Document ID: FDA-2009-N-0592-0001
Agency: fda
Document Type: Proposed Rule
Title: Informed Consent Elements
Posted Date: 2009-12-29T05:00Z

[Federal Register: December 29, 2009 (Volume 74, Number 248)]
[Proposed Rules]               
[Page 68750-68756]
From the Federal Register Online via GPO Access [wais.access.gpo.gov]
[DOCID:fr29de09-34]                         

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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: Proposed rule; opportunity for public comment.

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SUMMARY: The Food and Drug Administration (FDA or agency) is issuing a 
proposed rule that, if finalized, would amend the informed consent 
regulations to require that the informed consent documents and 
processes for applicable drug, biologic, and device clinical 
investigations include a statement that clinical trial information for 
such clinical investigations has been or will be submitted to the 
National Institutes of Health/National Library of Medicine (NIH/NLM) 
for inclusion in the clinical trial registry databank. The Food and 
Drug Administration Amendments Act of 2007 (FDAAA) requires that FDA 
update its informed consent regulations to require that the informed 
consent documents and processes for certain clinical investigations 
include a statement that clinical trial information for such 
investigations has been or will be submitted for inclusion in the 
clinical trial registry databank.

DATES: Submit written or electronic comments on the proposed rule by 
March 1, 2010.

ADDRESSES: You may submit comments, identified by Docket No. FDA-2009-
N-0592 and/or RIN number 0910-AG32, by any of the following methods.

Electronic Submissions

    Submit electronic comments in the following way:
     Federal eRulemaking Portal: http://www.regulations.gov. 
Follow the instructions for submitting comments.

Written Submissions

    Submit written submissions in the following ways:
     FAX: 301-827-6870.
     Mail/Hand delivery/Courier (for paper, disk, or CD-ROM 
submissions): Division of Dockets Management (HFA-305), Food and Drug 
Administration, 5630 Fishers Lane, rm. 1061, Rockville, MD 20852.
    Instructions: All submissions received must include the agency name 
and docket number and Regulatory Information Number (RIN) for this 
rulemaking. All comments received may be posted without change to 
http://www.regulations.gov, including any personal information 
provided. For additional information on submitting comments, see the 
``Comments'' heading of the SUPPLEMENTARY INFORMATION section of this 
document.
    Docket: For access to the docket to read background documents or 
comments received, go to http://www.regulations.gov and insert the 
docket number, found in brackets in the heading of this document, into 
the ``Search'' box and follow the prompts and/or go to the Division of 
Dockets Management, 5630 Fishers Lane, rm. 1061, Rockville, MD 20852.

FOR FURTHER INFORMATION CONTACT: Jarilyn Dupont, Office of Policy, 
Office of Commissioner, Food and Drug Administration, 10903 New 
Hampshire Ave., Bldg. 1, rm. 4305, Silver Spring, MD 20993-0002, 301-
796-4830.

SUPPLEMENTARY INFORMATION:

