drug Administration 

21 CFR Part 50 

[Docket No. FDA–2009–N–0592] 

RIN No. 0910–AG32 

Informed Consent Elements 

AGENCY: Food and Drug Administration, 

HHS. 

ACTION: Final rule. 

SUMMARY: The Food and Drug 

Administration (FDA) is amending the 

current informed consent regulations to 

require that informed consent 

documents and processes for applicable 

drug (including biological products) and 

device clinical trials include a specific 

statement that clinical trial information 

will be entered into a databank. The 

databank referred to in this final rule is 

the clinical trial registry databank 

maintained by the National Institutes of 

Health/National Library of Medicine 

(NIH/NLM) which was created by 

statute. The submission of clinical trial 

information to this data bank also is 

required by statute. This amendment to 

the informed consent regulations is 

required by the Food and Drug 

Administration Amendments Act of 

2007 (FDAAA) and is designed to 

promote transparency of clinical 

research to participants and patients. 

DATES: Effective date: This rule is 

effective March 7, 2011. 


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Federal Register / Vol. 76, No. 2 / Tuesday, January 4, 2011 / Rules and Regulations 257 

Compliance date: The compliance 

date of this final rule is March 7, 2012, 

for clinical trials that are initiated on or 

after the compliance date. See section III 

of this document for an additional 

explanation of the compliance date and 

required implementation of this final 

rule. 

FOR FURTHER INFORMATION CONTACT: 

Jarilyn Dupont, Office of Policy, Office 

of Commissioner, Food and Drug 

Administration, 10903 New Hampshire 

Ave., Bldg. 32, rm. 4248, Silver Spring, 

MD 20993–0002, 301–796–4830. 

SUPPLEMENTARY INFORMATION: 

Table of Contents 

I. Introduction 

II. Overview of the Final Rule 

III. Compliance Date 

IV. Comments on the Proposed Rule 

V. Legal Authority and Enforcement 

VI. Environmental Analysis 

VII. Analysis of Impacts 

VIII. Paperwork Reduction Act 

IX. Federalism 

X. References 

I. Introduction 

In the Federal Register of December 

29, 2009 (74 FR 68750), FDA issued a 

notice of proposed rulemaking (NPRM) 

to amend 21 CFR 50.25, its regulations 

governing informed consent documents 

and processes. This final rule revises the 

current informed consent regulations to 

require a new element for informed 

consent documents and processes that 

will inform the potential clinical trial 

participant that information about 

applicable clinical trials has been, or 

will be, entered into a databank that is 

publicly accessible at http:// 

www.ClinicalTrials.gov. (See section 

IV.F of this document for a discussion 

of applicable clinical trials.) The final 

rule adds this requirement in a new 

paragraph, § 50.25(c), and redesignates 

existing paragraphs. 

This final rule is issued under section 

801 of FDAAA (Pub. L. 110–85, 

September 27, 2007), which requires 

that information on an applicable 

clinical trial be submitted to NIH for 

inclusion in the clinical trial registry 

databank. This section also requires that 

the Secretary of the Department of 

Health and Human Services (HHS) 

update certain informed consent 

regulations to mandate that informed 

consent documents and processes 

include a statement that the required 

clinical trial information has been or 

will be submitted for inclusion in the 

registry databank. The current informed 

consent regulations do not include 

provisions similar to those required by 

FDAAA. (See parts 50 and 312 (21 CFR 

parts 50 and 312) and 21 CFR 

812.2(b)(1)(iii) and 812.25(g)). 

Section 801 of FDAAA amends the 

Public Health Service Act (the PHS Act) 

to require the Secretary, acting through 

the Director of NIH, to expand the 

existing clinical trial registry databank 

established under section 113 of the 

Food and Drug Administration 

Modernization Act (FDAMA), enacted 

November 21, 1997 (Pub. L. 105–115 

currently codified at 42 U.S.C. 282(i)). 

The new provision requires the Director 

to ensure that the databank is made 

publicly available through the Internet 

and to expand the databank to require 

the submission of specified information 

for applicable drug clinical trials and 

applicable device clinical trials. (The 

term ‘‘drug’’ includes biological products 

regulated under section 351 of the PHS 

Act (42 U.S.C. 262).) The provision also 

requires the Secretary of HHS to ensure 

that the databank includes links to 

results information for those clinical 

trials that form the primary basis of an 

efficacy claim or are conducted after the 

drug involved or device involved is 

cleared or approved. In addition, section 

801(b)(3)(A) of FDAAA states: 

NEW DRUGS AND DEVICES.— 

INVESTIGATIONAL NEW DRUGS.— 

Section 505(i) of the Federal Food, Drug, and 

Cosmetic Act (21 U.S.C. 355(i)) is amended 

in paragraph (4), by adding at the end the 

following: ‘‘The Secretary shall update such 

regulations to require inclusion in the 

informed consent documents and process a 

statement that clinical trial information for 

such clinical investigation has been or will 

be submitted for inclusion in the registry data 

bank pursuant to subsection (j) of section 402 

of the Public Health Service Act.’’ 

II. Overview of the Final Rule 

We considered all of the comments to 

the NPRM and the additional data and 

accompanying materials submitted with 

the comments. We also consulted with 

our internal experts on informed 

consent documents and processes as 

well as our internal experts in 

communicating health-related 

information to the public, clinical trial 

participants, and patients in evaluating 

the required statement. 

In response to the comments, and 

based on our internal reconsideration of 

the proposed requirements in the 

NPRM, we have amended the specific 

language of the statement required to be 

included in informed consent 

documents and processes. The 

mandatory statement is now shorter, 

less complex, and more understandable 

for potential clinical trial participants. 

Specific terms that are not commonly 

used by lay persons, or were deemed to 

be misleading or confusing, have been 

clarified and simplified. The mandatory 

statement has been revised to facilitate 

understanding while maintaining the 

purpose of the statutory provision. 

In response to comments expressing 

confusion and/or concern over the 

proposed placement of the new 

requirement as a ‘‘basic’’ element of 

informed consent under § 50.25(a), a 

new paragraph (c) has been added and 

the existing paragraphs have been 

redesignated. This separate new 

paragraph emphasizes the unique basis 

of the new element—required only for 

applicable clinical trials—as compared 

with existing basic elements which 

align with various ethics codes and 

apply to all clinical investigations 

regulated by FDA and clinical 

investigations that support applications 

for research or marketing permits for 

products regulated by FDA. 

New paragraph § 50.25(c) interacts 

with all other requirements of part 50 as 

do the other requirements and 

provisions of § 50.25. Similar to other 

informed consent elements, it is subject 

to the regulations governing 

documentation of informed consent 

(§ 50.27) and Institutional Review Board 

(IRB) waivers (§ 56.109(c)(1) (21 CFR 

56.109)). When a short form written 

consent document is chosen 

(§ 50.27(b)(2)), a short form and written 

summary must be provided to the 

clinical trial participant. All of these are 

considered ‘‘informed consent 

documents’’ and must contain the new 

statement (Ref. 1). For example, if an 

IRB waives the requirement for a signed 

written consent form under 

§ 56.109(c)(1), and requires ‘‘the 

investigator to provide subjects with a 

written statement regarding the 

research,’’ this written statement is 

considered a part of the documentation 

of ensuring the informed consent of the 

participant and thus, it must include the 

new statement (§ 56.109(d)). 

III. Compliance Date 

In response to comments, and after 

consideration of the intent and purpose 

of the new statutory requirement, we 

have determined that the compliance 

date of new § 50.25(c) will be 1 year 

after the effective date of this final rule 

for all informed consent documents and 

processes related to a clinical 

investigation that is initiated on or after 

the compliance date of this rule. In 

section IV.B of this document we 

provide, in our responses to the 

comments made concerning the 

effective date, additional explanation of 

the application of the compliance date 

to particular clinical investigations. 


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IV. Comments on the Proposed Rule 

We received 68 comments on the 

NPRM. Comments were received from 

IRBs, academic research centers, clinical 

investigators, physicians, health care 

professional societies, trade 

organizations representing clinical 

research organizations, drug and device 

sponsors, blood banks, clinical research 

organizations, research hospitals, 

medical device manufacturers, 

nonprofit organizations for ethical 

research, patient advocacy 

organizations, health care attorneys, 

pharmacy and law students, and others. 

To make it easier to identify 

comments and our responses, the word 

‘‘Comment,’’ in parentheses, will appear 

before each comment, and the word 

‘‘Response,’’ in parentheses, will appear 

before each response. We also have 

numbered the comments to make it 

easier to distinguish between comments; 

the numbers are for organizational 

purposes only and do not reflect the 

order in which we received the 

comments or any value associated with 

the comment. We have combined 

similar comments under one numbered 

comment. 

A. General Comments 

(Comment 1) We received comments 

that objected to adding any statement to 

informed consent documents about 

submitting information to the databank 

to be posted on the ClinicalTrials.gov 

Web site. The principal reasons given 

for these objections were that the 

additional statement: (1) Lengthens 

already lengthy informed consent 

documents, exacerbating potential 

participants’ confusion and anxiety 

upon reading consent forms; (2) 

unnecessarily burdens or overwhelms 

participants because it does not provide 

information necessary to make an 

informed decision about whether to 

participate in a clinical trial; (3) fails to 

advance human subject protection in 

any way; and (4) will cause patients to 

ignore more important aspects of the 

consent form or other research-related 

forms. Other comments approved the 

inclusion of a statement that alerted 

potential participants to the clinical 

trials registry databank to inform them 

how the data are generally used and to 

increase awareness of the clinical trial 

registry. 

(Response) We appreciate the 

concerns expressed by the comments 

regarding the increasing length of 

informed consent documents and the 

additional information required to be 

provided to potential clinical trial 

participants. Section 801(b)(3)(A) of 

FDAAA, however, requires the 

Secretary to update FDA’s regulations to 

‘‘require inclusion in the informed 

consent documents and process a 

statement that clinical trial information 

for such clinical investigations has been 

or will be submitted for inclusion in the 

registry data bank.’’ Thus, while we 

appreciate the concerns, Congress has 

directed that this be implemented by 

FDA. 

While FDA has been directed by 

statute to include this particular 

statement in informed consent 

documents and processes related to 

applicable clinical trials, there is 

increasing support for informing clinical 

trial participants about the clinical trials 

in which they participate and the 

outcome of those trials whether it is 

included in the informed consent 

document or through other efforts. The 

rationale for informed consent is to 

ensure that participants enter into the 

research voluntarily and with adequate 

information (Refs. 2, 3, and 4). 

Communications, other than the specific 

informed consent, may include 

informing the participant on how to 

obtain or access information relating to 

the outcomes of the research (Refs. 5 

and 6). Implementing the statutory 

provision by including the statement in 

the informed consent documents and 

processes, as required, also advances 

these other goals. 

We disagree with comments that the 

new statement does not provide any 

information necessary to make an 

informed decision about whether to 

participate in a clinical trial. As noted 

in the NPRM, alerting potential clinical 

trial participants to the existence of a 

publicly accessible databank, whether 

in the informed consent or during the 

process, can reassure them that a 

transparent system exists to help ensure 

greater accountability and responsibility 

of investigators (74 FR 68750 at 68752). 

Clinical research (as opposed to clinical 

practice) is not designed to deliver 

therapeutic benefits to individual 

patients, so it is possible that potential 

clinical trial participants would want to 

know the overall benefits that may 

accrue to society at large (Refs. 7 and 8). 

One of the basic elements of informed 

consent which investigators are required 

to inform participants of is ‘‘a 

description of any benefits to the subject 

or to others which may reasonably be 

expected from the research.’’ 

