[Federal Register Volume 76, Number 2 (Tuesday, January 4, 2011)]
[Rules and Regulations]
[Pages 256-270]
[FR Doc No: 2010-33193]

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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: Final rule.

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SUMMARY: The Food and Drug Administration (FDA) is amending the current
informed consent regulations to require that informed consent documents
and processes for applicable drug (including biological products) and
device clinical trials include a specific statement that clinical trial
information will be entered into a databank. The databank referred to
in this final rule is the clinical trial registry databank maintained
by the National Institutes of Health/National Library of Medicine (NIH/
NLM) which was created by statute. The submission of clinical trial
information to this data bank also is required by statute. This
amendment to the informed consent regulations is required by the Food
and Drug Administration Amendments Act of 2007 (FDAAA) and is designed
to promote transparency of clinical research to participants and
patients.

DATES: Effective date: This rule is effective March 7, 2011.

    Compliance date: The compliance date of this final rule is March 7,
2012, for clinical trials that are initiated on or after the compliance
date. See section III of this document for an additional explanation of
the compliance date and required implementation of this final rule.

FOR FURTHER INFORMATION CONTACT: Jarilyn Dupont, Office of Policy,
Office of Commissioner, Food and Drug Administration, 10903 New
Hampshire Ave., Bldg. 32, rm. 4248, Silver Spring, MD 20993-0002, 301-
796-4830.

SUPPLEMENTARY INFORMATION:

Table of Contents

I. Introduction
II. Overview of the Final Rule
III. Compliance Date
IV. Comments on the Proposed Rule
V. Legal Authority and Enforcement
VI. Environmental Analysis
VII. Analysis of Impacts
VIII. Paperwork Reduction Act
IX. Federalism
X. References

I. Introduction

    In the Federal Register of December 29, 2009 (74 FR 68750), FDA
issued a notice of proposed rulemaking (NPRM) to amend 21 CFR 50.25,
its regulations governing informed consent documents and processes.
This final rule revises the current informed consent regulations to
require a new element for informed consent documents and processes that
will inform the potential clinical trial participant that information
about applicable clinical trials has been, or will be, entered into a
databank that is publicly accessible at http://www.ClinicalTrials.gov.
(See section IV.F of this document for a discussion of applicable
clinical trials.) The final rule adds this requirement in a new
paragraph, Sec.  50.25(c), and redesignates existing paragraphs.
    This final rule is issued under section 801 of FDAAA (Pub. L. 110-
85, September 27, 2007), which requires that information on an
applicable clinical trial be submitted to NIH for inclusion in the
clinical trial registry databank. This section also requires that the
Secretary of the Department of Health and Human Services (HHS) update
certain informed consent regulations to mandate that informed consent
documents and processes include a statement that the required clinical
trial information has been or will be submitted for inclusion in the
registry databank. The current informed consent regulations do not
include provisions similar to those required by FDAAA. (See parts 50
and 312 (21 CFR parts 50 and 312) and 21 CFR 812.2(b)(1)(iii) and
812.25(g)).
    Section 801 of FDAAA amends the Public Health Service Act (the PHS
Act) to require the Secretary, acting through the Director of NIH, to
expand the existing clinical trial registry databank established under
section 113 of the Food and Drug Administration Modernization Act
(FDAMA), enacted November 21, 1997 (Pub. L. 105-115 currently codified
at 42 U.S.C. 282(i)). The new provision requires the Director to ensure
that the databank is made publicly available through the Internet and
to expand the databank to require the submission of specified
information for applicable drug clinical trials and applicable device
clinical trials. (The term ``drug'' includes biological products
regulated under section 351 of the PHS Act (42 U.S.C. 262).) The
provision also requires the Secretary of HHS to ensure that the
databank includes links to results information for those clinical
trials that form the primary basis of an efficacy claim or are
conducted after the drug involved or device involved is cleared or
approved. In addition, section 801(b)(3)(A) of FDAAA states:

    NEW DRUGS AND DEVICES.--
    INVESTIGATIONAL NEW DRUGS.--Section 505(i) of the Federal Food,
Drug, and Cosmetic Act (21 U.S.C. 355(i)) is amended in paragraph
(4), by adding at the end the following: ``The Secretary shall
update such regulations to require inclusion in the informed consent
documents and process a statement that clinical trial information
for such clinical investigation has been or will be submitted for
inclusion in the registry data bank pursuant to subsection (j) of
section 402 of the Public Health Service Act.''

II. Overview of the Final Rule

    We considered all of the comments to the NPRM and the additional
data and accompanying materials submitted with the comments. We also
consulted with our internal experts on informed consent documents and
processes as well as our internal experts in communicating health-
related information to the public, clinical trial participants, and
patients in evaluating the required statement.
    In response to the comments, and based on our internal
reconsideration of the proposed requirements in the NPRM, we have
amended the specific language of the statement required to be included
in informed consent documents and processes. The mandatory statement is
now shorter, less complex, and more understandable for potential
clinical trial participants. Specific terms that are not commonly used
by lay persons, or were deemed to be misleading or confusing, have been
clarified and simplified. The mandatory statement has been revised to
facilitate understanding while maintaining the purpose of the statutory
provision.
    In response to comments expressing confusion and/or concern over
the proposed placement of the new requirement as a ``basic'' element of
informed consent under Sec.  50.25(a), a new paragraph (c) has been
added and the existing paragraphs have been redesignated. This separate
new paragraph emphasizes the unique basis of the new element--required
only for applicable clinical trials--as compared with existing basic
elements which align with various ethics codes and apply to all
clinical investigations regulated by FDA and clinical investigations
that support applications for research or marketing permits for
products regulated by FDA.
    New paragraph Sec.  50.25(c) interacts with all other requirements
of part 50 as do the other requirements and provisions of Sec.  50.25.
Similar to other informed consent elements, it is subject to the
regulations governing documentation of informed consent (Sec.  50.27)
and Institutional Review Board (IRB) waivers (Sec.  56.109(c)(1) (21
CFR 56.109)). When a short form written consent document is chosen
(Sec.  50.27(b)(2)), a short form and written summary must be provided
to the clinical trial participant. All of these are considered
``informed consent documents'' and must contain the new statement (Ref.
1). For example, if an IRB waives the requirement for a signed written
consent form under Sec.  56.109(c)(1), and requires ``the investigator
to provide subjects with a written statement regarding the research,''
this written statement is considered a part of the documentation of
ensuring the informed consent of the participant and thus, it must
include the new statement (Sec.  56.109(d)).

III. Compliance Date

    In response to comments, and after consideration of the intent and
purpose of the new statutory requirement, we have determined that the
compliance date of new Sec.  50.25(c) will be 1 year after the
effective date of this final rule for all informed consent documents
and processes related to a clinical investigation that is initiated on
or after the compliance date of this rule. In section IV.B of this
document we provide, in our responses to the comments made concerning
the effective date, additional explanation of the application of the
compliance date to particular clinical investigations.

IV. Comments on the Proposed Rule

    We received 68 comments on the NPRM. Comments were received from
IRBs, academic research centers, clinical investigators, physicians,
health care professional societies, trade organizations representing
clinical research organizations, drug and device sponsors, blood banks,
clinical research organizations, research hospitals, medical device
manufacturers, nonprofit organizations for ethical research, patient
advocacy organizations, health care attorneys, pharmacy and law
students, and others.
    To make it easier to identify comments and our responses, the word
``Comment,'' in parentheses, will appear before each comment, and the
word ``Response,'' in parentheses, will appear before each response. We
also have numbered the comments to make it easier to distinguish
between comments; the numbers are for organizational purposes only and
do not reflect the order in which we received the comments or any value
associated with the comment. We have combined similar comments under
one numbered comment.

