[Federal Register Volume 62, Number 104 (Friday, May 30, 1997)]
[Notices]
[Pages 29540-29546]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 97-14139]
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Part III
Department of Health and Human Services
_______________________________________________________________________
Food and Drug Administration
_______________________________________________________________________
International Conference on Harmonisation; Draft Guidelines on General
Considerations for Clinical Trials; Availability; Notice
Federal Register / Vol. 62, No. 104 / Friday, May 30, 1997 /
Notices
[[Page 29540]]
DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
[Docket No. 97D-0188]
International Conference on Harmonisation; Draft Guideline on
General Considerations for Clinical Trials; 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, ``General Considerations for Clinical Trials.'' The
draft guideline was prepared under the auspices of the International
Conference on Harmonisation of Technical Requirements for Registration
of Pharmaceuticals for Human Use (ICH). The draft guideline sets forth
general scientific principles for the conduct, performance, and control
of clinical trials.
DATES: Written comments by July 1, 1997.
ADDRESSES: Submit written comments on the draft guideline to the
Dockets Management Branch (HFA-305), Food and Drug Administration,
12420 Parklawn Dr., rm. 1-23, Rockville, MD 20857. Copies of the draft
guideline are available from the Drug Information Branch (HFD-210),
Center for Drug Evaluation and Research, Food and Drug Administration,
5600 Fishers Lane, Rockville, MD 20857, 301-827-4573. Single copies of
the draft guideline may be obtained by mail from the Office of
Communication, Training and Manufacturers Assistance (HFM-40), Center
for Biologics Evaluation and Research (CBER), Food and Drug
Administration, 1401 Rockville Pike, Rockville, MD 20852-1448, or by
calling the CBER Voice Information System at 1-800-835-4709 or 301-827-
1800. Copies may be obtained from CBER's FAX Information System at 1-
888-CBER-FAX or 301-827-3844.
FOR FURTHER INFORMATION CONTACT:
Regarding the draft guideline: G. Alexander Fleming, Center for
Drug Evaluation and Research (HFD-510), Food and Drug Administration,
5600 Fishers Lane, Rockville, MD 20857, 301-443-3490.
Regarding the ICH: Janet J. Showalter, Office of Health Affairs
(HFY-20), Food and Drug Administration, 5600 Fishers Lane, Rockville,
MD 20857, 301-827-0864.
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 then 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 Industries
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 Associations (IFPMA).
The ICH Steering Committee includes representatives from each of
the ICH sponsors and the 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 on November 7, 1996, the ICH Steering Committee
agreed that a draft guideline entitled, ``General Considerations for
Clinical Trials'' should be made available for public comment. The
draft guideline is the product of the Efficacy Expert Working Group of
the ICH. Comments on this draft guideline will be considered by FDA and
the Efficacy Expert Working Group.
The draft guideline is intended to describe internationally
accepted principles and practices in the conduct of clinical trials and
development strategy for new drug products, and to facilitate the
evaluation and acceptance of foreign clinical trial data by promoting a
common understanding of general principles and approaches. The draft
guideline also presents an overview of ICH clinical safety and efficacy
documents.
This guideline represents the agency's current thinking on general
considerations for the conduct, performance, and control of clinical
trials. It does not create or confer any rights for or on any person
and does not operate to bind FDA or the public. An alternative approach
may be used if such approach satisfies the requirements of the
applicable statute, regulations, or both.
Interested persons may, on or before July 1, 1997, submit to the
Dockets Management Branch (address above) written comments on the draft
guideline. 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
draft guideline and received comments may be seen in the office above
between 9 a.m. and 4 p.m., Monday through Friday. An electronic version
of this draft guideline is available on the Internet using the World
Wide Web (WWW) (http://www.fda.gov/cder/guidance.htm) or through the
CBER home page (http://www.fda.gov/cber/cberftp.html).
The text of the draft guideline follows:
General Considerations for Clinical Trials
1. Objectives of This Document
In the three ICH regions, the evolution of drug development
strategies and evaluation processes has led to the issuance of
regional guidances on general considerations for clinical trials and
the clinical development process. This harmonized guideline is
derived from those regional documents as well as from ICH
guidelines.
The ICH document ``General Considerations for Clinical Trials''
is intended to:
(a) Describe internationally accepted principles and practices
in the conduct of both individual clinical trials and overall
development strategy for new medicinal products.
(b) Facilitate the evaluation and acceptance of foreign clinical
trial data by promoting a common understanding of general
principles, general approaches, and the definition of relevant
terms.
