[Federal Register Volume 78, Number 38 (Tuesday, February 26, 2013)]
[Rules and Regulations]
[Pages 12937-12951]
[FR Doc No: 2013-04387]

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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Parts 50 and 56

[Docket No. FDA-2000-N-0009] (formerly 2000N-0074)
RIN 0910-AG71

Additional Safeguards for Children in Clinical Investigations of
Food and Drug Administration-Regulated Products

AGENCY: Food and Drug Administration, HHS.

ACTION: Final rule.

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SUMMARY: The Food and Drug Administration (FDA) is amending its
regulations to provide additional safeguards for children enrolled in
clinical investigations of FDA-regulated products. This rule finalizes
the interim rule published in 2001 to bring FDA regulations into
compliance with provisions of the Children's Health Act of 2000 (the
Children's Health Act). The Children's Health Act requires that all
research involving children that is conducted, supported, or regulated
by the Department of Health and Human Services (HHS) be in compliance
with HHS regulations providing additional protections for children
involved as subjects in research. FDA is taking this action both to
comply with the congressional mandate and because of increases in the
enrollment of children in clinical investigations as a result of
ongoing pediatric initiatives.

DATES: This rule is effective March 28, 2013.

FOR FURTHER INFORMATION CONTACT:  Robert M. Nelson, Office of Pediatric
Therapeutics, Food and Drug Administration, 10903 New Hampshire Ave.
Bldg. 32, rm. 5126, Silver Spring, MD 20993-0002,<PHONE_NUMBER>.

SUPPLEMENTARY INFORMATION:

Table of Contents

I. Background
II. Highlights of the Final Rule
III. Comments and Agency Response
    A. Definitions
    B. IRB Membership and Continuing Education
    C. Risk Categories
    D. Obtaining Assent From Children
    E. Waiver of Permission
    F. Wards
    G. Biological Products
    H. Economic Analysis
    I. Requests for Additional Requirements
IV. Legal Authority
V. Environmental Impact
VI. Paperwork Reduction Act
VII. Analysis of Impacts
    A. Introduction
    B. Updated Analysis
VIII. Federalism
IX. References

I. Background

    In the Federal Register of April 24, 2001 (66 FR 20589), FDA
published an interim rule amending its regulations to provide
additional safeguards for children enrolled in clinical investigations
of FDA-regulated products (part 50 (21 CFR part 50, subpart D (FDA
subpart D))). The interim rule brought FDA regulations into compliance
with provisions of the Children's Health Act (Pub. L. 106-310). Title
XXVII, section 2701 of the Children's Health Act required that within 6
months of its enactment all research involving children conducted,
supported, or regulated by HHS be in compliance with HHS regulations
providing additional protections for children involved as subjects in
research (45 CFR part 46, subpart D (HHS subpart D)). The interim rule
was effective on April 30, 2001. Interested parties were given until
July 23, 2001, to comment on the interim rule.
    FDA is finalizing its interim final rule both to comply with the
congressional mandate in the Children's Health Act and because of
increases in the enrollment of children in clinical investigations, in
part as a result of ongoing pediatric initiatives. Some of these
pediatric initiatives were described in detail in the interim rule (66
FR 20589), including the Food and Drug Administration Modernization Act
of 1997 (FDAMA) and FDA's 1998 pediatric rule (63 FR 66632, December 2,
1998).
    FDAMA established economic incentives for manufacturers to conduct
pediatric studies on drugs for which exclusivity or patent protection
is

available under the Drug Price Competition and Patent Term Restoration
Act (Pub. L. 98-417) or the Orphan Drug Act (Pub. L. 97-414). These
provisions add 6 months of marketing exclusivity (known as pediatric
exclusivity) to any existing exclusivity or patent protection on a drug
moiety for which FDA has requested pediatric studies and the
manufacturer has conducted such studies in accordance with the
requirements of the statute. This exclusivity-based incentive was re-
authorized under the Best Pharmaceuticals for Children Act (BPCA) of
2002 (Pub. L. 107-109) and 2007 (Title V of Pub. L. 110-85). The
Patient Protection and Affordable Care Act of 2010 (section 7002(g)(1)
of Pub. L. 111-148) extended pediatric exclusivity and applicable
provisions of BPCA 2007 to biological products. Title V of the Food and
Drug Administration Safety and Innovation Act (FDASIA) (Pub. L. 112-
144) made permanent this exclusivity-based incentive for studies
conducted in response to a written request from FDA.
    Under FDA's 1998 pediatric rule, drug and biological product
approvals issued, or applications submitted, on or after April 1, 1999,
for a new active ingredient, new indication, new dosage form, new
dosing regimen, or new route of administration, were required to
include pediatric assessments for all indications for which applicants
were receiving or seeking approval, unless the requirement was waived
or deferred. Although the pediatric rule was suspended by court order
on October 17, 2002, the Pediatric Research Equity Act (PREA) of 2003
(Pub. L. 108-155) codified many of its elements. The Pediatric Research
Equity Act of 2007 (Title IV of Pub. L. 110-85) re-authorized and
expanded PREA 2003, continuing these pediatric requirements. FDASIA
also made permanent this requirement for pediatric assessments.
    Additionally, as noted in the interim final rule, FDA initiated
other actions to encourage the development of adequate pediatric use
information for FDA-regulated products, for example, through issuance
in 2000 of pediatric guidance titled ``E11 Clinical Investigation of
Medicinal Products in the Pediatric Population'' (ICH E11) (December
2000) (Ref. 1). This guidance was prepared under the auspices of the
International Conference on Harmonisation of Technical Requirements for
Registration of Pharmaceuticals for Human Use (ICH) as part of the ICH
effort to harmonize such requirements among the European Union, Japan,
and the United States. ICH E11 addresses issues in pediatric drug
development including ethical considerations in pediatric studies. It
states that pediatric populations represent a vulnerable subgroup and
special measures therefore are needed to protect the rights of
pediatric study participants. Section 2.6 of ICH E11 addresses relevant
issues including: the roles and responsibilities of institutional
review boards (IRBs) and independent ethics committees (IECs),
recruitment of study participants, consent and assent, and minimizing
risk and distress in pediatric studies.
    Additional examples of pediatric specific guidance include: (1) A
final guidance entitled ``Acute Bacterial Otitis Media: Developing
Drugs for Treatment'' (September 2012) (Ref. 2), which includes a
section on the ethical considerations under part 50, subpart D in
designing a clinical trial for acute bacterial otitis media; and (2) a
final guidance entitled ``Orally Inhaled and Intranasal
Corticosteroids: Evaluation of the Effects on Growth in Children''
(March 2007) (Ref. 3), which includes a section on the ethical concerns
raised by the choice of a comparator or control group for allergic
rhinitis and asthma studies.
    These (and other) regulatory actions, combined with the statutory
initiatives described previously, have resulted in increases in the
enrollment of children in clinical investigations (see information
provided at http://www.fda.gov/pediatrics).

II. Highlights of the Final Rule

    This final rule adopts the safeguards described in HHS subpart D
for children participating in clinical investigations regulated by FDA
under sections 505(i) and 520(g) of the Federal Food, Drug, and
Cosmetic Act (the FD&C Act) (21 U.S.C 355(i) and 360j(g)), as well as
clinical investigations that support applications for research or
marketing permits for products regulated by FDA, including human drug
and biological products; medical devices for human use; foods,
including dietary supplements, that bear a nutrient content claim or
health claim; infant formula; food and color additives; and electronic
products. (See Sec.  50.1) These safeguards are intended to ensure that
the rights and welfare of children who participate in clinical
investigations are adequately protected. Nothing in these regulations
is intended to preempt any applicable Federal, State, or local laws
that require additional safeguards for children participating in
clinical investigations.
    The final rule brings FDA's regulations into compliance with HHS
subpart D, as directed by Congress, with some changes reflecting
differences between FDA's and HHS's regulatory authority and other
changes made for clarification. In the preamble to the interim rule, we
provided a detailed explanation of the provisions of the rule. In the
final rule, we respond to comments received on the interim rule. Four
substantive changes have been made to the codified section of the final
rule: (1) The definition of guardian has been modified, (2) the
definition of permission has been modified, (3) paragraph (a) has been
added to Sec.  50.51 to require, consistent with Sec.  46.404 of HHS
subpart D, that IRBs assess the level of risk to children in clinical
investigations subject to Sec.  50.51, and (4) a phrase has been added
to Sec.  50.55(e) to make it clear that the exception for emergency
research described in Sec.  50.24 applies to research in children. In
addition, we have made changes on our own initiative for the purposes
of clarity and consistency. In addition to modifying the definitions of
guardian and permission, changes to the following sections were made in
order to be more consistent with HHS 45 CFR part 46, subpart D: 1)
Changing ``may'' to ``should'' in the definition of assent (Sec.
50.3(n)); (2) deleting ``and documents'' from Sec. Sec.  50.51 to
50.54; and (3) deleting ``if consistent with State law'' from Sec.
50.55(e)(1).

III. Comments and Agency Response

    The Agency received a total of 18 comments on the April 24, 2001,
interim rule. Five of those comments were from pharmaceutical
companies, four were from health care professionals, four were from
national membership organizations, three were from Federal Government
agencies, one was from a State legislator, and one was from a private
citizen. The majority of comments supported the rule. Most commenters
provided comment on specific provisions, including the areas on which
FDA solicited comment.