A. General Comments

    (Comment 1) We received comments that objected to adding any
statement to informed consent documents about submitting information to
the databank to be posted on the ClinicalTrials.gov Web site. The
principal reasons given for these objections were that the additional
statement: (1) Lengthens already lengthy informed consent documents,
exacerbating potential participants' confusion and anxiety upon reading
consent forms; (2) unnecessarily burdens or overwhelms participants
because it does not provide information necessary to make an informed
decision about whether to participate in a clinical trial; (3) fails to
advance human subject protection in any way; and (4) will cause
patients to ignore more important aspects of the consent form or other
research-related forms. Other comments approved the inclusion of a
statement that alerted potential participants to the clinical trials
registry databank to inform them how the data are generally used and to
increase awareness of the clinical trial registry.
    (Response) We appreciate the concerns expressed by the comments
regarding the increasing length of informed consent documents and the
additional information required to be provided to potential clinical
trial participants. Section 801(b)(3)(A) of FDAAA, however, requires
the Secretary to update FDA's regulations to ``require inclusion in the
informed consent documents and process a statement that clinical trial
information for such clinical investigations has been or will be
submitted for inclusion in the registry data bank.'' Thus, while we
appreciate the concerns, Congress has directed that this be implemented
by FDA.
    While FDA has been directed by statute to include this particular
statement in informed consent documents and processes related to
applicable clinical trials, there is increasing support for informing
clinical trial participants about the clinical trials in which they
participate and the outcome of those trials whether it is included in
the informed consent document or through other efforts. The rationale
for informed consent is to ensure that participants enter into the
research voluntarily and with adequate information (Refs. 2, 3, and 4).
Communications, other than the specific informed consent, may include
informing the participant on how to obtain or access information
relating to the outcomes of the research (Refs. 5 and 6). Implementing
the statutory provision by including the statement in the informed
consent documents and processes, as required, also advances these other
goals.
    We disagree with comments that the new statement does not provide
any information necessary to make an informed decision about whether to
participate in a clinical trial. As noted in the NPRM, alerting
potential clinical trial participants to the existence of a publicly
accessible databank, whether in the informed consent or during the
process, can reassure them that a transparent system exists to help
ensure greater accountability and responsibility of investigators (74
FR 68750 at 68752). Clinical research (as opposed to clinical practice)
is not designed to deliver therapeutic benefits to individual patients,
so it is possible that potential clinical trial participants would want
to know the overall benefits that may accrue to society at large (Refs.
7 and 8). One of the basic elements of informed consent which
investigators are required to inform participants of is ``a description
of any benefits to the subject or to others which may reasonably be
expected from the research.'' (Sec.  50.25(a)(3)). The reference to the
databank Web site allows participants to ascertain the nature, scope,
and progress of a registered applicable clinical trial, thus reassuring
the participant that participation in a trial contributes to the
advancement of medical knowledge, an important benefit in the full
disclosure of risks and benefits. Although the current statutory
requirement at 42 U.S.C. 282(j), section 402(j) of the PHS Act, only
requires registration at http://www.ClinicalTrials.gov for certain
applicable clinical trials, and not all clinical trials, this
limitation does not lessen the value of the information for
participants.
    We do not agree that the new required statement significantly
increases the length of consent forms to such a degree as to increase
participants' confusion and anxiety. The revised language consists of
four short sentences, which will minimally impact a potential subject's
reaction to a consent form. These additional sentences will not dwarf
or diminish other important information in informed consent forms and
documents. FDA responded to similar comments when it issued the final
rule that established Sec.  50.25 concerning the basic and additional
elements of informed consent. Many of the comments suggested that there
were too many elements, they were duplicative, and they would simply
confuse research participants. Other comments expressed the concern
that the elements would require a long, detailed consent form that
would be confusing and would detract from the intended purposes of the
regulation that relevant information about a study be conveyed to the
human subject (46 FR 8942 at 8949, January 27, 1981). In responding to
all of the comments, FDA defended the required elements, and, although
minor changes were made to simplify the final rule, FDA maintained that
the informed consent process involved ``giving the subject all the
information concerning the study that the subject would reasonably want
to know.'' (46 FR 8942 at 8949, January 27, 1981) This same reasoning
applies to the requirements of the new element in Sec.  50.25(c).
Congress has decided that clinical trial participants would reasonably
want to know that applicable clinical trials will be registered and
that certain results and other information will be available in a
publicly accessible databank.
    (Comment 2) One comment objected to the new statement as an
``inefficient method of implementing the statutory mandate of FDAAA.''
    (Response) We disagree. The statutory mandate of FDAAA is specific.
It requires FDA to update its regulations to ``require inclusion in the
informed consent documents and process a statement that clinical trial
information for such clinical investigation has been or will be
submitted for inclusion in the registry data bank.'' The NPRM proposed
to implement the statutory

mandate by requiring the new statement in informed consent documents
and processes and the final rule adopts that proposal. We believe the
short required statement accomplishes the statutory mandate in the most
efficient manner possible.
    (Comment 3) Two comments suggested that the new statement should
not be included because research involving de-identified data is exempt
from human-subjects regulation since only de-identified data are
submitted to http://www.ClinicalTrials.gov.
    (Response) We believe this comment reflects a misunderstanding
about the statutory requirements to register applicable clinical trials
with NIH at http://www.ClinicalTrials.gov. The new informed consent
element applies to ``applicable clinical trials,'' which necessarily
involve research on human subjects. The fact that only de-identified
data derived from the applicable clinical trial will be submitted to
the databank is irrelevant to the requirement to include the new
statement in informed consent documents. Human subjects are still
involved in the underlying ``applicable clinical trial'' and informed
consent regulations apply to the clinical investigation. We emphasize
that the new element is required by statute, and the subsequent
reporting of only de-identified data to NIH in no way creates an
exemption to the statutory or regulatory requirement.

B. Effective Date, Compliance Date, and Retroactivity

    (Comment 4) Many comments requested clarification on the effective
date of the regulation and whether it would be applied retroactively.
Specifically, comments requested clarification on the following
clinical trial scenarios: (1) Clinical studies that received favorable
ethics committee opinion but patient recruitment has not begun before
the effective date, (2) clinical studies that received favorable ethics
committee opinion and patient recruitment has begun before final rule,
(3) clinical studies where IRB rulings are pending or not yet submitted
to IRB, (4) protocol amendment (requiring re-consent) dated within 30
days of the final rule. Other comments stated that the rule should not
require re-consent of enrolled participants. One comment requested a 6-
month grace period for compliance after the rule takes effect.
    (Response) As discussed in section III of this document, we have
decided to make the compliance date 1 year after the effective date of
this final rule. This means that FDA intends to enforce this final
rule, new Sec.  50.25(c), only for informed consent documents and
processes for clinical investigations that are initiated on or after
the compliance date.
    To address the specific examples in the comments, we generally
would consider that for purposes of this final rule only, a clinical
investigation has been initiated if the sponsor/investigator has had
any informed consent documents for that clinical investigation cleared
or approved by an IRB, a regulatory body, or other human subjects
review entity. This interpretation of the initiation of the clinical
trial/investigation is limited to this final rule. If the clinical
investigation is a multi-site trial and informed consent documents have
been cleared or approved for one or more sites before the compliance
date of this final rule, but not for all sites, the clinical
investigation will be considered to have initiated before the
compliance date. The informed consent documents for the remaining
clinical investigation sites would be considered part of the clinical
investigation that initiated prior to the compliance date.
    Re-consent, based solely on the new requirement, of clinical trial
participants in clinical investigations that were initiated before the
compliance date will not be required. If a clinical investigation is
ongoing as of the final rule compliance date, the new requirement will
not be applicable. We recognize that this will mean that if the
informed consent documents and processes of the ongoing clinical
investigation are required to be amended for any other purpose and re-
consent of the already enrolled or actively participating clinical
trial participants is required for that other purpose, compliance with
new Sec.  50.25(c) will not be required.
    When the original informed consent regulations were issued in 1981,
we chose to impose those requirements strictly prospectively--only
clinical investigations that began on or after the effective date of
the regulation were required to comply with new parts 50 and 56 (21 CFR
part 56. (See 46 FR 8942 at 8945 to 8946, January 27, 1981.) In
determining that those new requirements should apply only
prospectively, we ``balanced the cost of compliance against possible
added protections to be gained by research participants, and determined
that the potential cost of imposing the requirements retroactively
outweighs the potential gain. The informed consent regulations that
will continue to be in effect until the effective date of part 50 have
assured that at least minimum standards of informed consent have been
met in studies initiated before the effective date * * *'' (46 FR 8942
at 8946). We believe the same principles apply in this final rule and
the regulation will not be applied retroactively. There is nothing in
this rule, however, that would prohibit inclusion of the statement in
circumstances in which there may be re-consent for other reasons.
    We are aware that many educational and governmental institutions,
IRBs, and industry sponsors have created model templates for informed
consent documents. These model templates generally are developed to
address various situations and include mandatory provisions to ensure
compliance with all regulatory requirements (Refs. 9 and 10). We
anticipate that the compliance date for the final rule will permit
sufficient time for this new required statement in Sec.  50.25(c) to be
added to existing model templates. While there is a benefit to
including the new statement in existing informed consent documents and
processes, we do not believe the benefit outweighs the difficulty,
cost, and complexity of requiring revision to all existing informed
consent documents.
    (Comment 5) One comment requested clarification on whether the new
element would require sponsors to re-consent participants enrolled in
clinical trials. This comment noted FDA's 1998 Information Sheet
Guidances for IRBs, Clinical Investigators, and Sponsors: Frequently
Asked Questions (No. 45), advising that enrolled and actively
participating subjects should be informed of a change that might relate
to a subject's willingness to participate in the study.
    (Response) As discussed in the Response to Comment 4, re-consent
will not be required solely based on the new requirements of Sec.
50.25(c). While the FDA's 1998 Information Sheets for IRBs, Clinical
Investigators, and Sponsors: Frequently Asked Questions (No. 45)
recommends that already enrolled and actively participating subjects be
informed of a change that might relate to a subject's willingness to
participate in the study, we are not requiring such a notification
based on this new requirement. If this recommendation were to be
followed by clinical investigators, we would expect that such notice,
if warranted, already had occurred, as applicable clinical trials have
been statutorily required to be registered with NIH at http://www.ClinicalTrials.gov since 2007 and results posting for certain
trials has been required since 2008.
    (Comment 6) One comment expressed concern that the specific
language of the new element would have to be revised

after NIH issued regulations to implement changes to
ClinicalTrials.gov. This comment recommended that FDA issue a guidance
instead of a regulation because a guidance would be easier to change,
if necessary, after the NIH regulations issued.
    (Response) We decline to issue a guidance in lieu of a regulation.
Section 801(b)(3)(A) of FDAAA makes clear that the ``Secretary shall
update [FDA's] regulations,'' not merely issue a guidance. NIH's
subsequent regulations will not impact the specific language of the new
element as the language of the required statement is not affected by
the statutory or regulatory interpretation of an ``applicable clinical
trial.'' There is a statutory definition of ``applicable clinical
trial'' and no matter what additional regulatory explanation of
``applicable clinical trial'' is provided in a future rulemaking, it
will not affect or change the required statement. Changes to the
definition only will impact the determination made by sponsors and
investigators about their clinical trial and whether it is an
``applicable clinical trial'' subject to the registration requirements
of 42 U.S.C. 282(j)(1)(A), section 402(j)(1)(A) of the PHS Act. That
separate determination is made prior to the inclusion of the mandatory
statement in informed consent documents and processes.