(§ 50.25(a)(3)). The reference to the 

databank Web site allows participants to 

ascertain the nature, scope, and progress 

of a registered applicable clinical trial, 

thus reassuring the participant that 

participation in a trial contributes to the 

advancement of medical knowledge, an 

important benefit in the full disclosure 

of risks and benefits. Although the 

current statutory requirement at 42 

U.S.C. 282(j), section 402(j) of the PHS 

Act, only requires registration at 

http://www.ClinicalTrials.gov for certain 

applicable clinical trials, and not all 

clinical trials, this limitation does not 

lessen the value of the information for 

participants. 

We do not agree that the new required 

statement significantly increases the 

length of consent forms to such a degree 

as to increase participants’ confusion 

and anxiety. The revised language 

consists of four short sentences, which 

will minimally impact a potential 

subject’s reaction to a consent form. 

These additional sentences will not 

dwarf or diminish other important 

information in informed consent forms 

and documents. FDA responded to 

similar comments when it issued the 

final rule that established § 50.25 

concerning the basic and additional 

elements of informed consent. Many of 

the comments suggested that there were 

too many elements, they were 

duplicative, and they would simply 

confuse research participants. Other 

comments expressed the concern that 

the elements would require a long, 

detailed consent form that would be 

confusing and would detract from the 

intended purposes of the regulation that 

relevant information about a study be 

conveyed to the human subject (46 FR 

8942 at 8949, January 27, 1981). In 

responding to all of the comments, FDA 

defended the required elements, and, 

although minor changes were made to 

simplify the final rule, FDA maintained 

that the informed consent process 

involved ‘‘giving the subject all the 

information concerning the study that 

the subject would reasonably want to 

know.’’ (46 FR 8942 at 8949, January 27, 

1981) This same reasoning applies to 

the requirements of the new element in 

§ 50.25(c). Congress has decided that 

clinical trial participants would 

reasonably want to know that applicable 

clinical trials will be registered and that 

certain results and other information 

will be available in a publicly accessible 

databank. 

(Comment 2) One comment objected 

to the new statement as an ‘‘inefficient 

method of implementing the statutory 

mandate of FDAAA.’’ 

(Response) We disagree. The statutory 

mandate of FDAAA is specific. It 

requires FDA to update its regulations to 

‘‘require inclusion in the informed 

consent documents and process a 

statement that clinical trial information 

for such clinical investigation has been 

or will be submitted for inclusion in the 

registry data bank.’’ The NPRM 

proposed to implement the statutory 


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mandate by requiring the new statement 

in informed consent documents and 

processes and the final rule adopts that 

proposal. We believe the short required 

statement accomplishes the statutory 

mandate in the most efficient manner 

possible. 

(Comment 3) Two comments 

suggested that the new statement should 

not be included because research 

involving de-identified data is exempt 

from human-subjects regulation since 

only de-identified data are submitted to 

http://www.ClinicalTrials.gov. 

(Response) We believe this comment 

reflects a misunderstanding about the 

statutory requirements to register 

applicable clinical trials with NIH at 

http://www.ClinicalTrials.gov. The new 

informed consent element applies to 

‘‘applicable clinical trials,’’ which 

necessarily involve research on human 

subjects. The fact that only de-identified 

data derived from the applicable clinical 

trial will be submitted to the databank 

is irrelevant to the requirement to 

include the new statement in informed 

consent documents. Human subjects are 

still involved in the underlying 

‘‘applicable clinical trial’’ and informed 

consent regulations apply to the clinical 

investigation. We emphasize that the 

new element is required by statute, and 

the subsequent reporting of only deidentified data to NIH in no way creates 

an exemption to the statutory or 

regulatory requirement. 

B. Effective Date, Compliance Date, and 

Retroactivity 

(Comment 4) Many comments 

requested clarification on the effective 

date of the regulation and whether it 

would be applied retroactively. 

Specifically, comments requested 

clarification on the following clinical 

trial scenarios: (1) Clinical studies that 

received favorable ethics committee 

opinion but patient recruitment has not 

begun before the effective date, (2) 

clinical studies that received favorable 

ethics committee opinion and patient 

recruitment has begun before final rule, 

(3) clinical studies where IRB rulings 

are pending or not yet submitted to IRB, 

(4) protocol amendment (requiring reconsent) dated within 30 days of the 

final rule. Other comments stated that 

the rule should not require re-consent of 

enrolled participants. One comment 

requested a 6-month grace period for 

compliance after the rule takes effect. 

(Response) As discussed in section III 

of this document, we have decided to 

make the compliance date 1 year after 

the effective date of this final rule. This 

means that FDA intends to enforce this 

final rule, new § 50.25(c), only for 

informed consent documents and 

processes for clinical investigations that 

are initiated on or after the compliance 

date. 

To address the specific examples in 

the comments, we generally would 

consider that for purposes of this final 

rule only, a clinical investigation has 

been initiated if the sponsor/investigator 

has had any informed consent 

documents for that clinical investigation 

cleared or approved by an IRB, a 

regulatory body, or other human 

subjects review entity. This 

interpretation of the initiation of the 

clinical trial/investigation is limited to 

this final rule. If the clinical 

investigation is a multi-site trial and 

informed consent documents have been 

cleared or approved for one or more 

sites before the compliance date of this 

final rule, but not for all sites, the 

clinical investigation will be considered 

to have initiated before the compliance 

date. The informed consent documents 

for the remaining clinical investigation 

sites would be considered part of the 

clinical investigation that initiated prior 

to the compliance date. 

Re-consent, based solely on the new 

requirement, of clinical trial 

participants in clinical investigations 

that were initiated before the 

compliance date will not be required. If 

a clinical investigation is ongoing as of 

the final rule compliance date, the new 

requirement will not be applicable. We 

recognize that this will mean that if the 

informed consent documents and 

processes of the ongoing clinical 

investigation are required to be 

amended for any other purpose and reconsent of the already enrolled or 

actively participating clinical trial 

participants is required for that other 

purpose, compliance with new 

§ 50.25(c) will not be required. 

When the original informed consent 

regulations were issued in 1981, we 

chose to impose those requirements 

strictly prospectively—only clinical 

investigations that began on or after the 

effective date of the regulation were 

required to comply with new parts 50 

and 56 (21 CFR part 56. (See 46 FR 8942 

at 8945 to 8946, January 27, 1981.) In 

determining that those new 

requirements should apply only 

prospectively, we ‘‘balanced the cost of 

compliance against possible added 

protections to be gained by research 

participants, and determined that the 

potential cost of imposing the 

requirements retroactively outweighs 

the potential gain. The informed 

consent regulations that will continue to 

be in effect until the effective date of 

part 50 have assured that at least 

minimum standards of informed 

consent have been met in studies 

initiated before the effective date * * *’’ 

(46 FR 8942 at 8946). We believe the 

same principles apply in this final rule 

and the regulation will not be applied 

retroactively. There is nothing in this 

rule, however, that would prohibit 

inclusion of the statement in 

circumstances in which there may be reconsent for other reasons. 

We are aware that many educational 

and governmental institutions, IRBs, 

and industry sponsors have created 

model templates for informed consent 

documents. These model templates 

generally are developed to address 

various situations and include 

mandatory provisions to ensure 

compliance with all regulatory 

requirements (Refs. 9 and 10). We 

anticipate that the compliance date for 

the final rule will permit sufficient time 

for this new required statement in 

§ 50.25(c) to be added to existing model 

templates. While there is a benefit to 

including the new statement in existing 

informed consent documents and 

processes, we do not believe the benefit 

outweighs the difficulty, cost, and 

complexity of requiring revision to all 

existing informed consent documents. 

(Comment 5) One comment requested 

clarification on whether the new 

element would require sponsors to reconsent participants enrolled in clinical 

trials. This comment noted FDA’s 1998 

Information Sheet Guidances for IRBs, 

Clinical Investigators, and Sponsors: 

Frequently Asked Questions (No. 45), 

advising that enrolled and actively 

participating subjects should be 

informed of a change that might relate 

to a subject’s willingness to participate 

in the study. 

(Response) As discussed in the 

Response to Comment 4, re-consent will 

not be required solely based on the new 

requirements of § 50.25(c). While the 

FDA’s 1998 Information Sheets for IRBs, 

Clinical Investigators, and Sponsors: 

Frequently Asked Questions (No. 45) 

recommends that already enrolled and 

actively participating subjects be 

informed of a change that might relate 

to a subject’s willingness to participate 

in the study, we are not requiring such 

a notification based on this new 

requirement. If this recommendation 

were to be followed by clinical 

investigators, we would expect that 

such notice, if warranted, already had 

occurred, as applicable clinical trials 

have been statutorily required to be 

registered with NIH at http:// 

www.ClinicalTrials.gov since 2007 and 

results posting for certain trials has been 

required since 2008. 

(Comment 6) One comment expressed 

concern that the specific language of the 

new element would have to be revised 


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after NIH issued regulations to 

implement changes to 

ClinicalTrials.gov. This comment 

recommended that FDA issue a 

guidance instead of a regulation because 

a guidance would be easier to change, 

if necessary, after the NIH regulations 

issued. 

(Response) We decline to issue a 

guidance in lieu of a regulation. Section 

801(b)(3)(A) of FDAAA makes clear that 

the ‘‘Secretary shall update [FDA’s] 

regulations,’’ not merely issue a 

guidance. NIH’s subsequent regulations 

will not impact the specific language of 

the new element as the language of the 

required statement is not affected by the 

statutory or regulatory interpretation of 

an ‘‘applicable clinical trial.’’ There is a 

statutory definition of ‘‘applicable 

clinical trial’’ and no matter what 

additional regulatory explanation of 

‘‘applicable clinical trial’’ is provided in 

a future rulemaking, it will not affect or 

change the required statement. Changes 

to the definition only will impact the 

determination made by sponsors and 

investigators about their clinical trial 

and whether it is an ‘‘applicable clinical 

trial’’ subject to the registration 

requirements of 42 U.S.C. 282(j)(1)(A), 

section 402(j)(1)(A) of the PHS Act. That 

separate determination is made prior to 

the inclusion of the mandatory 

statement in informed consent 

documents and processes. 

C. New Section 50.25(c) 

In order to address some of the 

concerns raised by comments, and on 

our own initiative, we have created a 

new paragraph (c) in § 50.25 to include 

the requirements of this final rule. 

While this is a ‘‘required’’ element of 

informed consent documents and 

processes, it is only required if the 

clinical trial is an ‘‘applicable clinical 

trial’’ as defined in FDAAA, 42 U.S.C. 

282(j)(1)(A), section 402(j)(1)(A) of the 

PHS Act, and any relevant regulation. 

Although there were comments 

suggesting that § 50.25(b) was the more 

appropriate location for the required 

provision, we are concerned that such 

placement would be confusing given the 

specific requirement of section 

801(b)(3)(A) of FDAAA and the 

mandatory nature of its inclusion when 

an applicable clinical trial is involved. 

To avoid any confusion, we have 

created a new paragraph (c) in § 50.25 

and redesignated existing paragraphs. 

(Comment 7) Many comments 

suggested that the rule should amend 

§ 50.25(b), ‘‘Additional Elements of 

Informed Consent,’’ rather than 

§ 50.25(a), ‘‘Basic Elements of Informed 

Consent.’’ Some comments reasoned that 

the new statement could not be 

considered a ‘‘basic element’’ because it 

would not apply to all clinical trials, 

only applicable clinical trials. For 

example, a phase 1 or device feasibility 

study would not be considered an 

applicable clinical trial under the 

statutory definition in FDAAA. These 

comments further reasoned that the new 

statement qualified as an ‘‘additional 

element’’ because it would be required 

only ‘‘when appropriate’’ (i.e., in 

applicable clinical trials). 