I. Introduction

    FDAAA was enacted on September 27, 2007. Section 801 of FDAAA 
amends the Public Health Service (PHS) Act to require the Secretary of 
the Department of Health and Human Services (HHS), acting through the 
Director of NIH, to expand the clinical trial registry databank 
established under section 113 of the 1997 Food and Drug Administration 
Modernization Act (FDAMA) (Public Law 105-115, currently codified at 42 
U.S.C. 282(i)) and to ensure that the databank is made publicly 
available through the Internet. Section 801 provides for the expansion 
of the registry databank through requiring investigators and sponsors 
to submit certain information about any applicable clinical trial to 
NIH/NLM for inclusion in the clinical trial registry databank. Section 
801's requirements apply to applicable device clinical trials or 
applicable drug clinical trials, as defined in the statute. Under 
FDAAA, applicable drug clinical trials include clinical trials for 
biological products regulated under section 351 of the PHS Act (42 
U.S.C. 262). Section 801 also requires the Secretary to ensure that the 
databank includes links to results information for those clinical 
investigations that form the primary basis of an efficacy claim or are 
conducted after the drug involved is approved or after the device 
involved is cleared or approved.
    Section 801(b)(3)(A) of FDAAA also amends section 505(i) of the 
Federal Food, Drug, and Cosmetic Act (the act) (21 U.S.C. 355(i)) to 
require that the Secretary update FDA's informed consent regulations to 
require that informed consent documents and processes for the clinical 
investigations in question include a statement that clinical trial 
information has been or will be submitted to this registry databank. 
The current informed consent regulations do not include provisions 
addressing the clinical trial registry databank. (See part 50 (21 CFR 
part 50); part 312 (21 CFR part 312); and 21 CFR 812.2(b)(1)(iii) and 
812.25(g).) Specifically, section 801(b)(3)(A) of FDAAA states:
    NEW DRUGS AND DEVICES.--
    (A) 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. Background

    FDA has various regulations that govern the conduct of clinical 
investigations. The informed consent regulations provide protection to 
subjects in clinical investigations conducted under FDA's jurisdiction. 
(See part 50.) These informed consent regulations are based on ethics 
codes such as the Nuremberg Code (Ref. 1), the Declaration of Helsinki 
(Ref. 2), the National Research Act (Ref. 3), and the Belmont Report 
(Ref. 4); these codes embody the basic ethical principles relevant to 
the protection of human research subjects. (See 60 FR 49086, September 
21, 1995, and 44 FR 47713, August 14, 1979, for a detailed discussion 
of the ethical basis for the agency's regulations governing human 
subject protection.) These principles identify standards to protect 
participants from unethical practices, allow subjects to have equal 
access to, opportunity to participate in, and the ability to withdraw 
from clinical trials voluntarily, educate participants so they make 
autonomous decisions, and

[[Page 68751]]