C. New Section 50.25(c)

    In order to address some of the concerns raised by comments, and on
our own initiative, we have created a new paragraph (c) in Sec.  50.25
to include the requirements of this final rule. While this is a
``required'' element of informed consent documents and processes, it is
only required if the clinical trial is an ``applicable clinical trial''
as defined in FDAAA, 42 U.S.C. 282(j)(1)(A), section 402(j)(1)(A) of
the PHS Act, and any relevant regulation. Although there were comments
suggesting that Sec.  50.25(b) was the more appropriate location for
the required provision, we are concerned that such placement would be
confusing given the specific requirement of section 801(b)(3)(A) of
FDAAA and the mandatory nature of its inclusion when an applicable
clinical trial is involved. To avoid any confusion, we have created a
new paragraph (c) in Sec.  50.25 and redesignated existing paragraphs.
    (Comment 7) Many comments suggested that the rule should amend
Sec.  50.25(b), ``Additional Elements of Informed Consent,'' rather
than Sec.  50.25(a), ``Basic Elements of Informed Consent.'' Some
comments reasoned that the new statement could not be considered a
``basic element'' because it would not apply to all clinical trials,
only applicable clinical trials. For example, a phase 1 or device
feasibility study would not be considered an applicable clinical trial
under the statutory definition in FDAAA. These comments further
reasoned that the new statement qualified as an ``additional element''
because it would be required only ``when appropriate'' (i.e., in
applicable clinical trials).
    (Response) We agree with the comments that the element should not
be included in Sec.  50.25(a) since the statutory provision limits it
to inclusion in informed consent documents and processes only for
``applicable clinical trials.'' We disagree, however, that the new
statement should be included as an ``additional element'' under Sec.
50.25(b) as this may raise further confusion as to the mandatory nature
of the requirement.
    As noted in the preamble to the final rule establishing the
original informed consent elements, ``[t]he elements listed as
`additional' are not material to every clinical investigation.'' (46 FR
8942 at 8949, comments 41 and 42) This new element, however, is
statutorily required, and therefore, is material to all applicable
clinical trials. Investigators do not have the discretion to determine
whether the element is ``appropriate'' for a particular applicable
clinical trial. Therefore, we decline to include the new element in
Sec.  50.25(b) and, instead, have created a new paragraph (c).
    Nothing in this preamble affects our explanation in the 1981 final
rule that ``when any one of those additional elements would be
appropriate, Sec.  50.25(b) requires that the additional information be
provided to the subject.'' (emphasis added)
    (Comment 8) One comment recommended that FDA accomplish its
statutory mandate to inform potential participants about the databank
by amending Sec.  50.25(a) to require a statement that describes
whether results or other aspects of the trial may be published. This
comment suggested that posting of results on http://www.ClinicalTrials.gov be treated like any other publication of
clinical trial results in journals or elsewhere.
    (Response) We do not agree that the statement proposed by the
comments would accomplish our statutory mandate, which specifies that
informed consent regulations be updated to require that a statement
that clinical trial information has been or will be submitted for
inclusion in the registry data bank. A statement that simply alludes to
the general possibility of publication does not accomplish the
statutory mandate or the objectives set forth in the NPRM and this
final rule: informing clinical trial participants and potential
patients about the data bank; directing them to the http://www.ClinicalTrials.gov Web site in order to enhance the system of
checks and balances for the research community and trial sponsors;
assisting individuals in deciding whether to participate in a trial;
and, providing patients with additional information beyond traditional
publications.
    (Comment 9) One comment recommended that the new element amend
Sec.  50.25(a)(5), which requires a statement describing the extent to
which confidentiality of records identifying the subject will be
maintained. This comment expressed concern that a wholly new provision
devoted to a new basic element in Sec.  50.25(a) would place undue
emphasis on ``low-risk'' reporting requirements to the detriment of the
other ``high-risk'' provisions of Sec.  50.25(a) devoted to protecting
clinical trial participants.
    (Response) We agree that the new element has a unique basis and
thus differs in a fundamental way from the basic consent elements in
Sec.  50.25(a) but disagree that the new element should be located in
Sec.  50.25(a)(5). Section 50.25(a)(5) requires that in seeking
informed consent, investigators provide to potential participants ``A
statement describing the extent, if any, to which confidentiality of
records identifying the subject will be maintained and that notes the
possibility that the Food and Drug Administration may inspect the
records.'' This statement concerning confidentiality is applicable to
all aspects of the clinical trial data. The same confidentiality
standards that apply to a submission of an article to a medical journal
also apply to a http://www.ClinicalTrials.gov submission--only
aggregate data are provided. Thus, creating a paragraph of Sec.
50.25(a) which would identify only the extent to which confidentiality
would be maintained with respect to submissions of data to http://www.ClinicalTrials.gov could be confusing and misleading.
    To avoid confusion and to emphasize the unique basis for the new
element, FDA has created a new paragraph (c) in Sec.  50.25. This
paragraph specifies that the new element is required for all applicable
clinical trials but not for non-applicable clinical trials. Thus, Sec.
50.25(c) is distinct from Sec.  50.25(a), which requires basic elements
for all clinical trials of FDA-regulated products whether or not they
are ``applicable clinical trials,'' and from Sec.  50.25(b), which
requires additional elements in informed consent documents and

processes ``when appropriate.'' Furthermore, the new element merits a
wholly new provision owing to its unique basis. The new element has an
external informational component directed to the participant, it
enhances the protection of the human subject participating in the
``applicable clinical trial,'' and is statutorily mandated.

D. Specific Language for Informed Consent Documents and Processes

    (Comment 10) Many comments objected to specific required language,
as opposed to a general requirement for the content of the message with
flexibility to craft the exact language. These comments stated that
specific language denies institutions the flexibility to tailor the
language to the local community, subject population, type of study, or,
in non-U.S. trials, other countries' unique data privacy concerns. One
comment stated that requiring specific language is inconsistent with
other elements of informed consent, which specifies content but not
language. Another comment objected to the specific language because it
would require additional clarifying language about other registries.
    (Response) In proposing specific language, we considered issues
similar to those raised by the comments but concluded that the risk of
inaccurate and confusing statements was too great to permit
investigators and sponsors to craft their own statements regarding the
inclusion of clinical trial information in http://www.ClinicalTrials.gov. The comments received in response to the NPRM
support our previous conclusion that specific language needs to be
provided. While we agree that the proposed language should be simpler
and more understandable, and has been made so in this final rule, the
diverse comments showed much confusion and misunderstanding about the
FDAAA statutory requirements for registration of clinical trials with
NIH and the type of information required to be provided to potential
clinical trial participants. Suggested revisions to simplify the
language resulted in very different, and often inaccurate, messages. If
each sponsor/entity were to craft their own individual statement, we
are concerned that participants in different clinical trials would
receive vastly different messages. Many statements could be inaccurate,
confusing, or different from that intended by the statutory
requirement. We want to ensure that potential clinical trial
participants receive a consistent and accurate message and are directed
to the specific Web site that contains the clinical trial databank.
Investigators, sponsors, and IRBs are not restricted from providing
additional explanation. It is essential, however, that one common
message appear consistently in all informed consent documents and
processes. The provision of the specific language also will make it
easier for IRBs and other review entities to identify the inclusion of
this statutorily required statement in their review of informed consent
documents and processes and to incorporate it into any model templates.

E. Communication and Readability of Language

    (Comment 11) Many comments criticized the new statement as too
complex or technical for many potential clinical trial participants to
understand. Some comments noted that the proposed language registered
approximately 18 on the Flesch-Kincaid reading grade level (Ref. 11)
Many recommended that the required new statement register at an eighth-
grade reading level (8 on the Flesch-Kincaid scale). Other comments
objected to undefined terms not commonly used (e.g., ``data bank,''
``registry''), phrases that were meaningful to sponsors but not trial
participants (submission ``at the appropriate and required time''), and
words perceived as too unspecific to be informative (e.g.,
``information,'' ``not personally identifiable,'' ``certain clinical
trials'').
    (Response) We agree that the language proposed in the NPRM was too
complex and may be too difficult for some potential participants to
understand. We consulted with our internal experts on risk
communication to identify specific problems with the proposed statement
and to devise a statement that was more understandable across a greater
range of reading skills (Ref. 12). We have revised the statement to
include simpler language, and removed many of the terms perceived as
objectionable. For example, the statement no longer contains the words
``data bank'' and ``registry;'' these are replaced by the more commonly
used term ``Web site.'' Sponsor-oriented phrases and some general words
also have been removed. The revised statement registers 7.2 on the
Flesch-Kincaid reading scale.
    We have not further defined the term ``information'' in the
statement. The definition depends on when data are submitted to the
databank and what would be included depends on the data fields being
completed. The word ``information'' is basic enough to encompass
anything that may be required to be submitted to the databank at any
point in time. The statement provides the specific Web address to the
databank so that clinical trial participants may visit the Web site to
see what ``information'' is included in a particular clinical trial
record. The new statement will read as follows:
    ``A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required by U.S. Law. This Web site will
not include information that can identify you. At most, the Web site
will include a summary of the results. You can search this Web site at
any time.''
    (Comment 12) Several comments expressed concern that a statement
using complex language would be difficult to translate into other
languages for international consent forms or for U.S. clinical trial
participants whose first language is not English.
    (Response) We have revised the required statement to use simpler
language and do not believe that the revised statement will pose
translation difficulties. See the response to Comment 18 for additional
discussion on translation of the required statement.
    (Comment 13) One comment objected to directing participants to a
Web site that promotes therapeutic misconception. Therapeutic
misconception is the common misunderstanding among clinical trial
participants that the primary purpose of a clinical trial is to provide
therapeutic treatment, rather than experimental research.
    (Response) We disagree that http://www.ClinicalTrials.gov promotes
therapeutic treatment as the primary focus of the clinical trials
posted to the databank. The ClinicalTrials.gov Web site makes clear
that clinical trials are research studies. Extensive questions and
answers are provided on the Web site detailing what a clinical trial is
and what participation encompasses. Regardless, the informed consent
documents and process, properly administered, should dispel any
misconception about the purpose of the clinical trial.
    (Comment 14) Several comments stated that the reference to the
ClinicalTrials.gov Web site should be omitted because: (1) It was not
necessary for a subject to make an informed decision about whether to
participate in the trial and (2) the Web site had no more information
than the informed consent document about the trial. Other comments
favored the reference to ClinicalTrials.gov, stating that this
information is consistent with the goals of enhancing transparency of
clinical trials, boosting public confidence in the clinical research
process, and better informing potential participants.

