[Federal Register: April 24, 2001 (Volume 66, Number 79)]
[Rules and Regulations]
[Page 20589-20600]
From the Federal Register Online via GPO Access [wais.access.gpo.gov]
[DOCID:fr24ap01-4]
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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://frwebgate.access.gpo.gov/cgi-bin/leaving.cgi?from=leavingFR.html&log=linklog&to=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 http://frwebgate.access.gpo.gov/cgi-bin/leaving.cgi?from=leavingFR.html&log=linklog&to=http://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