(Response) We agree with the 

comments that the element should not 

be included in § 50.25(a) since the 

statutory provision limits it to inclusion 

in informed consent documents and 

processes only for ‘‘applicable clinical 

trials.’’ We disagree, however, that the 

new statement should be included as an 

‘‘additional element’’ under § 50.25(b) as 

this may raise further confusion as to 

the mandatory nature of the 

requirement. 

As noted in the preamble to the final 

rule establishing the original informed 

consent elements, ‘‘[t]he elements listed 

as ‘additional’ are not material to every 

clinical investigation.’’ (46 FR 8942 at 

8949, comments 41 and 42) This new 

element, however, is statutorily 

required, and therefore, is material to all 

applicable clinical trials. Investigators 

do not have the discretion to determine 

whether the element is ‘‘appropriate’’ for 

a particular applicable clinical trial. 

Therefore, we decline to include the 

new element in § 50.25(b) and, instead, 

have created a new paragraph (c). 

Nothing in this preamble affects our 

explanation in the 1981 final rule that 

‘‘when any one of those additional 

elements would be appropriate, 

§ 50.25(b) requires that the additional 

information be provided to the subject.’’ 

(emphasis added) 

(Comment 8) One comment 

recommended that FDA accomplish its 

statutory mandate to inform potential 

participants about the databank by 

amending § 50.25(a) to require a 

statement that describes whether results 

or other aspects of the trial may be 

published. This comment suggested that 

posting of results on http:// 

www.ClinicalTrials.gov be treated like 

any other publication of clinical trial 

results in journals or elsewhere. 

(Response) We do not agree that the 

statement proposed by the comments 

would accomplish our statutory 

mandate, which specifies that informed 

consent regulations be updated to 

require that a statement that clinical 

trial information has been or will be 

submitted for inclusion in the registry 

data bank. A statement that simply 

alludes to the general possibility of 

publication does not accomplish the 

statutory mandate or the objectives set 

forth in the NPRM and this final rule: 

informing clinical trial participants and 

potential patients about the data bank; 

directing them to the http:// 

www.ClinicalTrials.gov Web site in 

order to enhance the system of checks 

and balances for the research 

community and trial sponsors; assisting 

individuals in deciding whether to 

participate in a trial; and, providing 

patients with additional information 

beyond traditional publications. 

(Comment 9) One comment 

recommended that the new element 

amend § 50.25(a)(5), which requires a 

statement describing the extent to which 

confidentiality of records identifying the 

subject will be maintained. This 

comment expressed concern that a 

wholly new provision devoted to a new 

basic element in § 50.25(a) would place 

undue emphasis on ‘‘low-risk’’ reporting 

requirements to the detriment of the 

other ‘‘high-risk’’ provisions of § 50.25(a) 

devoted to protecting clinical trial 

participants. 

(Response) We agree that the new 

element has a unique basis and thus 

differs in a fundamental way from the 

basic consent elements in § 50.25(a) but 

disagree that the new element should be 

located in § 50.25(a)(5). Section 

50.25(a)(5) requires that in seeking 

informed consent, investigators provide 

to potential participants ‘‘A statement 

describing the extent, if any, to which 

confidentiality of records identifying the 

subject will be maintained and that 

notes the possibility that the Food and 

Drug Administration may inspect the 

records.’’ This statement concerning 

confidentiality is applicable to all 

aspects of the clinical trial data. The 

same confidentiality standards that 

apply to a submission of an article to a 

medical journal also apply to a http:// 

www.ClinicalTrials.gov submission— 

only aggregate data are provided. Thus, 

creating a paragraph of § 50.25(a) which 

would identify only the extent to which 

confidentiality would be maintained 

with respect to submissions of data to 

http://www.ClinicalTrials.gov could be 

confusing and misleading. 

To avoid confusion and to emphasize 

the unique basis for the new element, 

FDA has created a new paragraph (c) in 

§ 50.25. This paragraph specifies that 

the new element is required for all 

applicable clinical trials but not for nonapplicable clinical trials. Thus, 

§ 50.25(c) is distinct from § 50.25(a), 

which requires basic elements for all 

clinical trials of FDA-regulated products 

whether or not they are ‘‘applicable 

clinical trials,’’ and from § 50.25(b), 

which requires additional elements in 

informed consent documents and 


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processes ‘‘when appropriate.’’ 

Furthermore, the new element merits a 

wholly new provision owing to its 

unique basis. The new element has an 

external informational component 

directed to the participant, it enhances 

the protection of the human subject 

participating in the ‘‘applicable clinical 

trial,’’ and is statutorily mandated. 

D. Specific Language for Informed 

Consent Documents and Processes 

(Comment 10) Many comments 

objected to specific required language, 

as opposed to a general requirement for 

the content of the message with 

flexibility to craft the exact language. 

These comments stated that specific 

language denies institutions the 

flexibility to tailor the language to the 

local community, subject population, 

type of study, or, in non-U.S. trials, 

other countries’ unique data privacy 

concerns. One comment stated that 

requiring specific language is 

inconsistent with other elements of 

informed consent, which specifies 

content but not language. Another 

comment objected to the specific 

language because it would require 

additional clarifying language about 

other registries. 

(Response) In proposing specific 

language, we considered issues similar 

to those raised by the comments but 

concluded that the risk of inaccurate 

and confusing statements was too great 

to permit investigators and sponsors to 

craft their own statements regarding the 

inclusion of clinical trial information in 

http://www.ClinicalTrials.gov. The 

comments received in response to the 

NPRM support our previous conclusion 

that specific language needs to be 

provided. While we agree that the 

proposed language should be simpler 

and more understandable, and has been 

made so in this final rule, the diverse 

comments showed much confusion and 

misunderstanding about the FDAAA 

statutory requirements for registration of 

clinical trials with NIH and the type of 

information required to be provided to 

potential clinical trial participants. 

Suggested revisions to simplify the 

language resulted in very different, and 

often inaccurate, messages. If each 

sponsor/entity were to craft their own 

individual statement, we are concerned 

that participants in different clinical 

trials would receive vastly different 

messages. Many statements could be 

inaccurate, confusing, or different from 

that intended by the statutory 

requirement. We want to ensure that 

potential clinical trial participants 

receive a consistent and accurate 

message and are directed to the specific 

Web site that contains the clinical trial 

databank. Investigators, sponsors, and 

IRBs are not restricted from providing 

additional explanation. It is essential, 

however, that one common message 

appear consistently in all informed 

consent documents and processes. The 

provision of the specific language also 

will make it easier for IRBs and other 

review entities to identify the inclusion 

of this statutorily required statement in 

their review of informed consent 

documents and processes and to 

incorporate it into any model templates. 

E. Communication and Readability of 

Language 

(Comment 11) Many comments 

criticized the new statement as too 

complex or technical for many potential 

clinical trial participants to understand. 

Some comments noted that the 

proposed language registered 

approximately 18 on the Flesch-Kincaid 

reading grade level (Ref. 11) Many 

recommended that the required new 

statement register at an eighth-grade 

reading level (8 on the Flesch-Kincaid 

scale). Other comments objected to 

undefined terms not commonly used 

(e.g., ‘‘data bank,’’ ‘‘registry’’), phrases 

that were meaningful to sponsors but 

not trial participants (submission ‘‘at the 

appropriate and required time’’), and 

words perceived as too unspecific to be 

informative (e.g., ‘‘information,’’ ‘‘not 

personally identifiable,’’ ‘‘certain clinical 

trials’’). 

(Response) We agree that the language 

proposed in the NPRM was too complex 

and may be too difficult for some 

potential participants to understand. We 

consulted with our internal experts on 

risk communication to identify specific 

problems with the proposed statement 

and to devise a statement that was more 

understandable across a greater range of 

reading skills (Ref. 12). We have revised 

the statement to include simpler 

language, and removed many of the 

terms perceived as objectionable. For 

example, the statement no longer 

contains the words ‘‘data bank’’ and 

‘‘registry;’’ these are replaced by the 

more commonly used term ‘‘Web site.’’ 

Sponsor-oriented phrases and some 

general words also have been removed. 

The revised statement registers 7.2 on 

the Flesch-Kincaid reading scale. 

We have not further defined the term 

‘‘information’’ in the statement. The 

definition depends on when data are 

submitted to the databank and what 

would be included depends on the data 

fields being completed. The word 

‘‘information’’ is basic enough to 

encompass anything that may be 

required to be submitted to the databank 

at any point in time. The statement 

provides the specific Web address to the 

databank so that clinical trial 

participants may visit the Web site to 

see what ‘‘information’’ is included in a 

particular clinical trial record. The new 

statement will read as follows: 

‘‘A description of this clinical trial 

will be available on http://www.Clinical 

Trials.gov, as required by U.S. Law. This 

Web site will not include information 

that can identify you. At most, the Web 

site will include a summary of the 

results. You can search this Web site at 

any time.’’ 

(Comment 12) Several comments 

expressed concern that a statement 

using complex language would be 

difficult to translate into other languages 

for international consent forms or for 

U.S. clinical trial participants whose 

first language is not English. 

(Response) We have revised the 

required statement to use simpler 

language and do not believe that the 

revised statement will pose translation 

difficulties. See the response to 

Comment 18 for additional discussion 

on translation of the required statement. 

(Comment 13) One comment objected 

to directing participants to a Web site 

that promotes therapeutic 

misconception. Therapeutic 

misconception is the common 

misunderstanding among clinical trial 

participants that the primary purpose of 

a clinical trial is to provide therapeutic 

treatment, rather than experimental 

research. 

(Response) We disagree that http:// 

www.ClinicalTrials.gov promotes 

therapeutic treatment as the primary 

focus of the clinical trials posted to the 

databank. The ClinicalTrials.gov Web 

site makes clear that clinical trials are 

research studies. Extensive questions 

and answers are provided on the Web 

site detailing what a clinical trial is and 

what participation encompasses. 

Regardless, the informed consent 

documents and process, properly 

administered, should dispel any 

misconception about the purpose of the 

clinical trial. 

(Comment 14) Several comments 

stated that the reference to the 

ClinicalTrials.gov Web site should be 

omitted because: (1) It was not 

necessary for a subject to make an 

informed decision about whether to 

participate in the trial and (2) the Web 

site had no more information than the 

informed consent document about the 

trial. Other comments favored the 

reference to ClinicalTrials.gov, stating 

that this information is consistent with 

the goals of enhancing transparency of 

clinical trials, boosting public 

confidence in the clinical research 

process, and better informing potential 

participants. 


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(Response) We decline to omit the 

reference to http:// 

www.ClinicalTrials.gov and agree the 

specific Web site is helpful to direct 

potential participants to that databank 

and to help them become better 

educated about clinical trials. The 

specific Web site address also 

eliminates the need for the participant 

to search the Internet for access to the 

databank Web site. The Web site 

address allows participants to more 

quickly take the opportunity to view the 

contents of the databank and review the 

types of information submitted to and 

posted on the Web site. The Web site is 

not intended to substitute for the 

information and description of the 

clinical trial in the consent form; 

however, the Web site also can provide 

reference to other related trials 

conducted before or after the clinical 

trial in which the participant took part. 

Furthermore, the Web site does have 

more information than the informed 

consent documents since the databank 

may eventually contain the final results 

of the specific clinical trial for which 

the participant consented—information 

the informed consent documents will 

not contain. 

