Federal Register / Vol. 62, No. 147 / Thursday, July 31, 1997 / Notices 41061

Appendix C: Pharmacokinetic,

Pharmacodynamic, and Dose-Response

Considerations

Evaluation of the pharmacokinetics and

pharmacodynamics, and their comparability,

in the three major racial groups (Asian,

Black, and Caucasian) is critical to the

registration of drugs in the ICH regions. Basic

pharmacokinetic evaluation should

characterize absorption, distribution,

metabolism, excretion (ADME), and where

appropriate, food-drug and drug-drug

interactions.

A sound pharmacokinetic comparison in

the foreign and new regions allows rational

consideration of what kinds of further

pharmacodynamic and clinical studies

(bridging studies) are needed in the new

region. In contrast to a medicine’s

pharmacokinetics, where differences between

populations may be attributed primarily to

intrinsic ethnic factors and are readily

identified, a medicine’s pharmacodynamic

response (clinical effectiveness, safety, and

dose response) may be influenced by both

intrinsic and extrinsic ethnic factors and this

may be difficult to identify except by

conducting clinical studies in the new

region.

The ICH E4 guideline describes various

approaches to dose-response evaluation. In

general, dose response (or concentration

response) should be evaluated for both

pharmacologic effect (where one is

considered pertinent) and clinical endpoints

in the foreign region. The pharmacologic

effect, including dose response, may also be

evaluated in the foreign region in a

population representative of the new region.

Depending on the situation, data on clinical

efficacy and dose response in the new region

may or may not be needed, e.g., if the drug

class is familiar and the pharmacologic effect

is closely linked to clinical effectiveness and

dose response, these foreign

pharmacodynamic data may be a sufficient

basis for approval and clinical endpoint and

dose-response data may not be needed in the

new region. The pharmacodynamic

evaluation, and possible clinical evaluation

(including dose response) is important

because of the possibility that the response

curve may be shifted in a new population.

Examples of this are well-documented, e.g.,

the decreased response in blood pressure of

blacks to angiotensin-converting enzyme

inhibitors.

Appendix D: A Drug’s Sensitivity to Ethnic

Factors

Characterization of a drug according to the

potential impact of ethnic factors upon its

pharmacokinetics, pharmacodynamics, and

therapeutic effects may be useful in

determining what sort of bridging study is

needed in the new region. The impact of

ethnic factors upon a drug’s effect will vary

depending upon the drug’s pharmacologic

class and indication and the age and gender

of the patient. No one property of the drug

is predictive of the compound’s relative

sensitivity to ethnic factors. The type of

bridging study needed is ultimately a matter

of judgment, but assessment of sensitivity to

ethnic factors may help in that judgment.

The following properties of a compound

make it less likely to be sensitive to ethnic

factors:

• Linear pharmacokinetics (PK).

• A flat pharmacodynamic (PD) (effectconcentration) curve for both efficacy and

safety in the range of the recommended

dosage and dose regimen (this may mean that

the drug is well-tolerated).

• A wide therapeutic dose range (again,

possibly an indicator of good tolerability).

• Minimal metabolism or metabolism

distributed among multiple pathways.

• High bioavailability, thus less

susceptibility to dietary absorption effects.

• Low potential for protein binding.

• Little potential for drug-drug, drug-diet,

and drug-disease interactions.

• Nonsystemic mode of action.

• Little potential for abuse.

The following properties of a compound

make it more likely to be sensitive to ethnic

factors:

• Nonlinear pharmacokinetics.

• A steep pharmacodynamic curve for

both efficacy and safety (a small change in

dose results in a large change in effect) in the

range of the recommended dosage and dose

regimen.

• A narrow therapeutic dose range.

• Highly metabolized, especially through

a single pathway, thereby increasing the

potential for drug-drug interaction.

• Metabolism by enzymes known to show

genetic polymorphism.

• Administration as a prodrug, with the

potential for ethnically variable enzymatic

conversion.

• High intersubject variation in

bioavailability.

• Low bioavailability, thus more

susceptible to dietary absorption effects.

• High likelihood of use in a setting of

multiple co-medications.

• High potential for abuse.

Dated: July 25, 1997.

William K. Hubbard,

Associate Commissioner for Policy

Coordination.

[FR Doc. 97–20246 Filed 7–30–97; 8:45 am]

BILLING CODE 4160–01–F

DEPARTMENT OF HEALTH AND

HUMAN SERVICES

Food and Drug Administration

[Docket No. 97N–0289]

Content and Format of Labeling for

Human Prescription Drugs; Pregnancy

Labeling; Public Hearing

AGENCY: Food and Drug Administration,

HHS.

ACTION: Notice of public hearing; request

for comments.