    (Response) We decline to omit the reference to http://www.ClinicalTrials.gov and agree the specific Web site is helpful to
direct potential participants to that databank and to help them become
better educated about clinical trials. The specific Web site address
also eliminates the need for the participant to search the Internet for
access to the databank Web site. The Web site address allows
participants to more quickly take the opportunity to view the contents
of the databank and review the types of information submitted to and
posted on the Web site. The Web site is not intended to substitute for
the information and description of the clinical trial in the consent
form; however, the Web site also can provide reference to other related
trials conducted before or after the clinical trial in which the
participant took part. Furthermore, the Web site does have more
information than the informed consent documents since the databank may
eventually contain the final results of the specific clinical trial for
which the participant consented--information the informed consent
documents will not contain.
    (Comment 15) Two comments recommended that the statement list Web
sites other than http://www.ClinicalTrials.gov because the link could
change in the future, or more common Web sites would be easier for
participants to find. The comment alternatively recommended that the
rule reference FDA's Web site, which should provide a link to the
clinical trials databank.
    (Response) We decline to replace http://www.ClinicalTrials.gov with
another or FDA's own Web site. In response to the comments that the Web
site might change, it is unlikely that this Web address will change,
since it has been in use for over 10 years. If in the future it is
altered, we can revise the final rule with an amendment identifying the
new Web address. We think it important that clinical trial participants
know specifically where to locate the clinical trial information
without having to perform an Internet search. We do not see any
advantage in referring potential participants to more ``common'' Web
sites that link to http://www.ClinicalTrials.gov instead of a direct
link. In fact, http://www.ClinicalTrials.gov has become quite well
known and could be considered a ``common'' Web site itself. The Web
site currently has over 50 million page views per month and 65,000
visitors daily.
    (Comment 16) One comment suggested that the new statement was
misleading in several ways: (1) It implies that the trial is registered
only at ClinicalTrials.gov and not elsewhere, (2) it implies that
results for all trials will be submitted to the databank; and (3) the
statement that U.S. law requires submission of information to the
databank does not take into account that some studies are voluntarily
registered.
    (Response) The new words have been carefully chosen to accurately
represent how clinical trial data are included in the databank. First,
the element states that ``A description of this clinical trial will be
available on http://www.ClinicalTrials.gov, as required by U.S. law.''
The new element is required only in informed consent documents and
processes related to applicable clinical trials, so this statement is
true. The new statement should not be included in informed consent
documents or processes for clinical trials that are not applicable
clinical trials because, as the regulation makes clear, only applicable
clinical trials are subject to the requirement. Second, we have chosen
to say ``will be available'' to generalize the statement for early-
phase participants (when the trial has not been registered yet) and
participants joining after the trial is registered at http://www.ClinicalTrials.gov. Under the statute, responsible parties for
applicable clinical trials must submit relevant clinical trial
information to NIH/NLM for inclusion in the registry databank no later
than 21 days after the first participant is enrolled in the applicable
clinical trial. We believe ``will be available'' reasonably applies to
all participants and is simpler than saying ``has been or will be
submitted.'' Third, the revised language states that ``At most, the Web
site will include a summary of the results.'' Thus, potential
participants will not expect that clinical trial results will always
appear on the Web site but, if results do appear, these will be in
summary form. Fourth, the statement makes no reference to non-
applicable or voluntarily registered trials, and we disagree that the
language misleads anyone about these other trials in any way. By
stating that ``this clinical trial will be available * * * as required
by U.S. law,'' the new element in no way implies that other types of
trials cannot be registered. The new language also does not imply that
all clinical trials must be registered; it only refers to the clinical
trial in which the participant is taking part.
    (Comment 17) Several comments suggested that the regulation also
should require an alternate statement for non-applicable, voluntarily
registered clinical trials that they will not be included in the
databank. These comments suggested that such a statement would be
necessary for potential participants to make an informed decision about
whether to participate in the trial.
    (Response) We decline to include an alternate statement for non-
applicable, voluntarily registered clinical trials, some of which may
be registered in the databank. Potential participants will have no
expectation that a non-applicable clinical trial will be registered,
since an informed consent document for a non-applicable clinical trial
is not required to include the new statement. If an investigator,
sponsor, or IRB feels that a potential participant would want to know
about the existence of a registry databank for trials other than the
one the participant is contemplating or for non-applicable clinical
trials, nothing in this regulation would prevent an investigator,
sponsor, or IRB from informing potential participants of such
information in an appropriate manner.
    (Comment 18) One comment requested that FDA provide translations
into other languages frequently encountered in the United States. This
comment also recommended that if FDA would not provide such
translations, then FDA should state in the regulation that the text may
be freely translated into other languages.
    (Response) Under Sec.  50.20, the informed consent document should
be in language understandable to the subject (or legally authorized
representative). When the potential participants are non-English
speaking or the clinical investigator or the IRB anticipates that the
consent interviews will be conducted in a language other than English,
the IRB should require a translated consent document to be prepared and
assure that the translation is accurate. As required by Sec.  50.27, a
copy of the consent document must be given to each subject. In the case
of non-English speaking participants, this would be the translated
document. While a translator may be helpful in facilitating
conversation with a non-English speaking subject, routine ad hoc
translation of the consent document should not be substituted for a
written translation. This is explained in more detail in our guidance
documents/information sheets concerning informed consent (Ref. 13). The
statement can be translated into languages other than English for
potential clinical trial participants. FDA will not provide
translations of the statement.
    (Comment 19) One comment recommended that the words ``federal law''
be replaced with a reference to U.S. law, since ``federal law'' might
cause

confusion in multinational clinical trials.
    (Response) We agree and the revised statement indicates that the
clinical trial description on http://www.ClinicalTrials.gov is required
by ``U.S. law.''

F. Applicable Clinical Trials

    (Comment 20) Several comments requested clarification on whether
certain types of clinical trials, such as investigational device trials
considered to be non-interventional, would be considered ``applicable
clinical trials.'' Several bloodbank organizations specifically
inquired about clinical studies done by blood centers under
investigational new drug applications (INDs) to validate new blood
screening tests.
    (Response) We decline to provide a more detailed definition of
``applicable clinical trial,'' as it is not necessary for the purposes
of this final rule. Section 801(a)(1) of FDAAA contains a statutory
definition of this term (section 402(j)(1)(A) of the PHS Act). NIH/NLM
also has elaborated on the meaning of ``applicable clinical trial'' at
http://prsinfo.clinicaltrials.gov/fdaaa.html and at http://prsinfo.clinicaltrials.gov/ElaborationsOnDefinitions.pdf (Ref. 14),
which represents NIH's current thinking on the definitions. It is
possible these definitions will be expanded upon in rulemaking by NIH.
It is the responsibility of the sponsors and investigators to determine
if their clinical trial meets the definition of an applicable clinical
trial and to ensure compliance with the most current applicable
statutory and regulatory requirements.
    (Comment 21) Several comments recommended that the new statement
not be required in the informed consent forms for clinical trials
conducted outside of the United States, even if done in support of U.S.
regulatory approval or conducted under an FDA IND. These comments
stated that the new element should be required only when the clinical
trials are conducted in the United States. These comments reasoned
that: (1) Institutions and patients in other countries may object to or
be offended by U.S.-centric language, (2) 21 other countries and
regions already have in place or are in the process of implementing
their own clinical trial registries, (3) foreign governments may prefer
references to their own countries' registries, and (4) foreign IRBs and
ethics committees may have their own informed consent requirements that
conflict with the new statement.
    (Response) We disagree. The new informed consent statement applies
to all ``applicable clinical trials'' as defined in section 801(a)(1)
of FDAAA. FDAAA does not limit ``applicable clinical trials'' to only
those conducted in the United States; it also includes clinical trials
that are not conducted in the United States that are subject to FDA's
jurisdiction. Thus, informed consent documents and processes of all
``applicable clinical trials,'' including those conducted in foreign
countries, must include this new statement regarding the inclusion of
information in the clinical trial databank. Congress did not provide an
exemption from this requirement for applicable clinical trials
conducted in foreign countries.
    (Comment 22) One comment requested clarification on whether the new
element is required only when a trial is conducted under a U.S. IND or
is otherwise subject to FDA regulation at the time the research
participant is enrolled. This comment focused in particular on data
from non-U.S. trials that were not conducted under a U.S. IND or
subject to FDA regulation at the time of inception but were later
submitted in support of a new drug application (NDA).
    (Response) Yes, the new requirement, Sec.  50.25(c), applies only
when a trial is conducted under a U.S. IND or is otherwise subject to
FDA regulation.
    (Comment 23) Several comments expressed concern that the new
element would conflict with or cause confusion about other countries'
registries or informed consent practices. One comment suggested that
the new statement might conflict with the informed consent practices of
IRBs and ethics committees residing outside the United States, and that
foreign governments may not want references to a U.S. database in the
informed consent forms for multinational trials being conducted in
their countries. This comment recommended that the new element apply to
informed consent documents used only at U.S. clinical trial sites and
not for clinical trials at foreign sites even if the clinical trial was
conducted under an FDA IND.
    (Response) See the response to Comment 21.
    (Comment 24) One comment suggested that U.S. participants in
international clinical trials be informed that information about the
trial also may be available in the registries of other countries. This
comment further suggested including the statement ``Information about
this trial may also be available on the Internet in the clinical trial
registries of other countries.''
    (Response) We decline to require a statement alerting potential
participants of information about clinical trial registries of other
countries. If other countries require the inclusion of such a
statement, we would not object. FDA is only requiring a reference to
the NIH/NLM databank as it has been directed to do by Congress. Nothing
in this final rule prevents investigators, sponsors, or IRBs from
advising potential participants that information about the clinical
trial may be found in other countries' registries.
    (Comment 25) One comment praised the Agency's decision to apply the
ClinicalTrials.gov reporting requirements to drug and device trials.
Another comment acknowledged the Agency's authority to issue a
regulation applying the statutory requirement to device trials but
requested that FDA use its discretion to not exercise that authority
until Congress explicitly indicated that drug and device trials should
be treated the same.
    (Response) FDA has decided to require that all applicable clinical
trials (including applicable device clinical trials) include the new
required statement for the reasons stated in the NPRM: To maintain
consistency of informed consent requirements for all applicable
clinical trials, to simplify informed consent requirements for clinical
trials involving both drugs and devices, to offer all potential
participants the same information that could affect their decisions to
enter a clinical trial, and to efficiently implement the statutory
mandate. Our legal authority to issue this regulation and require it to
be applied to applicable device clinical trials is further described in
section V of this document.