(Comment 15) Two comments 

recommended that the statement list 

Web sites other than http:// 

www.ClinicalTrials.gov because the link 

could change in the future, or more 

common Web sites would be easier for 

participants to find. The comment 

alternatively recommended that the rule 

reference FDA’s Web site, which should 

provide a link to the clinical trials 

databank. 

(Response) We decline to replace 

http://www.ClinicalTrials.gov with 

another or FDA’s own Web site. In 

response to the comments that the Web 

site might change, it is unlikely that this 

Web address will change, since it has 

been in use for over 10 years. If in the 

future it is altered, we can revise the 

final rule with an amendment 

identifying the new Web address. We 

think it important that clinical trial 

participants know specifically where to 

locate the clinical trial information 

without having to perform an Internet 

search. We do not see any advantage in 

referring potential participants to more 

‘‘common’’ Web sites that link to 

http://www.ClinicalTrials.gov instead of 

a direct link. In fact, http:// 

www.ClinicalTrials.gov has become 

quite well known and could be 

considered a ‘‘common’’ Web site itself. 

The Web site currently has over 50 

million page views per month and 

65,000 visitors daily. 

(Comment 16) One comment 

suggested that the new statement was 

misleading in several ways: (1) It 

implies that the trial is registered only 

at ClinicalTrials.gov and not elsewhere, 

(2) it implies that results for all trials 

will be submitted to the databank; and 

(3) the statement that U.S. law requires 

submission of information to the 

databank does not take into account that 

some studies are voluntarily registered. 

(Response) The new words have been 

carefully chosen to accurately represent 

how clinical trial data are included in 

the databank. First, the element states 

that ‘‘A description of this clinical trial 

will be available on http://www.Clinical 

Trials.gov, as required by U.S. law.’’ The 

new element is required only in 

informed consent documents and 

processes related to applicable clinical 

trials, so this statement is true. The new 

statement should not be included in 

informed consent documents or 

processes for clinical trials that are not 

applicable clinical trials because, as the 

regulation makes clear, only applicable 

clinical trials are subject to the 

requirement. Second, we have chosen to 

say ‘‘will be available’’ to generalize the 

statement for early-phase participants 

(when the trial has not been registered 

yet) and participants joining after the 

trial is registered at http:// 

www.ClinicalTrials.gov. Under the 

statute, responsible parties for 

applicable clinical trials must submit 

relevant clinical trial information to 

NIH/NLM for inclusion in the registry 

databank no later than 21 days after the 

first participant is enrolled in the 

applicable clinical trial. We believe 

‘‘will be available’’ reasonably applies to 

all participants and is simpler than 

saying ‘‘has been or will be submitted.’’ 

Third, the revised language states that 

‘‘At most, the Web site will include a 

summary of the results.’’ Thus, potential 

participants will not expect that clinical 

trial results will always appear on the 

Web site but, if results do appear, these 

will be in summary form. Fourth, the 

statement makes no reference to nonapplicable or voluntarily registered 

trials, and we disagree that the language 

misleads anyone about these other trials 

in any way. By stating that ‘‘this clinical 

trial will be available * * * as required 

by U.S. law,’’ the new element in no way 

implies that other types of trials cannot 

be registered. The new language also 

does not imply that all clinical trials 

must be registered; it only refers to the 

clinical trial in which the participant is 

taking part. 

(Comment 17) Several comments 

suggested that the regulation also 

should require an alternate statement for 

non-applicable, voluntarily registered 

clinical trials that they will not be 

included in the databank. These 

comments suggested that such a 

statement would be necessary for 

potential participants to make an 

informed decision about whether to 

participate in the trial. 

(Response) We decline to include an 

alternate statement for non-applicable, 

voluntarily registered clinical trials, 

some of which may be registered in the 

databank. Potential participants will 

have no expectation that a nonapplicable clinical trial will be 

registered, since an informed consent 

document for a non-applicable clinical 

trial is not required to include the new 

statement. If an investigator, sponsor, or 

IRB feels that a potential participant 

would want to know about the existence 

of a registry databank for trials other 

than the one the participant is 

contemplating or for non-applicable 

clinical trials, nothing in this regulation 

would prevent an investigator, sponsor, 

or IRB from informing potential 

participants of such information in an 

appropriate manner. 

(Comment 18) One comment 

requested that FDA provide translations 

into other languages frequently 

encountered in the United States. This 

comment also recommended that if FDA 

would not provide such translations, 

then FDA should state in the regulation 

that the text may be freely translated 

into other languages. 

(Response) Under § 50.20, the 

informed consent document should be 

in language understandable to the 

subject (or legally authorized 

representative). When the potential 

participants are non-English speaking or 

the clinical investigator or the IRB 

anticipates that the consent interviews 

will be conducted in a language other 

than English, the IRB should require a 

translated consent document to be 

prepared and assure that the translation 

is accurate. As required by § 50.27, a 

copy of the consent document must be 

given to each subject. In the case of nonEnglish speaking participants, this 

would be the translated document. 

While a translator may be helpful in 

facilitating conversation with a nonEnglish speaking subject, routine ad hoc 

translation of the consent document 

should not be substituted for a written 

translation. This is explained in more 

detail in our guidance documents/ 

information sheets concerning informed 

consent (Ref. 13). The statement can be 

translated into languages other than 

English for potential clinical trial 

participants. FDA will not provide 

translations of the statement. 

(Comment 19) One comment 

recommended that the words ‘‘federal 

law’’ be replaced with a reference to U.S. 

law, since ‘‘federal law’’ might cause 


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confusion in multinational clinical 

trials. 

(Response) We agree and the revised 

statement indicates that the clinical trial 

description on http:// 

www.ClinicalTrials.gov is required by 

‘‘U.S. law.’’ 

F. Applicable Clinical Trials 

(Comment 20) Several comments 

requested clarification on whether 

certain types of clinical trials, such as 

investigational device trials considered 

to be non-interventional, would be 

considered ‘‘applicable clinical trials.’’ 

Several bloodbank organizations 

specifically inquired about clinical 

studies done by blood centers under 

investigational new drug applications 

(INDs) to validate new blood screening 

tests. 

(Response) We decline to provide a 

more detailed definition of ‘‘applicable 

clinical trial,’’ as it is not necessary for 

the purposes of this final rule. Section 

801(a)(1) of FDAAA contains a statutory 

definition of this term (section 

402(j)(1)(A) of the PHS Act). NIH/NLM 

also has elaborated on the meaning of 

‘‘applicable clinical trial’’ at http:// 

prsinfo.clinicaltrials.gov/fdaaa.html and 

at http://prsinfo.clinicaltrials.gov/ 

ElaborationsOnDefinitions.pdf (Ref. 14), 

which represents NIH’s current thinking 

on the definitions. It is possible these 

definitions will be expanded upon in 

rulemaking by NIH. It is the 

responsibility of the sponsors and 

investigators to determine if their 

clinical trial meets the definition of an 

applicable clinical trial and to ensure 

compliance with the most current 

applicable statutory and regulatory 

requirements. 

(Comment 21) Several comments 

recommended that the new statement 

not be required in the informed consent 

forms for clinical trials conducted 

outside of the United States, even if 

done in support of U.S. regulatory 

approval or conducted under an FDA 

IND. These comments stated that the 

new element should be required only 

when the clinical trials are conducted in 

the United States. These comments 

reasoned that: (1) Institutions and 

patients in other countries may object to 

or be offended by U.S.-centric language, 

(2) 21 other countries and regions 

already have in place or are in the 

process of implementing their own 

clinical trial registries, (3) foreign 

governments may prefer references to 

their own countries’ registries, and (4) 

foreign IRBs and ethics committees may 

have their own informed consent 

requirements that conflict with the new 

statement. 

(Response) We disagree. The new 

informed consent statement applies to 

all ‘‘applicable clinical trials’’ as defined 

in section 801(a)(1) of FDAAA. FDAAA 

does not limit ‘‘applicable clinical trials’’ 

to only those conducted in the United 

States; it also includes clinical trials that 

are not conducted in the United States 

that are subject to FDA’s jurisdiction. 

Thus, informed consent documents and 

processes of all ‘‘applicable clinical 

trials,’’ including those conducted in 

foreign countries, must include this new 

statement regarding the inclusion of 

information in the clinical trial 

databank. Congress did not provide an 

exemption from this requirement for 

applicable clinical trials conducted in 

foreign countries. 

(Comment 22) One comment 

requested clarification on whether the 

new element is required only when a 

trial is conducted under a U.S. IND or 

is otherwise subject to FDA regulation at 

the time the research participant is 

enrolled. This comment focused in 

particular on data from non-U.S. trials 

that were not conducted under a U.S. 

IND or subject to FDA regulation at the 

time of inception but were later 

submitted in support of a new drug 

application (NDA). 

(Response) Yes, the new requirement, 

§ 50.25(c), applies only when a trial is 

conducted under a U.S. IND or is 

otherwise subject to FDA regulation. 

(Comment 23) Several comments 

expressed concern that the new element 

would conflict with or cause confusion 

about other countries’ registries or 

informed consent practices. One 

comment suggested that the new 

statement might conflict with the 

informed consent practices of IRBs and 

ethics committees residing outside the 

United States, and that foreign 

governments may not want references to 

a U.S. database in the informed consent 

forms for multinational trials being 

conducted in their countries. This 

comment recommended that the new 

element apply to informed consent 

documents used only at U.S. clinical 

trial sites and not for clinical trials at 

foreign sites even if the clinical trial was 

conducted under an FDA IND. 

(Response) See the response to 

Comment 21. 

(Comment 24) One comment 

suggested that U.S. participants in 

international clinical trials be informed 

that information about the trial also may 

be available in the registries of other 

countries. This comment further 

suggested including the statement 

‘‘Information about this trial may also be 

available on the Internet in the clinical 

trial registries of other countries.’’ 

(Response) We decline to require a 

statement alerting potential participants 

of information about clinical trial 

registries of other countries. If other 

countries require the inclusion of such 

a statement, we would not object. FDA 

is only requiring a reference to the NIH/ 

NLM databank as it has been directed to 

do by Congress. Nothing in this final 

rule prevents investigators, sponsors, or 

IRBs from advising potential 

participants that information about the 

clinical trial may be found in other 

countries’ registries. 

(Comment 25) One comment praised 

the Agency’s decision to apply the 

ClinicalTrials.gov reporting 

requirements to drug and device trials. 

Another comment acknowledged the 

Agency’s authority to issue a regulation 

applying the statutory requirement to 

device trials but requested that FDA use 

its discretion to not exercise that 

authority until Congress explicitly 

indicated that drug and device trials 

should be treated the same. 

(Response) FDA has decided to 

require that all applicable clinical trials 

(including applicable device clinical 

trials) include the new required 

statement for the reasons stated in the 

NPRM: To maintain consistency of 

informed consent requirements for all 

applicable clinical trials, to simplify 

informed consent requirements for 

clinical trials involving both drugs and 

devices, to offer all potential 

participants the same information that 

could affect their decisions to enter a 

clinical trial, and to efficiently 

implement the statutory mandate. Our 

legal authority to issue this regulation 

and require it to be applied to 

applicable device clinical trials is 

further described in section V of this 

document. 

G. Other Miscellaneous Comments 

(Comment 26) One comment stated 

that ‘‘the sharing of de-identified data 

falls under the category of exempt 

research or is not considered human 

subject research at all, and it is common 

for IRBs, following the regulations, to 

allow the research to go forward with a 

waiver of the consent requirement.’’ The 

comment apparently suggests that the 

new element can be or should be 

waived. 