require disclosure of the risks and benefits of participating in 
clinical research, with the goal of maximizing the benefit of clinical 
trial research and minimizing and protecting participants from harm.
    Section 113 of FDAMA required the Secretary, acting through the 
Director of NIH, to establish, maintain, and operate a databank of 
information on clinical trials for experimental treatments for serious 
or life-threatening diseases or conditions conducted under FDA's 
investigational new drug (IND) regulations (42 U.S.C. 282(i)(1)(A)). 
This databank is known as www.ClinicalTrials.gov. Section 113 of FDAMA 
required that the clinical trials databank contain: (1) Information 
about Federally- and privately-funded clinical trials for experimental 
treatments (drug and biological products) for serious or life-
threatening diseases and conditions, (2) a description of the purpose 
of each experimental drug, (3) participant eligibility criteria, (4) a 
description of the location of clinical trial sites, and (5) a point of 
contact for those wanting to enroll in the trial (42 U.S.C. 
282(i)(3)(A)). FDAMA also required that information provided through 
the clinical trials databank be in a form that can be readily 
understood by the public. Id. FDAMA was a response to efforts by 
patient advocacy groups and others toward obtaining greater access to 
clinical trials.
    After consulting with FDA and others, NIH, through NLM, developed 
the clinical trial registry databank. The first version of the registry 
databank was made available to the public on February 29, 2000, on the 
Internet. At that time, the registry databank included primarily NIH-
sponsored trials. In 2002, FDA published a guidance to provide 
recommendations for industry on submitting protocol information to the 
registry databank. (See ``Guidance for Industry: Information Program on 
Clinical Trials for Serious or Life-Threatening Diseases and 
Conditions,'' (March 18, 2002) available at http://www.fda.gov/
downloads/RegulatoryInformation/Guidances/ucm126838.pdf).
    In 2004, FDA published a revised draft guidance to update the 
earlier version to include recommendations for sponsors who would be 
submitting information required by the Best Pharmaceuticals for 
Children Act (BPCA, Public Law 107-109). (See ``Guidance for Industry: 
Information Program on Clinical Trials for Serious or Life-Threatening 
Diseases and Conditions'' (January 2004) available at http://
www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/
Guidances/ucm077229.pdf.) Under the BPCA, manufacturers or sponsors of 
clinical investigations are required to submit to the clinical trials 
registry databank a description of whether and through what procedure 
the manufacturer or sponsor will respond to requests for protocol 
exception for single-patient and expanded access use of investigational 
drugs.
    In September 2004, the members of the International Committee of 
Medical Journal Editors published a joint editorial aimed at promoting 
registration of all clinical trials. (Ref. 5) In that editorial, the 
members declared that they would consider an article related to a 
clinical trial for publication only if the clinical trial had been 
registered, before the enrollment of the first participant, in a 
publicly available database. (Id.; Ref. 6) This policy applies to 
trials that started recruiting on or after July 1, 2005. This was 
another step toward fostering a transparent, comprehensive, publicly 
available database of clinical trials.
    Although Section 113 of FDAMA required that the clinical trials 
databank be established, it was silent on the enforcement of that 
requirement. Subsequent legislative proposals addressed the 
shortcomings of the existing clinical trial registry databank. Versions 
of proposed legislation required registration of all clinical trials 
conducted in the United States and reporting of such details as 
research outcomes, basic demographic information, sources of funding, 
significant adverse events, and FDA approval status, and provided for 
strong enforcement measures such as civil money penalties. 
Subsequently, Title VIII of FDAAA was enacted.
    With the enactment of FDAAA, the registry requirements have been 
expanded and broadened to include not only trials in serious and life 
threatening diseases and conditions but to include any ``applicable 
clinical trial'' as defined in section 402(j)(1)(A) of the PHS Act (42 
U.S.C. 282(j)(1)(A)). Although not all clinical trials meet this 
definition, a significant portion of clinical trials involving FDA-
regulated drugs, biological products, or devices meet it. For this 
reason, revising the general informed consent provisions in part 50 
provides the most straightforward direction for clinical investigators 
and the most information to clinical trial participants.
    The basic elements of informed consent which also can be considered 
the ``essential'' elements, are set forth in Sec.  50.25(a) of the 
human subject projection regulations. These elements are required for 
all clinical investigations that are regulated by FDA or that support 
applications for research or marketing permits for products regulated 
by the agency. The statement required by section 801(b)(3)(A) of FDAAA 
that the information about the clinical investigation has been or will 
be submitted for inclusion in the clinical trial registry databank 
should be considered a basic, or essential, element of informed consent 
and should apply to all applicable clinical trials as defined in FDAAA. 
This statement is mandated by law under section 505(i) of the act; 
adding the requirement as a basic element of informed consent makes it 
clear that this requirement to inform subjects of the clinical trials 
registry databank is not discretionary. Furthermore, the required 
inclusion of clinical trial information in the registry databank is not 
limited to a small subset of clinical investigations; as such, it makes 
little sense to inform only a small subset of participants of 
applicable clinical trials about the registry databank and that the 
clinical trial information has been or will be submitted for inclusion 
in the registry databank. FDA thus proposes that this requirement be 
added as new Sec.  50.25(a)(9) since it is a basic, or essential, 
element of informed consent, which will apply to applicable clinical 
trials as defined in FDAAA.

