[Federal Register Volume 66, Number 79 (Tuesday, April 24, 2001)]
[Rules and Regulations]
[Pages 20589-20600]
From the Federal Register Online via the Government Printing Office [www.gpo.gov]
[FR Doc No: 01-10008]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

 21 CFR Parts 50 and 56

[Docket No. 00N-0074]
RIN 0910-AC07


Additional Safeguards for Children in Clinical Investigations of 
FDA-Regulated Products

AGENCY: Food and Drug Administration, HHS.

ACTION: Interim rule; opportunity for public comment.

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SUMMARY: The Food and Drug Administration (FDA) is issuing an interim 
rule to amend its regulations to provide additional safeguards for 
children enrolled in clinical investigations of FDA-regulated products. 
This interim rule is intended to bring FDA regulations into compliance 
with provisions of the Children's Health Act of 2000 (the Children's 
Health Act), which requires that within 6 months of its enactment 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. To comply with this congressionally 
mandated timeframe and for other reasons described in this document, 
FDA is publishing this regulation as an interim rule.
    FDA is requiring additional safeguards to protect children because 
of expected increases in the enrollment of children in clinical 
investigations as a result of recent pediatric initiatives. These 
initiatives include FDA's 1998 pediatric rule (the 1998 pediatric rule) 
and the pediatric provisions of the Food and Drug Administration 
Modernization Act of 1997 (the Modernization Act).

DATES: This interim rule is effective April 30, 2001. Submit written 
comments by July 23, 2001. Submit written comments on the information 
collection requirements by May 24, 2001.

ADDRESSES: Submit written comments to the Dockets Management Branch 
(HFA-305), Food and Drug Administration, 5630 Fishers Lane, rm. 1061, 
Rockville, MD 20857. Submit written comments on the information 
collection provisions to the Office of Information and Regulatory 
Affairs, Office of Management and Budget (OMB), New Executive Office 
Bldg., 725 17th St. NW., rm. 10235, Washington, DC 20503, Attn: Desk 
Officer for FDA.

FOR FURTHER INFORMATION CONTACT:  Carol Drew, Center for Drug 
Evaluation and Research (HFD-7), Food and Drug Administration, 5600 
Fishers Lane, Rockville, MD 20857, 301-594-2041.

SUPPLEMENTARY INFORMATION:

I. Background

    FDA's authority includes regulation of safety and effectiveness 
testing in humans of certain FDA-regulated products. FDA-regulated 
products include human drug and biological products, medical device 
products, and dietary supplements, nutritional, food additive, and 
foods. This rule covers safety and effectiveness testing of FDA-
regulated products in children. FDA expects an increase in testing of 
drug and biological products in children as a result of recent 
initiatives in pediatric research.

A. Recent Initiatives in Pediatric Research

    The 1998 pediatric rule (63 FR 66632, December 2, 1998) requires 
manufacturers to assess the safety and effectiveness of certain drug 
and biological products in pediatric patients. In the preamble to the 
1998 pediatric rule, FDA stated that many drug and biological products 
marketed in the United States that are or could be used in children are 
inadequately labeled for use in pediatric patients or specific 
pediatric subgroups. FDA concluded that the absence of pediatric 
labeling information for these drug and biological products posed 
significant risks for children.
    The 1998 pediatric rule establishes a presumption that certain drug 
and biological products will be studied in pediatric patients. The 1998 
pediatric rule also authorizes FDA to require pediatric studies of 
those marketed drug and biological products that: (1) Are used in a 
substantial number of pediatric patients for the labeled indications, 
and where the absence of adequate labeling could pose significant risks 
to pediatric patients; or (2) would provide a meaningful therapeutic 
benefit over existing treatments for pediatric patients for one or more 
of the claimed indications, and the absence of adequate labeling could 
pose significant risks to pediatric patients.
    The Modernization Act (Public Law 105-115) established economic 
incentives for manufacturers to conduct pediatric studies on drugs for 
which exclusivity or patent protection is available under the Drug 
Price Competition and Patent Term Restoration Act (Public Law 98-417) 
or the Orphan Drug Act (Public Law 97-414). These provisions attach 6 
months of marketing exclusivity to any existing exclusivity or patent 
protection on a drug for which FDA has requested pediatric studies and 
the manufacturer has conducted such studies in accordance with the 
requirements of the Modernization Act.
    As of October 1, 2000, FDA had received 194 proposed pediatric 
study requests under the exclusivity provisions of the Modernization 
Act and had issued 157 Written Requests for pediatric studies. A 
Written Request is

[[Page 20590]]

a specific document from FDA in which the agency requests submission of 
certain studies to determine if the use of a drug could have meaningful 
health benefits in the pediatric population. Sponsors have indicated 
they are conducting or planning to conduct over 80 percent of the 
studies for which Written Requests have been issued.
    FDA expects that the combination of the pediatric exclusivity 
incentive of the Modernization Act and the requirements of the 1998 
pediatric rule will significantly increase the number of FDA-regulated 
products for which pediatric studies will be conducted. This increase 
in studies has led to concern over the adequacy of existing safeguards 
for pediatric study subjects.
    In addition to the Modernization Act and the 1998 pediatric rule, 
FDA has initiated other actions to encourage the development of 
adequate pediatric use information for drug and biological products. 
Among other actions, FDA has published several pediatric guidance 
documents. (See FDA's pediatric website at http://www.fda.gov/cder/
pediatric.)
    FDA's view that additional pediatric safeguards are necessary is 
underscored by title XXVII, section 2701 of the Children's Health Act 
(Public Law 106-310), in which Congress directs the Secretary of HHS 
(the Secretary) to require all research involving children that is 
conducted, supported, or regulated by HHS to be in compliance with 45 
CFR part 46, subpart D (HHS subpart D) within 6 months of the date of 
enactment. The Children's Health Act was signed by the President on 
October 17, 2000. Clinical investigations involving FDA-regulated 
products, therefore, must comply with the standards of HHS subpart D by 
April 17, 2001. To respond to this congressionally mandated timeframe 
and for other reasons described in this document, FDA is publishing 
this regulation as an interim rule.
    In addition to requiring that HHS subpart D be applied to clinical 
investigations involving FDA-regulated products, Congress is requiring 
a substantive review of HHS subpart D. Title X, section 1003 of the 
Children's Health Act requires the Secretary to review HHS subpart D, 
consider any necessary modifications to ensure the adequate and 
appropriate protection of children participating in research, and 
report the findings to Congress. If, as a result of this evaluation, 
HHS proposes to modify HHS subpart D, FDA will review and modify this 
interim rule as appropriate.

B. Early Initiatives for Pediatric Safeguards

    The National Research Act (Public Law 93-348), signed into law on 
July 12, 1974, created the National Commission for the Protection of 
Human Subjects of Biomedical and Behavioral Research (the Commission). 
One of the Commission's charges was to make recommendations pertaining 
to research involving children, including the purposes of such 
research, the steps necessary to protect children as subjects, and 
requirements for the informed consent of children or their parents or 
guardians. The Commission was required to recommend to the Secretary 
(of HHS or the Department)\1\  policies defining circumstances under 
which research with and for children might be appropriate. The 
recommendations of the Commission pertaining to research involving 
children were published in the Federal Register of January 13, 1978 (43 
FR 2084). After review of the Commission's report, recommendations, and 
public comments, the Secretary published in the Federal Register of 
July 21, 1978 (43 FR 31786), a notice of proposed rulemaking on 
research involving children conducted or supported by HHS. HHS reviewed 
the public comments received on the proposal and also considered the 
Basic HHS Policy for the Protection of Human Research Subjects (45 CFR 
part 46). On March 8, 1983, HHS published its final rule incorporating 
requirements for the protection of children involved as subjects in 
HHS-conducted or HHS-supported research (48 FR 9814). This rule is 
codified at 45 CFR part 46, subpart D. These regulations supplemented 
basic regulations governing the protection of human subjects involved 
in research conducted or supported by HHS (30 FR 18914, May 30, 1974).
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    \1\ At the time, HHS was named the Department of Health, 
Education, and Welfare. To avoid confusion, this document uses only 
the Department's current name, HHS.
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    In the Federal Register of April 24, 1979 (44 FR 24106), FDA 
proposed regulations and solicited comments on applying the principles 
set forth in the HHS regulations to all pediatric research subject to 
FDA jurisdiction. This proposal was not finalized and was withdrawn on 
December 30, 1991 (56 FR 67440).