G. Other Miscellaneous Comments

    (Comment 26) One comment stated that ``the sharing of de-identified
data falls under the category of exempt research or is not considered
human subject research at all, and it is common for IRBs, following the
regulations, to allow the research to go forward with a waiver of the
consent requirement.'' The comment apparently suggests that the new
element can be or should be waived.
    (Response) Similar to other provisions required by Sec.  50.25, the
new element is waiveable only under the exceptions specified in
Sec. Sec.  50.23 and 50.24 for waiver of informed consent. Some
clinical trials (those that are conducted or supported by HHS) are also
governed by 45 CFR part 46, which permits an IRB to waive the
requirement for one or more elements of informed consent. It

should be noted for purposes of clarification that under 45 CFR
46.102(f) research using de-identified data would not be considered
research on a human subject and, thus, the waiver of the informed
consent requirement would not be applicable.
    As a general matter, clinical research that both involves FDA-
regulated products and is conducted or supported by HHS must meet the
requirements of both sets of regulations. If such clinical trials are
also applicable clinical trials under FDAAA, the new element must be
included in the informed consent documents and process for these trials
unless waived under part 50, regardless of whether an IRB determines
that one or more of the elements is waiveable under 45 CFR part 46.
    In some instances, review of records containing de-identified data
may be exempt from IRB review because such record review does not
qualify as human subject research. This is not always the case under
FDA regulations and there are some circumstances in which the use of
de-identified data requires IRB review. See Sec. Sec.  56.101 and
56.103 and ``Guidance for Sponsors, Institutional Review Boards,
Clinical Investigators and FDA Staff: Guidance on Informed Consent for
In Vitro Diagnostic Device Studies Using Leftover Human Specimens That
Are Not Individually Identifiable.'' (Ref. 15). The definition of an
``applicable clinical trial,'' however, necessarily involves human
subjects; thus an applicable clinical trial must comply with human
subject regulations. The use of the new statement would not be
implicated in research that does not qualify as human subject research
under the definition of applicable clinical trial (Ref. 14).
    It is also true that de-identified data (stripped of the 18
specified identifiers) fall outside of the Health Insurance Portability
and Accountability Act of 1996 (Pub. L. 104-191) (HIPAA) privacy
regulations and thus are not considered individually identifiable
health information. As a consequence, clinical investigators need not
obtain a subject's authorization to release de-identified data in a
HIPAA authorization form, which is often included in a research consent
form and accompanies an informed consent form. Regardless of whether an
IRB determines that the information concerning submission of aggregate
results to ClinicalTrials.gov does not need to be included in a HIPAA
authorization form, the new element is still required by statute to be
included in the informed consent documents and processes for applicable
clinical trials.
    (Comment 27) One comment suggested that the new element be included
in an information sheet separate from the informed consent document,
where the sheet explained the ClinicalTrials.gov Web site in simple
terms.
    (Response) FDAAA requires that the new element be included ``in the
informed consent documents and processes,'' not in an information sheet
that is separate from an informed consent document. There is nothing in
this final rule, however, that prevents an investigator, sponsor, or
IRB from providing additional information in an information sheet
further explaining ClinicalTrials.gov as part of the informed consent
process.
    (Comment 28) Many comments voiced a variety of opinions on the
issue that no personally identifiable information is submitted to the
databank or shown on the Web site. Several comments supported including
such a statement to that effect in the required statement. Several
comments requested that FDA include additional language in the new
element to clarify any potential confidentiality issues posed by the
databank. These comments suggested including: (1) Assurance that
participants' names and identities will not be posted on
ClinicalTrials.gov, will not be made available to employers, and will
not be discoverable in court proceedings; (2) a statement that it is
probable that participants' information will be re-identified; (3) a
lay person description of data submitted to ClinicalTrials.gov and the
Basic Element Results Definitions; and (4) an expanded description of
the clinical trial registry and databank. Other comments recognized
that no personal information about participants is submitted to
ClinicalTrials.gov, so there are no privacy or confidentiality issues.
Still another comment stated that its consent documents already contain
language that non-identifiable information may be made public in
scientific journals, presentations, and, if applicable, submitted to a
government data bank/registry.
    (Response) We have revised the new statement in the final rule so
that it is clear that the Web site does not include information that
can identify the clinical trial participant. We believe the new
statement will provide reassurance to potential participants. The only
results information submitted to the databank and posted on the Web
site are aggregate statistics, such as those that typically appear in
medical journals and product package inserts. No individual-level data
are submitted to the databank. A review of the data fields on http://www.ClinicalTrials.gov for which data are required to be submitted by
the sponsor/investigator confirms that there is no individual
information, only aggregate, overall data (Ref. 16). Furthermore, Sec.
50.25(a)(5) requires informed consent documents to explain the extent,
if any, to which confidentiality of clinical trial data and the records
of the clinical trial participant will be maintained. Nothing in this
rule prohibits an investigator, sponsor, or IRB from including further
explanation on the nature and confidentiality of information submitted
to ClinicalTrials.gov in the informed consent form or process or a
HIPAA authorization form.
    (Comment 29) One comment suggested that the new statement should be
inserted into the section of the consent document that invites the
potential or enrolled participant to ask questions of the individual
conducting the informed consent process. Such placement, according to
the comment, would facilitate communication and encourage participants
to ask questions.
    (Response) The final rule does not require that the new statement
be located in any particular section of the consent form.
Investigators, sponsors, and IRBs have the flexibility to place the new
statement in the consent form where they believe best serves
participants' interests.
    (Comment 30) One comment requested that the new statement include a
phrase indicating that the information would be submitted to
ClinicalTrials.gov ``if required by law.'' The comment requested this
change to eliminate the need for separate templates for studies that
require registry in the databank and those that do not. Anticipated
benefits were stated to be simplified documentation; reduced review
time by sponsors, investigators, and IRBs; and reduced likelihood of
using the incorrect consent template for a particular clinical study.
Other comments apparently read the NPRM to require the statement in
consent forms for all clinical trials and objected to the inclusion of
the statement for trials that did not require registry in the databank.
    (Response) We do not agree that it is necessary to include an
additional phrase that would allow for a universal consent template.
Sponsors and investigators already have to determine if a clinical
trial is an applicable clinical trial in order to comply with the
requirements of 42 U.S.C. 282(j), section 402(j) of the PHS Act. Adding
the required statement to informed consent documents and processes will
occur after that determination has been made

by the sponsor or investigator. Furthermore, because the mandatory
statement requires specific language, it should not be burdensome for
reviewers to determine whether the statement is included in the
informed consent documents.
    (Comment 31) Two comments expressed concern that the required new
element would create an inconsistency between regulations governing
applicable clinical trials of FDA-regulated products (part 50) and
regulations governing clinical trials funded or supported by HHS (45
CFR part 46). The comments perceived the new element as contrary to
FDA's objective to harmonize regulations of human-subject protection.
    (Response) FDA does not agree that the required element would
create an inconsistency or lack of harmony between the regulations on
human subjects in the two sets of regulations. The new element merely
entails an additional requirement for applicable clinical trials of
FDA-regulated products in accordance with a statutory mandate, whether
or not the trial is supported or funded by HHS. The new element does
not conflict with any existing regulations under 45 CFR part 46.
    (Comment 32) There were several comments that questioned the
estimates contained in the preliminary Analysis of Impacts including
the estimated time to explain the required statement if a potential
participant asked questions.
    (Response) These comments are addressed fully in section VII of
this document.

