11270 Federal Register / Vol. 60, No. 40 / Wednesday, March 1, 1995 / Notices

DEPARTMENT OF HEALTH AND

HUMAN SERVICES

Food and Drug Administration

[Docket No. 94D–0029]

International Conference on

Harmonisation; Guideline on the

Extent of Population Exposure

Required to Assess Clinical Safety for

Drugs Intended for Long-Term

Treatment of Non-Life-Threatening

Conditions; Availability

AGENCY: Food and Drug Administration,

HHS.

ACTION: Notice.

SUMMARY: The Food and Drug

Administration (FDA) is publishing a

final guideline entitled ‘‘The Extent of

Population Exposure Required to Assess

Clinical Safety for Drugs Intended for

Long-term Treatment of Non-lifethreatening Conditions.’’ This guideline

was prepared under the auspices of the

International Conference on

Harmonisation of Technical

Requirements for Registration of

Pharmaceuticals for Human Use (ICH).

The guideline is intended to present an

accepted set of principles for the safety

evaluation of drugs intended for the

long-term treatment (chronic or repeated

intermittent use for longer than 6

months) of non-life-threatening

diseases.

DATES: Effective on March 1, 1995.

Submit written comments at any time.

ADDRESSES: Submit written comments

on the guideline to the Dockets

Management Branch (HFA–305), Food

and Drug Administration, rm. 1–23,

12420 Parklawn Dr., Rockville, MD

20857. Copies of the guideline are

available from CDER Executive

Secretariat Staff (HFD–8), Center for

Drug Evaluation and Research, Food

and Drug Administration, 7500 Standish

Pl., Rockville, MD 20855.

FOR FURTHER INFORMATION CONTACT:

Regarding the guideline: Leah Ripper,

Center for Drug Evaluation and

Research (HFD–500), Food and

Drug Administration, 5600 Fishers

Lane, Rockville, MD 20857, 301–

443–2544.

Regarding ICH: Janet J. Showalter,

Office of Health Affairs (HFY–20),

Food and Drug Administration,

5600 Fishers Lane, Rockville, MD

20857, 301–443–1382.

SUPPLEMENTARY INFORMATION: In recent

years, many important initiatives have

been undertaken by regulatory

authorities and industry associations to

promote international harmonization of

regulatory requirements. FDA has

participated in many meetings designed

to enhance harmonization and is

committed to seeking scientifically

based harmonized technical procedures

for pharmaceutical development. One of

the goals of harmonization is to identify

and reduce differences in technical

requirements for drug development

among regulatory agencies.

ICH was organized to provide an

opportunity for tripartite harmonization

initiatives to be developed with input

from both regulatory and industry

representatives. FDA also seeks input

from consumer representatives and

others. ICH is concerned with

harmonization of technical

requirements for the registration of

pharmaceutical products among three

regions: The European Union, Japan,

and the United States. The six ICH

sponsors are the European Commission;

the European Federation of

Pharmaceutical Industry Associations;

the Japanese Ministry of Health and

Welfare; the Japanese Pharmaceutical

Manufacturers Association; the Centers

for Drug Evaluation and Research and

Biologics Evaluation and Research,

FDA; and the Pharmaceutical Research

and Manufacturers of America. The ICH

Secretariat, which coordinates the

preparation of documentation, is

provided by the International

Federation of Pharmaceutical

Manufacturers Association (IFPMA).

The ICH Steering Committee includes

representatives from each of the ICH

sponsors and IFPMA, as well as

observers from the World Health

Organization, the Canadian Health

Protection Branch, and the European

Free Trade Area.

Harmonization of the safety

evaluation of drugs intended for the

long-term treatment of non-lifethreatening diseases was selected as a

priority topic during the early stages of

the ICH initiative. In the Federal

Register of March 1, 1994 (59 FR 9746),

FDA published a draft tripartite

guideline entitled ‘‘Draft Guideline on

the Extent of Population Exposure

Required to Assess Clinical Safety for

Drugs Intended for Long-Term

Treatment of Non-Life-Threatening

Conditions.’’ The notice gave interested

persons an opportunity to submit

comments by May 16, 1994.

After consideration of the comments

received and revisions to the guideline,

a final draft of the guideline was

submitted to the ICH Steering

Committee and endorsed by the three

participating regulatory agencies at the

ICH meeting held in October 1994.