A. Definitions

    (Comment 1) We received one comment stating that our modification
of definitions creates several regulatory documents that are using
slightly different terms and definitions. The comment stated that these
differences would create challenges for sponsors as they try to meet
the requirements under one document but, due to slightly modified terms
and definitions, fail to meet requirements under another document.
    As we stated in the preamble to the interim rule, we are aware that
dissimilar or inconsistent Federal

requirements governing pediatric protections could be burdensome to
institutions, IRBs, and the process of clinical investigation (66 FR
20589 at 20591). The majority of modifications in the interim rule to
definitions from HHS subpart D were made only to the extent necessary
to make it clear that the definitions apply to participation in
clinical investigations regulated by FDA under sections 505(i) and
520(g) of the FD&C Act, as well as clinical investigations that support
applications for research or marketing permits for products regulated
by FDA. This final rule modifies some of the definitions in the interim
rule, resulting in greater consistency between HHS and FDA definitions,
as discussed further in this document.
1. Permission
    (Comment 2) Two comments supported our definition of ``permission''
at Sec.  50.3(r) and agreed that it was necessary to adopt this term.
We agree with those comments. However, we have decided to simplify the
definition by deleting the statement that permission must be obtained
in compliance with part 50, subpart B and must include the elements of
informed consent described in Sec.  50.25. As required under Sec.
50.55(f), permission by parents or guardians must be documented in
accordance with, and to the extent required by, Sec.  50.27, and thus
must include the elements of informed consent required by Sec.  50.25.
The identified language is therefore unnecessary. As a result of this
change, this definition and the definition of parental permission found
in 45 CFR 46.402(c) are the same.
2. Guardian
    We defined ``guardian'' at Sec.  50.3(s). In the preamble to the
interim rule, we explained that we were adopting the term because it is
currently used in HHS subpart D and is familiar to IRBs. Our
regulations at Sec.  50.3(l) use the term ``legally authorized
representative'' to describe an individual or judicial or other body
authorized under applicable law to consent on behalf of a prospective
subject to the subject's participation in the procedure(s) involved in
the research. Our definition of the term guardian was intended to make
it clear that, for purposes of FDA subpart D, a guardian must be an
individual who is legally authorized to consent to a child's
participation in research. We invited comment on our definition and any
implications under State or local law.
    (Comment 3) We received five comments on our definition of
guardian. All five comments raised concerns about our inclusion of
language stating that a guardian is an individual who is authorized to
consent on behalf of a child to participate in research.
    Two comments recommended that the definition of guardian at Sec.
50.3(s) should be the same as, or consistent with, the definition of
guardian at 45 CFR 46.402(e) of HHS subpart D. One comment noted that
under HHS subpart D, IRBs have been and continue to be responsible for
ensuring that HHS-sponsored or HHS-conducted studies involving children
comply with Federal, State, and local legal standards regarding
permission. The comment stated that it was unclear why a revised
definition was necessary in our regulation when no change is proposed
for the existing definition in the HHS regulation. The comment stated
that when HHS-sponsored research is also subject to FDA regulation, the
conflicting definitions will lead to confusion. The second comment
stated that our definition of guardian may result in unanticipated
consequences, since many State laws do not specifically authorize legal
guardians to provide consent to research. The comment stated that this
requirement would unnecessarily prevent some children with guardians
from participating in research from which they could benefit directly.
    Another comment stated that the additional language we suggested
represented a departure from the HHS definition and that it was unclear
whether State laws specifically authorize guardians to consent to
children's participation in clinical research. The comment stated that
FDA's change may represent a serious, unintended obstacle to children's
participation in research. The comment suggested defining a guardian as
an individual who is authorized under applicable State or local law to
consent on behalf of a child to general medical care and whose
consenting on behalf of the child to research participation is
consistent with applicable laws, if any.
    Two comments stated that our definition leaves open the possibility
that a guardian could be a person who is authorized to consent to a
child's participation in research, but not authorized to consent to
general medical care. These comments stated that this would be wholly
undesirable for the child and that the language should be clarified to
require that no one may consent to a child's participation in research
who is not also authorized to consent to the child's general medical
care. These comments also stated that it appears that many State laws
do not specifically authorize a guardian to permit a child's
involvement in research, so the definition may be very restrictive in
practice. These comments concluded that adequate protection for
children would result from the requirement that guardians should be
authorized to consent to general medical care and that they should be
in loco parentis, with a legally enforceable duty to care for the
totality of the child's interests.
    We appreciate the comments we received on State and local laws of
guardianship and the likelihood that many of these laws do not
specifically grant guardians the authority to consent to research. We
did not intend to create an obstacle to children's participation in
research or to prevent children under guardianship from participating
in beneficial research when we included authorization to consent to
research in the definition of guardian. We also did not intend to
suggest that it would be appropriate to allow a person who is
authorized to consent to research only, but not authorized to consent
to general medical care, to grant permission for a child to participate
in FDA-regulated research. We note, however, that we are not aware of
any State or local laws which authorize a guardian to consent to
research where the guardian does not have the authority to consent to
general medical care as well.
    After reviewing the comments submitted, we have decided to delete
the phrase ``when general medical care includes participation in
research,'' as State and local laws may be silent on whether general
medical care includes research participation. We have also deleted the
language stating that ``a guardian also means an individual who is
authorized to consent on behalf of a child to participate in
research.'' This revised definition makes it clear that under FDA
regulations a legally authorized guardian for general medical care may
consent on behalf of a child to participate in research in the absence
of specific laws granting (or restricting) that authority. It remains
the responsibility of an IRB to determine if there are any applicable
State or local laws that either grant or restrict that authority. This
revised definition of guardian is the same as the definition of
guardian in HHS 45 CFR 46.402(e) of HHS subpart D.

B. IRB Membership and Continuing Education

    (Comment 4) Two comments stated that IRB membership should include
professionals and lay persons with demonstrated competence working with
children, including pediatricians,

pediatric nurses, pediatric nutritionists, pediatric pharmacologists,
pediatric psychologists, nonclinical experts in pediatric issues, and
lay persons with a community sensitivity to the pediatric population
(e.g., preschool teachers). One comment suggested that an advisory
committee with specific expertise in pediatric areas of clinical
research be established for IRBs. This comment also stated that
processes need to be implemented to orient and educate IRB members on
an ongoing basis, as well as standards and procedures for self-
evaluation, including performance standards, self-assessment tools,
certification, and the development of peer-based accreditation systems.
One comment also suggested that all IRB members should complete a
course, such as the one offered by the Office for Human Research
Protections (OHRP), on IRB members' roles and responsibilities. This
comment suggested that FDA develop a course on additional safeguards
for children for those conducting research within the pediatric
population and that an intraregulatory approach between HHS and FDA
would provide consistency and uniformity in this educational process.
    FDA supports the intent of these comments to ensure IRB members are
adequately trained to make decisions on the unique aspects of
conducting clinical trials in children. Part 56 (21 CFR part 56) of our
regulations addresses IRBs generally. Section 56.107 requires IRBs to
have members with varying backgrounds to promote complete and adequate
review of research activities. This section requires the IRB to be
sufficiently qualified through the experience and expertise of its
members, the diversity of its members, and their sensitivity to issues
such as community attitudes, to promote respect for its advice and
counsel in safeguarding the rights and welfare of human subjects.
Section 56.107(a) specifically states that if an IRB regularly reviews
research that involves ``a vulnerable category of subjects, such as
children * * *, consideration shall be given to the inclusion of one or
more individuals who are knowledgeable about and experienced in working
with those subjects.'' Section 56.107(b) states that no IRB may consist
entirely of members of one profession. Section 56.107(c) requires that
each IRB shall include at least one member whose primary concerns are
in the scientific area and at least one member whose primary concerns
are in nonscientific areas. FDA Guidance (ICH E11) on ``Clinical
Investigation of Medicinal Products in the Pediatric Population''
advises that ``when protocols involving the pediatric population are
reviewed, there should be IRB/IEC members or experts consulted by the
IRB/IEC who are knowledgeable in pediatric ethical, clinical, and
psychosocial issues'' (Sec.  2.6.1, Ref. 1). In our view, these
provisions and guidance are adequate to ensure the appropriate
composition of members on IRBs reviewing clinical trials in children.
    We agree that it is important for members of an IRB reviewing such
trials to be educated and trained in appropriate areas. Although these
regulations do not require any specific training or continuing
education for IRB members, we discuss the programming and educational
needs for the IRB and investigator community with OHRP and others on an
ongoing basis. As part of our efforts, we will consider the need to
develop specific educational programs focusing on research involving
children.
    With regard to the comment requesting establishment of an advisory
committee for IRBs, we note that Sec.  56.107(f) provides that an IRB,
at its discretion, may invite individuals with competence in special
areas to assist in the review of complex issues that require expertise
beyond or in addition to that available on the IRB. These individuals
serve in an advisory capacity and do not vote with the IRB. We have
published extensive guidance for IRBs and clinical investigators to use
in conducting their reviews. This guidance is available on FDA's Web
site at http://www.fda.gov/ScienceResearch/SpecialTopics/RunningClinicalTrials/GuidancesInformationSheetsandNotices/default.htm.

C. Risk Categories

    As stated in the preamble to the interim rule, we adopted HHS
subpart D, as directed by Congress, with those changes necessary
because of differences between FDA's and HHS's regulatory authority.
Sections Sec.  50.51 through Sec.  50.53 describe the criteria under
which IRBs may approve clinical investigations of FDA-regulated
products in children. Section 50.54 describes the criteria under which
a clinical investigation that is otherwise not approvable by an IRB
under sections Sec.  50.51 through Sec.  50.53 may be referred to FDA
for review and consultation with a panel of experts.
1. Section 50.51--Clinical Investigations Not Involving Greater Than
Minimal Risk
    We received three comments on Sec.  50.51.
    (Comment 5) One comment requested a clearer definition of ``greater
than minimal risk.'' Although it noted that FDA provided examples of
types of procedures that fit the category of no more than minimal risk,
the comment stated that the term is vague and the definition is open to
interpretation.
    Another comment stated that the language of this provision deviated
in an important way from 45 CFR 46.404 of HHS subpart D, which places
responsibility for determining the level of risk with the IRB. The
comment stated that FDA only requires the IRB to find and document
adequate provisions for soliciting assent and permission, which may
create circumstances in which the investigator and the IRB disagree on
the level of risk. The comment acknowledged that any disagreement will
be resolved by the decision of the IRB, but the provision might cause
unnecessary conflict and confusion. The comment also stated that this
section appears internally inconsistent with Sec. Sec.  50.52 and 50.53
in which the IRB assesses the nature and level of risk and suggested
that the language of this provision should be consistent with 45 CFR
46.404 of HHS subpart D.
    Another comment stated that the rule should include a well-defined
scale system for risk assessment that would allow the IRB to classify
procedures and help in identifying the degree of minimal risk. As an
example, the comment stated that collecting a clean-catch urine sample
via a catheter has a potential to cause tissue injury and/or infection
and therefore has a higher degree of risk than testing devices
involving temperature readings orally or in the ear. The comment stated
that this type of scale would help IRBs in granting an approval for a
procedure by providing a specific ``distinction'' of the potential
risk.
    As stated in the preamble to the interim rule (66 FR 20589 at
20593), we previously adopted HHS's definition of minimal risk without
change in Sec.  50.3(k). The definition of minimal risk states that
``minimal risk means that the probability and magnitude of harm or
discomfort anticipated in the research are not greater in and of
themselves than those ordinarily encountered in daily life or during
the performance of routine physical or psychological examinations or
tests.'' As one comment noted, in the preamble to the interim rule we
provided examples of procedures and clinical investigations that may
present no greater than minimal risk to children.
    While we acknowledge that there is no specific definition of
``greater than minimal risk'' in these regulations, IRBs