V. Legal Authority and Enforcement

    Section 505(i)(4) of the Federal Food, Drug, and Cosmetic Act (the
FD&C Act) (21 U.S.C. 355(i)(4) requires drug manufacturers to ``inform
any human beings to whom [investigational] drugs * * * are being
administered * * * that such drugs are being used for investigational
purposes'' and obtain consent prior to administering such drugs.
Section 520(g)(3)(D) of the FD&C Act (21 U.S.C. 360j(g)(3)(D) contains
a similar requirement for medical device manufacturers. Sections 505(i)
and 520(g) of the FD&C Act also authorize the Secretary to issue
regulations for the protection of human subjects in clinical
investigations. Additionally, section 701(a) of the FD&C Act (21 U.S.C.
371(a)) confers general authority to the Secretary to issue regulations
for the efficient enforcement of the FD&C Act.
    Section 801(b)(3)A) of FDAAA amends section 505(i)(4) of the FD&C
Act by adding at the end the following: ``The Secretary shall update
such regulations to require inclusion in the informed consent documents
and process a statement that clinical trial information for such
clinical investigation has been or will be submitted for inclusion in
the registry data bank pursuant to subsection (j) of section 402 of the
Public Health Service Act.'' The regulations implementing section
505(i) of the FD&C Act can be found at parts 312 and 50. Part 312 sets
forth regulations governing drug IND applications, while part 50
includes general requirements for human subject protection in all FDA-
regulated clinical investigations and clinical investigations that
support applications for research or marketing permits for products
regulated by FDA, including trials for drugs and medical devices.
Section 801(b)(3)(A) of FDAAA does not amend section 520(g) of the FD&C
Act; however, in instances where the regulations have been amended to
address human subject protection, FDA has not made distinctions between
clinical investigations for drugs and medical devices.
    For example, FDA created a uniform system of human subject
protection when it initially amended its regulations governing human
subject protection in 1981 (46 FR 8942). In revising part 50, FDA aimed
to: (1) Address the informed consent provision included in the device
amendments, (2) create a uniform set of Agency-wide informed consent
standards for more effective administration of the Agency's bioresearch
monitoring program, (3) implement recommendations of the National
Commission for the Protection of Human Subjects of Biomedical and
Behavioral Research, and (4) harmonize FDA's rules with those of HHS
(then the department of Health, Education, and Welfare). Indeed, the
preamble expressed the Agency's intent to adopt a single standard that
reflected the most current congressional thinking on informed consent
and the important ethical principles and social policies underlying the
doctrine of informed consent (46 FR 8942 at 8943).
    Requiring a statement regarding the registry databank for informed
consent documents and processes for only applicable clinical drug
trials but not applicable clinical device trials would create a
disparity in FDA's policy on human subject protection. This disparity
could result in confusion among those who conduct such clinical trials
over what is required in informed consent documents and processes,
especially in the cases of applicable clinical trials involving both a
drug and device or for investigators conducting applicable clinical
trials of both types of regulated products.
    Thus, although section 801(b)(3)(A) of FDAAA requires the statement
regarding the clinical trial registry databank for informed consent
documents and processes only for applicable drug clinical trials
conducted under section 505(i) of the FD&C Act, under its general
authority to issue regulations for the efficient enforcement of the
FD&C Act (section 701(a) of the FD&C Act), FDA is requiring all
applicable clinical trials, including applicable device clinical
trials, to include this new statement in informed consent documents and
processes. Requiring an additional statement regarding the inclusion of
clinical trial information in the registry databank to be included in
the informed consent documents and processes for all applicable
clinical trials is the most efficient method of implementing the
statutory mandate. To prevent confusion that might result from
different requirements for informed consent for applicable clinical
drug and device trials and implement the congressional purpose
reflected in FDAAA, we will apply the same standards regarding elements
of informed consent to applicable clinical drug and device trials by
amending Sec.  50.25 to include a new paragraph (c) which requires a
statement about the registry databank in informed consent discussions
and documents for all applicable clinical trials under section 801 of
FDAAA.
    The Agency has several options available for enforcing the new
informed consent requirement. The authority to issue regulations for
the protection of human subjects is accompanied by the authority to
impose penalties for violations of such regulations. Specifically,
section 301(e) of the FD&C Act (21 U.S.C. 331(e)) makes the ``failure
to establish or maintain any record, or make any report, required under
section * * * 505(i) * * *'' and the ``failure or refusal to comply
with any requirement prescribed under section * * * 520(g)'' prohibited
acts. The FD&C Act and implementing regulations allow FDA to seek
administrative, civil, and criminal penalties for violations of section
301 of the FD&C Act. 21 U.S.C. Sec.  303(a); Sec. Sec.
312.44(b)(1)(ix), 312.70(a), 812.30(b)(4), 812.119(a), 56. 121(b).

VI. Environmental Analysis

    The Agency has determined under 21 CFR 25.30(h) that this action is
of a type that does not individually or cumulatively have a significant
effect on the human environment. Therefore, neither an environmental
assessment nor an environmental impact statement is required.

VII. Analysis of Impacts

A. Introduction

    FDA has examined the impacts of the final rule under Executive
Order 12866 and the Regulatory Flexibility Act (5 U.S.C. 601-612), and
the Unfunded Mandates Reform Act of 1995 (Pub. L. 104-4). Executive
Order 12866 directs agencies to assess all costs and benefits of
available regulatory alternatives and, when regulation is necessary, to
select regulatory approaches that maximize net benefits (including
potential economic, environmental, public health and safety, and other
advantages; distributive impacts; and equity). The Agency believes that
this final rule is not a significant regulatory action as defined by
the Executive order.
    The Regulatory Flexibility Act requires agencies to analyze
regulatory options that would minimize any significant impact of a rule
on small entities. Because the final rule is expected to impose costs
of about $3 per clinical trial participant or $611 to $1,061 per trial
protocol, the Agency certifies that it will not have a significant
economic impact on a substantial number of small entities.
    Section 202(a) of the Unfunded Mandates Reform Act of 1995 requires
that agencies prepare a written statement, which includes an assessment
of anticipated costs and benefits, before proposing ``any rule that
includes any Federal mandate that may result in the expenditure by
State, local, and tribal governments, in the aggregate, or by the
private sector, of $100,000,000 or more (adjusted annually for
inflation) in any one year.'' The current threshold after adjustment
for inflation is $135 million, using the most current (2009) Implicit
Price Deflator for the Gross Domestic Product. FDA does not expect this
final rule to result in any 1-year expenditure that would meet or
exceed this amount.

B. The Final Rule

    On December 29, 2009, FDA published a proposed rule that would
require that the informed consent documents for applicable drug and
device clinical trials include a statement that applicable clinical
trial information has been or will be submitted to the NIH/NLM for
inclusion in the statutorily required clinical trial databank. As it
pertains to applicable drug clinical trials, the final rule would
implement a requirement of FDAAA. As discussed previously in this
preamble, FDA also requires that the same statement be included in the
informed consent documents for applicable device clinical trials.
    The proposed rule included an analysis of impacts as required by
Executive Order 12866 and the Regulatory Flexibility Act (5 U.S.C. 601-
612), and the Unfunded Mandates Reform Act of 1995 (Pub. L. 104-4). FDA
received many public comments concerning its estimated costs and
benefits for the proposed rule. As a result of the review and
consideration of these and other comments to the proposed rule, FDA has
made changes to both the codified final rule and its analysis of
impacts section.

C. Need for the Final Rule

    The need for this rule arises from section 801(b)(3)(A) of FDAAA.
It requires that the current regulations for informed consent documents
and process be amended to include a statement that clinical trial
information from the clinical investigation has been or will be
submitted to the NIH/NLM clinical trial registry databank. FDA has
decided that revising the general informed consent section is the
appropriate course by which to fulfill the requirements of the statute,
and will provide the pertinent information and protection for clinical
trial participants.

D. Public Comments Concerning Impacts Analysis

    Several comments objected to the inclusion of the informed consent
statement for various reasons. Some believed the statement would cause
confusion or anxiety to the participants. Others believed it would
distract the participants from focusing on the substantive issues
concerning the study that would affect one's decision to participate in
the study. Some comments stated that the overall effect would be a
reduced participation rate for prospective participants. No estimates
of the size of this reduced participation rate were submitted.
Additional comments questioned whether any relevant or valuable
information could be acquired from an informed consent statement that
takes less than 1 minute to read and discuss, resulting in less benefit
to the participant than the administrative costs to the investigator.
    FDA acknowledges that additional time will be required to read and,
if necessary, discuss the statement that FDAAA mandates be included in
the informed consent documents and process. FDA does not agree,
however, that the benefit of the statement to the participant is
directly related to the time it takes to read and discuss the
statement. Further, FDA maintains that the benefits of the informed
consent statement would be difficult to estimate with any certainty,
making a meaningful comparison of benefits to costs impractical. FDA
also has revised the statement to make it shorter and easier to
understand by deleting those terms that could be expected to cause
anxiety and confusion. FDA believes that in doing so it has reduced the
theoretical possibility that the statement would cause some
participants to abandon the study as much as possible while still
fulfilling the FDAAA mandate.

E. Benefits of the Final Rule

    FDA published a qualitative explanation of the expected benefits to
clinical trial participants in its 2009 proposed rule. FDA received
some public comments that agreed with the expected benefits. Others
disagreed, criticizing the proposed rule for not educating the public
at large about the clinical trial registry databank. Some proposed that
FDA undertake a public education campaign to broaden awareness of the
clinical trial registry databank. That policy option, however laudable,
was not included in the FDAAA mandate concerning updating FDA's
regulations concerning informed consent documents and process. While an
educational campaign is not the subject of this rulemaking, there will
be other opportunities for improving awareness of the NIH clinical
trials databank. The comments as a whole did not contain any arguments
that convinced FDA that it should amend its initial explanation of
benefits. As a result, FDA restates the expected benefits for this
final rule.
    The rule would increase the transparency of clinical trials by
increasing participant and patient awareness of the existence of the
clinical trials databank and those trials that are registered in the
databank. By helping to create a system of checks and balances through
which participants, patients, and health care providers are encouraged
to check whether information about a trial of interest is registered in
the databank, it also would provide greater accountability of clinical
trial investigators for outcomes and adverse events, thereby raising
confidence in the validity of the research process. Last of all, it
would encourage physicians and patients to obtain more information in
order to make more educated treatment decisions. FDA has not attempted
to quantify these benefits, but believes that the overall effect of the
rule on public health would be positive.

F. Costs of the Final Rule

    FDA estimated the total costs of the proposed rule to both industry
and the

clinical trial participant population to range from $688,000 to
$2,398,000 annually. This equated to $98 to $342 per trial protocol, or
about $0.48 to $0.96 per clinical trial participant. These costs
included labor costs for both the investigator and the trial
participant, as well as document preparation costs and paper materials
costs. The cost of government oversight was not expected to be
significant. For the most part, the public comments on the proposed
rule did not address the structure of the cost analysis (except IRB
review costs). FDA retains much of the cost analysis of the proposed
rule for the final rule.
1. Labor Costs
    The costs of the final rule derive from complying with the
requirement to add another statement to the informed consent documents
and the additional time that medical professionals and clinical trial
participants spend reading and discussing this statement.
    We have revised the final cost estimate to account for the
administrative costs for companies involved in pharmaceutical,
biologic, and medical device research and manufacturing, and
administrative costs for IRB oversight. These additional labor costs
are due to the administrative review of the rule and the determination
of compliance responsibilities. All companies involved in this would
incur some labor costs, regardless of the frequency with which they
undertake clinical trials. Census data from 2002 list 5,666 companies
in the seven North American Industrial Classification System (NAICS)
categories that would be subject to this rule. FDA estimates that each
could expend about 2 hours to review the final rule and determine any
changes it needs to make to its internal administrative policies due to
this rule. The pharmaceutical and medicine manufacturing category of
the NAICS lists the hourly wage for a manager in this category at about
$54. A 35 percent adjustment to this figure for employee benefits
results in total hourly compensation costs of about $73. A one-time 2
hour review for each company would result in compliance costs of almost
$147 per company, and a total of about $830,000 for the industry. This
equates to an annualized cost (over 5 years at a 7 percent discount
rate) of about $202,000 for the entire industry. These estimates may
overstate true compliance costs for review of the rule since those
companies that rarely sponsor clinical trials on even an occasional
basis may not expend as much labor as those who do so more frequently.
    For the proposed rule, FDA estimated that it receives about 7,000
clinical trial protocol submissions annually for applicable clinical
trials that would be subject to this final rule, with the vast majority
of the submissions to the FDA's Center for Drug Evaluation and Research
(CDER). The public comments did not address the size of this estimate.
However, further analysis of the data upon which the estimates were
made shows that up to 30 percent of the CDER protocols may be for phase
1 clinical trials which would not be subject to the final rule. FDA has
adjusted the estimated number of CDER trial protocols accordingly,
which results in a reduction of the total trial protocols estimate to
5,146. FDA estimates of average numbers of participants per clinical
trial vary greatly across FDA Centers, from single-patient INDs to
vaccine trials with over 25,000 participants. Published data on average
number of participants per trial, therapeutic area, suggests that the
average number of participants in phase 1, 2, and 3 clinical trials of
pharmaceuticals, biotech, and medical device products may range from
about 200 to 360.\1\ FDA did not receive any comments on this estimate
of the average number of participants per clinical trial, and retains
it for the analysis of the final rule.
---------------------------------------------------------------------------

