[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]]
_______________________________________________________________________
Part X
Department of Health and Human Services
_______________________________________________________________________
Food and Drug Administration
_______________________________________________________________________
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