SUMMARY: The Food and Drug

Administration (FDA) is announcing a

public hearing regarding requirements

for the content and format of the

pregnancy subsection of labeling for

human prescription drugs. The public

hearing will focus on the requirement

that each drug product be classified in

one of five pregnancy categories

intended to aid clinicians and patients

with decisions about drug therapy.

Public comments and FDA’s

preliminary review of the pregnancy

category designations for marketed

drugs suggest that the categories may be

misleading and confusing, may not

accurately reflect reproductive and

developmental risk, and may be used

inappropriately by clinicians in making

decisions about drug therapy in

pregnant women and women of

childbearing potential and also in

making decisions about how to respond

to inadvertent fetal exposure. The

hearing is intended to elicit comments

on the practical utility, effects, and

limitations of the current pregnancy

labeling categories in order to help the

agency identify the range of problems

associated with the categories and to

identify and evaluate options that might

address identified problems, and to hear

the views of groups most affected.

DATES: The public hearing will be held

on Friday, September 12, 1997, from 9

a.m. to 5 p.m. Submit written notices of

participation and comments for

consideration at the hearing by August

28, 1997. Written comments will be

accepted after the hearing until

November 12, 1997.

ADDRESSES: The hearing will be held at

the Holiday Inn Bethesda, 8120

Wisconsin Ave.,Versailles I and II,

Bethesda, MD 20814. Submit written

notices of participation and comments

to the Advisors and Consultants Staff,

Center for Drug Evaluation and Research

(HFD–21), ATTN: Pregnancy Labeling

Hearing—Robin M. Spencer or Kimberly

L. Topper, Food and Drug

Administration, 5600 Fishers Lane,

Rockville, MD 20857, FAX 301–443–

0699. Federal Express deliveries need to

use the following street address: 1901

Chapman Ave., rm. 200, Rockville, MD

20852.

Transcripts of the hearing will be

available from the Freedom of

Information Office (HFI–35), Food and

Drug Administration, 5600 Fishers

Lane, Rockville, MD 20857, FAX 301–

443–1726, approximately 15 business

days after the hearing at a cost of 10

cents per page. Requests can also be

made for microfiche or computer disk

copies in place of paper copies.

FOR FURTHER INFORMATION CONTACT: Rose

E. Cunningham, Center for Drug

Evaluation and Research (HFD–6), Food

and Drug Administration, 5600 Fishers

Lane, Rockville, MD 20857, 301–594–

6779, or FAX 301–594–5493; or

Kimberly L. Topper, Advisors and
41062 Federal Register / Vol. 62, No. 147 / Thursday, July 31, 1997 / Notices

Consultants Staff (address above), 301–

443–5455, or FAX 301–443–0699.

SUPPLEMENTARY INFORMATION:

I. Background

Under the Federal Food, Drug, and

Cosmetic Act (the act), FDA has

responsibility for ensuring that

prescription drug and biological

products are accompanied by labeling

(prescribing information) that

summarizes essential scientific

information needed for their safe and

effective use. Unless a drug is not

absorbed systemically and is not known

to have a potential for indirect harm to

a fetus, its labeling must include a

‘‘Pregnancy subsection’’ containing

narrative information on the drug’s

teratogenic effects and other effects on

reproduction and pregnancy, and, when

relevant, effects on later growth,

development, and functional maturation

of the child (21 CFR 201.57(f)(6)). The

regulation also requires that each

product be classified under one of five

pregnancy categories (A, B, C, D, or X)

on the basis of risk of reproductive and

developmental adverse effects or, for

certain categories, on the basis of such

risk weighed against potential benefit. A

drug’s pregnancy category is identified

at the beginning of its pregnancy

labeling subsection.

Clinicians who treat pregnant women

and women of childbearing potential,

academic and specialty medical

organizations, women’s health

organizations and others have expressed

to FDA concern that the information

contained in the typical pregnancy

labeling subsection, and the manner in

which such information is presented,

are not sufficient to adequately inform

decisions about drug therapy in

pregnant women and women of

childbearing potential, or decisions

about how to respond to inadvertent

fetal drug exposure.

In response to these concerns and

FDA’s growing awareness of the

limitations of the pregnancy subsection

of the labeling, FDA is currently

engaged in a comprehensive evaluation

of the way the agency assesses

reproductive and developmental

toxicities associated with human drugs

and biologics, and the way the agency

communicates this information to

clinicians and patients. This evaluation

is focused on assessing the adequacy of

animal and human exposure data

currently developed or maintained,

developing consistency in interpretation

of reproductive and developmental risk

from animal and human exposure data,

and identifying means to optimize

communication of this risk information.

