Informed Consent Elements, 256-270 [2010-33193]

Agencies

• Food and Drug Administration
• DEPARTMENT OF HEALTH AND HUMAN SERVICES

[Federal Register Volume 76, Number 2 (Tuesday, January 4, 2011)]
[Rules and Regulations]
[Pages 256-270]
From the Federal Register Online via the Government Printing Office [www.gpo.gov]
[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.

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    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 https://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.

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IV. Comments on the Proposed Rule

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

A. General Comments

    (Comment 1) We received comments that objected to adding any 
statement to informed consent documents about submitting information to 
the databank to be posted on the ClinicalTrials.gov Web site. The 
principal reasons given for these objections were that the additional 
statement: (1) Lengthens already lengthy informed consent documents, 
exacerbating potential participants' confusion and anxiety upon reading 
consent forms; (2) unnecessarily burdens or overwhelms participants 
because it does not provide information necessary to make an informed 
decision about whether to participate in a clinical trial; (3) fails to 
advance human subject protection in any way; and (4) will cause 
patients to ignore more important aspects of the consent form or other 
research-related forms. Other comments approved the inclusion of a 
statement that alerted potential participants to the clinical trials 
registry databank to inform them how the data are generally used and to 
increase awareness of the clinical trial registry.
    (Response) We appreciate the concerns expressed by the comments 
regarding the increasing length of informed consent documents and the 
additional information required to be provided to potential clinical 
trial participants. Section 801(b)(3)(A) of FDAAA, however, requires 
the Secretary to update FDA's regulations to ``require inclusion in the 
informed consent documents and process a statement that clinical trial 
information for such clinical investigations has been or will be 
submitted for inclusion in the registry data bank.'' Thus, while we 
appreciate the concerns, Congress has directed that this be implemented 
by FDA.
    While FDA has been directed by statute to include this particular 
statement in informed consent documents and processes related to 
applicable clinical trials, there is increasing support for informing 
clinical trial participants about the clinical trials in which they 
participate and the outcome of those trials whether it is included in 
the informed consent document or through other efforts. The rationale 
for informed consent is to ensure that participants enter into the 
research voluntarily and with adequate information (Refs. 2, 3, and 4). 
Communications, other than the specific informed consent, may include 
informing the participant on how to obtain or access information 
relating to the outcomes of the research (Refs. 5 and 6). Implementing 
the statutory provision by including the statement in the informed 
consent documents and processes, as required, also advances these other 
goals.
    We disagree with comments that the new statement does not provide 
any information necessary to make an informed decision about whether to 
participate in a clinical trial. As noted in the NPRM, alerting 
potential clinical trial participants to the existence of a publicly 
accessible databank, whether in the informed consent or during the 
process, can reassure them that a transparent system exists to help 
ensure greater accountability and responsibility of investigators (74 
FR 68750 at 68752). Clinical research (as opposed to clinical practice) 
is not designed to deliver therapeutic benefits to individual patients, 
so it is possible that potential clinical trial participants would want 
to know the overall benefits that may accrue to society at large (Refs. 
7 and 8). One of the basic elements of informed consent which 
investigators are required to inform participants of is ``a description 
of any benefits to the subject or to others which may reasonably be 
expected from the research.'' (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 https://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

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mandate by requiring the new statement in informed consent documents 
and processes and the final rule adopts that proposal. We believe the 
short required statement accomplishes the statutory mandate in the most 
efficient manner possible.
    (Comment 3) Two comments suggested that the new statement should 
not be included because research involving de-identified data is exempt 
from human-subjects regulation since only de-identified data are 
submitted to https://www.ClinicalTrials.gov.
    (Response) We believe this comment reflects a misunderstanding 
about the statutory requirements to register applicable clinical trials 
with NIH at https://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 https://www.ClinicalTrials.gov since 2007 and results posting for certain 
trials has been required since 2008.
    (Comment 6) One comment expressed concern that the specific 
language of the new element would have to be revised

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

C. New Section 50.25(c)

    In order to address some of the concerns raised by comments, and on 
our own initiative, we have created a new paragraph (c) in 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 https://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 https://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 https://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 https://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

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

D. Specific Language for Informed Consent Documents and Processes

    (Comment 10) Many comments objected to specific required language, 
as opposed to a general requirement for the content of the message with 
flexibility to craft the exact language. These comments stated that 
specific language denies institutions the flexibility to tailor the 
language to the local community, subject population, type of study, or, 
in non-U.S. trials, other countries' unique data privacy concerns. One 
comment stated that requiring specific language is inconsistent with 
other elements of informed consent, which specifies content but not 
language. Another comment objected to the specific language because it 
would require additional clarifying language about other registries.
    (Response) In proposing specific language, we considered issues 
similar to those raised by the comments but concluded that the risk of 
inaccurate and confusing statements was too great to permit 
investigators and sponsors to craft their own statements regarding the 
inclusion of clinical trial information in https://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 https://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 https://www.ClinicalTrials.gov promotes 
therapeutic treatment as the primary focus of the clinical trials 
posted to the databank. The ClinicalTrials.gov Web site makes clear 
that clinical trials are research studies. Extensive questions and 
answers are provided on the Web site detailing what a clinical trial is 
and what participation encompasses. Regardless, the informed consent 
documents and process, properly administered, should dispel any 
misconception about the purpose of the clinical trial.
    (Comment 14) Several comments stated that the reference to the 
ClinicalTrials.gov Web site should be omitted because: (1) It was not 
necessary for a subject to make an informed decision about whether to 
participate in the trial and (2) the Web site had no more information 
than the informed consent document about the trial. Other comments 
favored the reference to ClinicalTrials.gov, stating that this 
information is consistent with the goals of enhancing transparency of 
clinical trials, boosting public confidence in the clinical research 
process, and better informing potential participants.

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    (Response) We decline to omit the reference to https://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 https://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 https://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 https://www.ClinicalTrials.gov instead of a direct 
link. In fact, https://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 https://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 https://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

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confusion in multinational clinical trials.
    (Response) We agree and the revised statement indicates that the 
clinical trial description on https://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 
https://prsinfo.clinicaltrials.gov/fdaaa.html and at https://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

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should be noted for purposes of clarification that under 45 CFR 
46.102(f) research using de-identified data would not be considered 
research on a human subject and, thus, the waiver of the informed 
consent requirement would not be applicable.
    As a general matter, clinical research that both involves FDA-
regulated products and is conducted or supported by HHS must meet the 
requirements of both sets of regulations. If such clinical trials are 
also applicable clinical trials under FDAAA, the new element must be 
included in the informed consent documents and process for these trials 
unless waived under part 50, regardless of whether an IRB determines 
that one or more of the elements is waiveable under 45 CFR part 46.
    In some instances, review of records containing de-identified data 
may be exempt from IRB review because such record review does not 
qualify as human subject research. This is not always the case under 
FDA regulations and there are some circumstances in which the use of 
de-identified data requires IRB review. See 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 https://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

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by the sponsor or investigator. Furthermore, because the mandatory 
statement requires specific language, it should not be burdensome for 
reviewers to determine whether the statement is included in the 
informed consent documents.
    (Comment 31) Two comments expressed concern that the required new 
element would create an inconsistency between regulations governing 
applicable clinical trials of 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 Anal