Guideline for Industry
The Extent of Population
Exposure to Assess
Clinical Safety:
For Drugs Intended for Long-
term Treatment of Non-Life-
Threatening Conditions
ICH-E1A
March 1995 GUIDELINE FOR INDUSTRY 1
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 (ADEs) derived from studies of shorter duration of exposure and
data from studies of longer duration, which frequently are nonconcurrently controlled
1This guideline was developed within the Expert Working Group (Efficacy) of the
International Conference on Harmonisation of the Technical Requirements for
Registration of Pharmaceuticals for Human Use (ICH) and has been subject to
consultation by the regulatory parties, in accordance with the ICH process.  This
document has been endorsed by the ICH Steering Committee at  Step 4 of the ICH
process, October 27, 1994.  At  Step 4 of the process, the final draft is recommended
for adoption to the regulatory bodies of the European Union, Japan and the USA.  This
guidance was published in the  Federal Register on March 1, 1995 (60 FR 11270) and
is applicable to drug and biological products.  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 that 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.  For additional copies of this
guideline, contact the Consumer Affairs Branch (formerly the Executive Secretariat
Staff), HFD-210, Center for Drug Evaluation and Research, 7500 Standish Place,
Rockville, MD  20855, 301-594-1012.  An electronic version of this guideline is also
available via Internet by connecting to the CDER file transfer protocol (FTP) server
(CDVS2.CDER.FDA.GOV). 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 1000 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 300 to 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 judgement based on the probability of
detecting a given ADE frequency level and practical considerations.
100 patients exposed for a minimum of one-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 one 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
to 1500 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 required by
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 require a larger
and/or longer-term safety data base. The concern could arise from:
I.Data from animal studies;
ii.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
ADEs.
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) 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 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 must include the 12 months
patient data.