C. Current Safeguards for Pediatric Research

    HHS subpart D provides protections for children involved in HHS-
conducted or HHS-supported research. If an FDA-regulated clinical 
investigation is not conducted or supported by HHS, HHS subpart D does 
not impose requirements on the investigation. Nevertheless, FDA has 
historically relied on the HHS regulations to provide appropriate 
guidance for pediatric studies. In addition, as described below, there 
are other safeguards in place for pediatric research.
    Current FDA regulations in part 56 (21 CFR part 56) governing 
institutional review boards (IRBs) include children as a class of 
vulnerable subjects, but do not specifically address the enrollment of 
children in clinical investigations. Portions of part 56 address 
pediatric issues. In Sec. 56.111(a)(3), IRBs are required to determine 
that the selection of subjects in research is equitable and, to do so, 
should be ``particularly cognizant of the special problems of research 
involving vulnerable populations, such as children * * *.'' Section 
56.111(b) states, ``When some or all of the subjects, such as children 
* * *, are likely to be vulnerable to coercion or undue influence [,] 
additional safeguards have been included in the study to protect the 
rights and welfare of these subjects.'' Section 56.107(a) addresses IRB 
membership and provides 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.''
    FDA's information sheets entitled ``Guidance for Institutional 
Review Boards and Clinical Investigators'' address issues regarding 
informed consent and the assent of children. This guidance states that 
although FDA regulations regarding informed consent do not specifically 
address the enrollment of children, the basic requirements of 
Sec. 50.20 (21 CFR 50.20) regarding informed consent apply. The 
information sheets also state that HHS regulations for conduct of 
studies in children may be used as guidance for all pediatric studies. 
These information sheets are available at www.fda.gov/oc/oha/IRB/
toc.html.
    FDA also has published a guidance entitled ``E11 Clinical 
Investigation of Medicinal Products in the Pediatric Population'' (ICH 
E11). This guidance was prepared by the International Conference on 
Harmonisation of Technical Requirements for Registration of 
Pharmaceuticals for Human Use (ICH) as part of the ICH effort to 
harmonize technical requirements for the registration of pharmaceutical 
products among the European Union, Japan, and

[[Page 20591]]

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 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 IRBs and independent 
ethics committees, recruitment of study participants, consent and 
assent, and minimizing risk and distress in pediatric studies.
    The documents described above provide considerable information and 
guidance regarding the participation of children in clinical trials. 
Nonetheless, given the expected increase in the number of children 
enrolled in clinical investigations as a result of recent pediatric 
initiatives, additional safeguards for children enrolled in clinical 
investigations of FDA-regulated products are appropriate.

II. Highlights of the Interim Rule

    This interim rule will apply the safeguards described in HHS 
subpart D to children participating in clinical investigations of FDA-
regulated products. These safeguards are also intended to ensure the 
adequate protection of the rights and welfare of children who 
participate in clinical investigations. Nothing in the regulations 
described in this interim rule is intended to preempt any applicable 
Federal, State, or local laws that require additional safeguards for 
children participating in clinical investigations.
    FDA is adopting HHS subpart D, as directed by Congress, with only 
those changes necessary due to differences between FDA's and HHS's 
regulatory authority. The agency is aware that dissimilar or 
inconsistent Federal requirements governing pediatric protections could 
be burdensome to institutions, IRBs, and the process of clinical 
investigation.
    FDA's regulations governing informed consent and IRBs apply to 
clinical investigations that are subject to FDA's jurisdiction. The 
scope of the regulations is described in Secs. 50.1 (21 CFR 50.1) and 
56.101 and includes all clinical investigations that are subject to 
requirements for prior submission under sections 505(i) and 520(g) of 
the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 355(i) and 360j(g)) 
or that support an application for a research or marketing permit for a 
product regulated by the agency as defined in Secs. 50.3(b) (21 CFR 
50.3(b)) and 56.102(b). This includes color additive petitions, 
petitions submitted to establish that a substance that may become a 
component of food is generally recognized as safe for use, food 
additive petitions and petitions for establishing a tolerance for 
unavoidable contaminants in food, drug applications, biologics 
licenses, and medical device applications. In contrast, HHS subpart D 
regulations cover research involving children as subjects, conducted or 
supported by the Department. With minor exceptions, FDA does not 
conduct or support research involving human subjects. Instead, FDA 
regulates research conducted by outside sponsors and investigators, 
where the research is subject to IRB review and approval. Because of 
these differences, FDA is making some modifications to HHS subpart D. 
For example, throughout the interim rule, FDA has modified the 
description of the scope of the rule from applying to research 
conducted or supported by the Department as described in HHS subpart D, 
to applying to clinical investigations subject to FDA's regulatory 
authority. Some research involving FDA-regulated products is also 
conducted or supported by HHS and falls within the scope of both HHS 
and FDA regulations.
    In addition, in its adoption of provisions of HHS subpart D, FDA 
has made minor editorial changes in response to the ongoing initiative 
regarding plain language in government writing. FDA solicits comments 
on all provisions in this interim rule and has identified certain 
points on which comments would be particularly useful.
    Finally, FDA has made changes to the scope and definitions sections 
of part 50 (21 CFR part 50) and part 56 to reflect that studies of 
certain foods, dietary supplements, and infant formulas are covered by 
these regulations. The regulations in part 101 (21 CFR part 101) 
governing petitions for nutrient content claims state that clinical 
studies submitted in support of such a petition must be conducted in 
accordance with the requirements of parts 50 and 56 (Sec. 101.69(f)). 
The regulations governing petitions for health claims contain the same 
requirement (Sec. 101.70(d)). Therefore, the agency is clarifying that 
parts 50 and 56 govern clinical investigations, including those 
involving children, when such investigations may be submitted in a 
petition under Sec. 101.69 or Sec. 101.70. Consistent with the 
congressional directive that the protections of the HHS subpart D 
regulations be extended to all research involving children regulated by 
FDA, studies in children in support of infant formulas and in support 
of premarket notification of dietary supplements that contain new 
dietary ingredients are also subject to parts 50 and 56.