are familiar with this category of research and have been applying it
for many years. Given this reality, we decline to add a definition of
``greater than minimal risk'' to our regulations at this time.
    The Children's Health Act also required a substantive review of HHS
subpart D, and required the Secretary to consider any necessary
modifications to ensure adequate and appropriate protection of children
participating in research. This review was conducted by OHRP and a
report was submitted to Congress in May 2001 entitled ``Protections for
Children in Research: A Report to Congress in Accord with Section 1003
of Public Law 106-310, Children's Health Act of 2000'' (2001 OHRP
report) (Ref. 4). While the 2001 OHRP report concluded that the current
HHS regulations under subpart D are sound, effective, and well-crafted,
the report identified terms and concepts for which further guidance is
needed. Among the terms and concepts identified in this report as
needing clarification are the terms ``minimal risk'' and ``minor
increase over minimal risk.''
    On January 4, 2002, the President signed BPCA 2002 into law. BPCA
2002 required HHS to contract with the Institute of Medicine (IOM) to
conduct a review of Federal regulations relating to research involving
children and report its findings to Congress. In the conduct of this
review, the IOM was required to consider the definition of minimal risk
with respect to children. The IOM published its report, ``Ethical
Conduct of Clinical Research Involving Children'' in 2004 (2004 IOM
report) (Ref. 5). The 2004 IOM report recommended that the Secretary's
Advisory Committee on Human Research Protections continue the work of
its predecessor committee (the National Human Research Protections
Advisory Committee) by developing additional consensus descriptions of
procedures or interventions that present minimal risk and no more than
a minor increase over minimal risk. The 2004 IOM report also
recommended that OHRP and FDA cooperate to develop and disseminate
guidance and examples for investigators and IRBs to clarify
definitions, including the definitions of minimal risk and minor
increase over minimal risk (2004 IOM report, p. 136) (Ref. 5).
    While both the 2001 OHRP report and the 2004 IOM report recommended
that further guidance may be appropriate to clarify the meaning of
minimal risk, neither report recommended changes to the current
regulatory definition of minimal risk. Although we will not change
FDA's definition of minimal risk at this time, we will consider
developing guidance to assist in determining whether a research
intervention poses minimal or more than minimal risk to children.
    We agree with the comment regarding the fact that Sec.  50.51 does
not specifically require IRBs to assess the level of risk in order to
approve a study under that provision. We have modified Sec.  50.51 to
make clear that it applies to clinical investigations involving
children as subjects where the IRB finds that no greater than minimal
risk to children is presented. This change is consistent with Sec.
46.404 of HHS subpart D and Sec. Sec.  50.52 and 50.53 of our
regulations, and clarifies that the IRB is responsible for reviewing,
assessing, and documenting the nature and level of risk in this
category. Furthermore, because an IRB is required to document its
findings under Sec.  56.115(a)(2), we also have deleted the phrase
``and documents'' as unnecessary, and have made the same change to
Sec. Sec.  50.51 through 50.54.
    While we appreciate the intent of the comment requesting a scale
system for assessing risk, attempting to identify and classify every
procedure that might be used in a clinical investigation as to its
appropriate risk category would be a difficult, if not impossible,
task. Rather, the broad categories laid out in the regulation will
assist IRBs in assessing the risk level for any specific intervention
and/or procedure in a clinical investigation on a case-by-case basis.
IRBs have been using this system of classification for many years.
However, if HHS proposes to change these risk categories, we will
review and consider modifying the corresponding provisions of our
regulations as appropriate.
2. Section 50.52--Clinical Investigations Involving Greater Than
Minimal Risk, But Presenting the Prospect of Direct Benefit to
Individual Subjects
    In our discussion of Sec.  50.52 in the preamble to the interim
rule (66 FR 20589 at 20593), we recognized that the requirement for the
prospect of direct benefit might create ambiguity as to whether
placebo-controlled clinical investigations may be conducted in children
under this section. We stated that placebo-controlled clinical
investigations in children may be conducted in accord with Sec.  50.52.
FDA invited comment on the issue of conducting placebo-controlled
investigations in children. We also noted that there is evidence of
direct benefit to children from participating in placebo-controlled
trials, including increased monitoring and care of subjects, even
though a child may not actually receive the test product. This
statement has been misinterpreted, and we provide clarification in the
paragraphs that follow.
    (Comment 6) Eight comments responded to FDA's request for comments
on the issue of placebo-controlled clinical investigations in children.
Five of the eight comments agreed with FDA that placebo-controlled
trials in children may be appropriate in certain circumstances. Two
comments opposed the conduct of placebo-controlled trials in healthy
children, and one comment opposed the conduct of placebo-controlled
trials in children with the active disease.
    Of the five comments that supported the use of placebo-controlled
clinical trials in children, four cited specific circumstances under
which placebo-controlled trials would be appropriate in children. One
comment stated that placebo-controlled trials should not be used in
serious diseases where the absence of an ``active substance'' might put
a child at undue risk. This comment stated that placebos should be used
only in ``benign'' diseases such as the common cold or mild to moderate
allergies because the absence of an active drug would not lead to a
permanent handicap. The comment also stated a belief that in a
controlled clinical trial, the active substance should be compared to
the best standard therapy for the disease, so that children with a
disease in a control group would be given the best standard therapy and
not a placebo.
    Another comment agreed with us that placebo-controlled trials may
be conducted in accord with the terms of Sec.  50.52. This comment
stated that certain vaccines and a number of drug trials for certain
non-life-threatening medical conditions may require use of placebo
designs in which the placebo does not provide a medical benefit. This
comment suggested that FDA evaluate specific circumstances on a study-
by-study basis.
    One comment noted that a prohibition or limitation on the use of
placebo-controlled trials in children would not assist us in our goals
of improving labeling and encouraging studies for children. This
comment also suggested that IRBs should retain broad latitude in
determining whether or not a particular placebo-controlled trial holds
out the prospect of direct benefit to the proposed subjects. This
comment cited guidelines established by the research community (ICH E
10 (Ref. 6); American Academy of Pediatrics (Ref. 7)) as support for
its position.

    One comment agreed with FDA that placebo-controlled trials in
children may be conducted if they are in accord with Sec.  50.51 or
Sec.  50.52; however, this comment suggested that an IRB's
determination of a prospect of direct benefit should be based primarily
on the potential benefit of the research intervention itself. The
comment suggested that FDA and HHS should develop guidance on what
benefits should be taken into account when determining whether a
protocol offers the prospect of direct benefit.
    Two comments expressed specific support for the view, which they
ascribed to the American Academy of Pediatrics, that placebos may be
used ethically in children only if their use does not place children at
increased risk. According to the comments, such increased risk includes
not only risk of mortality or increased or irreversible morbidity, but
also physical pain or other distress, including fear and inconvenience.
These comments suggested codifying these points in the rule.
    One comment was concerned with language in the preamble to the
interim rule stating that clinical investigations under Sec.  50.52
``generally are performed in children with the disease or condition for
which the product is intended'' (66 FR 20589 at 20593) (emphasis
added). This comment suggested that when a product presents more than
minimal risk to children, it should never be tested in children who do
not have the disease or condition for which the product is intended.
The comment stated a concern that healthy children are being recruited
to participate in clinical trials and should not be exposed to risk
unless their health is at stake. The comment suggested that if children
stand no chance of directly benefiting from the product being tested,
their participation in such trials should be prohibited. Similarly,
another comment stated that a healthy child should not be exposed to
any degree of risk, even if the clinical investigation may benefit
children with the disease.
    One comment was opposed to the use of placebo-controlled trials in
children. This comment stated that a child's development could be
affected by the use of placebos in Phase 1 trials. The comment also
stated that the use of placebos in Phase 2 trials could result in
negative outcomes. This comment stated that the rule should clearly
indicate that an investigational medicine would be compared against
another ``active medicine'' in the same class.
    We appreciate the numerous comments we received on this difficult
area. Our position on the conduct of placebo-controlled trials in
children takes into account the general guidance on the choice of
control groups found in FDA's guidance entitled ``International
Conference on Harmonisation E 10 Choice of Control Group and Related
Issues in Clinical Trials'' (May 2001) (Ref. 6) and the advice of the
Pediatric Subcommittee of the Anti-Infective Drugs Advisory Committee
(Pediatric Subcommittee) and the Pediatric Ethics Subcommittee (PES) of
FDA's Pediatric Advisory Committee (PAC). The PES and the PAC, and
previously the Pediatric Subcommittee, are charged with providing
advice and guidance on pediatric ethical issues.
    In general, the Pediatric Subcommittee has agreed that placebo-
controlled trials are acceptable in situations where there are no
approved or adequately studied therapies for children with the
condition under study. A Consensus Statement on the Pediatric
Subcommittee's September 11, 2000, meeting is available on FDA's Web
site at http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/ucm077894.htm (Ref. 8).
    The PES met in June 2008 to address the interpretation of prospect
of direct benefit as it relates to investigations conducted under the
FDA subpart D regulations, including placebo-controlled trials (Ref.
9). The PES specifically addressed the question of what benefits may be
considered ``direct'' under the FDA subpart D regulations, and whether
the benefits need to accrue to children in both the control and
treatment arms of a clinical trial. The general consensus of the PES
was that the placebo arm of a trial cannot be considered to confer the
prospect of direct benefit under Sec.  50.52 of the FDA subpart D
regulations. In general, the PES advised that the so-called
``inclusion'' benefit is not a ``direct'' benefit, and that children
enrolled in the placebo arm of a trial should be exposed to no more
than minimal risk or a minor increase over minimal risk (Ref. 9).
    FDA agrees with this position. Because we do not consider the
administration of a placebo to offer a prospect of direct benefit, part
50, subpart D, therefore requires that the placebo arm must present no
more than minimal risk (Sec.  50.51) or a minor increase over minimal
risk (Sec.  50.53), unless the clinical investigation is referred for
review under Sec.  50.54. As stated in ICH E10, in certain
circumstances a placebo-controlled study of an investigational drug or
biologic may involve the withholding of known effective treatment
(section 2.1.3., Ref. 6). In such situations, however, the risks of
such withholding of known effective treatment in the placebo control
group should present no more than minimal risk or a minor increase over
minimal risk, i.e. the placebo control arm of such a clinical trial
must be approvable under either Sec.  50.51 or Sec.  50.53. The arm
that receives the investigational product often would be approvable
under Sec.  50.52. With respect to the criteria that must be met for
approval underSec.  50.53, we note that the inclusion of children
without the disorder or condition under study would not meet the
requirement of Sec.  50.53(c) that ``the intervention or procedure is
likely to yield generalizable knowledge about the subjects' disorder or
condition.''
    With respect to the concern raised about physical pain or other
distress, including fear and inconvenience, we recognize that children
with a disorder or condition who are assigned to a placebo group might
experience physical pain or discomfort (although no serious risk). It
would usually be possible to design a trial to take this concern into
account (for example by introducing ``escape'' or withdrawal
provisions, such as defining an early escape as a treatment failure).
Regardless of the trial design, however, for such a clinical trial to
proceed, the risk of experiencing transient pain and/or discomfort
would need to represent no more than a minor increase over minimal
risk.
    This approach to the analysis of placebo-controlled trials is
consistent with the recommendation of the National Commission for the
Protection of Human Subjects of Biomedical and Behavioral Research
(created under the 1974 National Research Act, Public Law 93-348) that
the interventions that do and do not offer a prospect of direct benefit
in any given protocol must be analyzed separately (often called a
component analysis of risk) (43 FR 2084 at 2086 (January 13, 1978)).
This approach is applied to, for example, antimicrobial studies for the
treatment of acute bacterial otitis media in the FDA guidance entitled
``Acute Bacterial Otitis Media: Developing Drugs for Treatment''
(September 2012) (Ref. 2).
    (Comment 7) In the preamble to the interim rule, FDA discussed
strategies for mitigating risk in clinical investigations, including
exit strategies in the case of adverse events or a lack of efficacy or
establishing a data monitoring committee (DMC) to review ongoing data
collection and recommend