    \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 three 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 the informed consent
documents contain the required statement concerning the clinical
trial's inclusion in the clinical trial registry databank and provide
for any additional discussion concerning this statement between
participants and the medical professional administering the documents.
As discussed previously in this preamble, FDA received many comments
concerning the language used in the statement, as well as the length of
time necessary to read and, if necessary, discuss this statement with
the medical professional administering the study. Due to these
comments, FDA has both simplified the language used in the statement,
and reduced the length of the statement by about 50 percent.
Additionally, FDA has revised its estimate of the average number of
minutes that a clinical trial participant would require to read and
discuss the statement from a range of 30 seconds to 1 minute used in
the analysis of the proposed rule to 3 minutes for the analysis of the
final rule.
    Registered nurses, or other medical professionals with a similar
level of training, often administer and discuss the informed consent
forms with trial participants. The average compensation for a
registered nurse in 2008 was $40.54 per hour, including a 35 percent
increase to account for benefits. The increased labor cost for
administering the informed consent procedures for these medical
professionals in applicable clinical trials for all participants ranges
from $2.09 million to $3.76 million (see Table 1 of this document).
This estimate is the result of $40.54 per hour times 3 minutes per
participant times 200 to 360 participants per trial times 5,146
protocols per year. The cost to the sponsor per prospective participant
is estimated at $2.03 and the cost per trial protocol is estimated to
range from $405 to $730.

            Table 1--Costs of Informed Consent Proposed Rule
------------------------------------------------------------------------
                   Cost factor                          Annual cost
------------------------------------------------------------------------
Labor Cost--Administrative Review of Rule \1\....               $202,000
Labor Cost--Clinical Trial Administrator.........    2,086,000-3,755,000
Labor Cost--Clinical Trial Participant...........      801,000-1,442,000
Labor Cost--IRB Review...........................                 29,000
Document Preparation Cost........................                 17,000
Paper Cost.......................................           7,000-12,000
                                                  ----------------------

    Total Costs..................................    3,143,000-5,458,000
------------------------------------------------------------------------
\1\ This is a one-time cost of $830,000 annualized over 5 years at 7
  percent.

    Some clinical trial participants are compensated for their
participation in trials. Whether an individual participant receives
compensation or not, the additional time spent by all participants to
read and discuss the new informed consent statement represents a social
cost of the rule. Using the median U.S. wage rate of $15.57 per hour, a
clinical trial participant would be expected to incur a cost of $0.78
for the 3 minutes to read and, if necessary, discuss the proposed
informed consent statement. On an annual basis over the 5,146 clinical
trials, this would amount to about $0.80 million to $1.44 million.
    Comments to the proposed rule included a criticism that FDA had
failed to account for the costs to IRB for its oversight role of the
new statement. FDA agrees that the new informed consent statement will
require an additional amount of oversight from IRBs. FDA has added to
its cost elements a labor cost for the effort of the IRBs to determine
that the statement has been added to the model templates for informed
consent documents. Although IRBs can have many members, in practice,
only one or two members may be involved in reviewing the study
documents on behalf of the IRB for inclusion of all the necessary
informed consent statements. FDA estimates the additional review of the
entirety of consent forms and documents to determine that the new
statement is appropriately included could take an additional 3 minutes
of administrative effort for each of the 5,146 protocols. FDA bases its
cost estimate on the mean hourly pay rate for physicians, adjusted 35
percent for benefits, of $113.\2\ Using these factors, FDA estimates
that an additional $29,000 in labor costs will be incurred due to this
final rule.
---------------------------------------------------------------------------

    \2\ U.S. Department of Labor, Bureau of Labor Statistics, May
2009 National Occupational Employment and Wage Estimates United
States, p. 8.
---------------------------------------------------------------------------

    The cost of incorporating the new statement into the informed
consent documents is expected to be very small. The new statement would
only need to be written once per protocol and is estimated to take
about 5 minutes. Using the same wage rate as mentioned previously,
$40.54 per hour, the additional annual costs to write the statement for
the 5,146 annual protocols would total to about $17,000. The capital
cost of adding the new informed consent statement would only consist of
the additional paper. At a cost of about $0.02 per page and about one-
third of a page per participant, the total paper costs for this rule
are estimated to range from $7,000 to $12,000 annually.
2. Total Industry Costs
    The total costs of the final rule to both industry and the clinical
trial participant population are estimated to range from $3.14 million
to $5.46 million annually. This equates to $611 to $1,061 per trial
protocol, or about $2.95 to $3.05 per clinical trial participant.
3. Costs to Government
    FDA did not receive any comments on its estimate of the impacts of
the proposed rule on government costs, and retains its conclusions for
the final rule. The costs to government for oversight of this rule
would be extremely low as a review of a sample of informed consent
documents for each trial would only be increased, at most, by a few
minutes per clinical trial due to the additional informed consent
statement. FDA believes this cost would not be significant.
4. Alternatives to the Final Rule
    FDAAA specifically requires that the regulations concerning
informed consent documents include a statement that clinical trial
information has been or will be submitted for inclusion in the clinical
trial registry databank. It did not provide FDA with discretion
concerning the inclusion of a statement for applicable drug clinical
trials. For the reasons stated previously in this document, FDA has
decided to require the revised, shorter statement be included in the
informed consent documents for medical device trials as well. If the
final rule did not include the new informed consent statement for
applicable medical device clinical trials, the annual costs of the rule
would be reduced by $207,000 to $615,000 per year. If FDA had not
revised the informed consent statement to make it both shorter and
easier to understand, the compliance costs would have been larger than
those estimated in this analysis.
5. Regulatory Flexibility Act
Impacts on Small Entities
    The Regulatory Flexibility Act requires agencies to analyze
regulatory options that would minimize any significant impact of a rule
on small entities. The companies that would be affected are classified
in seven separate NAICS categories by the Census Bureau. The affected
industries are NAICS 325412--Pharmaceutical Preparation; NAICS 325414--
Biological Products (except diagnostic); NAICS 334510--Electromedical
and Electrotherapeutic Apparatus; NAICS 339112--Surgical and Medical
Instrument; NAICS 339113--Surgical Appliance and Supplies; NAICS
339114--Dental Equipment and Supplies; NAICS 339115--Opthalmic Goods.
    The Small Business Administration (SBA) size standards for all
these industries define small entities as those companies with less
than 500 employees, except for pharmaceutical preparation, for which it
defines a small entity as one with less than 750 employees. The most
recent Census of Manufacturers data that offers the level of detail for
establishments at or near the employee size limits as defined by SBA is
from 2002 (the 2007 Census data on the size distributions were not yet
available; using 2002 data for the calculations overstates the likely
effects on small businesses). In each of these establishment size
categories, large majorities of the establishments meet the criteria as
small entities. Even taking into account that many of these
establishments are parts of 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 sponsoring companies would still qualify as small
entities.
    The cost analysis concluded that the compliance cost of the
proposed rule per trial protocol would range from $611 to $1,061. Some
firms will direct

multiple applicable clinical trials in the same year. For large firms
that would administer the informed consent documents for 10 separate
trials, the cost would range from $6,110 to $10,610 per year. Using
2002 Census data, the average value of shipments for establishments in
these industries with one to four employees ranged from $244,000 to
$824,000 according to the Census of Manufacturers. Assuming that such
small operations had one applicable clinical trial administered each
year, the costs of the proposed rule would represent, at most, 0.43
percent of the annual value of shipments. For establishments with 50 or
more employees, the compliance costs would represent 0.11 percent or
less of the value of shipments even with 10 applicable clinical trials
administered annually. For establishments with 100 or more employees,
the compliance costs would represent 0.23 percent or less of the value
of shipments even with 50 applicable clinical trials administered
annually. Because of the small costs that would be incurred relative
both to the total cost of a clinical trial and the revenues of an
individual sponsor of a product undergoing a clinical trial, the Agency
certifies that the final rule would not have a significant economic
impact on a substantial number of small entities.

VIII. Paperwork Reduction Act

    FDA concludes that the informed consent requirement in this
document is not subject to review by the Office of Management and
Budget because it does not constitute a ``collection of information''
under the Paperwork Reduction Act of 1995 (44 U.S.C. 3501-3520).
Rather, the requirement to include a statement in informed consent
documents and processes on submission of information to the clinical
trial data bank is a ``public disclosure of information originally
supplied by the Federal government to the recipient for the purpose of
disclosure to the public'' (5 CFR 1320.3(c)(2)).