III. Description of Proposal

    The text of section 801(b)(3)(A) of FDAAA amends only section 
505(i) of the act, which is the statutory provision concerning INDs. 
The provision does not amend or refer to section 520(g) of the act (21 
U.S.C. 360j(g)), which is the statutory provision concerning 
investigational device exemptions. However, Title VIII of FDAAA 
generally applies to both drug and device clinical investigations. 
Human subject protection applies to all clinical trials, regardless of 
the type of treatment being studied, and FDA can find no justification 
for a scheme that would result in device trials having different or 
lesser requirements for human subject protection and informed consent. 
In addition, knowledge of existence of the clinical trial registry 
databank and of the fact that information about a particular clinical 
investigation may be included in the registry databank could affect an 
individual's decision to participate in a clinical trial; as such, 
knowledge of this information is equally important for potential 
participants in clinical device trials as it is for potential 
participants in clinical drug trials. Therefore, FDA proposes to amend 
the regulatory language in the general informed

[[Page 68752]]

consent regulations in Sec.  50.25, which will apply to all applicable 
clinical trials as defined by FDAAA.
    Requiring investigators to provide information regarding the 
possible inclusion of clinical trial information in the clinical trial 
registry databank in informed consent documents and processes for only 
clinical drug trials would create a disparity in FDA's policy on human 
subject protection and could result in confusion among those who 
conduct clinical trials over what is required in informed consent 
documents and processes. In addition, as stated previously, to the 
extent that knowledge of the fact that the clinical trial information 
could be included in the clinical trial registry databank could affect 
an individual's decision to participate in a clinical trial, this 
information is as important for potential participants in clinical 
device trials as it is for potential participants in clinical drug 
trials.
    The existing informed consent basic, or essential, elements do not 
include a requirement to inform potential participants that a clinical 
trial they may be invited to participate in is registered, or will be 
registered, in the clinical trial registry databank. The proposed rule, 
if finalized, would require that investigators include a statement in 
their informed consent documents and processes that the clinical trial 
information has been or will be submitted for inclusion in the clinical 
trial registry databank. Under Sec.  50.27(b)(1), the informed consent 
must be documented by the use of a written consent document that 
embodies the elements of informed consent required by Sec.  50.25. A 
proposed specific statement required in informed consent documents is 
set forth in the codified language of this proposed rule. A specific 
statement will help ensure that consistent information about the 
clinical trial databank is provided to clinical trial participants. In 
addition to the required language regarding the inclusion of clinical 
trial information in the clinical trial registry databank, the specific 
statement includes a descriptive explanation of the clinical trials 
registry that will be useful for informing clinical trial participants 
of the nature and purpose of the clinical trial registry databank. 
Investigators and Institutional Review Boards may include other 
information about the clinical trial registry databank in addition to 
the required statement in informed consent documents. The required 
statement, however, must be used to satisfy the requirements of this 
rule, if finalized.
    There are several benefits to requiring investigators to include in 
informed consent documents and processes for all applicable clinical 
trials a statement that clinical trial information has been or will be 
submitted for inclusion in the clinical trial registry databank. First, 
it would increase public awareness of the existence of the database and 
thereby increase transparency of clinical trials. In particular, it 
would enable individuals to access more detailed information about 
trials relevant to their medical conditions of interest. Furthermore, 
to the extent that information about the clinical trial registry 
databank would affect individuals' decisions to participate in clinical 
research, requiring investigators to provide such information to 
potential participants would foster individuals' ability to make a 
fully informed decision about participating in a clinical trial. 
Second, it would provide greater accountability and responsibility of 
investigators for outcomes and adverse events and improve transparency 
of all clinical trial outcomes information. Informing clinical trial 
participants and potential patients about the databank and directing 
them to www.ClinicalTrials.gov would become part of a system of checks 
and balances for the research community and a means of ensuring that 
researchers, investigators, and manufacturers or sponsors comply with 
their legal requirements under FDAAA. Third, it would increase public 
confidence in the validity of the research process. With the knowledge 
that the information generated by the clinical investigation is likely 
to be made public, and thus subject to additional scrutiny, 
participants can anticipate that the trial ``results'' could have more 
impact on other medical research and analysis. ``Individuals 
voluntarily participate in trials expecting that the results will be 
used to improve medical knowledge in general, and not only to serve 
proprietary or commercial interests. These ethical obligations to the 
public good are in addition to the obligations to protect individual 
participants during a trial (e.g., informed consent), and they extend 
to all trials regardless of study design or trial population.'' (Ref. 
7) Finally, it would give sponsors, physicians, and patients access to 
more information and thus enable them to make more educated treatment 
decisions. In these ways, amending the basic elements of the informed 
consent provision to require a statement regarding the inclusion of 
clinical trial information in the clinical trial registry databank 
would lead to better promotion and protection of public health, help 
foster innovation to further the scientific process, and reduce 
duplicative research efforts.