study changes (66 FR 20589 at 20593). One comment suggested that while
these strategies may be appropriate measures for an IRB when the
clinical trial is conducted by the IRB's institution, they may not be
appropriate actions for a local IRB involved in a sponsored global
clinical trial in which a DMC is part of the protocol and amendments
are generated by the responsible sponsor.
    Since we published the interim rule, we have issued a final
guidance for clinical trial sponsors on the establishment and operation
of clinical trial DMCs entitled ``Guidance for Clinical Trial Sponsors:
Establishment and Operation of Clinical Trial Data Monitoring
Committees'' (March 2006) (Ref. 10). This document discusses the role
of DMCs and other oversight groups, including IRBs, and the
relationship between sponsors and DMCs. As part of its initial
evaluation, an IRB may appropriately inquire as to whether a DMC has
been established and, if so, seek information about its scope and
composition. For ongoing trials, an IRB is responsible for considering
information arising from the trial that may bear on the continued
acceptability of the trial at the study site(s) it oversees. A DMC
generally has access to much more data than the IRB during the trial,
including interim efficacy and safety outcomes by treatment arm, and
makes recommendations with regard to the entire trial. Given its
obligation to minimize the risks to patients, an IRB may take action
based on information from any appropriate source, including
recommendations from a DMC to the sponsor. A trial may have multiple
IRBs, each responsible for the patients at a single site, but only one
DMC. Individual investigators (or the sponsor of investigational
devices) are responsible for assuring that IRBs are made aware of
significant new information that arises about a clinical trial. Such
information may include DMC recommendations to the sponsor that are
communicated to IRB(s), either directly or through individual
investigators or sponsors. Additionally, it may be useful for sponsors
to ensure that IRBs are informed when DMCs have met, even when no
problems have been identified and the DMC has recommended continuation
of the trial as designed.
3. Section 50.53--Clinical Investigations Involving Greater Than
Minimal Risk and No Prospect of Direct Benefit to Individual Subjects,
But Likely To Yield Generalizable Knowledge About the Subjects'
Disorder or Condition
    We solicited comments on Sec.  50.53, particularly on whether
further definitional criteria should be provided to aid IRBs in
understanding certain concepts, including: (1) How to measure a minor
increase in risk, (2) at what point a minimal risk develops into a
major risk, and (3) whether IRBs have the expertise necessary to
determine minor increases over minimal risk. We received four comments
on this section.
    (Comment 8) One comment expressed support for this provision,
stating that the regulations provide adequate protections for children
in research with more than minimal risk and provide IRBs with
sufficient criteria for review. The comment stated that IRBs have been
assessing ``increases over minimal risk and the balance between the
prospects of benefit to the individual participant or generalizable
knowledge and can continue to make these assessments on a case-by-case
basis.'' Citing documents currently available to guide IRBs, the
comment stated that there is no need for further definition or
elaboration of criteria in the regulations. The comment concluded that
additional criteria or definitions in the regulation would not provide
greater protections for research participants.
    In contrast, another comment expressed great concern regarding
``the power that has been bestowed upon IRBs.'' This comment stated
that protection of pediatric populations requires a high degree of
competency on the part of IRBs and pointed out that inappropriate
practices have been detected in the past. The comment stated that only
FDA should determine adequate guidelines for the procedures and that we
should be the only authority that decides whether a clinical
investigation in this category goes forward.
    Two comments on this section responded to our solicitation of
comments on appropriate criteria for an IRB to use in assessing more
than minimal risk. Both comments listed the critical factors as: (1)
Age and degree of physiological maturity of the child, (2) nature and
natural history of the clinical condition to be treated, (3) presence
of complicating clinical conditions, (4) efficacy and safety of the
treatment that may have been demonstrated in older patients, or that is
expected on the basis of other clinical or preclinical investigations,
and (5) likely duration of treatment and its impact upon the growth and
development of the child.
    We do not agree that only FDA should determine whether research in
this category proceeds. Further, IRBs are required to comply with all
applicable federal requirements, including those set forth in subpart
D, in their review of clinical investigations. To the extent concerns
have arisen, or may arise, concerning their compliance with Federal
requirements, both OHRP and FDA have taken regulatory action against
non-compliant IRBs and/or institutions and have worked to help
eliminate non-compliant procedures used by IRBs.
    Although there are many documents to guide IRBs in their
decisionmaking, we recognize that further elaboration of the criteria
set out in these final regulations may prove helpful. This may involve
a long-term process of coordination with other Agencies, including
OHRP. We appreciate comments received on the appropriate criteria for
an IRB to use in assessing more than minimal risk and, although we are
not incorporating these suggestions into the regulations at this time,
we will consider these suggestions in the future. As previously stated,
OHRP identified in its 2001 report to Congress the need for guidance on
terms and concepts in HHS subpart D, including the terms ``minimal
risk,'' ``the prospect of direct benefit for the individual subject,''
``condition,'' and ``disorder'' (Ref. 4) Should HHS propose changes to
HHS subpart D, we will review and consider modifying the corresponding
provisions of our regulations as appropriate.
4. Section 50.54--Clinical Investigations Not Otherwise Approvable That
Present an Opportunity To Understand, Prevent, or Alleviate a Serious
Problem Affecting the Health or Welfare of Children
    (Comment 9) We received five comments on this provision. One
comment stated that the requirement for public review and comment on
study proposals from private industry under Sec.  50.54 ``should be
reconsidered in view of the commercial confidential nature of clinical
drug development studies.'' This comment suggested that a closed
advisory committee meeting in which the committee would be supplemented
with invited guests should permit full consideration of the issues and
would satisfy the requirement for public review and comment. Three
comments supported the requirement for public review and comment, with
two of these comments recommending that FDA ``suspend'' a clinical
trial referred under Sec.  50.54 absent a sponsor's willingness to

publicly disclose the necessary information. One comment suggested that
ethical issues would stem from the unwillingness of a sponsor to
disclose needed information to the public, and that the ``secrecy'' of
the clinical investigation and its conduct would raise suspicion and
make people uncomfortable. The comment stressed that the rule should
emphasize our authority to ``suspend'' clinical investigations pending
the sponsor's willingness to share information with the public after
referral of the protocol for review under Sec.  50.54.
    Another comment requested that we clarify the requirements for the
review of research under Sec.  50.54. This comment stated that in cases
where a research study involving children is subject to both FDA and
HHS regulations, it is unclear which entity will make the determination
that the research can proceed, and that requiring a determination by
both entities might be unnecessarily duplicative. The comment also
noted that the preamble to the interim rule stated that FDA may not be
able to provide public review and comment if the sponsor is unwilling
to publicly disclose necessary information. The comment suggested that
the text of the regulation state explicitly that public review and
comment may not be possible in all cases given the FDA regulations
relevant to sponsor confidentiality.
    From the comments we received, it appears that confusion exists as
to the intent of our statements in the preamble to the interim rule
about the necessity of public review and comment. In the preamble we
stated ``Because FDA believes full public review and comment is
critical in determining whether a clinical investigation should proceed
under these circumstances, if a sponsor is unwilling to waive this
privilege, FDA may not be able to satisfy the public review and comment
requirement and any such clinical investigation could not proceed'' (66
FR 20589 at 20594). The intent of this statement was to make it clear
that if the public review and comment requirement could not be met
because some or all of the information necessary for that public review
and comment was trade secret and/or confidential commercial
information, and therefore could not be discussed publicly unless the
sponsor gave consent to have that information discussed publicly, the
criteria under Sec.  50.54 could not be met and thus the investigation
could not go forward.
    Because closed advisory committee meetings do not allow for public
participation or review of issues under discussion, we do not agree
that a closed advisory committee meeting satisfies the requirement for
public review and comment. The Agency would be unable to proceed with a
referral of a clinical investigation involving children under Sec.
50.54 unless there is full opportunity for public review and comment as
provided in this section.
    In December 2006, FDA published a final guidance document entitled
``Guidance for Clinical Investigators, Institutional Review Boards and
Sponsors; Process for Handling Referrals to FDA Under 21 CFR 50.54:
Additional Safeguards for Children in Clinical Investigations'' (Ref.
11). This final guidance describes the procedures FDA generally will
follow in handling clinical investigations referred for review under
Sec.  50.54 and in reaching final determinations under this regulation.
The guidance is based in part on FDA's experience to date with such
referrals. This guidance also addresses situations in which a clinical
investigation being referred involves an FDA-regulated product and is
conducted or supported by HHS, and therefore is subject to both FDA's
regulations (Sec.  50.54) and HHS regulations (45 CFR 46.407). If there
is a referral of a clinical investigation subject to both FDA and HHS
regulations, FDA's PAC is chartered to advise both the Commissioner of
FDA and the Secretary of HHS on referrals under Sec.  50.54 of FDA
subpart D and Sec.  46.407 of HHS subpart D.
    OHRP's guidance on the review process under 45 CFR 46.407, issued
in May 2005, is available on OHRP's Web page at http://www.hhs.gov/ohrp/policy/populations/guidance_407process.html (Ref. 12).