IX. Federalism

    FDA has analyzed this final rule in accordance with the principles
set forth in Executive Order 13132. FDA has determined that the final
rule does not contain policies that have substantial direct effects on
the States, on the relationship between the National Government and the
States, or on the distribution of power and responsibilities among the
various levels of government. Accordingly, the Agency has concluded
that the final rule does not contain policies that have federalism
implications as defined in the Executive order and, consequently, a
federalism summary impact statement is not required.

X. References

    The following references have been placed on display in the
Division of Dockets Management, Food and Drug Administration, 5630
Fishers Lane, rm. 1061, Rockville, MD 20857 and may be seen by
interested persons between 9 a.m. and 4 p.m., Monday through Friday. We
have verified the Web site addresses, but we are not responsible for
any subsequent changes to the Web sites after this document publishes
in the Federal Register.

    1. Food and Drug Administration, ``Protection of Human Subjects;
Informed Consent Final Rule'' (46 FR 8942, January 27, 1981). ``FDA
recognizes that the documentation of informed consent represents
only one part of the entire consent process. The consent form itself
is merely an aid to assure that a required minimum of information is
provided to the subject and that the subject consents. The entire
informed consent process involves giving the subject all the
information concerning the study that the subject would reasonably
want to know; assuring that the subject has comprehended this
information; and finally, obtaining the subject's consent to
participate.'' 46 FR 8942 at 8945. Available at: http://www.fda.gov/ScienceResearch/SpecialTopics/RunningClinicalTrials/ucm113818.htm,
accessed August 9, 2010.
    2. National Commission for the Protection of Human Subjects of
Biomedical and Behavioral Research, ``The Belmont Report: Ethical
Principles and Guidelines for the Protection of Human Subjects of
Research.'' Part A: Boundaries Between Practice & Research, April
18, 1979, available at: http://www.hhs.gov/ohrp/humansubjects/guidance/belmont.htm, accessed August 9, 2010.
    3. National Research Act, Title II (Pub. L. 93-348, July 12,
1974).
    4. Trials of War Criminals Before the Nuremberg Military
Tribunals Under Control Council Law, No. 10, Vol. 2, pp. 181-182;
Washington, DC, U.S. Government Printing Office (1949), available
at: http://www.loc.gov/rr/frd/Military_Law/pdf/NT_war-criminals_Vol-II.pdf, accessed August 9, 2010.
    5. Council for International Organizations of Medical Sciences,
International Ethical Guidelines for Biomedical Research Involving
Human Subjects (2002), Guideline 5, No. 7 states that the informed
consent process include information that subjects, after completion
of the study, will be provided with general research results and any
findings relating to their particular health status. Guideline 5,
No. 11 states that the subject be informed of ``the expected
benefits of the research to the community or to society at large.'',
available at: http://www.cioms.ch/publications/layout_guide2002.pdf, accessed August 9, 2010.
    6. World Medical Association, Declaration of Helsinki, Ethical
Principles for Medical Research Involving Human Subjects, 59th WMA
General Assembly, Seoul, October 2008, Section C.33 states that:
``At the conclusion of the study, patients entered into the study
are entitled to be informed about the outcome of the study and to
share any benefits that result from it. * * *'', available at:
http:[sol][sol]www.wma.net/en/30publications/10policies/b3/17c.pdf,
accessed August 9, 2010.
    7. Sim, I., A. Chan, A. G[uuml]lmezoglu, ``Clinical Trial
Registration: Transparency is the Watchword,'' The Lancet, Vol. 367,
Issue 9523, p. 1631, May 2006.
    8. De Angelis, C., J. M. Drazen, et al. ``Is This Clinical Trial
Fully Registered?: A Statement From the International Committee of
Medical Journal Editors,'' International Committee of Medical
Journal Editors, available at: http:[sol][sol]www.icmje.org/update_
may05.html, accessed October 4, 2010.
    9. Several examples of model templates can be found at:
    a. Mayo Clinic, Institutional Review Board, IRB Consent Form
Template, available at: http:[sol][sol]mayoresearch.mayo.edu/mayo/
research/irb/upload/irb10294.pdf accessed July 7, 2010;
    b. Stanford University Research Compliance Office, Human
Subjects Research, ``Stanford University Consent (includes HIPAA),
available at: http:[sol][sol]humansubjects.stanford.edu/consents/
SUSampCons--CA--privacy.doc, accessed July 7, 2010;
    c. Duke University School of Medicine, Institutional Review
Board, ``Sample Consent,'' available at:
http:[sol][sol]irb.duhs.duke.edu/wysiwyg/downloads/Consent--
Template-----Long--Form--102--01-02-09--JW.doc, accessed July 7,
2010;
    d. University of Michigan Medical School, Informed Consent &
Assent Templates, ``Informed Consent Template (Standard) Version 3-
29-10,'' available at: http:[sol][sol]med.umich.edu/irbmed/ict.htm,
accessed July 7, 2010;
    e. University of Texas at Austin, Office of Research Support,
``Consent Form 1--For Greater Than Minimal Risk Studies,'' available
at: http:[sol][sol]www.utexas.edu/research/rsc/humansubjects/forms/
consent_form_1.doc, accessed on July 7, 2010;
    f. Children's Hospital Boston, Office of Clinical Investigation,
``English Informed Consent Template,'' available at:
http:[sol][sol]www.childrenshospital.org/cfapps/research/data_
admin/Site2206/Documents/Consent_Template.doc, accessed July 8,
2010;
    g. Partners Human Research Committee, Consent Forms, ``Drug
Trial Consent Form Template,'' available at:
http:[sol][sol]healthcare.partners.org/phsirb/irbforms/Consent--
Templates--and--Instructions/PHS--Research--Consent--Form--Adult--
Surrogate--Drug--2.2010.doc, accessed July 8, 2010;
    h. Walter Reed Army Medical Center, NCA Templates, ``Informed
Consent Form.'' Available at: http:[sol][sol]www.wramc.army.mil/
Patients/healthcare/dci/protocols/ncatemplates/
INFORMED%20CONSENT%20FORM%20(ICF)/WRNMMC--ClinicalTrialsICF.doc,
accessed July 8, 2010;

    i. American College of Radiology Imaging Network, Protocol
Development & Regulatory Resources, ``Informed Consent Template &
Checklist,'' available at: http:[sol][sol]www.acrin.org/Portals/0/
Administration/Regulatory/ICF_Template.doc, accessed July 8, 2010;
    j. National Cancer Institute, ``Simplification of Informed
Consent Documents,'' available at: http:[sol][sol]www.cancer.gov/
clinicaltrials/education/simplification-of-informed-consent-docs/
allpages, accessed July 7, 2010.
    10. Institutional Review Board: Management and Function (edited
by Bankert, E. A. and R. J. Amdur), 2d Ed., 2006 (Chapter 6-1, The
Institutional Review Board's Role in Editing Consent Documents,
Pensha, R. L., pp. 199-201 and Chapter 6-2, The Consent Documents,
Brown, A., pp 202-204).
    11. Flesch-Kincaid Reading Scale Information, Rudolf Flesch, ``A
New Readability Yardstick,'' Journal of Applied Psychology, vol. 32,
pp. 221-233, 1948.
    12. FDA, Office of Planning, Risk Communication Staff, ANALYSIS
NOTE: Note No. 2010-001, July 30, 2010.
    13. FDA: A Guide to Informed Consent--Information Sheet,
available at: http:[sol][sol]www.fda.gov/RegulatoryInformation/
Guidances/ucm126431.htm#nonenglish, accessed August 8, 2010.
    14. NIH: ClinicalTrials.gov: Protocol Registration System: PRS
and U.S. Public Law 110-85: ``Applicable Clinical Trials,''
available at: http:[sol][sol]prsinfo.clinicaltrials.gov/fdaaa.html
and http:[sol][sol]prsinfo.clinicaltrials.gov/
ElaborationsOnDefinitions.pdf, accessed August 8, 2010.
    15. ``Guidance for Sponsors, Institutional Review Boards,
Clinical Investigators and FDA Staff: Guidance on Informed Consent
for In Vitro Diagnostic Device Studies Using Leftover Human
Specimens That Are Not Individually Identifiable,'' available at:
http:[sol][sol]www.fda.gov/MedicalDevices/
DeviceRegulationandGuidance/GuidanceDocuments/ucm078384.htm,
accessed August 8, 2010.
    16. NIH: ClinicalTrials.gov ``Basic Results Data Element
Definitions (DRAFT),'' available at:
http:[sol][sol]prsinfo.clinicaltrials.gov/results--definitions.html,
accessed August 8, 2010.

List of Subjects in 21 CFR Part 50

    Human research subjects, Prisoners, Reporting and recordkeeping
requirements, Safety.

0
Therefore, under the Federal Food, Drug, and Cosmetic Act, the Public
Health Service Act, and under authority delegated to the Commissioner
of Food and Drugs, 21 CFR part 50 is amended as follows:

PART 50--PROTECTION OF HUMAN SUBJECTS

0
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.

0
2. Section 50.25 is amended by redesignating paragraphs (c) and (d) as
paragraphs (d) and (e), and by adding new paragraph (c) to read as
follows:

Sec.  50.25  Elements of informed consent.

* * * * *
    (c) When seeking informed consent for applicable clinical trials,
as defined in 42 U.S.C. 282(j)(1)(A), the following statement shall be
provided to each clinical trial subject in informed consent documents
and processes. This will notify the clinical trial subject that
clinical trial information has been or will be submitted for inclusion
in the clinical trial registry databank under paragraph (j) of section
402 of the Public Health Service Act. The statement is: ``A description
of this clinical trial will be available on
http:[sol][sol]www.ClinicalTrials.gov, as required by U.S. Law. This
Web site will not include information that can identify you. At most,
the Web site will include a summary of the results. You can search this
Web site at any time.''
* * * * *

    Dated: December 28, 2010.
Leslie Kux,
Acting Assistant Commissioner for Policy.
[FR Doc. 2010-33193 Filed 1-3-11; 8:45 am]
BILLING CODE 4160-01-P