IV. What Clinical Trials Require a Revised Informed Consent Document 
and Process?

    The statute defines an ``applicable clinical trial'' in section 
402(j)(1)(A)(i) of the PHS Act (42 U.S.C. 282(j)(1)(A)(i)) as follows:
    (j) EXPANDED CLINICAL TRIAL REGISTRY DATA BANK.--
    (1) DEFINITIONS; REQUIREMENT.--
    (A) DEFINITIONS.--In this subsection: ``(i) APPLICABLE CLINICAL 
TRIAL.--The term `applicable clinical trial' means an applicable 
device clinical trial or an applicable drug clinical trial.
    (ii) APPLICABLE DEVICE CLINICAL TRIAL.--The term `applicable 
device clinical trial' means--
    (I) a prospective clinical study of health outcomes comparing an 
intervention with a device subject to section 510(k), 515, or 520(m) 
of the Federal Food, Drug, and Cosmetic Act against a control in 
human subjects (other than a small clinical trial to determine the 
feasibility of a device, or a clinical trial to test prototype 
devices where the primary outcome measure relates to feasibility and 
not to health outcomes); and
    (II) a pediatric postmarket surveillance as required under 
section 522 of the Federal Food, Drug, and Cosmetic Act.
    (iii) APPLICABLE DRUG CLINICAL TRIAL.--
    (I) IN GENERAL.--The term `applicable drug clinical trial' means 
a controlled clinical investigation, other than a phase I clinical 
investigation, of a drug subject to section 505 of the Federal Food, 
Drug, and Cosmetic Act or to section 351 of this Act.
    (II) CLINICAL INVESTIGATION.--For purposes of subclause (I), the 
term `clinical investigation' has the meaning given that term in 
section 312.3 of title 21, Code of Federal Regulations (or any 
successor regulation).
    Additional information to improve understanding of the common 
terminology and the applicability of the requirements used in 
implementing the clinical trial databank can be found at 
www.ClinicalTrials.gov and the database registry Web site at 
www.prsinfo.clinicaltrials.gov.

V. Legal Authority

    Section 505(i) of the act requires drug manufacturers or sponsors 
of investigations to ensure that experts using investigational drugs in 
clinical trials ``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 (21 U.S.C. 355(i)). Similarly, section 520(g) 
of the act requires individuals applying for investigational device 
exemptions to ensure that informed consent will be obtained from each 
human subject of

[[Page 68753]]