(Response) Similar to other provisions 

required by § 50.25, the new element is 

waiveable only under the exceptions 

specified in §§ 50.23 and 50.24 for 

waiver of informed consent. Some 

clinical trials (those that are conducted 

or supported by HHS) are also governed 

by 45 CFR part 46, which permits an 

IRB to waive the requirement for one or 

more elements of informed consent. It 


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should be noted for purposes of 

clarification that under 45 CFR 46.102(f) 

research using de-identified data would 

not be considered research on a human 

subject and, thus, the waiver of the 

informed consent requirement would 

not be applicable. 

As a general matter, clinical research 

that both involves FDA-regulated 

products and is conducted or supported 

by HHS must meet the requirements of 

both sets of regulations. If such clinical 

trials are also applicable clinical trials 

under FDAAA, the new element must 

be included in the informed consent 

documents and process for these trials 

unless waived under part 50, regardless 

of whether an IRB determines that one 

or more of the elements is waiveable 

under 45 CFR part 46. 

In some instances, review of records 

containing de-identified data may be 

exempt from IRB review because such 

record review does not qualify as 

human subject research. This is not 

always the case under FDA regulations 

and there are some circumstances in 

which the use of de-identified data 

requires IRB review. See §§ 56.101 and 

56.103 and ‘‘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.’’ (Ref. 15). 

The definition of an ‘‘applicable clinical 

trial,’’ however, necessarily involves 

human subjects; thus an applicable 

clinical trial must comply with human 

subject regulations. The use of the new 

statement would not be implicated in 

research that does not qualify as human 

subject research under the definition of 

applicable clinical trial (Ref. 14). 

It is also true that de-identified data 

(stripped of the 18 specified identifiers) 

fall outside of the Health Insurance 

Portability and Accountability Act of 

1996 (Pub. L. 104–191) (HIPAA) privacy 

regulations and thus are not considered 

individually identifiable health 

information. As a consequence, clinical 

investigators need not obtain a subject’s 

authorization to release de-identified 

data in a HIPAA authorization form, 

which is often included in a research 

consent form and accompanies an 

informed consent form. Regardless of 

whether an IRB determines that the 

information concerning submission of 

aggregate results to ClinicalTrials.gov 

does not need to be included in a 

HIPAA authorization form, the new 

element is still required by statute to be 

included in the informed consent 

documents and processes for applicable 

clinical trials. 

(Comment 27) One comment 

suggested that the new element be 

included in an information sheet 

separate from the informed consent 

document, where the sheet explained 

the ClinicalTrials.gov Web site in 

simple terms. 

(Response) FDAAA requires that the 

new element be included ‘‘in the 

informed consent documents and 

processes,’’ not in an information sheet 

that is separate from an informed 

consent document. There is nothing in 

this final rule, however, that prevents an 

investigator, sponsor, or IRB from 

providing additional information in an 

information sheet further explaining 

ClinicalTrials.gov as part of the 

informed consent process. 

(Comment 28) Many comments 

voiced a variety of opinions on the issue 

that no personally identifiable 

information is submitted to the 

databank or shown on the Web site. 

Several comments supported including 

such a statement to that effect in the 

required statement. Several comments 

requested that FDA include additional 

language in the new element to clarify 

any potential confidentiality issues 

posed by the databank. These comments 

suggested including: (1) Assurance that 

participants’ names and identities will 

not be posted on ClinicalTrials.gov, will 

not be made available to employers, and 

will not be discoverable in court 

proceedings; (2) a statement that it is 

probable that participants’ information 

will be re-identified; (3) a lay person 

description of data submitted to 

ClinicalTrials.gov and the Basic Element 

Results Definitions; and (4) an expanded 

description of the clinical trial registry 

and databank. Other comments 

recognized that no personal information 

about participants is submitted to 

ClinicalTrials.gov, so there are no 

privacy or confidentiality issues. Still 

another comment stated that its consent 

documents already contain language 

that non-identifiable information may 

be made public in scientific journals, 

presentations, and, if applicable, 

submitted to a government data bank/ 

registry. 

(Response) We have revised the new 

statement in the final rule so that it is 

clear that the Web site does not include 

information that can identify the 

clinical trial participant. We believe the 

new statement will provide reassurance 

to potential participants. The only 

results information submitted to the 

databank and posted on the Web site are 

aggregate statistics, such as those that 

typically appear in medical journals and 

product package inserts. No individuallevel data are submitted to the databank. 

A review of the data fields on http:// 

www.ClinicalTrials.gov for which data 

are required to be submitted by the 

sponsor/investigator confirms that there 

is no individual information, only 

aggregate, overall data (Ref. 16). 

Furthermore, § 50.25(a)(5) requires 

informed consent documents to explain 

the extent, if any, to which 

confidentiality of clinical trial data and 

the records of the clinical trial 

participant will be maintained. Nothing 

in this rule prohibits an investigator, 

sponsor, or IRB from including further 

explanation on the nature and 

confidentiality of information submitted 

to ClinicalTrials.gov in the informed 

consent form or process or a HIPAA 

authorization form. 

(Comment 29) One comment 

suggested that the new statement should 

be inserted into the section of the 

consent document that invites the 

potential or enrolled participant to ask 

questions of the individual conducting 

the informed consent process. Such 

placement, according to the comment, 

would facilitate communication and 

encourage participants to ask questions. 

(Response) The final rule does not 

require that the new statement be 

located in any particular section of the 

consent form. Investigators, sponsors, 

and IRBs have the flexibility to place the 

new statement in the consent form 

where they believe best serves 

participants’ interests. 

(Comment 30) One comment 

requested that the new statement 

include a phrase indicating that the 

information would be submitted to 

ClinicalTrials.gov ‘‘if required by law.’’ 

The comment requested this change to 

eliminate the need for separate 

templates for studies that require 

registry in the databank and those that 

do not. Anticipated benefits were stated 

to be simplified documentation; 

reduced review time by sponsors, 

investigators, and IRBs; and reduced 

likelihood of using the incorrect consent 

template for a particular clinical study. 

Other comments apparently read the 

NPRM to require the statement in 

consent forms for all clinical trials and 

objected to the inclusion of the 

statement for trials that did not require 

registry in the databank. 

(Response) We do not agree that it is 

necessary to include an additional 

phrase that would allow for a universal 

consent template. Sponsors and 

investigators already have to determine 

if a clinical trial is an applicable clinical 

trial in order to comply with the 

requirements of 42 U.S.C. 282(j), section 

402(j) of the PHS Act. Adding the 

required statement to informed consent 

documents and processes will occur 

after that determination has been made 


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by the sponsor or investigator. 

Furthermore, because the mandatory 

statement requires specific language, it 

should not be burdensome for reviewers 

to determine whether the statement is 

included in the informed consent 

documents. 

(Comment 31) Two comments 

expressed concern that the required new 

element would create an inconsistency 

between regulations governing 

applicable clinical trials of FDAregulated products (part 50) and 

regulations governing clinical trials 

funded or supported by HHS (45 CFR 

part 46). The comments perceived the 

new element as contrary to FDA’s 

objective to harmonize regulations of 

human-subject protection. 

(Response) FDA does not agree that 

the required element would create an 

inconsistency or lack of harmony 

between the regulations on human 

subjects in the two sets of regulations. 

The new element merely entails an 

additional requirement for applicable 

clinical trials of FDA-regulated products 

in accordance with a statutory mandate, 

whether or not the trial is supported or 

funded by HHS. The new element does 

not conflict with any existing 

regulations under 45 CFR part 46. 

(Comment 32) There were several 

comments that questioned the estimates 

contained in the preliminary Analysis of 

Impacts including the estimated time to 

explain the required statement if a 

potential participant asked questions. 

(Response) These comments are 

addressed fully in section VII of this 

document. 

V. Legal Authority and Enforcement 

Section 505(i)(4) of the Federal Food, 

Drug, and Cosmetic Act (the FD&C Act) 

(21 U.S.C. 355(i)(4) requires drug 

manufacturers to ‘‘inform any human 

beings to whom [investigational] drugs 

* * * are being administered * * * that 

such drugs are being used for 

investigational purposes’’ and obtain 

consent prior to administering such 

drugs. Section 520(g)(3)(D) of the FD&C 

Act (21 U.S.C. 360j(g)(3)(D) contains a 

similar requirement for medical device 

manufacturers. Sections 505(i) and 

520(g) of the FD&C Act also authorize 

the Secretary to issue regulations for the 

protection of human subjects in clinical 

investigations. Additionally, section 

701(a) of the FD&C Act (21 U.S.C. 

371(a)) confers general authority to the 

Secretary to issue regulations for the 

efficient enforcement of the FD&C Act. 

Section 801(b)(3)A) of FDAAA 

amends section 505(i)(4) of the FD&C 

Act by adding at the end the following: 

‘‘The Secretary shall update such 

regulations to require inclusion in the 

informed consent documents and 

process a statement that clinical trial 

information for such clinical 

investigation has been or will be 

submitted for inclusion in the registry 

data bank pursuant to subsection (j) of 

section 402 of the Public Health Service 

Act.’’ The regulations implementing 

section 505(i) of the FD&C Act can be 

found at parts 312 and 50. Part 312 sets 

forth regulations governing drug IND 

applications, while part 50 includes 

general requirements for human subject 

protection in all FDA-regulated clinical 

investigations and clinical 

investigations that support applications 

for research or marketing permits for 

products regulated by FDA, including 

trials for drugs and medical devices. 

Section 801(b)(3)(A) of FDAAA does not 

amend section 520(g) of the FD&C Act; 

however, in instances where the 

regulations have been amended to 

address human subject protection, FDA 

has not made distinctions between 

clinical investigations for drugs and 

medical devices. 

For example, FDA created a uniform 

system of human subject protection 

when it initially amended its 

regulations governing human subject 

protection in 1981 (46 FR 8942). In 

revising part 50, FDA aimed to: (1) 

Address the informed consent provision 

included in the device amendments, (2) 

create a uniform set of Agency-wide 

informed consent standards for more 

effective administration of the Agency’s 

bioresearch monitoring program, (3) 

implement recommendations of the 

National Commission for the Protection 

of Human Subjects of Biomedical and 

Behavioral Research, and (4) harmonize 

FDA’s rules with those of HHS (then the 

department of Health, Education, and 

Welfare). Indeed, the preamble 

expressed the Agency’s intent to adopt 

a single standard that reflected the most 

current congressional thinking on 

informed consent and the important 

ethical principles and social policies 

underlying the doctrine of informed 

consent (46 FR 8942 at 8943). 

Requiring a statement regarding the 

registry databank for informed consent 

documents and processes for only 

applicable clinical drug trials but not 

applicable clinical device trials would 

create a disparity in FDA’s policy on 

human subject protection. This 

disparity could result in confusion 

among those who conduct such clinical 

trials over what is required in informed 

consent documents and processes, 

especially in the cases of applicable 

clinical trials involving both a drug and 

device or for investigators conducting 

applicable clinical trials of both types of 

regulated products. 

Thus, although section 801(b)(3)(A) of 

FDAAA requires the statement 

regarding the clinical trial registry 

databank for informed consent 

documents and processes only for 

applicable drug clinical trials conducted 

under section 505(i) of the FD&C Act, 

under its general authority to issue 

regulations for the efficient enforcement 

of the FD&C Act (section 701(a) of the 

FD&C Act), FDA is requiring all 

applicable clinical trials, including 

applicable device clinical trials, to 

include this new statement in informed 

consent documents and processes. 