D. Obtaining Assent From Children

    We defined ``assent'' at Sec.  50.3(n). In Sec.  50.55 we listed
our requirements for assent by children, and in the preamble to the
interim rule we solicited comments on how to ensure that age-
appropriate explanations are provided to children. We received three
comments on soliciting and documenting assent and three comments on
ensuring age-appropriate explanations.
    (Comment 10) One comment suggested that the consent/assent of a
child or family member should be witnessed by an independent person at
the research facility and/or videotaped to ensure that proper and
truthful information has been provided in an understandable fashion to
children. A second comment requested that FDA define a minimum standard
for documentation of assent similar to that of informed consent. The
comment stated that a minimum standard would assist sponsors in
monitoring and other quality assurance efforts and would facilitate
increased consistency across clinical sites. The comment expressed
concern that if an IRB determined that pediatric assent was warranted
for a trial, but decided that documentation of the assent was
unnecessary, both sponsors and FDA would be unable to determine that
assent actually occurred. A third comment suggested that persons with
demonstrated competence in dealing with children be added to the assent
process to evaluate the cognitive levels of understanding for children
in various age groups.
    The requirements for assent listed at Sec.  50.55 are the same as
those in 45 CFR 46.408 of HHS subpart D. Because of the unique issues
raised when soliciting assent from children, permission (i.e., consent)
from one or both parents is required. This permission must be
documented in accordance with and to the extent required by Sec.
50.27. We do not agree that requiring an independent witness and/or
videotape of the process of soliciting parental permission or child
assent would, in every study, be necessary or would act as a safeguard.
We conclude that the procedures in Sec.  50.27 for documenting consent
are sufficient for an adult providing parental or guardian permission.
Additionally, in certain circumstances the use of videotape or the
presence of an independent witness might intimidate a child being asked
to provide assent. Under Sec.  50.55(g), the IRB determines whether and
how assent must be documented. If an IRB determines that videotaping
the assent process is appropriate or that an independent witness is
warranted, the IRB can require such procedures at its discretion as a
condition of study approval. We do not agree that adding a formal
evaluation of the cognitive levels of understanding for children in
various age groups is routinely warranted.
    FDA's guidance entitled ``E6 Good Clinical Practice: Consolidated
Guidance'' (ICH E6) (Ref. 13) recommends that a child ``should be
informed about the trial to the extent compatible with the [child]'s
understanding and, if capable, the [child] should assent, sign and
personally date the written informed consent'' (Sec.  4.8.12, ICH E6,
Ref. 13). In addition, the ``language used in the oral and written
information about the trial * * * should be understandable'' to the
child or the child's parent or guardian (Sec.  4.8.6, ICH E6, Ref. 13).
If a child is

deemed capable of assent, and the assent requirement is not waived
under Sec.  50.55(c) or (d), the language used should be understandable
to the child in order for the child's assent to be meaningful (Sec.
2.6.3, ICH E 11, Ref. 1). We are aware that some IRBs do not use a
separate child assent form, preferring an oral explanation along with
some form of documentation of a child's assent. At this time, we do not
plan to articulate a single standard similar to informed consent for
obtaining or documenting assent. Although adults are presumed to have
the level of competency necessary to grant informed consent, children's
levels of competency differ on an individual basis, and therefore there
is no one standard that would or could apply to all situations. In
Sec.  50.55, we have stated our requirements for the assent process and
left IRBs discretion to determine whether children in a particular
study are capable of providing assent. IRBs must determine for the
clinical trial as a whole, or for each child or group of children
within a trial, the appropriateness of obtaining assent, the ability of
children to understand the subject of their assent, and the method of
documentation appropriate to that understanding. Similarly, while we
encourage IRBs to require documentation of assent when appropriate, as
evidenced by Sec.  50.55(g), we consider the issue of whether and how
to document assent as appropriately left to the discretion of the IRB
based on its own assessment. The requirement that in all cases parental
or guardian permission must be granted and documented in accordance
with and to the extent required by Sec.  50.27 acts as a safeguard to
the assent process.
    (Comment 11) Three comments responded to our solicitation on
ensuring age-appropriate explanations to children. The first comment
stated that age-appropriate assent has long been a part of the HHS
regulations and that current, available guidance is sufficient to
assist IRBs in meeting their responsibilities. This comment stated that
there is no need for further definition or elaboration of criteria to
aid IRBs in ensuring age-appropriate explanations. A second comment
stated that FDA should encourage the study and publication of
techniques for securing the assent of pediatric patients. A third
comment stated that ensuring that children are provided with age-
appropriate explanations is both important and difficult. The comment
supported the factors listed in the regulation and added the following
factors: The environment in which the research will be conducted, the
expertise of the researchers, and the risks and benefits of the
specific protocol. The comment concluded that since these are matters
of informed judgment, the assessment of the appropriateness of the
explanation to children at a particular research site is best made by a
duly constituted IRB that, as necessary, consults with individuals with
expertise and experience in age-appropriate explanations.
    We agree with the comment that ensuring that children are provided
with age-appropriate explanations is important and difficult. We also
agree that the assessment of appropriateness is best left to the IRB
responsible for review of any specific protocol. However, if child
assent is required, persons who are knowledgeable and skilled in
dealing with children should be involved in the assent process to
detect and/or minimize child distress (Sec.  2.6.3 and 2.6.5; ICH E 11,
Ref. 1). While we acknowledge that age-appropriate assent has long been
a part of HHS regulations, we support the continued study and
publication of techniques for securing the assent of pediatric patients
in the best ways possible.

E. Waiver of Permission

    Consistent with the interim rule, we are not adopting the
provisions of HHS subpart D at 45 CFR 46.408(c) that allow IRBs to
waive the requirements for obtaining permission in certain
circumstances. The policy decision not to adopt the waiver of parental
or guardian permission found in 45 CFR 46.408(c) stems from FDA's
specific regulatory scheme. We explained in the preamble to the interim
rule that the only exceptions to our requirements for informed consent
are found in the emergency exceptions listed in part 50 of our
regulations.
    (Comment 12) We received six comments on this provision. Four
comments supported our decision not to adopt the waiver provision for
permission by parents or guardians. Two comments objected to our
decision not to adopt the waiver provision.
    Of the two comments that objected to our decision not to adopt the
waiver provision, one comment suggested that the waiver provision for
parental permission in HHS subpart D is appropriate in certain, unusual
circumstances and suggested that we adopt it in limited, appropriate
circumstances. The comment provided two possible examples of
circumstances it considered unusual: (1) The development of a new test
kit for a sexually transmitted disease or (2) studies involving
children who have been the victims of sexual abuse. The comment also
asked that FDA clarify that the option to waive informed consent in
emergency settings applies to pediatric research and that FDA
specifically state that the possible exceptions in Sec.  50.24 apply to
children as well.
    The other comment that objected to our decision not to adopt the
provision for waiver of parental permission asked us to interpret the
FD&C Act to enable mature adolescents to consent to involvement in
certain types of clinical studies without parental permission. The
comment stressed that if such an interpretation of the law is not
possible, we should seek to change the law to allow FDA and HHS
regulations to be consistent in this area. The comment stated that if
the waiver provision is not adopted, vital research involving mature
adolescents for whom seeking parental permission is not in their best
interest will not be conducted.
    The comment cited the example of research studies using new
therapeutic modalities for the human immunodeficiency virus (HIV) and
the acquired immunodeficiency virus (AIDS) in the HIV epidemic in the
late 1980s and early 1990s and stated that many adolescents who sought
treatment for HIV requested that their diagnosis be kept confidential
from their parents. The comment stated that such confidential treatment
was provided to these adolescents based on State laws allowing
physicians to treat adolescents for sexually transmitted diseases
without parental involvement. The comment continued that when new drugs
became available only under research protocols, these adolescents would
not have been afforded the potential benefits from participation in
such clinical trials if parental permission were required. The comment
stated that clinicians responded to this problem by asking IRBs to
invoke 45 CFR 46.408(c) of HHS subpart D to allow the research to
proceed without informing the parents of adolescents who requested
confidentiality. This comment also urged the development of guidance to
protect the interests of adolescents and children who are research
subjects.
    We have reviewed this issue and have decided not to adopt the
waiver of parental or guardian permission. We acknowledge that FDA and
HHS regulations are not harmonized on this point; however, as discussed
in the paragraphs that follow, we consider this difference to be
necessary and appropriate in light of FDA's existing