proposed clinical testing involving the device (21 U.S.C. 360j(g)). 
Sections 505(i) and 520(g) of the act also require the Secretary to 
issue regulations for the protection of human subjects in clinical 
investigations (21 U.S.C. 355(i)(4) and 360j(g)(2)). Additionally, 
section 701(a) of the act (21 U.S.C. 371) confers general authority on 
the Secretary to issue regulations for the efficient enforcement of the 
act.
    Section 801(b)(3)(A) of FDAAA amends section 505(i)(4) of the 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 act can be found at 
parts 312 and 50. Part 312 sets forth regulations governing drug and 
biological product IND applications; part 50 sets forth 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, biological products, and medical devices. 
Section 801(b)(3)(A) of FDAAA does not amend section 520(g) of the act; 
however, in instances where the regulations are amended to address 
human subject protection, FDA has not in the past made distinctions 
among clinical investigations for drugs, biological products, and 
medical devices.
    FDA created a uniform system of human subject protection when it 
initially amended its regulations governing human subject protection in 
1981 (46 FR 8942, January 27, 1981). 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 clinical trial registry 
databank in informed consent documents and process for only clinical 
investigations for drugs but not devices would create a disparity in 
FDA's policy on human subject protection and could result in confusion 
among those who conduct clinical trials over what is required in 
informed consent documents and processes, especially in the cases of 
trials involving both a drug and device or for investigators conducting 
trials of both types of regulated products. Furthermore, knowledge of 
the existence of the clinical trial registry databank and of the fact 
that information about a particular clinical investigation has been or 
will be submitted for inclusion in the registry databank could affect 
an individual's decision to participate in a clinical trial; as such, 
this knowledge is equally important for potential participants of 
clinical device trials as it is for potential participants of clinical 
drug trials.
    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 clinical investigations conducted 
under section 505(i) of the act, under its general authority, FDA 
proposes to require that all applicable clinical trials, including 
applicable medical device trials, include this new statement. This 
proposed rule requiring that a statement regarding the inclusion of 
clinical trial information in the clinical trial registry databank 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 drug and device 
research, FDA is proposing, by this rule, to apply the same standards 
regarding elements of informed consent to drug and device research. As 
such, FDA is proposing to amend Sec.  50.25 to require a statement 
about the registry databank in informed consent documents and processes 
for all applicable clinical trials under section 801 of FDAAA.

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.

VII. Analysis of Impacts

    FDA has examined the impacts of the proposed rule under Executive 
Order 12866 and the Regulatory Flexibility Act (5 U.S.C. 601-612), and 
the Unfunded Mandates Reform Act of 1995 (Public Law 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 proposed 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 rule is likely to impose costs of less 
than $1 per clinical trial participant, the agency proposes to certify 
that the final rule will not have a significant economic impact on a 
substantial number of small entities.
    Section 202(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 $133 million, using the most current (2008) Implicit 
Price Deflator for the Gross Domestic Product. FDA does not expect this 
proposed rule to result in any 1-year expenditure that would meet or 
exceed this amount.

A. The Proposed Rule

    This rule would require that the informed consent documents and 
processes for applicable clinical drug trials and applicable clinical 
device trials as defined by section 801 of FDAAA include a statement 
that clinical trial information has been or will be submitted to NIH/
NLM for inclusion in the clinical trial registry databank. As it 
pertains to applicable clinical drug trials, the rule would implement a 
requirement of FDAAA. As discussed previously in this preamble, FDA is 
also proposing to require that the same statement be included in the 
informed consent documents for applicable clinical device trials.

[[Page 68754]]

B. Need for the Proposed Rule

    FDAAA section 801(b)(3)(A) amends section 505(i) of the act to 
require that the Secretary update regulations for informed consent 
documents and process to require inclusion of a statement that clinical 
trial information has been or will be submitted to NIH/NLM for 
inclusion in the clinical trial registry databank. FDA has determined 
that revising the general informed consent provision is the most 
appropriate course by which to fulfill the requirements of the statute, 
in a way that will provide the pertinent information to and protection 
for clinical trial participants.

C. Benefits of the Proposed Rule

    As discussed in this preamble, this proposed rule would provide 
several benefits to clinical trial participants. 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. The rule would 
also provide greater accountability of clinical trial investigators for 
outcomes and adverse events by helping to create a system of checks and 
balances through which participants, patients and healthcare providers 
are encouraged to check whether information about a trial of interest 
is registered in the databank. Furthermore, the rule would increase 
public 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; however, the agency believes that 
the overall effect of the rule on public health will be positive.