Requiring an additional statement 

regarding the inclusion of clinical trial 

information in the registry databank to 

be included in the informed consent 

documents and processes for all 

applicable clinical trials is the most 

efficient method of implementing the 

statutory mandate. To prevent confusion 

that might result from different 

requirements for informed consent for 

applicable clinical drug and device 

trials and implement the congressional 

purpose reflected in FDAAA, we will 

apply the same standards regarding 

elements of informed consent to 

applicable clinical drug and device 

trials by amending § 50.25 to include a 

new paragraph (c) which requires a 

statement about the registry databank in 

informed consent discussions and 

documents for all applicable clinical 

trials under section 801 of FDAAA. 

The Agency has several options 

available for enforcing the new 

informed consent requirement. The 

authority to issue regulations for the 

protection of human subjects is 

accompanied by the authority to impose 

penalties for violations of such 

regulations. Specifically, section 301(e) 

of the FD&C Act (21 U.S.C. 331(e)) 

makes the ‘‘failure to establish or 

maintain any record, or make any 

report, required under section * * * 

505(i) * * *’’ and the ‘‘failure or refusal 

to comply with any requirement 

prescribed under section * * * 520(g)’’ 

prohibited acts. The FD&C Act and 

implementing regulations allow FDA to 

seek administrative, civil, and criminal 

penalties for violations of section 301 of 

the FD&C Act. 21 U.S.C. § 303(a); 

§§ 312.44(b)(1)(ix), 312.70(a), 

812.30(b)(4), 812.119(a), 56. 121(b). 

VI. Environmental Analysis 

The Agency has determined under 21 

CFR 25.30(h) that this action is of a type 

that does not individually or 

cumulatively have a significant effect on 

the human environment. Therefore, 

neither an environmental assessment 

nor an environmental impact statement 

is required. 


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VII. Analysis of Impacts 

A. Introduction 

FDA has examined the impacts of the 

final rule under Executive Order 12866 

and the Regulatory Flexibility Act (5 

U.S.C. 601–612), and the Unfunded 

Mandates Reform Act of 1995 (Pub. L. 

104–4). Executive Order 12866 directs 

agencies to assess all costs and benefits 

of available regulatory alternatives and, 

when regulation is necessary, to select 

regulatory approaches that maximize 

net benefits (including potential 

economic, environmental, public health 

and safety, and other advantages; 

distributive impacts; and equity). The 

Agency believes that this final rule is 

not a significant regulatory action as 

defined by the Executive order. 

The Regulatory Flexibility Act 

requires agencies to analyze regulatory 

options that would minimize any 

significant impact of a rule on small 

entities. Because the final rule is 

expected to impose costs of about $3 per 

clinical trial participant or $611 to 

$1,061 per trial protocol, the Agency 

certifies that it will not have a 

significant economic impact on a 

substantial number of small entities. 

Section 202(a) of the Unfunded 

Mandates Reform Act of 1995 requires 

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.’’ The current threshold 

after adjustment for inflation is $135 

million, using the most current (2009) 

Implicit Price Deflator for the Gross 

Domestic Product. FDA does not expect 

this final rule to result in any 1-year 

expenditure that would meet or exceed 

this amount. 

B. The Final Rule 

On December 29, 2009, FDA 

published a proposed rule that would 

require that the informed consent 

documents for applicable drug and 

device clinical trials include a statement 

that applicable clinical trial information 

has been or will be submitted to the 

NIH/NLM for inclusion in the 

statutorily required clinical trial 

databank. As it pertains to applicable 

drug clinical trials, the final rule would 

implement a requirement of FDAAA. As 

discussed previously in this preamble, 

FDA also requires that the same 

statement be included in the informed 

consent documents for applicable 

device clinical trials. 

The proposed rule included an 

analysis of impacts as required by 

Executive Order 12866 and the 

Regulatory Flexibility Act (5 U.S.C. 

601–612), and the Unfunded Mandates 

Reform Act of 1995 (Pub. L. 104–4). 

FDA received many public comments 

concerning its estimated costs and 

benefits for the proposed rule. As a 

result of the review and consideration of 

these and other comments to the 

proposed rule, FDA has made changes 

to both the codified final rule and its 

analysis of impacts section. 

C. Need for the Final Rule 

The need for this rule arises from 

section 801(b)(3)(A) of FDAAA. It 

requires that the current regulations for 

informed consent documents and 

process be amended to include a 

statement that clinical trial information 

from the clinical investigation has been 

or will be submitted to the NIH/NLM 

clinical trial registry databank. FDA has 

decided that revising the general 

informed consent section is the 

appropriate course by which to fulfill 

the requirements of the statute, and will 

provide the pertinent information and 

protection for clinical trial participants. 

D. Public Comments Concerning 

Impacts Analysis 

Several comments objected to the 

inclusion of the informed consent 

statement for various reasons. Some 

believed the statement would cause 

confusion or anxiety to the participants. 

Others believed it would distract the 

participants from focusing on the 

substantive issues concerning the study 

that would affect one’s decision to 

participate in the study. Some 

comments stated that the overall effect 

would be a reduced participation rate 

for prospective participants. No 

estimates of the size of this reduced 

participation rate were submitted. 

Additional comments questioned 

whether any relevant or valuable 

information could be acquired from an 

informed consent statement that takes 

less than 1 minute to read and discuss, 

resulting in less benefit to the 

participant than the administrative costs 

to the investigator. 

FDA acknowledges that additional 

time will be required to read and, if 

necessary, discuss the statement that 

FDAAA mandates be included in the 

informed consent documents and 

process. FDA does not agree, however, 

that the benefit of the statement to the 

participant is directly related to the time 

it takes to read and discuss the 

statement. Further, FDA maintains that 

the benefits of the informed consent 

statement would be difficult to estimate 

with any certainty, making a meaningful 

comparison of benefits to costs 

impractical. FDA also has revised the 

statement to make it shorter and easier 

to understand by deleting those terms 

that could be expected to cause anxiety 

and confusion. FDA believes that in 

doing so it has reduced the theoretical 

possibility that the statement would 

cause some participants to abandon the 

study as much as possible while still 

fulfilling the FDAAA mandate. 

E. Benefits of the Final Rule 

FDA published a qualitative 

explanation of the expected benefits to 

clinical trial participants in its 2009 

proposed rule. FDA received some 

public comments that agreed with the 

expected benefits. Others disagreed, 

criticizing the proposed rule for not 

educating the public at large about the 

clinical trial registry databank. Some 

proposed that FDA undertake a public 

education campaign to broaden 

awareness of the clinical trial registry 

databank. That policy option, however 

laudable, was not included in the 

FDAAA mandate concerning updating 

FDA’s regulations concerning informed 

consent documents and process. While 

an educational campaign is not the 

subject of this rulemaking, there will be 

other opportunities for improving 

awareness of the NIH clinical trials 

databank. The comments as a whole did 

not contain any arguments that 

convinced FDA that it should amend its 

initial explanation of benefits. As a 

result, FDA restates the expected 

benefits for this final rule. 

The rule would increase the 

transparency of clinical trials by 

increasing participant and patient 

awareness of the existence of the 

clinical trials databank and those trials 

that are registered in the databank. By 

helping to create a system of checks and 

balances through which participants, 

patients, and health care providers are 

encouraged to check whether 

information about a trial of interest is 

registered in the databank, it also would 

provide greater accountability of clinical 

trial investigators for outcomes and 

adverse events, thereby raising 

confidence in the validity of the 

research process. Last of all, it would 

encourage physicians and patients to 

obtain more information in order to 

make more educated treatment 

decisions. FDA has not attempted to 

quantify these benefits, but believes that 

the overall effect of the rule on public 

health would be positive. 

F. Costs of the Final Rule 

FDA estimated the total costs of the 

proposed rule to both industry and the 


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1Parexel’s Bio/Pharmaceutical R&D Statistical 

Sourcebook 2008/2009, Parexel International Corp., 

copyright 2008, p. 160. The average number of 

participants (not weighted by therapeutic area) in 

phase 1, 2, and 3 clinical trials in 2006 was 27, 141, 

and 444, respectively. The unweighted average of 

these numbers is 204. As an upper bound, FDA uses 

the average of the numbers representing the 

therapeutic area with the largest average number of 

participants in each of the three clinical phases, 

which would tend to overstate the average size of 

participants. This upper bound is calculated at 360 

participants per trial protocol. 

clinical trial participant population to 

range from $688,000 to $2,398,000 

annually. This equated to $98 to $342 

per trial protocol, or about $0.48 to 

$0.96 per clinical trial participant. 

These costs included labor costs for 

both the investigator and the trial 

participant, as well as document 

preparation costs and paper materials 

costs. The cost of government oversight 

was not expected to be significant. For 

the most part, the public comments on 

the proposed rule did not address the 

structure of the cost analysis (except IRB 

review costs). FDA retains much of the 

cost analysis of the proposed rule for the 

final rule. 

1. Labor Costs 

The costs of the final rule derive from 

complying with the requirement to add 

another statement to the informed 

consent documents and the additional 

time that medical professionals and 

clinical trial participants spend reading 

and discussing this statement. 

We have revised the final cost 

estimate to account for the 

administrative costs for companies 

involved in pharmaceutical, biologic, 

and medical device research and 

manufacturing, and administrative costs 

for IRB oversight. These additional labor 

costs are due to the administrative 

review of the rule and the determination 

of compliance responsibilities. All 

companies involved in this would incur 

some labor costs, regardless of the 

frequency with which they undertake 

clinical trials. Census data from 2002 

list 5,666 companies in the seven North 

American Industrial Classification 

System (NAICS) categories that would 

be subject to this rule. FDA estimates 

that each could expend about 2 hours to 

review the final rule and determine any 

changes it needs to make to its internal 

administrative policies due to this rule. 

The pharmaceutical and medicine 

manufacturing category of the NAICS 

lists the hourly wage for a manager in 

this category at about $54. A 35 percent 

adjustment to this figure for employee 

benefits results in total hourly 

compensation costs of about $73. A onetime 2 hour review for each company 

would result in compliance costs of 

almost $147 per company, and a total of 

about $830,000 for the industry. This 

equates to an annualized cost (over 5 

years at a 7 percent discount rate) of 

about $202,000 for the entire industry. 

These estimates may overstate true 

compliance costs for review of the rule 

since those companies that rarely 

sponsor clinical trials on even an 

occasional basis may not expend as 

much labor as those who do so more 

frequently. 

For the proposed rule, FDA estimated 

that it receives about 7,000 clinical trial 

protocol submissions annually for 

applicable clinical trials that would be 

subject to this final rule, with the vast 

majority of the submissions to the FDA’s 

Center for Drug Evaluation and Research 

(CDER). The public comments did not 

address the size of this estimate. 

However, further analysis of the data 

upon which the estimates were made 

shows that up to 30 percent of the CDER 

protocols may be for phase 1 clinical 

trials which would not be subject to the 

final rule. FDA has adjusted the 

estimated number of CDER trial 

protocols accordingly, which results in 

a reduction of the total trial protocols 

estimate to 5,146. FDA estimates of 

average numbers of participants per 

clinical trial vary greatly across FDA 

Centers, from single-patient INDs to 

vaccine trials with over 25,000 

participants. Published data on average 

number of participants per trial, 

therapeutic area, suggests that the 

average number of participants in phase 

1, 2, and 3 clinical trials of 

pharmaceuticals, biotech, and medical 

device products may range from about 

200 to 360.1 FDA did not receive any 

comments on this estimate of the 

average number of participants per 

clinical trial, and retains it for the 

analysis of the final rule. 