The guideline presents an accepted

set of principles for the safety

evaluation of drugs intended for the

long-term treatment of non-lifethreatening diseases. The guideline

distinguishes between clinical data on

adverse drug events (ADE’s) derived

from studies of shorter duration of

exposure and data from studies of

longer duration, which frequently

include nonconcurrently controlled

studies. The principles discussed in the

guideline are summarized as follows: (1)

Regulatory standards are valuable for

the extent and duration of treatment

needed to provide the safety data base

for drugs intended for long-term

treatment of non-life-threatening

conditions; however, there are a number

of circumstances where harmonized

regulatory standards for the clinical

safety evaluation may not be applicable;

(2) further investigation is needed about

the occurrence of ADE’s in relation to

duration of treatment for different drug

classes; (3) because most ADE’s first

occur within the first 3 to 6 months of

drug treatment, many patients should be

treated and observed for 6 months at

dosage levels intended for clinical use;

and (4) because some serious ADE’s may

occur only after drug treatment for more

than 6 months, some patients should be

treated with the drug for 12 months.

In the past, guidelines have generally

been issued under § 10.90(b) (21 CFR

10.90(b)), which provides for the use of

guidelines to state procedures or

standards of general applicability that

are not legal requirements but are

acceptable to FDA. The agency is now

in the process of revising § 10.90(b).

Therefore, this guideline is not being

issued under the authority of § 10.90(b),

and it does not create or confer any

rights, privileges, or benefits for or on

any person, nor does it operate to bind

FDA in any way.

As with all of FDA’s guidelines, the

public is encouraged to submit written

comments with new data or other new

information pertinent to this guideline.

The comments in the docket will be

periodically reviewed, and, where

appropriate, the guideline will be

amended. The public will be notified of

any such amendments through a notice

in the Federal Register.

Interested persons may, at any time,

submit written comments on the

guideline to the Dockets Management

Branch (address above). 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. The guideline and received

comments may be seen in the office

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

Monday through Friday.

The text of the guideline follows:
Federal Register / Vol. 60, No. 40 / Wednesday, March 1, 1995 / Notices 11271

The Extent of Population Exposure to Assess

Clinical Safety for Drugs Intended for LongTerm Treatment of Non-Life-Threatening

Conditions

The objective of this guideline is to present

an accepted set of principles for the safety

evaluation of drugs intended for the longterm treatment (chronic or repeated

intermittent use for longer than 6 months) of

non-life-threatening diseases. The safety

evaluation during clinical drug development

is expected to characterize and quantify the

safety profile of a drug over a reasonable

duration of time consistent with the intended

long-term use of the drug. Thus, duration of

drug exposure and its relationship to both

time and magnitude of occurrence of adverse

events are important considerations in

determining the size of the data base

necessary to achieve such goals.

For the purpose of this guideline, it is

useful to distinguish between clinical data on

adverse drug events (ADE’s) derived from

studies of shorter duration of exposure and

data from studies of longer duration, which

frequently are nonconcurrently controlled

studies. It is expected that short-term event

rates (cumulative 3-month incidence of about

1 percent) will be well characterized. Events

where the rate of occurrence changes over a

longer period of time may need to be

characterized depending on their severity

and importance to the risk-benefit assessment

of the drug. The safety evaluation during

clinical drug development is not expected to

characterize rare adverse events, for example,

those occurring in less than 1 in 1,000

patients.

The design of the clinical studies can

significantly influence the ability to make

causality judgments about the relationships

between the drug and adverse events. A

placebo-controlled trial allows the adverse

event rate in the drug-treated group to be

compared directly with the background event

rate in the patient population being studied.

Although a study with a positive or active

control will allow a comparison of adverse

event rates to be made between the test drug

and the control drug, no direct assessment of

the background event rate in the population

studied can be made. A study that has no

concurrent control group makes it more

difficult to assess the causality relationship

between adverse events observed and the test

drug.

There was general agreement on the

following:

1. A harmonized regulatory standard is of

value for the extent and duration of treatment

needed to provide the safety data base for

drugs intended for long-term treatment of

non-life-threatening conditions. Although

this standard covers many indications and

drug classes, there are exceptions.

