Federal Register / Vol. 66, No. 79 / Tuesday, April 24, 2001 / Rules and Regulations 20589

be misleading and is in need of

clarification.

Need for Correction

Specifically, the final rule document

amended the authority citation for part

159, Customs Regulations (19 CFR part

159), by moving specific authority

citations for certain regulatory sections

in the part to the authority citation

section set forth at the beginning of the

part from parenthetical references set

forth immediately following the text of

the particular sections. However, it has

come to Customs attention that these

same changes relating to the authority

citation for part 159 were previously

made in an interim rule document that

was published in the Federal Register

(64 FR 56433) on October 20, 1999, as

T.D. 99–75.

Correction of Publication

Accordingly, the publication on

March 26, 2001, of the final regulations

concerning foreign repairs to American

vessels (T.D. 01–24) (FR Doc. 01–7325)

is corrected as follows:

1. On page 16399, in the third

column, under the heading, ‘‘PART

159—LIQUIDATION OF DUTIES’’,

correct amendatory instruction number

1 to read: ‘‘The authority citation for

part 159 continues to read as follows:’’

2. On page 16400, in the first column,

under the heading, ‘‘PART 159—

LIQUIDATION OF DUTIES’’, remove

amendatory instruction number 2.

3. On page 16400, in the first and

second columns, again under the

heading, ‘‘PART 159—LIQUIDATION

OF DUTIES’’, renumber amendatory

instruction numbers 3, 4 and 5 as

amendatory instruction numbers 2, 3,

and 4, respectively.

Dated: April 19, 2001.

Harold M. Singer,

Chief, Regulations Branch.

[FR Doc. 01–10163 Filed 4–23–01; 8:45 am]

BILLING CODE 4820–02–P

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 FDARegulated Products

AGENCY: Food and Drug Administration,

HHS.

ACTION: Interim rule; opportunity for

public comment.

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 FDAregulated 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

20590 Federal Register / Vol. 66, No. 79 / Tuesday, April 24, 2001 / Rules and Regulations

1At 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.

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 HHSsupported 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).

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 FDAregulated 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 § 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 § 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

Federal Register / Vol. 66, No. 79 / Tuesday, April 24, 2001 / Rules and Regulations 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 §§ 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 §§ 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

(§ 101.69(f)). The regulations governing

petitions for health claims contain the

same requirement (§ 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 § 101.69 or § 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

§ 50.3. These include the terms ‘‘assent’’

(§ 50.3(n)), ‘‘children’’ (§ 50.3(o)),

‘‘parent’’ (§ 50.3(p)), ‘‘permission’’

(§ 50.3(r)), and ‘‘guardian’’ (§ 50.3(s)).

The definitions of these terms in § 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’’ (§ 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 § 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

§ 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 § 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

§ 50.3(q), FDA has developed a

definition for ward that is consistent

with the use of the term in HHS subpart

D. Under § 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.

20592 Federal Register / Vol. 66, No. 79 / Tuesday, April 24, 2001 / Rules and Regulations

5. What Does ‘‘Permission’’ Mean, and

How Is It Different From Informed

Consent?

The definition of ‘‘permission’’ at

§ 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 § 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 § 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 § 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 § 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 § 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 § 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 § 50.51, § 50.52,

or § 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 § 56.111. New

§ 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 § 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

§ 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

(§ 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 § 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 § 50.51, § 50.52, or § 50.53.

If an IRB determines that the research

does not fit any of these three categories,

but that the research may fit under

§ 50.54, the IRB should contact FDA for

further guidance. FDA emphasizes that

it expects the volume of studies that are

Federal Register / Vol. 66, No. 79 / Tuesday, April 24, 2001 / Rules and Regulations 20593

candidates for classification under

§ 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 § 56.113. Under § 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 § 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

§ 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 FDAregulated 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 § 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 § 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 § 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 FDAregulated products in children will be

allowed to proceed under § 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 placebocontrolled clinical investigations may be

conducted in children. FDA believes

that clinical investigations involving

placebos in children may be conducted

in accord with § 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 § 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 § 50.53 raises

issues similar to those raised by § 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

20594 Federal Register / Vol. 66, No. 79 / Tuesday, April 24, 2001 / Rules and Regulations

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 § 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 § 50.51, § 50.52, or §

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

§ 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 § 50.54(b)(1), that the

clinical investigation satisfies the

conditions of § 50.51, § 50.52, or § 50.53

or, under § 50.54(b), that three

conditions are met. The conditions in

§ 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 § 50.54 generally

follows the provisions in 45 CFR 46.407

of HHS subpart D with some

modification. In § 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 § 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 § 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

Federal Register / Vol. 66, No. 79 / Tuesday, April 24, 2001 / Rules and Regulations 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 § 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 § 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 § 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 § 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 § 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 § 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

20596 Federal Register / Vol. 66, No. 79 / Tuesday, April 24, 2001 / Rules and Regulations

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

2001 Per year 2002 through

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 FDAregulated 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

Federal Register / Vol. 66, No. 79 / Tuesday, April 24, 2001 / Rules and Regulations 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 onetime 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.