A. What Definitions Is FDA Adopting From HHS Subpart D?

    FDA is adopting several terms from 45 CFR 46.402 of HHS subpart D 
for inclusion in the FDA definitions at Sec. 50.3. These include the 
terms ``assent'' (Sec. 50.3(n)), ``children'' (Sec. 50.3(o)), 
``parent'' (Sec. 50.3(p)), ``permission'' (Sec. 50.3(r)), and 
``guardian'' (Sec. 50.3(s)). The definitions of these terms in 
Sec. 50.3 generally follow the definitions in HHS subpart D, with 
changes as identified and discussed below. In addition, FDA is defining 
the term ``ward'' (Sec. 50.3(q)) in a manner that is consistent with 
its use in HHS subpart D.
1. What is Assent?
    The definition of ``assent'' at Sec. 50.3(n) is adopted from HHS 
subpart D with a minor change to clarify that the assent applies to 
participation in clinical investigations involving FDA-regulated 
products. FDA's regulation, like the HHS regulation, defines assent as 
a child's affirmative agreement to participate in research. FDA's 
definition also states that mere failure to object to participation in 
clinical investigations should not, absent affirmative agreement, be 
considered assent.
2. What Does the Term ``Children'' Mean?
    The definition of ``children'' at Sec. 50.3(o) includes persons who 
have not attained the legal age for consent to treatments or procedures 
involved in clinical investigations as determined under the applicable 
law of the jurisdiction in which the research will be conducted. This 
provision means that the law of the site of the research will determine 
the legal age of consent of the participant.
3. What Does ``Parent'' Mean?
    FDA did not previously have a definition for parent at Sec. 50.3 
and is adopting the definition from HHS subpart D. ``Parent'' is 
defined as a child's biological or adoptive parent.
4. What Does the Term ``Ward'' Mean?
    The term ``ward'' is used in HHS subpart D but is not defined. In 
Sec. 50.3(q), FDA has developed a definition for ward that is 
consistent with the use of the term in HHS subpart D. Under 
Sec. 50.3(q), a ward is a child who is placed in the legal custody of 
the State or other agency, institution, or entity, consistent with 
applicable Federal, State, or local law.

[[Page 20592]]

5. What Does ``Permission'' Mean, and How Is It Different From Informed 
Consent?
    The definition of ``permission'' at Sec. 50.3(r) is adopted from 45 
CFR 46.402(c) of HHS subpart D with a minor change to clarify that 
permission applies to participation in clinical investigations 
involving FDA-regulated products. FDA's definition at Sec. 50.3(r) 
generally adopts the HHS definition and states that permission is the 
agreement of parent(s) or guardian to their child's or ward's 
participation in a clinical investigation.
    FDA's regulation at Sec. 50.3(r) adds a sentence clarifying that 
permission must be obtained in compliance with part 50, subpart B and 
must include the elements of informed consent described in FDA's 
regulations at Sec. 50.25. This approach is consistent with HHS's 
interpretation of the term ``permission.'' Under the requirements for 
permission by parents or guardians and assent by children, 45 CFR 
46.408(d) of HHS subpart D states that permission by parents or 
guardians shall be documented in accordance with and to the extent 
required by 45 CFR 46.117 of HHS subpart A (45 CFR part 46, subpart A). 
Section 46.117 of HHS supbart A outlines the requirements for 
documenting informed consent. Addressing comments made on requiring 
parental consent to participation in research in the preamble to its 
final rule (48 FR 9814), the Department stated that inserting this 
reference to 45 CFR 46.117 of HHS subpart A clarified that the 
requirements for informed consent shall apply to permission.
    The agency is retaining the term permission because this term is 
used in HHS subpart D and is familiar to IRBs. The term permission also 
distinguishes children from other participants in clinical 
investigations. Children are defined as persons who have not attained 
the legal age for consent to treatments or procedures involved in 
clinical investigations under the applicable law of the jurisdiction in 
which the clinical investigation will be conducted. Because children 
are unable, due to age, to give consent themselves, permission is 
provided by a parent or guardian on their behalf. The term informed 
consent under Sec. 50.20 applies to other participants in clinical 
investigations. FDA solicits comments on its definition of permission.
6. What Is a ``Guardian,'' and What Is the Difference Between a 
Guardian and a Legally Authorized Representative?
    FDA's current regulations do not have a definition for guardian in 
part 50. In this interim rule, FDA is adopting a modification of the 
term ``guardian'' as used in HHS subpart D. In HHS subpart D, a 
guardian is an individual who is authorized under applicable State or 
local law to consent on behalf of a child to general medical care. FDA 
is adopting this definition and is adding text to clarify that 
authorization to consent to general medical care must include 
participation in research and, for purposes of this rule, a guardian is 
also an individual authorized to consent to a child's participation in 
research. FDA is adding this clarification because of concern that, in 
some cases, authorization to consent to general medical care may not 
extend to consent to participation in research. For a guardian to be 
able to grant permission for a child to participate in research, the 
guardian must either have authority to consent to a child's general 
medical care (where participation in clinical research falls within 
general medical care) or must have authority to consent to a child's 
participation in research.
    FDA is adopting the term guardian because this term is currently 
used in HHS subpart D in the context of research involving children, 
and is familiar to IRBs. In contrast, FDA's regulations at Sec. 50.3 
and HHS's regulations at 45 CFR 46.102(c) use the term ``legally 
authorized representative'' for 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 procedures involved in 
the research. FDA's definition of the term guardian is intended to 
clarify that a guardian must be an individual authorized to consent to 
a child's participation in research. FDA seeks comments on its 
definition of the term guardian and any implications under State or 
local law.

B. What New Duties Do IRBs Assume Under This Interim Rule?

    FDA has adopted the provisions in 45 CFR 46.403 of HHS subpart D 
with minor changes. The provisions are included in FDA regulations at 
Sec. 50.50. Section 50.50 directs that in addition to other 
responsibilities assigned under parts 50 and 56, IRBs must now review 
research covered by subpart D of part 50 and approve only research that 
satisfies the criteria described in Sec. 50.51, Sec.  50.52, or Sec.  
50.53 and the conditions of all other applicable sections of part 50, 
subpart D.
    FDA has also made conforming changes to part 56 of its regulations 
governing IRBs. Under part 56, subpart C, describing IRB functions and 
operations, FDA is adding new paragraph (c) to Sec. 56.111. New 
Sec. 56.111(c) requires that to approve research in which some or all 
of the subjects are children, an IRB must determine that all such 
research is in compliance with part 50, subpart D.
    Similarly, FDA has added new paragraph (h) to Sec. 56.109 on IRB 
review of research to require that when some or all of the subjects of 
ongoing research are children, an IRB must conduct a review of the 
research to determine compliance with part 50, subpart D. This review 
of research that is ongoing on the effective date of this rule must be 
conducted either at the time of continuing review or, at the discretion 
of an IRB, at an earlier date. Under Sec. 56.109(f), IRBs conduct 
continuing review of research at intervals appropriate to the degree of 
risk of the research, but not less than once per year. FDA expects that 
the degree of risk posed to children will be considered by the IRB in 
determining when to conduct a continuing review of an ongoing trial for 
compliance with part 50, subpart D.
    FDA regulations set out criteria to be satisfied if an IRB is to 
approve research (Sec. 56.111). These criteria are the same for initial 
review and continuing review and include a determination by the IRB 
that:
    (1) Risks to subjects are minimized,
    (2) Risks to subjects are reasonable in relation to anticipated 
benefits,
    (3) Selection of subjects is equitable,
    (4) Informed consent is adequate and appropriately documented,
    (5) Where appropriate, the research plan makes adequate provision 
for monitoring the data collected to ensure the safety of subjects,
    (6) Where appropriate, there are adequate provisions to protect the 
privacy of subjects and to maintain the confidentiality of data, and
    (7) Appropriate safeguards have been included to protect vulnerable 
subjects.
    Under new Sec. 56.109(h), at the time of continuing review, or at 
an earlier date if the IRB so determines, the IRB must review research 
involving children, with reference to the risk categories and criteria 
as defined in part 50, subpart D, to determine if an ongoing clinical 
investigation fits into one of the risk categories at Sec. 50.51, 
Sec. 50.52, or Sec. 50.53. If an IRB determines that the research does 
not fit any of these three categories, but that the research may fit 
under Sec. 50.54, the IRB should contact FDA for further guidance. FDA 
emphasizes that it expects the volume of studies that are

[[Page 20593]]

candidates for classification under Sec. 50.54 to be extremely small. 
FDA believes it is appropriate to permit review of ongoing 
investigations for compliance with part 50, subpart D at the time of 
continuing review or at an earlier date identified by the IRB because 
this is the least disruptive way to ensure compliance. If an IRB 
determines that research in progress does not fit any of the four risk 
categories defined in part 50, subpart D, the IRB has authority to 
suspend or terminate approval of the research under Sec. 56.113. Under 
Sec. 56.113, the IRB must report any such action to FDA. FDA notes that 
many ongoing pediatric studies have been approved by IRBs based upon 
the standards described in HHS subpart D, so the agency anticipates 
that very few, if any, ongoing studies will be suspended or terminated.