D. Costs of the Proposed Rule

1. Labor Costs
    The costs of the proposed 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.
    FDA estimates that it receives about 7,000 clinical trial protocol 
submissions annually for applicable clinical trials that would be 
subject to this proposed rule, with the vast majority of the 
submissions going to the FDA's Center for Drug Evaluation and Research. 
FDA estimates of average numbers of participants per clinical trial 
vary greatly across FDA Centers, from single-patient INDs to vaccine 
trials with over twenty-five thousand 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, biotechnology, and medical device products 
may range from about 200 to 360.\1\ FDA uses this estimated range for 
the average number of participants per clinical trial, and invites 
public comment on the estimated average number of participants per 
clinical trial.
---------------------------------------------------------------------------

    \1\ Parexel'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 3 clinical phases, which would tend to overstate the 
average size of participants. This upper bound is calculated at 360 
participants per trial protocol.
---------------------------------------------------------------------------

    Compliance with the rule would require that investigators include 
in informed consent documents and processes the required statement 
concerning the submission of clinical trial information for 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. FDA does not expect 
that this statement will provoke any controversy. It is expected that 
in most cases, after reading the proposed statement, the clinical trial 
participant will not choose to discuss it with the investigator. In 
some cases, however, it is possible that a short discussion will occur. 
FDA estimates that, on average, a clinical trial participant would 
require an additional 30 seconds to 1 minute to read and, if necessary, 
discuss the added statement with the medical professional administering 
the informed consent documents.
    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 $473,000 to $1,704,000 (see Table 1 of this document). This 
estimate is the result of $42.27 per hour, times 30 to 60 seconds per 
participant, times 200 to 360 participants per trial times 7,000 
protocols per year. The cost to the sponsor per prospective participant 
would range from $0.34 to $0.68 and the cost per trial protocol would 
range from $68 to $243.

            Table 1.--Costs of Informed Consent Proposed Rule
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                 Cost Factor                          Annual Cost
------------------------------------------------------------------------
Labor Cost for Clinical Trial Administrator   $473,000 to $1,704,000
------------------------------------------------------------------------
Labor Cost for Clinical Trial Participant     $182,000 to $654,000
------------------------------------------------------------------------
Document Preparation Cost                     $17,000
------------------------------------------------------------------------
Paper Cost                                    $9,000 to $18,000
------------------------------------------------------------------------
Total Costs                                   $688,000 to $2,398,000
------------------------------------------------------------------------

    Whether or not clinical trial participants receive compensation for 
their participation in clinical trials, 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 ranging from $0.13 to $0.26 to read and, if necessary, 
discuss the proposed informed consent statement concerning the 
inclusion of clinical trial information in the clinical trial registry 
databank. On an annual basis, this would amount to about $182,000 to 
$654,000 for 7,000 clinical trials.
    The cost of writing 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 shown previously, $40.54 per hour, 
the additional annual costs to write the statement for the 7,000 annual 
protocols would total about $24,000.
    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 $9,000 to $17,000 annually.
    The total costs of the proposed rule to both industry and the 
clinical trial participant population are estimated to range from 
$688,000 to $2,398,000 annually. This equates to $98 to $342 per trial 
protocol, or about $0.48 to $0.96 per clinical trial participant.
2. Costs to Government
    The costs to government for oversight of this rule would be 
extremely low as

[[Page 68755]]

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.

E. Alternatives to the Proposed Rule

    FDAAA specifically requires that the regulations concerning 
informed consent documents include the statement that clinical trial 
information has been or will be submitted for inclusion in the clinical 
trial registry databank. It does not give FDA discretion concerning the 
inclusion of this language in informed consent documents and processes 
for applicable clinical drug trials. For the reasons stated previously 
in this preamble, FDA has decided to require the language be included 
in the informed consent documents and processes for applicable clinical 
medical device trials as well. If the proposed 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 $36,000 to 
$124,000 per year.