(c) Present an overview of the ICH clinical safety and efficacy
documents and facilitate the user's access to guidance pertinent to
clinical trials within these documents. The relevant ICH documents
are listed in Annex 1.
(d) Provide a glossary of terms (under development) used in the
ICH clinical safety and efficacy related documents that pertain to
clinical trials and indicate which documents contain these terms.
For the sake of brevity, the term ``drug'' has been used in this
document. It should be
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considered synonymous with ``medicinal product'' and
``pharmaceutical'' including vaccines and other biological products.
2. General Principles
2.1 Protection of clinical trial subjects
The principles and practices concerning protection of trial
subjects are stated in the ICH Guideline on Good Clinical Practice
(ICH E6). These principles have their origins in The Declaration of
Helsinki and should be observed in the conduct of all human drug
investigations.
Before any clinical trial is carried out, results of nonclinical
investigations or previous human studies should be sufficient to
indicate that the drug is safe for the proposed investigation in
humans. The purpose and timing of animal pharmacology and toxicology
studies intended to support studies of a given duration are
discussed in ICH M3. The role of such studies for biotechnology
products is cited in ICH S6.
Throughout drug development, emerging animal toxicological and
clinical data should be reviewed and evaluated by competent
clinicians and other experts to assess their implications for the
safety of the trial subjects. In response to such findings, future
studies and, when necessary, those in progress should be
appropriately modified in a timely fashion to maintain the safety of
trial participants. The investigator and sponsor share
responsibility for the protection of clinical trial subjects
together with the Institutional Review Board/Independent Ethics
Committee. The responsibilities of these parties are described in
ICH E6.
2.2 Scientific approach in design and analysis
Clinical trials should be designed, conducted, and analyzed
according to sound scientific principles to achieve their
objectives, and should be reported appropriately. The essence of
rational drug development is to ask key questions and answer them
with well-controlled clinical studies. The primary objectives of any
study should be clear and explicitly stated.
Clinical studies can be classified according to objective (see
Table 1). The cardinal logic behind serially conducted studies of a
medicinal product is that the results of prior studies should
influence the plan of later studies. Emerging data will frequently
prompt a modification of the development strategy. For example,
results of controlled trials may suggest further need for
pharmacology studies. The availability of foreign clinical data,
which can be extrapolated, may obviate the need to generate similar
data in the new region (see ICH E5).
Table 1.--An Approach to Classifying Clinical Studies According to Objective
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Type of Study Objective of Study Study Examples
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Human Assess tolerance Dose-tolerance studies
Pharmacology Define/describe Single and multiple dose PK
pharmacokinetic (PK) and and/or PD studies
pharmacodynamic (PD) Drug interaction studies
Explore drug metabolism and Absorption, distribution,
drug interactions metabolism, excretion (ADME)
Estimate activity studies
Therapeutic Explore use for the targeted Earliest controlled trials
Exploratory indication in narrow populations of relatively
Estimate dosage regimen short duration, using surrogate or
Provide basis for pharmacologic endpoints
confirmatory study design,
endpoints, methodologies
Therapeutic Demonstrate/confirm Adequate and well controlled
Confirmatory effectiveness efficacy studies
Establish safety profile Safety studies
Provide a basis for Large simple trials
favorable benefit/risk relationship
to support licensing
Therapeutic Use Refine understanding of Comparative efficacy studies
benefit/risk relationship in Studies of mortality/
general or special populations and/ morbidity outcomes
or environments Large simple trials
Identify less common adverse Pharmacoeconomic studies
reactions
Refine dosing recommendation
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3. Development Methodology
This section covers issues and considerations relating to the
development plan and to its individual component studies.
3.1 Considerations for the development plan
3.1.1 Nonclinical studies
Important considerations for determining the nature of
nonclinical studies and their timing with respect to clinical trials
include:
(a) Duration and total exposure proposed in individual patients.
(b) Characteristics of the drug (e.g., long half life,
biotechnology products).
(c) Disease or condition targeted for treatment.
(d) Use in special populations (e.g., women of childbearing
potential).
(e) Route of administration.
The need for nonclinical information including toxicology,
pharmacology, and pharmacokinetics to support clinical trials is
addressed in the ICH M3 and S6 documents.
3.1.1.1 Safety studies. For first studies in humans, the dose
that is administered should be determined by careful examination of
the prerequisite nonclinical pharmacological and toxicological
evaluations (see ICH M3). Early nonclinical studies should provide
sufficient information to support selection of the initial human
dose and safe duration of exposure, and to provide information about
physiological and toxicological effects of a new drug.