2. Regulatory standards for the safety

evaluation of drugs should be based on

previous experience with the occurrence and

detection of ADE’s, statistical considerations

of the probability of detecting specified

frequencies of ADE’s, and practical

considerations.

3. Information about the occurrence of

ADE’s in relation to duration of treatment for

different drug classes is incomplete, and

further investigations to obtain this

information would be useful.

4. Available information suggests that most

ADE’s first occur, and are most frequent,

within the first few months of drug

treatment. The number of patients treated for

6 months at dosage levels intended for

clinical use, should be adequate to

characterize the pattern of ADE’s over time.

To achieve this objective, the cohort of

exposed subjects should be large enough to

observe whether more frequently occurring

events increase or decrease over time as well

as to observe delayed events of reasonable

frequency (e.g., in the general range of 0.5

percent to 5 percent). Usually 300 to 600

patients should be adequate.

5. There is concern that, although they are

likely to be uncommon, some ADE’s may

increase in frequency or severity with time or

that some serious ADE’s may occur only after

drug treatment for more than 6 months.

Therefore, some patients should be treated

with the drug for 12 months. In the absence

of more information about the relationship of

ADE’s to treatment duration, selection of a

specific number of patients to be followed for

1 year is to a large extent a judgment based

on the probability of detecting a given ADE

frequency level and practical considerations.

One hundred patients exposed for a

minimum of 1 year are considered to be

acceptable to include as part of the safety

data base. The data should come from

prospective studies appropriately designed to

provide at least 1-year exposure at dosage

levels intended for clinical use. When no

serious ADE is observed in a 1-year exposure

period, this number of patients can provide

reasonable assurance that the true cumulative

1-year incidence is no greater than 3 percent.

6. It is anticipated that the total number of

individuals treated with the investigational

drug, including short-term exposure, will be

about 1,500. Japan currently accepts 500 to

1,500 patients; the potential for a smaller

number of patients is due to the

postmarketing surveillance requirement, the

actual number for a specific drug being

determined by the information available on

the drug and drug class.

7. There are a number of circumstances

where the harmonized general standards for

the clinical safety evaluation may not be

applicable. Reasons for, and examples of,

these exceptions are listed below. It is

expected that additional examples may arise.

It should also be recognized that the clinical

data base required for efficacy testing may be

occasionally larger or may require longer

patient observation than that suggested by

this guideline.

Exceptions:

a. Instances where there is concern that the

drug will cause late developing ADE’s, or

cause ADE’s that increase in severity or

frequency over time, would require a larger

and/or longer-term safety data base. The

concern could arise from:

(1) Data from animal studies;

(2) Clinical information from other agents

with related chemical structures or from a

related pharmacologic class;

(3) Pharmacokinetic or pharmacodynamic

properties known to be associated with such

ADE’s.

b. Situations in which there is a need to

quantitate the occurrence rate of an expected

specific low frequency ADE will require a

greater long-term data base. Examples would

include situations where a specific serious

ADE has been identified in similar drugs or

where a serious event that could represent an

alert event is observed in early clinical trials.

c. Larger safety data bases may be needed

to make risk/benefit decisions in situations

where the benefit from the drug is either: (1)

small (e.g., symptomatic improvement in less

serious medical conditions), (2) will be

experienced by only a fraction of the treated

patients (e.g., certain preventive therapies

administered to healthy populations), or (3)

is of uncertain magnitude (e.g., efficacy

determination on a surrogate endpoint).

d. In situations where there is concern that

a drug may add to an already significant

background rate of morbidity or mortality,

clinical trials may need to be designed with

a sufficient number of patients to provide

adequate statistical power to detect

prespecified increases over the baseline

morbidity or mortality.

e. In some cases, a smaller number of

patients may be acceptable, for example,

where the intended treatment population is

small.

8. Filing for approval will usually be

possible based on the data from patients

treated through 6 months. Data on patients

treated through 12 months should be

submitted as soon as available and prior to

approval in the United States and Japan but

may be submitted after approval in the

European Union. In the United States, the

initial submission for those drugs designated

as priority drugs should include the 12-

month patient data.

Dated: February 23, 1995.

William B. Schultz,

Deputy Commissioner for Policy.

[FR Doc. 95–4958 Filed 2–28–95; 8:45 am]

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