C. When May IRBs Approve a Clinical Investigation Not Involving Greater 
Than Minimal Risk?

    Under Sec. 50.51, an IRB may approve a clinical investigation in 
which no greater than minimal risk is presented only if an IRB finds 
and documents that adequate provisions are made for soliciting the 
assent of the children involved and the permission of their parents or 
guardians as set forth in Sec. 50.55. In adopting this provision, FDA 
has made minor changes to the language used in 45 CFR 46.404 of HHS 
subpart D. Rather than stating that HHS will ``conduct or fund 
research'' in which the IRB finds no greater than minimal risk to 
children, FDA has modified this language to state the conditions under 
which an IRB may approve a clinical investigation involving an FDA-
regulated product in which there is no greater than minimal risk to 
children. FDA believes this change is required by the scope of FDA's 
regulatory authority. Similar changes have been made as necessary 
throughout the codified section to reflect the scope of FDA's 
regulatory authority.
    FDA previously adopted the Department's definition of minimal risk 
(45 CFR 46.102(g) of subpart A) without change in Sec. 50.3. FDA 
anticipates that among the types of procedures that might be used in a 
clinical investigation that would present no more than minimal risk to 
children would be clean-catch urinalysis, obtaining stool samples, 
administering electroencephalograms, requiring minimal changes in diet 
or daily routine, or the use of standard psychological tests. Examples 
of the types of clinical investigations that would present no more than 
minimal risk would include a taste test of an excipient or tests of 
devices involving temperature readings orally or in the ear. FDA 
anticipates that there may be circumstances under which products with 
an established safety profile in adults may present no more than 
minimal risk in children.

D. When May IRBs Approve Clinical Investigations Involving Greater Than 
Minimal Risk But Presenting the Prospect of Direct Benefit to the 
Individual Subjects?

    Under Sec. 50.52, an IRB may approve a clinical investigation in 
which an IRB finds more than minimal risk to children but that presents 
the prospect of direct benefit to individual subjects only if the IRB 
finds and documents that:
    (1) The risk is justified by the anticipated benefit to the 
subjects,
    (2) The relation of the anticipated benefit to the risk is at least 
as favorable to the subjects as that presented by available alternative 
approaches, and
    (3) Adequate provisions are made for soliciting the assent of the 
children and permission of their parents or guardians, as set forth in 
Sec. 50.55.
Section 50.52 adopts the provisions of 45 CFR 46.405 of HHS subpart D 
with minor changes to conform to FDA's regulatory authority. FDA 
expects that many clinical investigations of FDA-regulated products in 
children will be allowed to proceed under Sec. 50.52. These clinical 
investigations generally are performed in children with the disease or 
condition for which the product is intended.
    FDA recognizes that in the case of clinical investigations of FDA-
regulated products conducted under an investigational new drug 
application (IND) or investigational device exemption (IDE), it may not 
always be possible to know the level of risk the subject will be 
exposed to ahead of time. This may create difficulties for IRBs trying 
to assess whether a clinical investigation involves more than minimal 
risk. IRBs may need to make such judgments on a case-by-case basis.
    While the level of risk in a clinical investigation may change 
during the course of a study, appropriate strategies may be included in 
the study design that may mitigate risks. These might include exit 
strategies in the case of adverse events or a lack of efficacy, or 
establishing a data monitoring committee (DMC) to review ongoing data 
collection and recommend study changes, including stopping a trial on 
the basis of safety information. FDA invites comment on appropriate 
criteria for IRBs to use in assessing when a clinical investigation may 
involve more than minimal risk to children.
    The agency also recognizes that the requirement for the prospect of 
direct benefit to individual subjects may create ambiguity about 
whether placebo-controlled clinical investigations may be conducted in 
children. FDA believes that clinical investigations involving placebos 
in children may be conducted in accord with Sec. 50.52. There is 
evidence of direct benefit to subjects from participating in placebo-
controlled trials, including increased monitoring and care of subjects, 
even though a subject may not actually receive the test product. FDA 
invites comment on the issue of conducting placebo-controlled trials in 
children.

E. When May an IRB Approve a Clinical Investigation 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?

    Section 50.53 provides that in certain circumstances an IRB may 
approve a clinical investigation in which the IRB finds that more than 
minimal risk to children is presented: (1) By an intervention or 
procedure that does not hold out the prospect of direct benefit for the 
individual subject, or (2) by a monitoring procedure that is not likely 
to contribute to the well-being of the subject. The clinical 
investigation may be approved only if the IRB finds and documents that:
    (1) The risk represents a minor increase over minimal risk;
    (2) The intervention or procedure presents experiences to subjects 
that are reasonably commensurate with those inherent in their actual or 
expected medical, dental, psychological, social, or educational 
situations;
    (3) The intervention or procedure is likely to yield generalizable 
knowledge about the subjects' disorder or condition that is of vital 
importance for the understanding or amelioration of the subjects' 
disorder or condition; and
    (4) Adequate provisions are made for soliciting the assent of the 
children and permission of their parents or guardians as set forth in 
Sec. 50.55.
    FDA has adopted these requirements from 45 CFR 46.406 of HHS 
subpart D, with minor modifications to conform to FDA's regulatory 
authority.
    FDA recognizes that Sec. 50.53 raises issues similar to those 
raised by Sec. 50.52 about standards for IRBs to use in assessing when 
a clinical investigation involves more than minimal risk. Some comments 
submitted previously on HHS's proposed rule (43 FR 31786, July

[[Page 20594]]

21, 1978) indicated that no attempt should be made to define the 
concept of ``minor increase'' or to provide guidance to IRBs on 
evaluating whether a ``minor increase over minimal risk'' is involved. 
These comments stated that because of varying situations and 
circumstances, IRBs would need to make judgments on a case-by-case 
basis. FDA believes that IRBs are qualified to assess and document when 
a specific protocol falls under this category. However, FDA is 
soliciting comments on whether further definition should be provided to 
aid IRBs in making such determinations, 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.
    Section 50.53(c) contains the phrase ``likely to yield 
generalizable knowledge about the subjects' disorder or condition.'' 
The criterion in Sec. 50.53(c) raises the question whether clinical 
investigations of FDA-regulated products conducted to determine the 
safety and effectiveness of such products yield generalizable knowledge 
about a subject's disorder or condition that is of vital importance for 
the understanding or amelioration of the subjects' disorder or 
condition. FDA believes there are circumstances in which clinical 
investigations yield such information. Such circumstances may include 
cases where a child has been identified as at high risk for a disease 
and receives investigational interventions to prevent the disease or 
ameliorate manifestations of the disease in the future. In these 
situations, even in children who would not otherwise have manifested 
the disease, the clinical investigations may yield important 
information that might contribute to the understanding of a disease, 
disorder, or condition. FDA believes that IRBs are capable of making 
this assessment. Therefore, FDA is adopting this provision from HHS 
subpart D.