3.1.1.2 Pharmacological studies. The basis and direction of the
clinical exploration and development rests on the nonclinical
pharmacology profile, which includes information such as:
(a) Pharmacological basis of principal effects (mechanism of
action).
(b) Dose-response or concentration-response relationships and
duration of action.
(c) Study of the potential clinical routes of administration.
(d) Systemic general pharmacology, including pharmacological
effects on major organ systems and physiological responses.
3.1.2 Quality of investigational medicinal products
Formulations used in clinical trials should be well
characterized, including information on bioavailability wherever
feasible. The formulation should be appropriate for the stage of
drug development. Ideally, the supply of a formulation will be
adequate to allow testing in a series of studies that examine a
range of doses. During drug development different formulations of a
drug are usually tested. Links between formulations established by
bioequivalence studies or other means are important in interpreting
clinical study results across the development program.
3.1.3 Phases of clinical development
Although clinical studies may be classified according to their
objectives, the concept that clinical drug development is comprised
of four temporal phases (I-IV) is widely used. It is important to
appreciate that this is a description, not a set of requirements,
and that for some drugs and development programs the typical
sequence will not be appropriate or necessary. Each of the four
individual categories of studies by objective roughly corresponds to
one of the four temporal phases of drug development. For example,
human pharmacology studies are typically conducted during Phase I.
However, many such studies are conducted at each of
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the other three stages, but nonetheless sometimes labeled as Phase I
studies. Figure 1 demonstrates this close but variable correlation
between the two classification systems. The distribution of the
points of the graph shows that the types of study are not synonymous
with the phases of development.
BILLING CODE 4160-01-F
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[GRAPHIC] [TIFF OMITTED] TN30MY97.004
BILLING CODE 4160-01-C
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Figure 1--This matrix graph illustrates the relationship between the
phases of development and types of study by objective that may be
conducted during the clinical development of a new medicinal
product. The shaded circles show the types of study most usually
conducted in a certain phase of development; the open circles show
certain types of study that may be conducted in a phase of
development which may be less usual (see text for details). Each
circle represents an individual study. To illustrate, one circle is
joined by a dotted line to an inset column which depicts the
elements and sequence of an individual study.
Drug development is ideally a step-wise procedure in which
information from small early studies is used to support and plan
later larger, more definitive studies. To develop new drugs
efficiently, it is essential to identify important characteristics
of the investigational medicine in the early stages of development
and to plan an appropriate development based on this profile.
Initial trials provide an early evaluation of short-term safety
and tolerability and can provide pharmacodynamic and pharmacokinetic
information needed to choose a suitable dosage range and
administration schedule for initial exploratory therapeutic trials.
Later confirmatory studies are generally larger and longer and
include a more diverse patient population. Dose-response information
should be obtained at all stages of development, from early
tolerance studies, to studies of short-term pharmacodynamic effect,
to large effectiveness studies (see ICH E4). Throughout development,
new data may suggest the need for additional studies that are
typically part of an earlier phase. For example, blood level data in
a late trial may suggest a need for a drug-drug interaction study or
adverse effects may suggest the need for further dose finding and/or
additional nonclinical studies. Other open circles represent
preplanned studies conducted in a less usual phase, e.g., drug-drug
interaction studies in Phase III. These studies are represented by
open circles in Figure 1.
3.1.3.1 Phase I (Most typical kind of study: Human
pharmacology). Phase 1 starts with the initial administration of an
investigational new drug into humans.
While human pharmacology studies are typically identified with
Phase I, they may also be indicated at other points in the
development sequence. Studies in this phase of development usually
have nontherapeutic objectives and may be conducted in healthy
volunteer subjects or certain types of patients, e.g., patients with
mild hypertension. Drugs with significant potential toxicity, e.g.,
cytotoxic drugs, are usually studied in patients. Studies in this
phase can be open, baseline controlled or may use randomization with
or without blinding, to improve the validity of observations.
Studies conducted in Phase I typically involve one or a
combination of the following aspects:
(a) Estimation of initial safety and tolerability
The initial and subsequent administration of an investigational
new drug into humans are usually intended to determine the
tolerability, and in particular, the highest dose with acceptable
tolerability. These studies typically include both single and
multiple dose administration.
