[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]
-----------------------------------------------------------------------
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.
-----------------------------------------------------------------------
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