§ 50.1 [Amended]

2. Amend § 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 § 50.3 by adding paragraphs

(b)(23), (b)(24), (b)(25), (n), (o), (p), (q),

(r), and (s) to read as follows:

20598 Federal Register / Vol. 66, No. 79 / Tuesday, April 24, 2001 / Rules and Regulations

§ 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 § 101.69 of this

chapter, or for a health claim, described

in § 101.70 of this chapter.

(25) Data and information from

investigations involving children

submitted in a new dietary ingredient

notification, described in § 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 § 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

§ 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 § 50.51, § 50.52, or

§ 50.53 and the conditions of all other

applicable sections of this subpart D.

§ 50.51 Clinical investigations not

involving greater than minimal risk.

Any clinical investigation within the

scope described in §§ 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 § 50.55.

§ 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 §§ 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 § 50.55.

§ 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 §§ 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 § 50.55.

§ 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 §§ 50.1 and 56.101 of this

chapter and involving children as

subjects meets the requirements of

§ 50.51, § 50.52, or § 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:

Federal Register / Vol. 66, No. 79 / Tuesday, April 24, 2001 / Rules and Regulations 20599

(1) That the clinical investigation in

fact satisfies the conditions of § 50.51,

§ 50.52, or § 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 § 50.55.

§ 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 wellbeing 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

§ 50.51 or § 50.52.

(2) Where clinical investigations are

covered by § 50.53 or § 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 § 50.27.

(g) When the IRB determines that

assent is required, it must also

determine whether and how assent must

be documented.

§ 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 § 50.53

or § 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.

§ 56.101 [Amended]

6. Amend § 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 § 56.102 by adding

paragraphs (b)(21), (b)(22), and (b)(23) to

read as follows:

§ 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 § 101.69 of this

chapter, and for a health claim,

described in § 101.70 of this chapter.

(23) Data and information from

investigations involving children

submitted in a new dietary ingredient

notification, described in § 190.6 of this

chapter.

8. Amend § 56.109 by adding

paragraph (h) to read as follows:

§ 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 § 56.111 by adding

paragraph (c) to read as follows:

§ 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.

20600 Federal Register / Vol. 66, No. 79 / Tuesday, April 24, 2001 / Rules and Regulations

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

DEPARTMENT OF THE INTERIOR

Office of Surface Mining Reclamation

and Enforcement

30 CFR Part 944

[SPATS UT–038–FOR]

Utah Regulatory Program

AGENCY: Office of Surface Mining

Reclamation and Enforcement, Interior.

ACTION: Final rule; approval of

amendment.

SUMMARY: The Office of Surface Mining

Reclamation and Enforcement (OSM) is

approving a proposed amendment to the

Utah regulatory program (hereinafter,

the ‘‘Utah program’’) under the Surface

Mining Control and Reclamation Act of

1977 (SMCRA). Utah’s amendment

proposed to change the State’s rules

pertaining to: Definitions of ‘‘abandoned

site,’’ ‘‘other treatment facilities,’’

‘‘previously mined area,’’ ‘‘qualified

laboratory,’’ and ‘‘significant

recreational, timber, economic, or other

values incompatible with coal mining

and reclamation operations;’’

engineering requirements for

impoundments and for backfilling and

grading; hydrologic requirements for

impoundments; requirements for bond

release applications; prime farmland

acreage; inspection frequency for

abandoned sites; and the period in

which to pay a penalty when requesting

a formal hearing. Utah intended to

revise its program to make it consistent

with the corresponding Federal

regulations and SMCRA.

EFFECTIVE DATE: April 24, 2001.

FOR FURTHER INFORMATION CONTACT:

James F. Fulton, Denver Field Division

Chief; telephone: (303) 844–1400,

extension 1424; e-mail:

jfulton@osmre.gov.