Compliance with the rule would 

require that the informed consent 

documents contain the required 

statement concerning the clinical trial’s 

inclusion in the clinical trial registry 

databank and provide for any additional 

discussion concerning this statement 

between participants and the medical 

professional administering the 

documents. As discussed previously in 

this preamble, FDA received many 

comments concerning the language used 

in the statement, as well as the length 

of time necessary to read and, if 

necessary, discuss this statement with 

the medical professional administering 

the study. Due to these comments, FDA 

has both simplified the language used in 

the statement, and reduced the length of 

the statement by about 50 percent. 

Additionally, FDA has revised its 

estimate of the average number of 

minutes that a clinical trial participant 

would require to read and discuss the 

statement from a range of 30 seconds to 

1 minute used in the analysis of the 

proposed rule to 3 minutes for the 

analysis of the final rule. 

Registered nurses, or other medical 

professionals with a similar level of 

training, often administer and discuss 

the informed consent forms with trial 

participants. The average compensation 

for a registered nurse in 2008 was 

$40.54 per hour, including a 35 percent 

increase to account for benefits. The 

increased labor cost for administering 

the informed consent procedures for 

these medical professionals in 

applicable clinical trials for all 

participants ranges from $2.09 million 

to $3.76 million (see Table 1 of this 

document). This estimate is the result of 

$40.54 per hour times 3 minutes per 

participant times 200 to 360 participants 

per trial times 5,146 protocols per year. 

The cost to the sponsor per prospective 

participant is estimated at $2.03 and the 

cost per trial protocol is estimated to 

range from $405 to $730. 

TABLE 1—COSTS OF INFORMED CONSENT PROPOSED RULE

Cost factor Annual cost 

Labor Cost—Administrative Review of Rule 1 ....................................................................................................................... $202,000 

Labor Cost—Clinical Trial Administrator ............................................................................................................................... 2,086,000–3,755,000 

Labor Cost—Clinical Trial Participant .................................................................................................................................... 801,000–1,442,000 

Labor Cost—IRB Review ....................................................................................................................................................... 29,000 

Document Preparation Cost .................................................................................................................................................. 17,000 

Paper Cost ............................................................................................................................................................................. 7,000–12,000 


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2U.S. Department of Labor, Bureau of Labor 

Statistics, May 2009 National Occupational 

Employment and Wage Estimates United States, 

p. 8. 

TABLE 1—COSTS OF INFORMED CONSENT PROPOSED RULE—Continued 

Cost factor Annual cost 

Total Costs ..................................................................................................................................................................... 3,143,000–5,458,000 

1This is a one-time cost of $830,000 annualized over 5 years at 7 percent. 

Some clinical trial participants are 

compensated for their participation in 

trials. Whether an individual participant 

receives compensation or not, the 

additional time spent by all participants 

to read and discuss the new informed 

consent statement represents a social 

cost of the rule. Using the median U.S. 

wage rate of $15.57 per hour, a clinical 

trial participant would be expected to 

incur a cost of $0.78 for the 3 minutes 

to read and, if necessary, discuss the 

proposed informed consent statement. 

On an annual basis over the 5,146 

clinical trials, this would amount to 

about $0.80 million to $1.44 million. 

Comments to the proposed rule 

included a criticism that FDA had failed 

to account for the costs to IRB for its 

oversight role of the new statement. 

FDA agrees that the new informed 

consent statement will require an 

additional amount of oversight from 

IRBs. FDA has added to its cost 

elements a labor cost for the effort of the 

IRBs to determine that the statement has 

been added to the model templates for 

informed consent documents. Although 

IRBs can have many members, in 

practice, only one or two members may 

be involved in reviewing the study 

documents on behalf of the IRB for 

inclusion of all the necessary informed 

consent statements. FDA estimates the 

additional review of the entirety of 

consent forms and documents to 

determine that the new statement is 

appropriately included could take an 

additional 3 minutes of administrative 

effort for each of the 5,146 protocols. 

FDA bases its cost estimate on the mean 

hourly pay rate for physicians, adjusted 

35 percent for benefits, of $113.2 Using 

these factors, FDA estimates that an 

additional $29,000 in labor costs will be 

incurred due to this final rule. 

The cost of incorporating the new 

statement into the informed consent 

documents is expected to be very small. 

The new statement would only need to 

be written once per protocol and is 

estimated to take about 5 minutes. Using 

the same wage rate as mentioned 

previously, $40.54 per hour, the 

additional annual costs to write the 

statement for the 5,146 annual protocols 

would total to about $17,000. The 

capital cost of adding the new informed 

consent statement would only consist of 

the additional paper. At a cost of about 

$0.02 per page and about one-third of a 

page per participant, the total paper 

costs for this rule are estimated to range 

from $7,000 to $12,000 annually. 

2. Total Industry Costs 

The total costs of the final rule to both 

industry and the clinical trial 

participant population are estimated to 

range from $3.14 million to $5.46 

million annually. This equates to $611 

to $1,061 per trial protocol, or about 

$2.95 to $3.05 per clinical trial 

participant. 

3. Costs to Government 

FDA did not receive any comments on 

its estimate of the impacts of the 

proposed rule on government costs, and 

retains its conclusions for the final rule. 

The costs to government for oversight of 

this rule would be extremely low as a 

review of a sample of informed consent 

documents for each trial would only be 

increased, at most, by a few minutes per 

clinical trial due to the additional 

informed consent statement. FDA 

believes this cost would not be 

significant. 

4. Alternatives to the Final Rule 

FDAAA specifically requires that the 

regulations concerning informed 

consent documents include a statement 

that clinical trial information has been 

or will be submitted for inclusion in the 

clinical trial registry databank. It did not 

provide FDA with discretion concerning 

the inclusion of a statement for 

applicable drug clinical trials. For the 

reasons stated previously in this 

document, FDA has decided to require 

the revised, shorter statement be 

included in the informed consent 

documents for medical device trials as 

well. If the final rule did not include the 

new informed consent statement for 

applicable medical device clinical trials, 

the annual costs of the rule would be 

reduced by $207,000 to $615,000 per 

year. If FDA had not revised the 

informed consent statement to make it 

both shorter and easier to understand, 

the compliance costs would have been 

larger than those estimated in this 

analysis. 

5. Regulatory Flexibility Act 

Impacts on Small Entities 

The Regulatory Flexibility Act 

requires agencies to analyze regulatory 

options that would minimize any 

significant impact of a rule on small 

entities. The companies that would be 

affected are classified in seven separate 

NAICS categories by the Census 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—Opthalmic 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 Census of 

Manufacturers data that offers the level 

of detail for establishments at or near 

the employee size limits as defined by 

SBA is from 2002 (the 2007 Census data 

on the size distributions were not yet 

available; using 2002 data for the 

calculations overstates the likely effects 

on small businesses). 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 multiestablishment corporations, significant 

numbers of companies would still 

qualify as small entities. Preliminary 

Census data from 2007, though less 

detailed, shows that significant numbers 

of establishments continue to have less 

than 100 employees across all of these 

categories. While FDA expects that most 

companies sponsoring applicable 

clinical trials would be larger than the 

average-sized company in their 

industry, FDA concludes that a 

substantial number of sponsoring 

companies would still qualify as small 

entities. 

The cost analysis concluded that the 

compliance cost of the proposed rule 

per trial protocol would range from 

$611 to $1,061. Some firms will direct 


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Federal Register / Vol. 76, No. 2 / Tuesday, January 4, 2011 / Rules and Regulations 269 

multiple applicable clinical trials in the 

same year. For large firms that would 

administer the informed consent 

documents for 10 separate trials, the 

cost would range from $6,110 to $10,610 

per year. Using 2002 Census data, the 

average value of shipments for 

establishments in these industries with 

one to four employees ranged from 

$244,000 to $824,000 according to the 

Census of Manufacturers. Assuming that 

such small operations had one 

applicable clinical trial administered 

each year, the costs of the proposed rule 

would represent, at most, 0.43 percent 

of the annual value of shipments. For 

establishments with 50 or more 

employees, the compliance costs would 

represent 0.11 percent or less of the 

value of shipments even with 10 

applicable clinical trials administered 

annually. For establishments with 100 

or more employees, the compliance 

costs would represent 0.23 percent or 

less of the value of shipments even with 

50 applicable clinical trials 

administered annually. Because of the 

small costs that would be incurred 

relative both to the total cost of a 

clinical trial and the revenues of an 

individual sponsor of a product 

undergoing a clinical trial, the Agency 

certifies that the final rule would not 

have a significant economic impact on 

a substantial number of small entities. 

VIII. Paperwork Reduction Act 

FDA concludes that the informed 

consent requirement in this document is 

not subject to review by the Office of 

Management and Budget because it does 

not constitute a ‘‘collection of 

information’’ under the Paperwork 

Reduction Act of 1995 (44 U.S.C. 3501– 

3520). Rather, the requirement to 

include a statement in informed consent 

documents and processes on submission 

of information to the clinical trial data 

bank is a ‘‘public disclosure of 

information originally supplied by the 

Federal government to the recipient for 

the purpose of disclosure to the public’’ 

(5 CFR 1320.3(c)(2)). 

IX. Federalism 

FDA has analyzed this final rule in 

accordance with the principles set forth 

in Executive Order 13132. FDA has 

determined that the final rule does not 

contain policies that have substantial 

direct effects on the States, on the 

relationship between the National 

Government and the States, or on the 

distribution of power and 

responsibilities among the various 

levels of government. Accordingly, the 

Agency has concluded that the final rule 

does not contain policies that have 

federalism implications as defined in 

the Executive order and, consequently, 

a federalism summary impact statement 

is not required. 

X. References 

The following references have been 

placed on display in the Division of 

Dockets Management, Food and Drug 

Administration, 5630 Fishers Lane, rm. 

1061, Rockville, MD 20857 and may be 

seen by interested persons between 

9 a.m. and 4 p.m., Monday through 

Friday. We have verified the Web site 

addresses, but we are not responsible for 

any subsequent changes to the Web sites 

after this document publishes in the 

Federal Register. 

1. Food and Drug Administration, 

‘‘Protection of Human Subjects; Informed 

Consent Final Rule’’ (46 FR 8942, January 27, 

1981). ‘‘FDA recognizes that the 

documentation of informed consent 

represents only one part of the entire consent 

process. The consent form itself is merely an 

aid to assure that a required minimum of 

information is provided to the subject and 

that the subject consents. The entire 

informed consent process involves giving the 

subject all the information concerning the 

study that the subject would reasonably want 

to know; assuring that the subject has 

comprehended this information; and finally, 

obtaining the subject’s consent to 

participate.’’ 46 FR 8942 at 8945. Available at: 

http://www.fda.gov/ScienceResearch/

SpecialTopics/RunningClinicalTrials/

ucm113818.htm, accessed August 9, 2010. 

2. National Commission for the Protection 

of Human Subjects of Biomedical and 

Behavioral Research, ‘‘The Belmont Report: 

Ethical Principles and Guidelines for the 

Protection of Human Subjects of Research.’’ 

Part A: Boundaries Between Practice & 

Research, April 18, 1979, available at: http:// 

www.hhs.gov/ohrp/humansubjects/

guidance/belmont.htm, accessed August 9, 

2010. 

3. National Research Act, Title II (Pub. L. 

93–348, July 12, 1974). 

4. Trials of War Criminals Before the 

Nuremberg Military Tribunals Under Control 

Council Law, No. 10, Vol. 2, pp. 181–182; 

Washington, DC, U.S. Government Printing 

Office (1949), available at: http:// 

www.loc.gov/rr/frd/Military_Law/pdf/ 

NT_war-criminals_Vol-II.pdf, accessed 

August 9, 2010. 

