[Federal Register Volume 74, Number 248 (Tuesday, December 29, 2009)]
[Proposed Rules]
[Pages 68750-68756]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: E9-30751]
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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
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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
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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
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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.
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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.
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\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.
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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
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Document Preparation Cost $17,000
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Paper Cost $9,000 to $18,000
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Total Costs $688,000 to $2,398,000
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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