statutory and regulatory scheme. Furthermore, we conclude that,
notwithstanding the decision not to adopt the waiver of parental or
guardian permission, FDA's regulations will ensure that, as required by
section 2701 of the Children's Health Act, all FDA-regulated clinical
investigations are in compliance with 45 CFR part 46. Section 46.408(c)
of HHS subpart D does not represent a requirement that must be met in
order for a clinical investigation to be conducted in compliance with
HHS subpart D; rather, this waiver provision allows for a waiver of
certain requirements of HHS subpart D.
    We recognize that mature adolescents may contract diseases such as
HIV-AIDS and other sexually transmissible diseases, and that there are
important issues relating to the confidentiality of treatment sought.
We note that in some situations a State may grant certain classes of
mature adolescents of a specific age the right to consent to treatments
or procedures involved in a clinical investigation. These mature minors
would not meet the definition of children under Sec.  50.3(o) and thus
would not be subject to the requirements of this subpart. Similarly,
minors deemed ``emancipated'' by state law also would not meet the
definition of children under Sec.  50.3(o) and would not be subject to
the requirements of this subpart. Mature or emancipated minors would be
allowed to consent to participation in FDA-regulated research without
the need for parental or guardian permission. Thus, we consider
reliance on established state and/or local laws that establish an
adolescent as mature and/or emancipated to be appropriate in this
context. Furthermore, it would be difficult to limit the interpretation
and application of a waiver provision to narrowly apply to a limited
set of circumstances or appropriate conditions, as suggested by one
comment.
    In FDA's view, adopting the waiver provision in 45 CFR 46.408(c)
would be prohibited by the FD&C Act in certain circumstances, and would
be inconsistent with FDA's implementing regulations. Specifically,
section 520(g)(3) of the FD&C Act, which was added to the FD&C Act as
part of the Medical Device Amendments of 1976 (Pub. L. 94-295),
requires that informed consent be obtained from each human subject in a
clinical trial of a device, except when an exception is granted in
certain narrow emergency situations. Thus, the circumstances in which
an exception from the requirement for informed consent can be granted
in a clinical investigation of a medical device are specifically set
forth in FDA's statute. When FDA issued its informed consent
regulations (46 FR 8942, January 27, 1981), the agency sought to create
a single set of informed consent regulations (part 50), including
provisions for an exception from the requirement for informed consent,
that would provide consistent protections for subjects in trials
subject to FDA jurisdiction, regardless of the type of product being
investigated. Accordingly, the provisions in part 50 pertaining to
exceptions from the requirement for informed consent are based on those
in section 520(g)(3) of the FD&C Act, and apply to all FDA-regulated
clinical investigations.
    Because parental or guardian permission takes the place of informed
consent when the human subject is a child, a waiver of permission (as
in 45 CFR 46.408(c) of the HHS regulations) is equivalent to a waiver
of or exception from the requirement for informed consent, regardless
of whether child assent is obtained. If we were to amend our
regulations to allow for IRB waiver of or exception from the
requirement to obtain permission in certain clinical investigations
involving children, we would be prohibited from doing so by section
520(g)(3) of the FD&C Act with regard to medical device trials. Thus,
we would have two disparate standards of human subject protection (one
for clinical trials of devices and one for other trials regulated by
FDA) based not on ethical considerations, but rather based solely on
the type of product being studied. We conclude that this result would
not be in the interest of public health and safety, and that public
health and safety is best served by having uniform informed consent
requirements across medical product categories and that the informed
consent requirements should not vary depending on whether a clinical
trial regulated by FDA involves a drug, biological product, device, or
other product subject to FDA jurisdiction.
    We note that Sec.  50.23 sets forth an exception from the general
requirement to obtain informed consent in certain situations when a
human subject is confronted by a life-threatening situation
necessitating the use of a test article when there is not sufficient
time to obtain consent from the subject or the subject's legal
representative. FDA interprets this provision to apply to children when
there is not sufficient time to obtain parental or guardian permission.
The regulation therefore allows a test article to be administered to a
child if the investigator and an independent physician who is not
otherwise participating in the clinical investigation certify in
writing, before use of the test article, that certain conditions are
met, including that there is no alternative method of approved or
generally recognized therapy that provides an equal or greater
likelihood of saving the life of the child. However, Sec.  50.23 also
provides that, if immediate use of the test article is, in the
investigator's opinion, required to preserve the life of the subject
(in this context, the child), and time is not sufficient to obtain the
required independent determination in advance of using the test
article, the determinations of the clinical investigator shall be made
and, within 5 working days after the use of the article, be reviewed
and evaluated in writing by a physician who is not participating in the
clinical investigation. In either situation, the written documentation
must be submitted to the IRB within 5 working days after the use of the
test article.
    With regard to the concerns in the comment about emergency research
involving children, we wish to clarify that the emergency research
provisions in Sec.  50.24 apply, and always were intended to apply, to
clinical investigations involving children. We have added language to
Sec.  50.55(e) that originates from Sec.  46.408(b) of HHS subpart D
and was inadvertently omitted from the interim rule, indicating that
the exceptions from informed consent for emergency research described
in Sec.  50.24 apply to research in children. Section 50.55(e) now
reads, ``In addition to the determinations required under other
applicable sections of this subpart D, the IRB must determine, in
accordance with and to the extent that consent is required under part
50, that the permission of each child's parents or guardian is
granted'' (emphasis added). This change is being made to confirm that
the emergency provisions in part 50 apply to clinical investigations
involving children.

F. Wards

    (Comment 13) We received five comments on the participation of
children who are wards in clinical investigations. One comment
supported the appointment of an advocate for children who are wards.
One comment asked for clarification about the appointment process,
noting that the preamble to the interim rule states that the IRB itself
must appoint the advocate rather than assure that an advocate has been
appointed. Two comments asked for clarification about the role and
responsibilities of an advocate, and the obligations of a central IRB
and sponsor in monitoring the appointment of

advocates. One comment stated that the text of the preamble overstated
the meaning of Sec.  50.56 by specifying that an IRB appoint an
advocate for each child, noting that an IRB-appointed advocate would
essentially duplicate the role of an advocate who may already have been
appointed by the State or any other agency, institution, or entity. The
comment stated that the role of the IRB should be to review and confirm
that an advocate who meets the requirements of Sec.  50.56 has been
appointed. The comment stated that the advocate need not be the same
individual appointed by the State to serve as a guardian or in loco
parentis and that IRBs should be empowered to reject the selection of
the advocate presented for confirmation if the IRB believes that
individual to be unsuitable.
    We agree with the comment that the preamble overstated the
requirement, as set forth in Sec.  50.56, for the appointment of an
advocate. As Sec.  50.56 states, the IRB must require appointment of an
advocate for each child who is a ward, not appoint the advocate itself.
This advocate will serve in addition to any other individual acting on
behalf of the child as guardian or in loco parentis and will act in the
best interest of the child for the duration of the child's
participation in the clinical investigation. We note that Sec.  50.56
only addresses the circumstances in which wards can be included in
clinical investigations approved under Sec.  50.53 or Sec.  50.54, and
therefore only requires the appointment of an advocate in such clinical
investigations. It does not address the appointment of an advocate in
clinical investigations approved under Sec.  50.51 or Sec.  50.52;
however, the regulations do not preclude an IRB from considering the
appointment of an advocate in such clinical investigations in order to
assure that there is someone who will act in the best interest of the
child for the duration of the child's participation in the clinical
investigation. Before enrolling any child who is a ward in a clinical
investigation, IRBs should ensure that each child has a guardian and/or
advocate with the background, experience and commitment to act in the
best interest of the child.
    We do not consider it necessary to codify a provision specifically
empowering the IRB to reject the selection of an advocate if the IRB
finds that individual to be unsuitable. Other regulatory provisions,
including Sec.  56.113, provide the IRB with authority to suspend or
terminate research if it determines that any aspect of the research is
not in conformance with the regulations. This would include any
noncompliance with Sec.  50.56.

G. Biological Products

    (Comment 14) One comment requested that we clarify that the
regulations apply to biological products. Section 50.1 of part 50--
Protection of Human Subjects, and Sec.  56.101 of part 56--
Institutional Review Boards, clearly state that they apply to clinical
investigations regulated by FDA under sections 505(i) and 520(g) of the
FD&C Act, as well as clinical investigations that support applications
for research or marketing permits for products regulated by FDA,
including human drug and biological products; medical devices for human
use; foods, including dietary supplements, that bear a nutrient content
claim or health claim; infant formula; food and color additives; and
electronic products. Because Sec. Sec.  50.1 and 56.101 apply to this
final rule, it is unnecessary for us to include specific language in
this final rule indicating that it applies to biological products.

H. Economic Analysis

    We received three comments on the economic analysis in the interim
rule.
    (Comment 15) One comment stated that the estimate of additional
time to be spent by IRBs to review and document the level of risk may
be underestimated at one person-hour. The comment also raised concern
that the additional IRB responsibilities, including ensuring age-
appropriate explanations for assent and assessing strategies for the
appointment of advocates, will add to the time spent by IRBs to ensure
the safe conduct of pediatric clinical trials. The comment requested
clarification on the nature and scope of the documentation necessary.
    Under current regulations and guidance, IRBs are already required
to make several determinations concerning risk to participants and to
document those risks. The additional requirements of this rule state
that IRBs must specifically identify which of the four risk categories
applies to children in a clinical trial. We expect that this
determination will require some additional effort, but take at most one
person-hour of additional time. This estimate includes time for the
documentation required to identify the selected risk category.
    (Comment 16) Two comments stated that they did not agree with our
assumption that there would be no costs associated with clinical holds.
These comments noted that we did not calculate the potential impact of
the widespread accreditation of IRBs. These comments stated that
inspection of studies will be common as IRBs go through the
accreditation process and that, particularly in the pediatric area,
IRBs themselves may increase their inspection of studies to avoid
findings of ``noncompliance'' by accrediting bodies. The comments
concluded that increased inspections will probably uncover more
circumstances in which studies will be put on clinical hold.
    This rule does not require IRBs to undergo any accreditation
process. We do not know of any plans to require federally mandated
accreditation of IRBs, nor do we endorse any particular accreditation
body. Therefore, there are no costs from accreditation related to this
rule. While IRB reviews of pediatric clinical trials may become more
comprehensive if there are concerns about noncompliance, any increase
in IRB reviews because of noncompliance would not be attributable to
this rule, but to problems with noncompliance generally.