F. When May an IRB Allow a Clinical Investigation to Proceed That Is 
Not Otherwise Approvable But Presents an Opportunity to Understand, 
Prevent, or Alleviate a Serious Problem Affecting the Health or Welfare 
of Children?

    An IRB may allow a clinical investigation that does not meet the 
requirements of Sec. 50.51, Sec. 50.52, or Sec.  50.53 to proceed only 
if the IRB finds and documents 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 the Commissioner of Food and Drugs (the Commissioner) 
determines that the conditions of Sec. 50.54(b) are met. After 
consultation with a panel of experts and following opportunity for 
public review and comment, the Commissioner must determine, under 
Sec. 50.54(b)(1), that the clinical investigation satisfies the 
conditions of Sec. 50.51, Sec. 50.52, or Sec. 50.53 or, under 
Sec. 50.54(b), that three conditions are met. The conditions in 
Sec. 50.54(b) are as follows:
    (1) 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,
    (2) The clinical investigation will be conducted in accordance with 
sound ethical principles, and
    (3) Adequate provisions are made for soliciting the assent of the 
children and the permission of their parents or guardians.
    FDA's regulation in Sec. 50.54 generally follows the provisions in 
45 CFR 46.407 of HHS subpart D with some modification. In 
Sec. 50.54(b), FDA has charged the Commissioner with determining 
whether such a clinical investigation can proceed. The Commissioner is 
to consult with a panel of experts. FDA anticipates that this panel may 
include an advisory committee supplemented, if needed, by appropriate 
experts. This provision also provides for public review and comment on 
the Commissioner's pending decision. However, FDA may not be able to 
provide for public review and comment on the Commissioner's pending 
decision if the sponsor is unwilling to publicly disclose necessary 
information. FDA's trade secret and commercial confidentiality 
requirements (21 CFR 20.61) protect certain types of information from 
public disclosure. This type of privileged information is sometimes 
included in INDs and IDEs. 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.

G. When May an IRB Waive the Assent Requirement?

    FDA has adopted in Sec. 50.55 the provisions of 45 CFR 46.408 of 
HHS subpart D, describing when assent may be waived. Even in cases 
where an IRB determines waiver of assent is necessary, FDA regulations 
require the permission of parents or guardians to the extent informed 
consent is required in part 50. Documentation of permission must be 
consistent with the documentation required for informed consent at 
Sec. 50.27.
    Section 50.55(a) allows an IRB to make a judgment as to whether 
children are capable of providing assent. Section 50.55(b) states that 
in making this determination, an IRB must take into account the ages, 
maturity, and psychological state of the children involved. An IRB may 
make this determination for each individual child to be involved in the 
clinical investigation or for all children under a particular protocol. 
FDA has made format changes in adopting 45 CFR 46.408 to clarify the 
conditions for waiving the assent requirement. Section 50.55(c) states 
that assent is not a necessary condition for proceeding with a clinical 
investigation if the IRB determines: (1) That the capability of some or 
all of the children is so limited that they cannot reasonably be 
consulted, or (2) that the intervention or procedure involved in the 
clinical investigation presents a prospect of direct benefit that is 
important to the health or well-being of the children and is available 
only in the context of the clinical investigation. Section 50.55(d) 
states that even where an IRB determines the children are capable of 
assenting, the IRB may still waive the assent requirement if: (1) The 
clinical investigation involves no more than minimal risk to the 
subjects, (2) the waiver will not adversely affect the rights and 
welfare of the subjects, (3) the clinical investigation could not 
practicably be carried out without the waiver, and (4) when 
appropriate, the children will be provided with additional pertinent 
information after participation. Section 50.55(g) provides that when an 
IRB determines that assent is required, the IRB must determine whether 
and how assent must be documented. FDA solicits comments on how to 
ensure that age-appropriate explanations are provided to children.

H. May an IRB Waive the Permission Requirement for Parents or 
Guardians?

    FDA has not adopted the provisions of 45 CFR 46.408(c) that allow 
an IRB to waive the requirements for obtaining permission in certain 
circumstances. Section 46.408(c) of HHS subpart D allows an IRB to 
determine that a research protocol is designed for conditions or for a 
subject population for which the permission of parents or guardians is 
not a reasonable requirement to protect the subjects. This

[[Page 20595]]

provision allows the IRB to substitute an appropriate mechanism to 
protect children who will participate as subjects in research.
    Section 46.408(c) of HHS subpart D allows IRBs to waive the 
permission of parents or guardians in certain circumstances in which 
waiver of informed consent would not be permitted under FDA 
regulations. Therefore FDA is not adopting the exceptions described in 
HHS subpart D. The only exceptions to FDA's requirements for informed 
consent, and thus for obtaining permission, are found in part 50 of 
FDA's regulations.

I. Can Wards of the State Ever Be Included in Clinical Investigations?

    FDA has adopted in Sec. 50.56 the provisions of 45 CFR 46.409 of 
HHS subpart D describing when children who are wards of the State or 
any other agency, institution, or entity may be included in research.
    Under Sec. 50.3(q), a ward is defined as a child who is placed in 
the legal custody of the State or other agency, institution, or entity, 
consistent with applicable Federal, State, or local law. Under 
Sec. 50.56(a), wards can be included in clinical investigations only if 
such research is: (1) Related to their status as wards, or (2) 
conducted in schools, camps, hospitals, institutions, or similar 
settings in which the majority of children involved as subjects are not 
wards. Section 50.56(a) is written to ensure that if wards of the State 
participate in clinical investigations, they do so not because it is 
administratively convenient for a clinical investigator or sponsor to 
include them as participants, but because they are subject to potential 
benefit from the clinical investigation.
    If an IRB approves such research, the IRB must appoint an advocate 
for each child who is a ward, in addition to any other individual 
acting on behalf of the child as a guardian or in loco parentis. 
Section 50.56(b) provides that one individual may serve as advocate for 
more than one child. The advocate must be an individual who has the 
background and experience to act in the best interest of the child for 
the duration of the child's participation in the clinical 
investigation. The advocate must not be associated in any way with the 
clinical investigation, the investigator(s), or the guardian 
organization. FDA interprets the term ``guardian organization'' to 
refer to the State, agency, institution, or other entity in whose legal 
custody the child is placed.
    FDA believes that wards require special protections. FDA also 
believes that Sec. 50.56(b) provides protection from any conflict of 
interest issues that may arise in the appointment of an advocate. FDA 
notes that any issues relating to compensation or funding for advocates 
or the liability of advocates are left to the IRBs and other involved 
institutions, agencies, or entities to resolve. FDA is soliciting 
comments on any difficulties such entities may have with the 
appointment of advocates.

