[Federal Register Volume 60, Number 40 (Wednesday, March 1, 1995)]
[Notices]
[Pages 11270-11271]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 95-4958]




[[Page 11269]]

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Part X





Department of Health and Human Services





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Food and Drug Administration



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International Conference on Harmonisation; Guideline on Extent of 
Population Exposure Required to Assess Clinical Safety for Drugs; 
Notice

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

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.

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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-life-threatening 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-life-threatening 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-
life-threatening 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 
Sec. 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 Sec. 10.90(b). Therefore, this 
guideline is not being issued under the authority of Sec. 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: [[Page 11271]] 

 The Extent of Population Exposure to Assess Clinical Safety for Drugs 
Intended for Long-Term 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 
long-term 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]
BILLING CODE 4160-01-F