I. Requests for Additional Requirements

    (Comment 17) Two comments raised concerns that ethical standards
were not codified in the regulation. One comment called on us to ensure
that the pharmaceutical industry focuses on the ethical conduct of
clinical trials in children and not financial gain. The other comment
raised concern that the regulations do not include standards for
conflict of interest or require that such conflicts by investigators or
institutions be revealed on informed consent documents to parents or
guardians. The comment also noted that the regulations do not mention
rules for recruitment. This comment suggested that there should be
prohibitions against ``bribing'' parents with high payments to offer
their children for research and that compensation should cover only
direct expenses such as travel, meals and lodging costs, and daycare
for other children.
    FDA's regulations under 21 CFR part 54 govern financial disclosure
by clinical investigators and requires disclosure of certain financial
relationships between the sponsors of covered studies and the clinical
investigators, including interests of the clinical investigators in the
product under study or in the sponsor of the covered studies. We use
this information in conjunction with information about the design and
purpose of the study, as well as information obtained through onsite
inspections, in our assessment of the reliability of data presented.
    In August 2000, HHS held a conference on human subject protection
and financial conflicts of interest. As a result of this conference,
HHS issued a

final guidance in May 2004 entitled ``Financial Relationships and
Interests in Research Involving Human Subjects: Guidance for Human
Subject Protection'' (Ref. 14). Since that time, FDA has issued
additional guidance related to this issue, including a draft guidance
issued in May 2011 entitled ``Guidance for Clinical Investigators,
Industry, and FDA Staff: Financial Disclosure by Clinical
Investigators'' (Ref. 15), and a final guidance issued in October 2009
entitled ``Guidance for Industry: Investigator Responsibilities--
Protecting the Rights, Safety, and Welfare of Study Subjects'' (Ref.
16).
    Additionally, we note that ethical considerations for IRBs are
covered under several provisions of our regulations. Sections 56.107(a)
and 56.111 require IRBs to ensure that appropriate safeguards exist to
protect the rights and welfare of research subjects. In fulfilling
these responsibilities, an IRB is expected to review all the research
documents and activities that bear directly on the rights and welfare
of the subjects of proposed research. The protocol, the consent
document and, for studies conducted under the Investigational New Drug
(IND) regulations, the investigator's brochure are examples of
documents that the IRB should review. The IRB should also review the
methods and material that investigators propose to use to recruit
subjects (see ``Recruiting Study Subjects--Information Sheet,'' Ref.
17). Section 56.107 on IRB membership contains several provisions
designed to prevent conflicts of interest. Section 56.107(e) states
that no IRB may have a member participate in the IRB's initial or
continuing review of any project in which the member has a conflicting
interest, except to provide information requested by the IRB.
    Regulatory requirements for recordkeeping and retention of records
provide one means for FDA oversight of IRBs. Section 56.115(c) states
that we may refuse to consider a clinical investigation in support of
an application for a research or marketing permit if the institution or
the IRB that reviewed the investigation refuses to allow inspections of
its records or reports. Similarly, subpart E of part 56 outlines
various actions we may take against IRBs if we observe during an
inspection that an IRB is not complying with the regulations. These
actions include disqualification of an IRB, referral for civil or
criminal judicial proceedings, and any other appropriate regulatory
action. We may also refer matters to another Federal, State, or local
government Agency for any action that the Agency determines to be
appropriate.
    Although it is always possible that an IRB will not be in
compliance with all of our regulations, our current IRB regulations,
along with other human subject protection regulations, provide us with
multiple tools to ensure ethical conduct by IRBs, clinical
investigators, and sponsors. The 2001 OHRP report identified the need
for guidance on payment (financial or otherwise) that may be provided
either to children involved in research as subjects or to their
parents, under circumstances that minimize the possibility of coercion
or undue influence (Ref. 4). While the 2004 IOM report concluded that
payments related to research participation have a role to play in
reducing barriers and equalizing access to research participation, it
recommended that IRBs should develop written guidance and policies on
payments to children or parents related to research participation (Ref.
5). Should HHS propose changes to its regulations pertaining to IRB
oversight, we will review our regulations and consider revising them as
appropriate.

IV. Legal Authority

    This rule finalizes the interim rule published in 2001 to bring FDA
regulations into compliance with provisions of the Children's Health
Act (Pub. L. 103-310). Title XXVII, section 2701 of the Children's
Health Act required that within 6 months of enactment all research
involving children that is conducted, supported, or regulated by HHS be
in compliance with HHS regulations providing additional protections for
children involved as subjects in research. The HHS regulations are
codified at 45 CFR part 46 subpart D. FDA interprets the Children's
Health Act to require FDA to issue regulations to ensure that clinical
investigations of FDA-regulated products are conducted in compliance
with HHS subpart D.
    Additional authority for this rule derives from sections 505(i) and
520(g) of the FD&C Act regarding clinical investigations of FDA-
regulated drugs, biological products, and devices for human use. These
provisions direct the Commissioner to issue regulations for exempting
such investigational products from the general requirements for
preapproval or presubmission review. Among other stated objectives,
this final rule fulfills that mandate by enhancing protections for
children involved as subjects in clinical research of FDA-regulated
drugs, biological products, and devices for human use.
    A further source of authority for this rule is section 701 of the
FD&C Act (21 U.S.C. 371), which authorizes the Commissioner to issue
regulations for the efficient enforcement of the FD&C Act. This final
rule helps the efficient enforcement of the FD&C Act by enhancing
clarity and certainty in FDA's oversight of clinical investigations
involving children as subjects.

V. Environmental Impact

    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.

VI. Paperwork Reduction Act

    This final rule contains no new collection of information under the
Paperwork Reduction Act of 1995 (44 U.S.C. 3501-3520), and therefore
review by the Office of Management and Budget (OMB) is not required.
The information requested for clinical investigations in children of
FDA-regulated products is already covered by the collections of
information in the IND regulations (21 CFR part 312), the
investigational device exemption (IDE) regulations (21 CFR part 812),
the IRB regulations (Sec.  56.115), the food additive petition and
nutrient content claim petition regulations (21 CFR 101.69 and 101.70),
and the infant formula regulations (21 CFR parts 106 and 107), all of
which are approved by OMB. Specifically, the information collected
under the IND regulations is currently approved under OMB control
number 0910-0014. The information collected under the IDE regulations
is currently approved under OMB control number 0910-0078. The
information collected under the IRB regulations is currently approved
under OMB control number 0910-0130. The information collected in food
additive and nutrient content claim petitions is currently approved
under OMB control number 0910-0381 (general requirements) and 0910-0016
(FDA Form 3503). The information collected under the infant formula
regulations is currently approved under OMB control number 0910-0256
(general requirements) and 0910-0188 (infant formula recalls).

VII. Analysis of Impacts

A. Introduction

    FDA has examined the impacts of the final rule under Executive
Order 12866, Executive Order 13563, the Regulatory Flexibility Act (5
U.S.C. 601-612), and

the Unfunded Mandates Reform Act of 1995 (Pub. L. 104-4). Executive
Orders 12866 and 13563 direct 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 under Executive
Order 12866.
    The Regulatory Flexibility Act requires Agencies to analyze
regulatory options that would minimize any significant impact of a rule
on small entities. The Agency certifies that the final rule will not
have a significant economic impact on a substantial number of small
entities.
    Section 202(a) of the Unfunded Mandates Reform Act of 1995 requires
that Agencies prepare a written statement, which includes an assessment
of anticipated costs and benefits, before proposing ``any rule that
includes any Federal mandate that may result in the expenditure by
State, local, and tribal governments, in the aggregate, or by the
private sector, of $100,000,000 or more (adjusted annually for
inflation) in any one year.'' The current threshold after adjustment
for inflation is $139 million, using the most current (2011) 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. Updated Analysis

    The interim final rule (66 FR 20589 at 20596, April 24, 2001)
imposed an additional burden on IRBs reviewing investigations which
involve children. The estimated costs of the interim final rule were
estimated to be small ($933,000 in year 2001 and $23,550 per year in
years 2002 through 2009). As the interim final rule has been in effect
since April 2001, the publication of this final rule will have little
additional impact. However, we update the estimated costs of the
interim rule for the post-2001 period to adjust for inflation and
availability of more recent data. The total annual cost of reviewing
pediatric clinical trials remains at $933,000 (this includes a one-time
cost of $900,000 to conduct a one-time review and update standard
operating procedures plus $33,000 for annual reviews) for the year
2001. The revised annual review cost for the post-2001 period ranges
between $79,817 and $112,357 per year (see table 1 in this document).
    The revised post-2001 costs per year are revised as follows. First,
the annual IRB costs per year are in inflation-adjusted (2010) dollars.
Second, we use recent data from the various FDA centers reviewing
protocols involving pediatrics, and update the total number of studies
affected by the rule to be between 872 and 1,227 per year. We note that
given data limitations we are unable to use the same period of analysis
across centers. To the extent that there has been an increase in the
number of protocols involving children since 2001, then using the most
recently available data would provide an upper bound estimate on the
average number of protocols received after 2001. However, over the past
few years, most offices within FDA's Center for Drug Evaluation and
Research (CDER) did not observe a significant increase in the
percentage change of protocols received. Thus, we believe that the
impact of using different periods of data is negligible. The data and
methodology used are discussed in more detail in the paragraphs that
follow.
    The estimated number of drug- and biologics-related protocols
involving pediatrics ranges from 561 to 637. The number of drug-related
or biologics-related protocols (553 to 610) provided by CDER was based
on data from fiscal year 2011. The range of protocols related to
biological products regulated by FDA's Center for Biologics Evaluation
and Research (CBER) represents the minimum (8 in fiscal year 2004) and
maximum (27 in fiscal year 2011) number of pediatric protocols received
by CBER during fiscal years 2002-2011. The count is adjusted up 30
percent \1\ to account for IND-exempt protocols.
---------------------------------------------------------------------------

    \1\ This estimate is determined based on discussions with
academic and commercial IRBs on the estimated percent of pediatric
protocols which are exempt from filing an IND application.
---------------------------------------------------------------------------

    We estimate that 305 to 572 medical device protocols involve
pediatrics. This is calculated by using the average number of
applications or submissions (including supplements) reviewed by FDA's
Center for Devices and Radiological Health per year and an estimate on
the percent of medical device applications involving children. We
estimate that, using the number of approved IDE pediatric studies as
reported by FDA's Center Tracking System (7 to 13), and the average
number of original IDE submissions (219) in fiscal years 2008-2009, 3
percent to 6 percent of medical device protocols involve pediatrics. We
note that there could be some high-risk medical devices which might not
be included in our estimated number of protocols for medical devices;
however, data limitations do not permit us to quantify the extent to
which our estimates would have to be adjusted up.
    Finally, the estimated number of protocols for food additives and
infant formula are extrapolated using the average High-to-Low ratio (3-
to-1) across the other products and the initial estimates in the final
rule. For instance, to determine the upper-bound estimate for infant
formula we multiply the 2001 estimate by the High-to-Low ratio (5 x 3).