III. Effective Date

    The agency is issuing this regulation as an interim rule effective 
April 30, 2001. This action is being issued in accordance with title 
XXVII, section 2701 of the Children's Health Act. Section 2701 requires 
that 6 months after enactment, all research involving children 
conducted, supported, or regulated by HHS be in compliance with HHS 
subpart D. The Children's Health Act was signed by the President on 
October 17, 2000. FDA interprets the Children's Health Act to require 
FDA to adopt HHS subpart D by April 17, 2001.
    FDA is issuing this interim rule to comply with the Children's 
Health Act. Generally, the Administrative Procedure Act and FDA 
regulations require notice to the public and an opportunity for comment 
prior to the effective date of a rule (5 U.S.C. 553(b) through (d); 21 
CFR 10.40(b)). This process may be dispensed with under 5 U.S.C. 
553(b)(3)(B) and Sec. 10.40(e)(1) (21 CFR 10.40(e)(1)) if the 
Commissioner finds, for good cause, that notice and public procedures 
would be impracticable, unnecessary, or contrary to the public 
interest. This interim rule meets these standards.
    Section 2701 of the Children's Health Act requires FDA to adopt 
specific existing HHS regulations within 6 months. Because of the 
specificity of Congress's directive and FDA's limited discretion in 
adopting the standards of HHS subpart D, notice and an opportunity to 
comment is unnecessary. As described in section I.B of this document, 
HHS subpart D was itself issued through notice-and-comment rulemaking. 
Moreover, Congress has specifically identified in section 1003 of the 
Children's Health Act the process, timetable, and specific 
considerations for review of the regulations in HHS subpart D and, by 
implication, the regulations adopted in this interim rule. Depending 
upon the outcome of the review, it is possible that HHS and relevant 
agencies will propose new regulations addressing the protection of 
children involved in research. These regulations would be adopted with 
notice and an opportunity for public comment. Finally, FDA believes the 
anticipated increase in pediatric research makes it important to the 
public health that the requirements described in this rule become 
effective as soon as possible.
    In addition, for the reasons described above, the Commissioner of 
Food and Drugs also finds good cause under 5 U.S.C. 553(d)(3) and 
Sec. 10.40(c)(4)(ii) for making this interim rule effective in less 
than 30 days.

IV. Analysis of Economic Impacts

    FDA has examined the impacts of this interim rule under Executive 
Order 12866 and the Regulatory Flexibility Act (5 U.S.C. 601-612 (as 
amended by subtitle D of the Small Business Regulatory Fairness Act of 
1996 (Public Law 104-121))), and the Unfunded Mandates Reform Act of 
1995 (Public Law 104-4). Executive Order 12866 directs agencies to 
assess all costs and benefits of available regulatory alternatives and, 
when regulation is necessary, to select regulatory approaches that 
maximize net benefits (including potential economic, environmental, 
public health and safety, and other advantages; distributive impacts; 
and equity). Under the Regulatory Flexibility Act, if a rule has a 
significant economic impact on a substantial number of small entities, 
an agency must analyze regulatory options that would minimize any 
significant economic impact of the rule on small entities. Section 
202(a) of the Unfunded Mandates Reform Act of 1995 (Public Law 104-4) 
requires that agencies prepare a written statement of anticipated costs 
and benefits before proposing any rule that may result in an 
expenditure by State, local, and tribal governments, in the aggregate, 
or by the private sector, of $100 million in any one year (adjusted 
annually for inflation).
    This interim rule is consistent with the principles set forth in 
Executive Order 12866 and these two statutes. The interim rule is a 
``significant regulatory action'' as defined in section (3)(f) of 
Executive Order 12866. However, as explained below, the rule is not an 
economically significant regulatory action as defined in the Executive 
order and does not require a Regulatory Flexibility Analysis. The 
Unfunded Mandates Reform Act does not require FDA to prepare a 
statement of costs and benefits for the interim rule because the rule 
is not expected to have an effect on the economy that exceeds $100 
million adjusted for inflation in any one year. The current inflation-
adjusted statutory threshold is about $110 million.
    This interim rule requires IRBs reviewing FDA-regulated clinical

[[Page 20596]]

investigations involving children to apply FDA's new regulations 
establishing additional safeguards for children in clinical 
investigations, as adopted from HHS subpart D. Until now, FDA has 
relied primarily on its own regulations governing adult studies, in 
combination with HHS subpart D, as guidance for the review of clinical 
investigations in children. In this rule, FDA requires the IRB to 
review and document the risks to children participating in clinical 
investigations before the clinical trial may proceed. In some 
instances, this may be a departure from current practice and may place 
additional requirements on IRBs. FDA believes the burden of these added 
requirements to be small. Under current standards, IRBs are already 
required to make several determinations concerning subject risk and to 
document subject risks. The additional requirements of this rule state 
that IRBs must specifically identify which of the four risk categories 
applies to pediatric subjects in a clinical investigation. We expect 
that this determination would require some additional effort, but take 
at most one person-hour of additional time. To estimate costs, FDA 
multiplied the estimated number of clinical investigations in children 
subject to the rule's requirements by the estimated additional time 
required of the affected IRBs for each trial reviewed. Then FDA 
multiplied the total estimated time by a standardized cost of $75 per 
man-hour.
    Table 1 below presents, for several different product categories, 
an estimate of the number of FDA-regulated clinical investigations in 
children that will require review by IRBs. Estimates are provided for 
new drug and biological products (based on numbers of approved new 
molecular entities and important new biological products), medical 
devices (based on premarket approval applications (PMAs) and 510(k) 
premarketing submissions (510(k)s)), and infant formula and food 
additives that require premarket approval by FDA's Center for Food 
Safety and Applied Nutrition (CFSAN).
    Under current law, manufacturers may receive additional economic 
incentives to conduct pediatric studies on drugs for which FDA has 
requested pediatric studies. For currently marketed drugs, 
approximately 175 pediatric studies have already been reviewed by IRBs 
and of these studies, about 100 have been completed. However, FDA 
estimates that 51 studies have yet to be reviewed by an IRB and another 
75 will require an annual review by an IRB. In future years, 
manufacturers of many newly approved drugs will be required, as a 
condition of approval, to conduct pediatric studies. Assuming that 3 
pediatric studies per new drug require review, FDA estimates that about 
138 pediatric studies per year will be conducted for new drugs and 
biologics. The estimate includes pediatric clinical trials for new drug 
and biological products that are approved, as well as trials for 
investigational drugs that reach phase 3 but are not approved. 
Approximately one-third of investigational drugs reaching phase 3 (when 
pediatric trials may commence) are never approved for marketing in the 
United States.

           Table 1.-- Estimated Number of IRB Reviews Per Year for Clinical Investigations in Children
----------------------------------------------------------------------------------------------------------------
                                                                                          Per year 2002 through
                                                                          2001                     2009
----------------------------------------------------------------------------------------------------------------
New drug and biological products
    New trials for pre-2001 drug and biological products                             51
    Annual review of ongoing trials                                                  75
    Post-1/1/2001 drug and biological products                                      138                      138
New devices (PMAs and 510(k)s)
    Post-1/1/2001 devices                                                           170                      170
Foods and Food Additives
    Infant formula                                                                    5                        5
    Food additives                                                                    1                        1
Total IRB reviews per year                                                          440                      314
Total IRB costs per year                                                        $33,000                  $23,550
----------------------------------------------------------------------------------------------------------------

    For medical devices, FDA expects about 170 pediatric studies per 
year to be reviewed by IRBs. About 20 of these pediatric studies per 
year are for submitted PMAs and the remainder are for submitted 
510(k)s. These figures reflect discussions with officials from FDA's 
Center for Devices and Radiological Health and a review of recent 
approvals, which found that only about 10 percent of PMAs and 1 percent 
of 510(k)s are likely to involve pediatric trials. Similar to the 
estimates shown for drug and biological products, FDA assumed that 
three pediatric trials were conducted for each submitted PMA or 510(k) 
involving trials with children.
    CFSAN regulates infant formula and food additives. Unlike the 
regulation of human drugs and medical devices, which require INDs, 
there is no requirement for sponsors to notify FDA when they are 
conducting clinical investigations of infant formula and food 
additives. FDA learns of these trials only when applications are 
submitted to CFSAN for product review and premarket approval. 
Therefore, we are less certain of the number of pediatric clinical 
trials involving these kinds of products, but have based our estimate 
for these products on the number of pediatric trials in applications 
submitted to CFSAN. Over the last 5 years, CFSAN has received data from 
about five trials per year with applications for infant formula. 
Pediatric trials of food additives are highly unusual. According to one 
CFSAN official, only a handful of applications containing data from 
pediatric trials have been received by CFSAN over the last 20 years. 
(One example is data received on the food additive Olestra that was 
tested in children because it was known to cause mild diarrhea in 
adults.) Therefore, we estimated that, per year, one pediatric trial 
studying food additives is conducted in the United States. The agency 
seeks particular industry comment on this figure, because of the 
uncertainty of this estimate.
    The total annual cost of reviewing ongoing and future pediatric 
clinical trials, as shown in table 1 of this document, is estimated to 
be $33,000 for the year 2001 and $23,550 per year in years 2002 through 
2009.
    In addition to these annual costs, we assume that each IRB 
reviewing FDA-regulated pediatric clinical trials will have to conduct 
a one-time review and update of their standard operating procedure 
(SOP) documents to include the requirements of this rule. Experts at