FDA has created a multidisciplinary

task force to explore these issues. This

group intends to develop, for use by

FDA reviewers and industry, a guidance

document on interpretation of

reproductive and developmental

toxicity data from animals and a

guidance document on interpretation of

human exposure data. The task force

will also consider other possible actions

that may be necessary to make

pregnancy labeling content more

consistent, informative, and accessible

including: (1) Changing, or creating

alternatives to, the pregnancy labeling

categories; (2) clearly distinguishing in

labeling between information that

addresses whether to prescribe a

therapeutic option during pregnancy,

whether to prescribe a therapeutic

option in a woman of childbearing

potential, and the potential

consequences of inadvertent fetal

exposure; and (3) attempting to better

delineate the different types of

reproductive and developmental risks

associated with a product. This hearing

is intended to gather information to

inform future task force

recommendations.

II. The Pregnancy Categories

FDA’s information gathering and

evaluation to date have identified the

pregnancy categories as a source of

concern for those who use or are

affected by pregnancy labeling. The

categories have been criticized for being

confusing and misleading because they

convey the impression that there is a

gradation of reproductive risk from drug

exposure across categories (i.e., that risk

increases from A to B to C to D to X)

and that there is similar risk within any

given category, but the criteria for

designating drugs in particular

categories are not consistent with these

impressions.

The confusion concerning gradation

of risk across categories is believed to be

due, in part, to the fact that the criteria

for inclusion in categories A, B, and to

a certain extent C, are based primarily

on risk with risk increasing from A to

C, while criteria for inclusion in

categories D, X, and to a certain extent

C, are based on risk weighed against

potential benefit. Thus, while it is

intended that there be gradation of risk

for categories A through C, drugs

designated D, X, and in some cases C,

may pose a very similar risk, but be

categorized differently on the basis of

potential benefit.

The impression that there is similar

risk for drugs within the same category

is undercut by inclusion criteria that

permit a broad range of risk within

certain categories. For example, category

C (the largest category) is intended to

include both drugs with demonstrated

adverse reproductive effects in animals

and drugs for which there are no animal

studies at all, situations that may be

quite different in terms of risk. For the

category C drugs that were tested in

animals, moreover, there is a wide range

of severity of adverse effects and often

no distinction between teratogenic and

other toxic effects.

The confusion inherent in the current

category designations may be

exacerbated by inconsistent application

of category classifications in certain

instances, such that drugs with similar

risk, or with similar risk-benefit

assessments, may be found in different

categories.

Some who expressed concern to the

agency about pregnancy labeling argue

that failure of the category designations

to accurately reflect reproductive and

developmental risk, either across

categories or within a category, presents

potentially serious public health

consequences. They maintain that many

clinicians assume the categories reflect

gradation of risk from category A

through X, that any given category is

homogenous in terms of risk, and based

on those assumptions make decisions

based largely or entirely on category

designation rather than on careful

evaluation of the available data. They

also argue that, in addition to the

potential for category designations to be

misleading, the mere presence of

category designations affords an overly

simplistic evaluation of a complex

problem that can deter the clinician

from seeking additional information that

could lead to a better informed decision.

They maintain that clinicians making

decisions based on category designation

alone are more likely to overestimate

risk, with potentially profound

consequences. For example, decisions

based on an overestimation of

teratogenic risk may result in

unnecessary withholding of beneficial

therapy or in termination of wanted

pregnancies.

III. Scope of the Hearing

Because of the breadth and

complexity of issues involved in

assessing, interpreting, and

communicating information that bears

on therapeutic use and exposure to

drugs in pregnancy and in women of

childbearing potential, this part 15 (21

CFR part 15) hearing will focus on the

pregnancy categories. To guide its future

decision making, the agency is seeking

public comment and data on the

practical utility and effects of the

pregnancy categories, problems

associated with the categories, and the
Federal Register / Vol. 62, No. 147 / Thursday, July 31, 1997 / Notices 41063

means to address problems associated

with the categories, including possible

alternatives to the categories for

communicating information on

reproductive and developmental

toxicity. The agency is specifically

seeking comment and data on the

following:

(1) The extent to which the category

designations are relied upon in making

decisions about drug therapy in

pregnant women and women of

childbearing potential and decisions

about inadvertent fetal exposure, the

extent to which such reliance may be

misplaced, and the extent to which such

reliance may have untoward public

health consequences;

(2) The extent to which current

pregnancy labeling (category

designation and accompanying narrative

text) is effective in communicating risk

of reproductive and developmental

toxicity;

(3) The extent to which current

pregnancy labeling may not adequately

address the range of issues that may

bear on decisions about drug therapy in

pregnant women and women of

childbearing potential and decisions

about inadvertent fetal exposure (e.g.,

indication-specific concerns, pregnancy

status, magnitude of exposure,

incidental exposure, chronic exposure,

timing of exposure);

(4) Additional information (data or

interpretation of data) that could be

included in pregnancy labeling to better

address the range of issues that bear on

decisions about drug therapy in

pregnant women and women of

childbearing potential and decisions

about inadvertent fetal exposure; and

(5) Options to improve

communication of reproductive and

developmental risk in labeling, which

could include alternatives to the

categories (both content and format

options) or efforts to make the current

category scheme and accompanying

narrative text more consistent and

informative.

