
[Federal Register Volume 78, Number 38 (Tuesday, February 26, 2013)]
[Rules and Regulations]
[Pages 12937-12951]
From the Federal Register Online via the Government Printing Office [www.gpo.gov]
[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, 301-796-8659.

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

[[Page 12938]]

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

[[Page 12939]]

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,

[[Page 12940]]

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

[[Page 12941]]

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.

[[Page 12942]]

    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

[[Page 12943]]

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

[[Page 12944]]

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

[[Page 12945]]

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

[[Page 12946]]

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

[[Page 12947]]

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

[[Page 12948]]

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

[[Page 12949]]

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
----------------------------------------------------------------------------------------------------------------


[[Page 12950]]

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:

[[Page 12951]]

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