[[Page 20597]]

FDA estimate that up to 1,500 IRBs may review protocols for research 
performed under an IND or IDE. Because we believe that most IRBs 
currently follow procedures similar to those required by this rule, we 
estimate that changes to existing SOPs will require no more than 8 man-
hours. Multiplying the 1,500 IRBs by 8 and applying a standardized cost 
of $75 per man-hour equals a one-time cost of $900,000. This one-time 
cost would occur in the year 2001, following implementation of the 
rule.
    This rule specifies that IRBs review ongoing pediatric trials to 
verify compliance with the requirements of this rule. These reviews are 
to occur during the first periodic review following the implementation 
of this rule or sooner, at the discretion of the IRB. If the ongoing 
trial is not in compliance with the requirements of the rule, the 
trial, under certain circumstances, could be placed on clinical hold. 
FDA believes that the likelihood of this occurrence is remote, because 
IRBs currently reviewing pediatric research are already routinely 
following HHS subpart D regulations, which are essentially similar to 
the requirements of this rule (see FDA's information sheets, ``Guidance 
for Institutional Review Boards and Clinical Investigators''). 
Furthermore, by the time this rule becomes effective, most pediatric 
studies conducted in response to FDA requests for studies of marketed 
drugs under the pediatric exclusivity provision of the Modernization 
Act will be completed. We therefore have assumed no costs associated 
with clinical holds, but seek industry comment on this assumption.
    We estimate that the costs of this rule will total $933,000 in the 
year 2001 and $23,550 per year in years 2002 through 2009.
    The Regulatory Flexibility Act requires agencies to analyze 
regulatory options that would minimize any significant impact of a rule 
on small entities, unless the rule is not expected to have a 
significant economic impact on a substantial number of small entities. 
Although many IRBs are components of small entities, this rule imposes 
very modest new costs on any individual IRB. The estimated one-time 
cost of SOP review and revision for any individual IRB is only $600. 
The estimated additional cost per clinical trial review amounts to only 
$75. FDA expects that any given IRB will conduct no more than a few 
reviews of trials involving children. Therefore, under the Regulatory 
Flexibility Act, the Commissioner of Food and Drugs certifies that this 
rule will not have a significant economic effect on a substantial 
number of small entities.

V. Paperwork Reduction Act of 1995

    This interim rule contains no new collections of information. The 
information requested for clinical investigations in children is 
already covered by the collection of information in IND regulations (21 
CFR part 312), IDE regulations (21 CFR part 812), IRB regulations (21 
CFR 56.115), food additive petition and nutrient content claim petition 
regulations (21 CFR 101.69 and 101.70), and infant formula regulations 
(21 CFR parts 106 and 107) approved by the Office of Management and 
Budget (OMB).
    In accordance with the Paperwork Reduction Act of 1995 (44 U.S.C. 
3501-3520), OMB approved the information collection in IND regulations 
and assigned OMB control number 0910-0014. The approval expires on 
September 30, 2002. OMB approved the information collection in IDE 
regulations and assigned OMB control number 0910-0078. The approval 
expires on August 31, 2003. OMB approved the information collection in 
IRB regulations and assigned OMB control number 0910-0130. The approval 
expires on October 31, 2001. OMB approved the information collection in 
food additive and nutrient content claim petitions and assigned OMB 
control number 0910-0381. The approval expires on September 30, 2001. 
OMB approved the information collection in infant formula regulations 
and assigned OMB control number 0910-0188. The approval expires on 
February 29, 2004. An agency may not conduct or sponsor, and a person 
is not required to respond to, a collection of information unless it 
displays a currently valid OMB control number.

VI. Environmental Impact

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

VII. Federalism

    FDA has analyzed this interim rule in accordance with the 
principles set forth in Executive Order 13132. FDA has determined that 
the interim 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 interim rule does not contain 
policies that have federalism implications as defined in the order and, 
consequently, a federalism summary impact statement is not required.

VIII. Opportunity for Public Comment

    Interested persons may submit to the Dockets Management Branch 
(address above) written comments regarding this interim rule by July 
23, 2001. Two copies of any comments are to be submitted, except that 
individuals may submit one copy. Comments are to be identified with the 
docket number found in brackets in the heading of this document. 
Received comments may be seen in the office above between 9 a.m. and 4 
p.m., Monday through Friday. Submit written comments on the information 
collection provisions to the Office of Information and Regulatory 
Affairs, OMB (address above) by May 23, 2001.

List of Subjects

21 CFR Part 50

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

21 CFR Part 56

    Human research subjects, Reporting and recordkeeping requirements, 
Safety.

    Therefore, under the Federal Food, Drug, and Cosmetic Act and under 
authority delegated to the Commissioner of Food and Drugs, 21 CFR parts 
50 and 56 are amended as follows:

PART 50--PROTECTION OF HUMAN SUBJECTS

    1. The authority citation for 21 CFR part 50 is revised 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. 50.1  [Amended]

    2. Amend Sec. 50.1 Scope as follows:
    a. In the first sentence of paragraph (a) after the word 
``including'' add the phrase ``foods, including dietary supplements, 
that bear a nutrient content claim or a health claim, infant 
formulas,''.
    b. In the third sentence of paragraph (a) add numerically to the 
list of Federal Food, Drug, and Cosmetic Act sections the numbers 
``403,'' ``412,'' and ``413,''.
    3. Amend Sec. 50.3 by adding paragraphs (b)(23), (b)(24), (b)(25), 
(n), (o), (p), (q), (r), and (s) to read as follows:

[[Page 20598]]

Sec. 50.3  Definitions.

* * * * *
    (b) * * *
    (23) Data and information about a clinical study of an infant 
formula when submitted as part of an infant formula notification under 
section 412(c) of the Federal Food, Drug, and Cosmetic Act.
    (24) Data and information submitted in a petition for a nutrient 
content claim, described in Sec. 101.69 of this chapter, or for a 
health claim, described in Sec. 101.70 of this chapter.
    (25) Data and information from investigations involving children 
submitted in a new dietary ingredient notification, described in 
Sec. 190.6 of this chapter.
* * * * *
    (n) Assent means a child's affirmative agreement to participate in 
a clinical investigation. Mere failure to object may not, absent 
affirmative agreement, be construed as assent.
    (o) Children means persons who have not attained the legal age for 
consent to treatments or procedures involved in clinical 
investigations, under the applicable law of the jurisdiction in which 
the clinical investigation will be conducted.
    (p) Parent means a child's biological or adoptive parent.
    (q) Ward means a child who is placed in the legal custody of the 
State or other agency, institution, or entity, consistent with 
applicable Federal, State, or local law.
    (r) Permission means the agreement of parent(s) or guardian to the 
participation of their child or ward in a clinical investigation. 
Permission must be obtained in compliance with subpart B of this part 
and must include the elements of informed consent described in 
Sec. 50.25.
    (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 when general medical care includes participation in research. For 
purposes of subpart D of this part, a guardian also means an individual 
who is authorized to consent on behalf of a child to participate in 
research.
    4. Add subparts C and D to part 50 to read as follows:

Subpart C--[Reserved]

Subpart D--Additional Safeguards for Children in Clinical 
Investigations

    Sec.
50.50  IRB duties.
50.51  Clinical investigations not involving greater than minimal 
risk.
50.52  Clinical investigations involving greater than minimal risk 
but presenting the prospect of direct benefit to individual 
subjects.
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.
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.
50.55  Requirements for permission by parents or guardians and for 
assent by children.
50.56  Wards.

