[Federal Register Volume 59, Number 40 (Tuesday, March 1, 1994)]
[Unknown Section]
[Page 0]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 94-4567]


[[Page Unknown]]

[Federal Register: March 1, 1994]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
[Docket No. 94D-0029]

 

International Conference on Harmonisation; 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; Availability

AGENCY: Food and Drug Administration, HHS.

ACTION: Notice.

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SUMMARY: The Food and Drug Administration (FDA) is publishing a draft 
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 draft guideline was prepared by 
the Expert Group on Efficacy of the International Conference on 
Harmonisation of Technical Requirements for Registration of 
Pharmaceuticals for Human Use (ICH). The draft 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: Submit written comments by May 16, 1994.

ADDRESSES:  Submit written comments on the draft guideline to the 
Dockets Management Branch (HFA-305), Food and Drug Administration, rm. 
1-23, 12420 Parklawn Dr., Rockville, MD 20857.

FOR FURTHER INFORMATION CONTACT:
     Regarding the draft 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 Showalter, Office of Health Affairs (HFY-50), 
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 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 then reduce differences in technical 
requirements for drug development.
     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 other interested parties. Through notices 
such as this, FDA invites public comment on ICH initiatives that have 
reached the draft guideline stage. 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, FDA, and the U.S. Pharmaceutical 
Manufacturers Association. The ICH Secretariat, which coordinates the 
preparation of documentation, is provided by the International 
Federation of Pharmaceutical Manufacturers Associations (IFPMA).
     The ICH Steering Committee includes representatives from each of 
the organizing bodies and IFPMA, as well as observers from the World 
Health Organization, the Canadian Health Protection Branch, and the 
European Free Trade Area.
     At a meeting held from October 27 through 29, 1993, the ICH 
Steering Committee agreed that 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'' should be made available for public 
comment. The draft guideline will be made available for comment by the 
European Commission and Japanese Ministry of Health and Welfare, as 
well as by FDA, in accordance with their respective consultation 
procedures. After analyzing the comments and revising the guideline if 
appropriate, FDA will determine whether it will adopt and issue the 
guideline.
     The draft 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 draft guideline distinguishes between 
clinical data on adverse drug events (ADE's) derived from studies of 
shorter duration and of exposure and data from studies of longer 
duration, which frequently include nonconcurrently controlled studies. 
The principles discussed in the draft 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.
     Guidelines are generally issued under Secs. 10.85(d) and 10.90(b) 
(21 CFR 10.85(d) and 10.90(b)), which provide for the use of guidelines 
to establish procedures or standards of general applicability that are 
not legal requirements but that are acceptable to FDA. The agency is 
now in the process of considering whether to revise Secs. 10.85(d) and 
10.90(b). Therefore, if the agency issues this guideline in final form, 
the guideline would not be issued under the authority of Secs. 10.85(d) 
and 10.90(b), and would not create or confer any rights, privileges, or 
benefits for or on any person, nor would it operate to bind FDA in any 
way.
     Interested persons may, on or before May 16, 1994, submit written 
comments on the draft guideline to the Dockets Management Branch 
(address above). Two copies 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.
     The text of the draft guideline follows:

 The Extent of Population Exposure Required 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 (ADEs) derived from 
studies of shorter duration of exposure and data from studies of 
longer duration, which frequently are non-concurrently controlled 
studies. It is expected that short-term event rates (cumulative 3 
month incidence of about 1% ) 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 adverse drug events (ADEs), statistical considerations 
of the probability of detecting specified frequencies of ADEs, and 
practical considerations.
     3. Information about the occurrence of ADEs 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 ADEs 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 ADEs 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%-5%). 
Usually from 300-600 patients should be adequate.
     5. There is concern that, although they are likely to be 
uncommon, some ADEs may increase in frequency or severity with time 
or that some serious ADEs 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 ADEs 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.
     100 patients exposed for a minimum of 1 year is 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 one year exposure at dosage levels intended for 
clinical use. When no serious ADE is observed in a one year exposure 
period this number of patients can provide reasonable assurance that 
the true cumulative 1-year incidence is no greater than 3%.
     6. It is anticipated that the total number of individuals 
treated with the investigational drug, including short-term 
exposure, will be about 1500. Japan currently accepts 500-1500 
patients; the potential for a smaller number of patients is due to 
the post-marketing 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 needed for 
efficacy testing may be occasionally larger or may give rise to a 
need for longer patient observation than that acceptable under this 
guideline.

 Exceptions:

     a. Instances where there is concern that the drug will cause 
late developing ADEs, or cause ADEs that increase in severity or 
frequency over time, would result in a need for 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; and
    (3). pharmacokinetic or pharmacodynamic properties known to be 
associated with such ADEs.
     b. Situations in which there is a need to quantitate the 
occurrence rate of an expected specific low frequency ADE will 
result in a need for 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) or (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 are to be submitted as soon as available 
and prior to approval in the United States and Japan but may be 
submitted after approval in the E.C. In the U.S. the initial 
submission for those drugs designated as priority drugs is expected 
to include the 12 months patient data.

    Dated: February 23, 1994.
Michael R. Taylor,
Deputy Commissioner for Policy.
[FR Doc. 94-4567 Filed 2-24-94; 1:35 pm]
BILLING CODE 4160-01-F