F. 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. Because of the small costs that would be incurred by 
an individual sponsor of a product undergoing a clinical trial, the 
agency believes that the final rule is not likely to have a significant 
economic impact on a substantial number of small entities.
    The companies that would be affected are classified in seven 
separate North American Industrial Classification System (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. In each of these establishment size categories, large 
majorities of the establishments meet the criteria as small entities. 
Even taking into account that many of these establishments are parts of 
multi-establishment corporations, significant numbers of companies 
would still qualify as small entities. 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 
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 $98 to $342. Some 
firms will direct 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 $980 to $3,420 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, 0.14% of the annual value of shipments. For establishments 
with 50 or more employees, the compliance costs would represent 0.04% 
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 0.08% or less of the 
value of shipments even with 50 applicable clinical trials administered 
annually. FDA concludes that this proposed 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 proposed 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 proposed requirement to include a statement in informed 
consent documents regarding submission of clinical trial information to 
the clinical trial registry databank 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. Comments

    Interested persons may submit to the Division of Dockets Management 
(see ADDRESSES) written or electronic comments regarding this document. 
Submit a single copy of electronic comments or two paper copies of any 
mailed comments, except that individuals may submit one paper copy. 
Comments are to be identified with the docket number found in brackets 
in the heading of this document. Received comments may be seen in the 
Division of Dockets Management between 9 a.m. and 4 p.m., Monday 
through Friday.

X. Federalism

    FDA has analyzed this proposed rule in accordance with the 
principles set forth in Executive Order 13132. FDA has determined that 
the proposed 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 proposed 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.

XI. References

    The following references have been placed on display in the 
Division of Dockets Management (see ADDRESSES), and may be seen by 
interested persons between 9 a.m. and 4 p.m., Monday through Friday. 
(FDA has verified the Web site addresses, but we are not responsible 
for any subsequent changes to the Web sites after the document 
publishes in the Federal Register.)
    1. ``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.
    2. World Medical Association Declaration of Helsinki Ethical 
Principles for Medical Research Involving Human Subjects, available 
at http://www.wma.net/e/policy/b3.htm; accessed on July 30, 2009.
    3. National Research Act, Title II (Public Law 93-348, July 12, 
1974).
    4. 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,''

[[Page 68756]]

April 18, 1979, available at http://www.hhs.gov/ohrp/humansubjects/
guidance/belmont.htm, accessed July 30, 2009.
    5. De Angelis C., J.M. Drazen , F.A. Frizelle, et al., 
``Clinical Trial Registration: A Statement From the International 
Committee of Medical Journal Editors, '' Annals of Internal 
Medicine, 2004;141:477-8, electronically published on September 8, 
2004.
    6. 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/clin_
trialup.htm, accessed on July 30, 2009.
    7. Sim, I., A. Chan, A. G[uuml]lmezoglu, T. Evans, et al., 
``Clinical Trial Registration: Transparency Is the Watchword,'' The 
Lancet, Vol. 367, Issue 9523, pp. 1631-33, May 2006.

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, it is proposed that 21 CFR part 50 be 
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, 360c-360f, 360h-360j, 371, 379e, 381; 42 U.S.C. 216, 
241, 262, 263b-263n.
    2. Section 50.25 is amended by adding paragraph (a)(9) to read as 
follows:

Sec.  50.25   Elements of informed consent.

    (a) * * *
* * * * *
    (9) For applicable clinical trials, as defined in 42 U.S.C. 
282(j)(1)(A), the following statement, notifying the 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: Information, that does not 
include personally identifiable information, concerning this clinical 
trial has been or will be submitted, at the appropriate and required 
time, to the government-operated clinical trial registry data bank, 
which contains registration, results, and other information about 
registered clinical trials. This data bank can be accessed by you and 
the general public at www.ClinicalTrials.gov. Federal law requires 
clinical trial information for certain clinical trials to be submitted 
to the data bank.
* * * * *

    Dated: December 23, 2009.
David Horowitz,
Assistant Commissioner for Policy.
[FR Doc. E9-30751 Filed 12-28-09; 8:45 am]

BILLING CODE 4160-01-S