The agency encourages individuals,

industry, consumer groups, health care

professionals, and researchers with

particular expertise in this area, as well

as other interested persons, to respond

to this notice. The agency strongly

encourages persons who cannot attend

the hearing to send information relevant

to the topics and questions listed above

to the Dockets Management Branch

(HFA–305), Food and Drug

Administration, 12420 Parklawn Dr., rm

1–23, Rockville, MD 20857. Two copies

of any comments are to be submitted,

except that individuals may submit one

copy. Comments are to be identified

with Docket No. 97N–0289. Received

comments may be seen in the office

above between 9 a.m. and 4 p.m.,

Monday through Friday.

IV. Notice Of Hearing Under Part 15

The Commissioner of Food and Drugs

(the Commissioner) is announcing that

the public hearing will be held in

accordance with part 15. The presiding

officer will be the Commissioner or his

designee. The presiding officer will be

accompanied by a panel of Public

Health Service employees with relevant

expertise.

Persons who wish to participate in the

part 15 hearing must file a written or

facsimile notice of participation with

the Advisors and Consultants Staff by

August 28, 1997. To ensure timely

handling, the outer envelope or

facsimile cover sheet should be clearly

marked with Docket No. 97N–0289 and

the statement ‘‘Pregnancy Labeling

Hearing.’’ Groups should submit two

copies. The notice of participation

should contain the speaker’s name,

address, telephone number, FAX

number, title, business affiliation, if any,

a brief summary of the presentation, and

approximate amount of time requested

for the presentation.

The agency requests that persons or

groups having similar interests

consolidate their presentations and

present them through a single

representative. FDA will allocate the

time available for the hearing among the

persons who properly file notices of

participation. If time permits, FDA may

allow participation at the conclusion of

the hearing from interested persons

attending the hearing who did not

submit a written notice of participation.

After reviewing the notices of

participation and accompanying

information, FDA will schedule each

appearance and notify each participant

by mail, telephone, or FAX, of the time

allotted to the person and the

approximate time the person’s

presentation is scheduled to begin. The

hearing schedule will be available at the

hearing. After the hearing the schedule

will be placed on file in the Dockets

Management Branch (address above)

under Docket Number 97N–0289.

Under § 15.30(f), the hearing is

informal and the rules of evidence do

not apply. The presiding officer and any

panel members may question any

person during or at the conclusion of

their presentation. No other person

attending the hearing may question a

person making a presentation or

interrupt the presentation of a

participant.

Public hearings under part 15 are

subject to FDA’s guideline (part 10,

subpart C (21 CFR part 10, subpart C))

concerning the policy and procedures

for electronic media coverage of FDA’s

public administrative proceedings.

Under § 10.205, representatives of the

electronic media may be permitted,

subject, to certain limitations, to

videotape, film, or otherwise record

FDA’s public administrative

proceedings, including presentations by

participants. Representatives of the

electronic media are urged to provide

advance notice of their planned

attendance, to the identified contact

person for the hearing, so that their

needs for space and technical assistance

can be anticipated and accommodated.

The hearing will be transcribed as

required in § 15.30(b). Orders for copies

of the transcript can be placed through

the Dockets Management Branch

(address above).

Any disabled persons requiring

special accommodations in order to

attend the hearing should direct those

needs to the contact person listed above.

To the extent that the conditions for

the hearing, as described in this notice,

conflict with any provisions set out in

part 15, this notice acts as a waiver of

those provisions as specified in

§ 15.30(h).

To permit time for all interested

persons to submit data, information, or

views on this subject, the administrative

record will remain open following the

hearing until November 12, 1997.

Dated: July 23, 1997.

William K. Hubbard,

Associate Commissioner for Policy

Coordination.

[FR Doc. 97–20247 Filed 7-30-97; 8:45 am]

BILLING CODE 4160–01–F

DEPARTMENT OF HEALTH AND

HUMAN SERVICES

Health Care Financing Administration

[Form #HCFA–R–200]

Emergency Clearance: Public

Information Collection Requirements

Submitted to the Office of Management

and Budget (OMB)

In compliance with the requirement

of section 3506(c)(2)(A) of the

Paperwork Reduction Act of 1995, the

Health Care Financing Administration

(HCFA), Department of Health and

Human Services (DHHS), has submitted

to the Office of Management and Budget

(OMB) the following request for

Emergency review. We are requesting an

emergency review because the

collection of this information is needed

prior to the expiration of the normal

time limits under OMB’s regulations at