5. Council for International Organizations 

of Medical Sciences, International Ethical 

Guidelines for Biomedical Research Involving 

Human Subjects (2002), Guideline 5, No. 7 

states that the informed consent process 

include information that subjects, after 

completion of the study, will be provided 

with general research results and any 

findings relating to their particular health 

status. Guideline 5, No. 11 states that the 

subject be informed of ‘‘the expected benefits 

of the research to the community or to 

society at large.’’, available at: http:// 

www.cioms.ch/publications/layout_

guide2002.pdf, accessed August 9, 2010. 

6. World Medical Association, Declaration 

of Helsinki, Ethical Principles for Medical 

Research Involving Human Subjects, 59th 

WMA General Assembly, Seoul, October 

2008, Section C.33 states that: ‘‘At the 

conclusion of the study, patients entered into 

the study are entitled to be informed about 

the outcome of the study and to share any 

benefits that result from it. * * *’’, available 

at: http://www.wma.net/en/30publications/ 

10policies/b3/17c.pdf, accessed August 9, 

2010. 

7. Sim, I., A. Chan, A. Gu ̈lmezoglu, 

‘‘Clinical Trial Registration: Transparency is 

the Watchword,’’ The Lancet, Vol. 367, Issue 

9523, p. 1631, May 2006. 

8. De Angelis, C., J. M. Drazen, et al. ‘‘Is 

This Clinical Trial Fully Registered?: A 

Statement From the International Committee 

of Medical Journal Editors,’’ International 

Committee of Medical Journal Editors, 

available at: http://www.icmje.org/ 

update_may05.html, accessed October 4, 

2010. 

9. Several examples of model templates 

can be found at: 

a. Mayo Clinic, Institutional Review Board, 

IRB Consent Form Template, available at: 

http://mayoresearch.mayo.edu/mayo/ 

research/irb/upload/irb10294.pdf accessed 

July 7, 2010; 

b. Stanford University Research 

Compliance Office, Human Subjects 

Research, ‘‘Stanford University Consent 

(includes HIPAA), available at: http://

humansubjects.stanford.edu/consents/ 

SUSampCons_CA_privacy.doc, accessed July 

7, 2010; 

c. Duke University School of Medicine, 

Institutional Review Board, ‘‘Sample 

Consent,’’ available at: http://

irb.duhs.duke.edu/wysiwyg/downloads/

Consent_Template_-_Long_Form_102_01-02- 

09_JW.doc, accessed July 7, 2010; 

d. University of Michigan Medical School, 

Informed Consent & Assent Templates, 

‘‘Informed Consent Template (Standard) 

Version 3–29–10,’’ available at: http://

med.umich.edu/irbmed/ict.htm, accessed 

July 7, 2010; 

e. University of Texas at Austin, Office of 

Research Support, ‘‘Consent Form 1—For 

Greater Than Minimal Risk Studies,’’ 

available at: http://www.utexas.edu/research/ 

rsc/humansubjects/forms/consent_

form_1.doc, accessed on July 7, 2010; 

f. Children’s Hospital Boston, Office of 

Clinical Investigation, ‘‘English Informed 

Consent Template,’’ available at: http://

www.childrenshospital.org/cfapps/research/ 

data_admin/Site2206/Documents/

Consent_Template.doc, accessed July 8, 

2010; 

g. Partners Human Research Committee, 

Consent Forms, ‘‘Drug Trial Consent Form 

Template,’’ available at: http://

healthcare.partners.org/phsirb/irbforms/

Consent_Templates_and_Instructions/

PHS_Research_Consent_Form_

Adult_Surrogate_Drug_2.2010.doc, accessed 

July 8, 2010; 

h. Walter Reed Army Medical Center, NCA 

Templates, ‘‘Informed Consent Form.’’ 

Available at: http://www.wramc.army.mil/

Patients/healthcare/dci/protocols/nca

templates/INFORMED%20CONSENT%

20FORM%20(ICF)/WRNMMC_ClinicalTrials

ICF.doc, accessed July 8, 2010; 


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i. American College of Radiology Imaging 

Network, Protocol Development & Regulatory 

Resources, ‘‘Informed Consent Template & 

Checklist,’’ available at: http://www.acrin.org/ 

Portals/0/Administration/Regulatory/ICF_

Template.doc, accessed July 8, 2010; 

j. National Cancer Institute, ‘‘Simplification 

of Informed Consent Documents,’’ available 

at: http://www.cancer.gov/clinicaltrials/ 

education/simplification-of-informedconsent-docs/allpages, accessed July 7, 2010. 

10. Institutional Review Board: 

Management and Function (edited by 

Bankert, E. A. and R. J. Amdur), 2d Ed., 2006 

(Chapter 6–1, The Institutional Review 

Board’s Role in Editing Consent Documents, 

Pensha, R. L., pp. 199–201 and Chapter 6–2, 

The Consent Documents, Brown, A., pp 202– 

204). 

11. Flesch-Kincaid Reading Scale 

Information, Rudolf Flesch, ‘‘A New 

Readability Yardstick,’’ Journal of Applied 

Psychology, vol. 32, pp. 221–233, 1948. 

12. FDA, Office of Planning, Risk 

Communication Staff, ANALYSIS NOTE: 

Note No. 2010–001, July 30, 2010. 

13. FDA: A Guide to Informed Consent— 

Information Sheet, available at: http://

www.fda.gov/RegulatoryInformation/

Guidances/ucm126431.htm#nonenglish, 

accessed August 8, 2010. 

14. NIH: ClinicalTrials.gov: Protocol 

Registration System: PRS and U.S. Public 

Law 110–85: ‘‘Applicable Clinical Trials,’’ 

available at: http://prsinfo.clinicaltrials.gov/

fdaaa.html and http://

prsinfo.clinicaltrials.gov/Elaborations

OnDefinitions.pdf, accessed August 8, 2010. 

15. ‘‘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,’’ available at: http://

www.fda.gov/MedicalDevices/

DeviceRegulationandGuidance/

GuidanceDocuments/ucm078384.htm, 

accessed August 8, 2010. 

16. NIH: ClinicalTrials.gov ‘‘Basic Results 

Data Element Definitions (DRAFT),’’ available 

at: http://prsinfo.clinicaltrials.gov/results_

definitions.html, accessed August 8, 2010. 

List of Subjects in 21 CFR Part 50 

Human research subjects, Prisoners, 

Reporting and recordkeeping 

requirements, Safety. 

■ Therefore, under the Federal Food, 

Drug, and Cosmetic Act, the Public 

Health Service Act, and under authority 

delegated to the Commissioner of Food 

and Drugs, 21 CFR part 50 is amended 

as follows: 

PART 50—PROTECTION OF HUMAN 

SUBJECTS 

■ 1. The authority citation for 21 CFR 

part 50 continues to read as follows: 

Authority: 21 U.S.C. 321, 343, 346, 346a, 

348, 350a, 350b, 352, 353, 355, 360, 360c360f, 360h-360j, 371, 379e, 381; 42 U.S.C. 

216, 241, 262, 263b-263n. 

■ 2. Section 50.25 is amended by 

redesignating paragraphs (c) and (d) as 

paragraphs (d) and (e), and by adding 

new paragraph (c) to read as follows: 

§ 50.25 Elements of informed consent. 

* * * * * 

(c) When seeking informed consent 

for applicable clinical trials, as defined 

in 42 U.S.C. 282(j)(1)(A), the following 

statement shall be provided to each 

clinical trial subject in informed consent 

documents and processes. This will 

notify the clinical trial subject that 

clinical trial information has been or 

will be submitted for inclusion in the 

clinical trial registry databank under 

paragraph (j) of section 402 of the Public 

Health Service Act. The statement is: ‘‘A 

description of this clinical trial will be 

available on http://

www.ClinicalTrials.gov, as required by 

U.S. Law. This Web site will not include 

information that can identify you. At 

most, the Web site will include a 

summary of the results. You can search 

this Web site at any time.’’ 

* * * * * 

Dated: December 28, 2010. 

Leslie Kux, 

Acting Assistant Commissioner for Policy. 

[FR Doc. 2010–33193 Filed 1–3–11; 8:45 am] 

BILLING CODE 4160–01–P 

ENVIRONMENTAL PROTECTION 

AGENCY 

40 CFR Parts 239 and 258 

[EPA–R10–RCRA–2010–0953; FRL–9247–6] 

Alaska: Adequacy of Alaska Municipal 

Solid Waste Landfill Permit Program 

AGENCY: Environmental Protection 

Agency (EPA). 

ACTION: Direct final rule. 

SUMMARY: This action approves a 

modification to Alaska’s approved 

Municipal Solid Waste Landfill 

(MSWLF) permit program. The 

approved modification allows the State 

to issue Research, Development, and 

Demonstration (RD&D) permits to 

owners and operators of MSWLFs in 

accordance with its State law. On March 

22, 2004, EPA issued final regulations 

allowing RD&D permits to be issued to 

certain MSWLFs by approved States. On 

September 7, 2010, the State of Alaska 

submitted an application to EPA Region 

10 seeking Federal approval of its RD&D 

requirements. After thorough review, 

EPA Region 10 has determined that 

Alaska’s RD&D permit requirements are 

adequate through this direct final 

action. 

DATES: This direct final rule will 

become effective March 7, 2011 without 

further notice unless EPA receives 

adverse comments on or before February 

3, 2011. If adverse comments are 

received, EPA will publish a timely 

withdrawal of this direct final rule in 

the Federal Register informing the 

public that the rule will not take effect. 

EPA will then review the comments and 

then will publish a final rule in the 

Federal Register responding to the 

comments and affirming or revising its 

initial decision. 

ADDRESSES: Submit your comments, 

identified by Docket ID No. EPA–R10– 

RCRA–2010–0953, by one of the 

following methods: 

• http://www.regulations.gov: Follow 

the on-line instructions for submitting 

comments. 

• E-mail: calabro.domenic@epa.gov. 

• Fax: (206) 553–8509, to the 

attention of Domenic Calabro. 

• Mail: Domenic Calabro, Office of 

Air, Waste and Toxics, U.S. EPA, Region 

10, 1200 Sixth Avenue, Suite 900, 

Mailstop: AWT–122, Seattle, WA 98101. 

• Hand Delivery or Courier: Deliver 

your comments to Domenic Calabro, 

Office of Air, Waste and Toxics, U.S. 

EPA, Region 10, 1200 Sixth Avenue, 

Suite 900, Mailstop: AWT–122, Seattle, 

WA 98101. Such deliveries are only 

accepted during the Office’s normal 

hours of operation. 

Instructions: Identify your comments 

as relating to Docket ID No. EPA–R10– 

RCRA–2010–0953. EPA’s policy is that 

all comments received will be included 

in the public docket without change and 

may be made available online at http://

www.regulations.gov, including any 

personal information provided, unless 

the comment includes information 

claimed to be Confidential Business 

Information (CBI) or claimed to be other 

information whose disclosure is 

restricted by statute. Do not submit 

information that you consider to be CBI 

or otherwise protected through http://

www.regulations.gov or e-mail. The 

http://www.regulations.gov Web site is 

an ‘‘anonymous access’’ system, which 

means EPA will not know your identity 

or contact information unless you 

provide it in the body of your comment. 

If you send an e-mail comment directly 

to EPA without going through http://

www.regulations.gov, your e-mail 

address will be automatically captured 

and included as part of the comment 

that is placed in the public docket and 

made available on the Internet. If you 

submit an electronic comment, EPA 

recommends that you include your 

name and other contact information in 

the body of your comment and with any 


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