SUPPLEMENTARY INFORMATION:

I. Background on the Utah Program

II. Submission of the Proposed Amendment

III. Director’s Findings

IV. Summary and Disposition of Comments

V. Director’s Decision

VI. Procedural Determinations

I. Background on the Utah Program

On January 21, 1981, the Secretary of

the Interior conditionally approved the

Utah program. You can find background

information about Utah’s program,

including the Secretary’s findings, the

disposition of comments, and the

conditions of approval of the Utah

program in the January 21, 1981,

Federal Register (46 FR 5899). You can

also find later actions concerning Utah’s

program and program amendments at 30

CFR 944.15 and 944.30.

II. Submission of the Proposed

Amendment

By letter dated December 23, 1999,

Utah sent to us an amendment (UT–

038–FOR, administrative record No.

UT–1133) to its program under SMCRA

(30 U.S.C. 1201 et seq.). The State sent

the amendment in response to a June 19,

1997, letter (administrative record No.

UT–1093) that we sent to Utah in

accordance with 30 CFR 732.17(c).

Changes to the Utah Administrative

Rule (Utah Admin. R.) that the State

proposed to make are summarized

below.

A. Changes to Definitions at Utah

Admin. R. 645–100–200

1. ‘‘Abandoned site:’’ Utah proposed

to revise its definition of this term by

changing the conditions sites must meet

to be considered abandoned and

allowing the Division of Oil, Gas and

Mining (the Division) to decide if it

wants to inspect abandoned sites less

than 12 times a year. The proposed

changes also require the Division to

make written findings on specific topics

to justify a decision to set an alternative

inspection frequency;

2. ‘‘Other treatment facilities:’’ The

State proposed to change this definition

to include neutralization and

precipitators. Utah also proposed to

include in this definition those facilities

used to prevent additional contributions

of dissolved solids to streamflow or

runoff outside the permit area or to

comply with all applicable State and

Federal water quality laws and

regulations;

3. ‘‘Previously mined area:’’ Utah

proposed to change its definition of this

term to mean land affected by coal

mining and reclamation operations prior

to August 3, 1977, that has not been

reclaimed to the standards of Utah

Admin. R. 645 or 30 CFR Chapter VII;

4. ‘‘Qualified laboratory:’’ The State

proposed to change this definition to

include those facilities that can provide

other services specified at Utah Admin.

R. 645–302–299;

5. ‘‘Significant recreational, timber,

economic, or other values incompatible

with coal mining operations:’’ Utah

proposed to change its definition of this

term by removing the qualifying

statement that damage to these values

caused by mining must be beyond an

operator’s ability to repair or restore in

order for these values’ significance to be

evaluated;

B. Changes to Engineering Requirements

for Impoundments

1. At Utah Admin. R. 645–301–

514.320 and –514.330, Utah proposed to

change its description of inspection

requirements for impoundments that

meet, and those that do not meet, the

Class B or C criteria of the Natural

Resources Conservation Service’s

(NRCS) Technical Release 60 (TR–60) or

the size or other criteria of 30 CFR

77.216;

2. At Utah Admin. R. 645–301–531,

the State proposed to require permit

applications to contain detailed design

plans for siltation structures, water

impoundments, and coal processing

waste banks, dams, or embankments

located inside the permit area;

3. At Utah Admin. R. 645–301–

533.100 and –533.110, Utah proposed to

include references to provisions of TR–

60 in its descriptions of safety factors

required for different sizes and types of

impoundments;

4. At Utah Admin. R. 645–301–

533.200 and –533.210, the State

proposed to include references to

provisions of TR–60 for, and expand its

description of, foundation safety factors

and stability, investigation, and testing

requirements for different sizes and

types of impoundments;

5. At Utah Admin. R. 645–301–

533.610, Utah proposed to include TR–

60 in its rules by reference and to

require impoundments meeting the

Class B or C criteria of TR–60 or the size

or other criteria of 30 CFR 77.216 to

comply with this section of its rules.

Further, at Utah Admin. R. 645–301–

533.610 through –533.714, Utah

proposed to change its description of

the information to be included in

detailed design plans for various types

and sizes of impoundments;

C. Changes to Engineering Requirements

for Backfilling and Grading

At Utah Admin R.645–553.700 and

–553.800, the State proposed to revise

its definitions of ‘‘thin overburden’’ and

‘‘thick overburden,’’ respectively, for the

purposes of surface coal mining and

reclamation activities;

D. Changes to Hydrologic Requirements

for Impoundments

1. At Utah Admin. R. 645–301–

733.100, Utah proposed to require

permit applications to contain detailed

design plans for water impoundments

located inside the permit area;

2. At Utah Admin. R. 645–301–

733.210, the State proposed to allow the