            Table 1--Estimated Number of IRB Reviews per Year for Clinical Investigations in Children
----------------------------------------------------------------------------------------------------------------
                                                                                Per year post-2001
                                                                 -----------------------------------------------
                                                                       2001             Low            High
----------------------------------------------------------------------------------------------------------------
Drugs and Biological Products...................................             264             561             637
Medical Devices.................................................             170             305             572
Foods and Food Additives:
    Infant Formula..............................................               5               5              15
    Food Additives..............................................               1               1               3
                                                                 -----------------------------------------------
        Total IRB Reviews per year..............................             440             872           1,227
                                                                 -----------------------------------------------
            Total IRB Costs per year............................         $33,000         $79,817        $112,357
----------------------------------------------------------------------------------------------------------------

VIII. Federalism

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

IX. 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,
and are available electronically at http://www.regulations.go. (FDA has
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. FDA ``Guidance for Industry: ICH E11 Clinical Investigation of
Medicinal Products in the Pediatric Population,'' December 2000,
available at http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM073143.pdf,
accessed June 21, 2012.
    2. FDA ``Guidance for Industry: Acute Bacterial Otitis Media:
Developing Drugs for Treatment,'' September 2012, available at http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM070947.pdf, accessed October 15, 2012.
    3. FDA ``Guidance for Industry: Orally Inhaled and Intranasal
Corticosteroids: Evaluation of the Effects on Growth in Children,''
March 2007, available at http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm071968.pdf,
accessed June 21, 2012.
    4. OHRP ``Protections for Children in Research: A Report to
Congress in Accord with Section 1003 of P.L. 106-310, Children's Health
Act of 2000,'' May 2001, available at: http://www.hhs.gov/ohrp/archive/reports/ohrp502.pdf, accessed June 21, 2012.
    5. Committee on Clinical Research Involving Children, Board on
Health Sciences Policy, Institute of Medicine of the National
Academies, ``Ethical Conduct of Clinical Research Involving Children,''
Marilyn J. Field and Richard E. Behrman, Eds., The National Academies
Press, 2004, available at http://www.iom.edu/Reports/2004/Ethical-Conduct-of-Clinical-Research-Involving-Children.aspx, accessed June 21,
2012.
    6. FDA ``Guidance for Industry: E 10 Choice of Control Group and
Related Issues in Clinical Trials,'' May 2001, available at http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM073139.pdf, accessed June 25, 2012.
    7. Committee on Drugs, American Academy of Pediatrics, ``Guidelines
for the Ethical Conduct of Studies to Evaluate Drugs in Pediatric
Populations,'' Pediatrics, vol. 95, No. 2, pp. 286-294, February 1995.
    8. FDA ``FDA Pediatric Ethics Working Group Consensus Statement on
Pediatric Advisory Subcommittee's September 11, 2000,'' available at
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/ucm077894.htm, accessed June 25, 2012.
    9. FDA Pediatric Ethics Subcommittee of the Pediatric Advisory
Committee, June 9-10, 2008 meeting. The agenda, briefing information,
slides, minutes and transcripts can be found at http://www.fda.gov/ohrms/dockets/ac/oc08.html#pac, accessed June 27, 2012. Relevant
excerpts of the transcripts are on display in the FDA Division of
Dockets Management.
    10. FDA ``Guidance for Clinical Trial Sponsors: Establishment and
Operation of Clinical Trial Data Monitoring Committees,'' March 2006,
available at http://www.fda.gov/downloads/RegulatoryInformation/Guidances/ucm127073.pdf, accessed June 25, 2012.
    11. FDA ``Guidance for Clinical Investigators, Institutional Review
Boards and Sponsors; Process for Handling Referrals to FDA Under 21 CFR
50.4: Additional Safeguards for Children in Clinical Investigations, ''
December 2006, available at http://www.fda.gov/downloads/RegulatoryInformation/Guidances/ucm127605.pdf, accessed June 25, 2012.
    12. HHS Office of Human Research Protections ``Children Involved as
Subjects in Research: Guidance on the HHS 45 CFR 46.407 (``407'')
Review Process,'' May 2005, available at http://www.hhs.gov/ohrp/policy/populations/guidance_407process.html, accessed on June 25,
2012.
    13. FDA ``Guidance for Industry: E6 Good Clinical Practice:
Consolidated Guidance,'' April 1996, available at http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM073122.pdf, accessed June 25, 2012.
    14. Department of Health and Human Services, ``Final Guidance
Document: Financial Relationships and Interests in Research Involving
Human Subjects: Guidance for Human Subject Protection'' May 2004,
available at http://www.hhs.gov/ohrp/policy/fguid.pdf, accessed June
25, 2012.
    15. FDA ``Guidance for Clinical Investigators, Industry, and FDA
Staff: Financial Disclosure by Clinical Investigators,'' May 2011,
available at http://www.fda.gov/downloads/RegulatoryInformation/Guidances/UCM256525.pdf, accessed June 25, 2012.
    16. FDA ``Guidance for Industry: Investigator Responsibilities--
Protecting the Rights, Safety, and Welfare of Study Subjects,'' October
2009, available at http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM187772.pdf,
accessed on June 25, 2012.
    17. FDA ``Recruiting Study Subjects--Information Sheet. Guidance
for Institutional Review Boards and Clinical Investigators,'' page last
updated: 10/18/2010, available at http://www.fda.gov/RegulatoryInformation/Guidances/ucm126428.htm, accessed June 25, 2012.

List of Subjects

21 CFR Part 50

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

21 CFR Part 56

    Human research subjects, Report and recordkeeping requirements,
Safety.

    Accordingly, the interim rule amending 21 CFR parts 50 and 56 which
was published at 66 FR 20589, on April 24, 2001, is adopted as a final
rule with the following changes:

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.

Sec.  50.3  [Amended]

0
2. Amend Sec.  50.3 by revising paragraphs (n), (r), and (s) to read as
follows:

Sec.  50.3  Definitions.

* * * * *
    (n) Assent means a child's affirmative agreement to participate in
a clinical investigation. Mere failure to object should not, absent
affirmative agreement, be construed as assent.
* * * * *
    (r) Permission means the agreement of parent(s) or guardian to the
participation of their child or ward in a clinical investigation.
    (s) Guardian means an individual who is authorized under applicable
State or local law to consent on behalf of a child to general medical
care.

0
3. Revise Sec.  50.51 to read as follows:

Sec.  50.51  Clinical investigations not involving greater than minimal
risk.

    Any clinical investigation within the scope described in Sec. Sec.
50.1 and 56.101 of this chapter in which no greater than minimal risk
to children is presented may involve children as subjects only if the
IRB finds that:
    (a) No greater than minimal risk to children is presented; and
    (b) Adequate provisions are made for soliciting the assent of the
children and the permission of their parents or guardians as set forth
in Sec.  50.55.

0
4. Revise the introductory text of Sec.  50.52 to read as follows:

Sec.  50.52  Clinical investigations involving greater than minimal
risk but presenting the prospect of direct benefit to individual
subjects.

    Any clinical investigation within the scope described in Sec. Sec.
50.1 and 56.101 of this chapter in which more than minimal risk to
children is presented by an intervention or procedure that holds out
the prospect of direct benefit for the individual subject, or by a
monitoring procedure that is likely to contribute to the subject's
well-being, may involve children as subjects only if the IRB finds
that:
* * * * *

0
5. Revise the introductory text of Sec.  50.53 to read as follows:

Sec.  50.53  Clinical investigations involving greater than minimal
risk and no prospect of direct benefit to individual subjects, but
likely to yield generalizable knowledge about the subjects' disorder or
condition.

    Any clinical investigation within the scope described in Sec. Sec.
50.1 and 56.101 of this chapter in which more than minimal risk to
children is presented by an intervention or procedure that does not
hold out the prospect of direct benefit for the individual subject, or
by a monitoring procedure that is not likely to contribute to the well-
being of the subject, may involve children as subjects only if the IRB
finds that:
* * * * *

0
6. Revise paragraph (a) of Sec.  50.54 to read as follows:

Sec.  50.54  Clinical investigations not otherwise approvable that
present an opportunity to understand, prevent, or alleviate a serious
problem affecting the health or welfare of children.

* * * * *
    (a) The IRB finds that the clinical investigation presents a
reasonable opportunity to further the understanding, prevention, or
alleviation of a serious problem affecting the health or welfare of
children; and
* * * * *

0
7. Revise paragraph (e) of Sec.  50.55 to read as follows:

Sec.  50.55  Requirements for permission by parents or guardians and
for assent by children.

* * * * *
    (e) In addition to the determinations required under other
applicable sections of this subpart D, the IRB must determine, in
accordance with and to the extent that consent is required under part
50, that the permission of each child's parents or guardian is granted.
    (1) Where parental permission is to be obtained, the IRB may find
that the permission of one parent is sufficient for clinical
investigations to be conducted under Sec.  50.51 or Sec.  50.52.
    (2) Where clinical investigations are covered by Sec.  50.53 or
Sec.  50.54 and permission is to be obtained from parents, both parents
must give their permission unless one parent is deceased, unknown,
incompetent, or not reasonably available, or when only one parent has
legal responsibility for the care and custody of the child.
* * * * *

PART 56--INSTITUTIONAL REVIEW BOARDS

0
8. The authority citation for 21 CFR part 56 continues to read as
follows:

    Authority:  21 U.S.C. 321, 343, 346, 346a, 348, 350a, 350b, 351,
352, 353, 355, 360, 360c-360f, 360h-360j, 371, 379e, 381; 42 U.S.C.
216, 241, 262, 263b-263n.

0
9. Revise in Sec.  56.109 the second sentence of paragraph (h) to read
as follows:

Sec.  56.109  IRB review of research.

* * * * *
    (h) * * * When some or all of the subjects in a study that was
ongoing on April 30, 2001, are children, an IRB must conduct a review
of the research to determine compliance with part 50, subpart D of this
chapter, either at the time of continuing review or, at the discretion
of the IRB, at an earlier date.

    Dated: February 21, 2013.
Leslie Kux,
Assistant Commissioner for Policy.
[FR Doc. 2013-04387 Filed 2-25-13; 8:45 am]
BILLING CODE 4160-01-P