Subpart C--[Reserved]

Subpart D--Additional Safeguards for Children in Clinical 
Investigations


Sec. 50.50  IRB duties.

    In addition to other responsibilities assigned to IRBs under this 
part and part 56 of this chapter, each IRB must review clinical 
investigations involving children as subjects covered by this subpart D 
and approve only those clinical investigations that satisfy the 
criteria described in Sec. 50.51, Sec. 50.52, or Sec. 50.53 and the 
conditions of all other applicable sections of this subpart D.


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

    Any clinical investigation within the scope described in Secs. 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 and documents that 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.


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 Secs. 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 and 
documents that:
    (a) The risk is justified by the anticipated benefit to the 
subjects;
    (b) The relation of the anticipated benefit to the risk is at least 
as favorable to the subjects as that presented by available alternative 
approaches; and
    (c) Adequate provisions are made for soliciting the assent of the 
children and permission of their parents or guardians as set forth in 
Sec. 50.55.


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 Secs. 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 
and documents that:
    (a) The risk represents a minor increase over minimal risk;
    (b) The intervention or procedure presents experiences to subjects 
that are reasonably commensurate with those inherent in their actual or 
expected medical, dental, psychological, social, or educational 
situations;
    (c) The intervention or procedure is likely to yield generalizable 
knowledge about the subjects' disorder or condition that is of vital 
importance for the understanding or amelioration of the subjects' 
disorder or condition; and
    (d) Adequate provisions are made for soliciting the assent of the 
children and permission of their parents or guardians as set forth in 
Sec. 50.55.


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.

    If an IRB does not believe that a clinical investigation within the 
scope described in Secs. 50.1 and 56.101 of this chapter and involving 
children as subjects meets the requirements of Sec. 50.51, Sec. 50.52, 
or Sec. 50.53, the clinical investigation may proceed only if:
    (a) The IRB finds and documents 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
    (b) The Commissioner of Food and Drugs, after consultation with a 
panel of experts in pertinent disciplines (for example: science, 
medicine, education, ethics, law) and following opportunity for public 
review and comment, determines either:

[[Page 20599]]

    (1) That the clinical investigation in fact satisfies the 
conditions of Sec. 50.51, Sec. 50.52, or Sec. 50.53, as applicable, or
    (2) That the following conditions are met:
    (i) 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;
    (ii) The clinical investigation will be conducted in accordance 
with sound ethical principles; and
    (iii) Adequate provisions are made for soliciting the assent of 
children and the permission of their parents or guardians as set forth 
in Sec. 50.55.


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

    (a) In addition to the determinations required under other 
applicable sections of this subpart D, the IRB must determine that 
adequate provisions are made for soliciting the assent of the children 
when in the judgment of the IRB the children are capable of providing 
assent.
    (b) In determining whether children are capable of providing 
assent, the IRB must take into account the ages, maturity, and 
psychological state of the children involved. This judgment may be made 
for all children to be involved in clinical investigations under a 
particular protocol, or for each child, as the IRB deems appropriate.
    (c) The assent of the children is not a necessary condition for 
proceeding with the clinical investigation if the IRB determines:
    (1) That the capability of some or all of the children is so 
limited that they cannot reasonably be consulted, or
    (2) That the intervention or procedure involved in the clinical 
investigation holds out a prospect of direct benefit that is important 
to the health or well-being of the children and is available only in 
the context of the clinical investigation.
    (d) Even where the IRB determines that the subjects are capable of 
assenting, the IRB may still waive the assent requirement if it finds 
and documents that:
    (1) The clinical investigation involves no more than minimal risk 
to the subjects;
    (2) The waiver will not adversely affect the rights and welfare of 
the subjects;
    (3) The clinical investigation could not practicably be carried out 
without the waiver; and
    (4) Whenever appropriate, the subjects will be provided with 
additional pertinent information after participation.
    (e) In addition to the determinations required under other 
applicable sections of this subpart D, the IRB must determine 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, if consistent with 
State law, 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 if 
consistent with State law.
    (f) Permission by parents or guardians must be documented in 
accordance with and to the extent required by Sec. 50.27.
    (g) When the IRB determines that assent is required, it must also 
determine whether and how assent must be documented.


Sec. 50.56  Wards.

    (a) Children who are wards of the State or any other agency, 
institution, or entity can be included in clinical investigations 
approved under Sec. 50.53 or Sec. 50.54 only if such clinical 
investigations are:
    (1) Related to their status as wards; or
    (2) Conducted in schools, camps, hospitals, institutions, or 
similar settings in which the majority of children involved as subjects 
are not wards.
    (b) If the clinical investigation is approved under paragraph (a) 
of this section, the IRB must require appointment of an advocate for 
each child who is a ward.
    (1) The advocate will serve in addition to any other individual 
acting on behalf of the child as guardian or in loco parentis.
    (2) One individual may serve as advocate for more than one child.
    (3) The advocate must be an individual who has the background and 
experience to act in, and agrees to act in, the best interest of the 
child for the duration of the child's participation in the clinical 
investigation.
    (4) The advocate must not be associated in any way (except in the 
role as advocate or member of the IRB) with the clinical investigation, 
the investigator(s), or the guardian organization.

PART 56--INSTITUTIONAL REVIEW BOARDS

    5. The authority citation for 21 CFR part 56 is revised 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.


Sec. 56.101  [Amended]

    6. Amend Sec. 56.101 Scope in the first sentence of paragraph (a) 
by adding after the word ``including'' the phrase ``foods, including 
dietary supplements, that bear a nutrient content claim or a health 
claim, infant formulas,''.
    7. Amend Sec. 56.102 by adding paragraphs (b)(21), (b)(22), and 
(b)(23) to read as follows:


Sec. 56.102  Definitions.

* * * * *
    (b) * * *
    (21) Data and information about a clinical study of an infant 
formula when submitted as part of an infant formula notification under 
section 412(c) of the Federal Food, Drug, and Cosmetic Act.
    (22) Data and information submitted in a petition for a nutrient 
content claim, described in Sec. 101.69 of this chapter, and for a 
health claim, described in Sec. 101.70 of this chapter.
    (23) Data and information from investigations involving children 
submitted in a new dietary ingredient notification, described in 
Sec. 190.6 of this chapter.
    8. Amend Sec. 56.109 by adding paragraph (h) to read as follows:


Sec. 56.109  IRB review of research.

* * * * *
    (h) When some or all of the subjects in a study are children, an 
IRB must determine that the research study is in compliance with part 
50, subpart D of this chapter, at the time of its initial review of the 
research. When some or all of the subjects in a study that is 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.
    9. Amend Sec. 56.111 by adding paragraph (c) to read as follows:


Sec. 56.111  Criteria for IRB approval of research.

* * * * *
    (c) In order to approve research in which some or all of the 
subjects are children, an IRB must determine that all research is in 
compliance with part 50, subpart D of this chapter.


[[Page 20600]]


    Dated: February 28, 2001.
Ann M. Witt,
Acting Associate Commissioner for Policy.
[FR Doc. 01-10008 Filed 4-18-01; 4:24 pm]
BILLING CODE 4160-01-F