(b) Determination of pharmacokinetics
Preliminary characterization of a drug's absorption,
distribution, metabolism, and excretion is almost always an
important goal of Phase I. Pharmacokinetics may be assessed via
separate studies or as a part of safety and tolerance studies.
Pharmacokinetic studies are performed to assess the presence of
accumulation of parent drug or metabolites and to assess
pharmacokinetic changes over time. Some pharmacokinetic studies are
commonly conducted in later phases to answer more specialized
questions. For many orally administered drugs, especially modified
release products, the study of food effects on bioavailability is
important. Obtaining pharmacokinetic information in subpopulations
such as patients with impaired elimination (renal or hepatic
failure), the elderly, children, women, and ethnic subgroups should
be considered. Drug-drug interaction studies are important for many
drugs but are generally performed in phases beyond Phase I.
(c) Assessment of pharmacodynamics
Depending on the drug and the endpoint studied, pharmacodynamic
studies and studies relating drug blood levels to response (PK/PD
studies) may be conducted in healthy volunteer subjects or in
patients with the target disease. In patients, if there is an
appropriate measure, pharmacodynamic data can provide early
estimates of activity and potential effectiveness and may guide the
dosage and dose regimen in later studies.
(d) Early measurement of activity
Preliminary studies of activity or potential therapeutic benefit
may be conducted in Phase I as a secondary objective. Such studies
may be appropriate when effectiveness is readily measurable with a
short duration of drug exposure. At this early stage, use in
patients and/or use in healthy volunteer subjects may be justified,
depending on the drug.
3.1.3.2 Phase II (Most typical kind of study: Therapeutic
exploratory). Phase II is usually considered to start with the
initiation of studies in which the primary objective is to explore
therapeutic effectiveness in patients.
Initial therapeutic exploratory studies may use a variety of
study designs, such as randomized controls and comparisons with
baseline status. Subsequent trials are usually randomized and
controlled to evaluate the efficacy of the drug and its safety for a
particular therapeutic indication. Studies in Phase II are typically
conducted in a group of patients who are selected by clearly defined
criteria and who are closely monitored.
An important goal for this phase is to determine the dose(s) and
regimen for Phase III trials. Studies in this phase may utilize dose
response designs (see ICH E4) to estimate and/or confirm the dose
response relationship for the indication in question. Alternatively,
confirmatory dose response studies may be left for Phase III. Doses
used in Phase II are usually but not always less than the highest
doses used in Phase I.
Additional objectives of clinical trials conducted in Phase II
may include evaluation of potential study endpoints, therapeutic
regimens (including concomitant medications), and target populations
(e.g., mild versus severe disease) for further study in Phase II or
III. These objectives may be served by exploratory analyses,
examining subsets of data, and by including multiple endpoints in
trials.
3.1.3.3 Phase III (Most typical kind of study: Therapeutic
confirmatory). Phase III usually is considered to begin with the
initiation of studies in which the primary objective is to confirm
therapeutic effectiveness.
Key studies in Phase III are designed to confirm the preliminary
evidence accumulated in Phase II that a drug is safe and effective
for use in the intended indication and recipient population. These
well-controlled studies are intended to provide an adequate basis
for marketing approval. Studies in Phase III may also further
explore the dose-response relationship, or explore the drug's use in
wider populations, in different stages of disease, or in combination
with another drug. For drugs intended to be administered for long
periods, trials involving extended exposure to the recipient
population to the drug are ordinarily conducted in Phase III,
although they may be started in Phase II (see ICH E1). ICH E1 and
ICH E7 describe the overall clinical safety database considerations
for chronically administered drugs and drugs used in the elderly.
3.1.3.4 Phase IV (Variety of studies: See Table 1--Therapeutic
Use). Phase IV begins after drug approval. Therapeutic use studies
are considered to be those trials that go beyond the prior
demonstration of the drug's safety, effectiveness, and dose
definition.
Studies in Phase IV are all studies (other than routine
surveillance) performed after drug approval and related to the
approved indication. They are not considered necessary for approval
but are often important for optimizing the drug's use. They may be
of any type but should have valid scientific objectives. Commonly
conducted studies include additional drug-drug interaction, dose-
response, or safety studies and studies designed to support an
extended claim under the approved indication, e.g., mortality/
morbidity studies.
Development of an application unrelated to the original approved
use should be seen as needing a separate development program, though
the need for some studies may be obviated by the availability of
data from the original development program.
After initial approval, drug development may require continued
study of new or modified indications, new dosage regimens, new
routes of administration, or additional patient populations. If a
new dose, formulation, or combination is studied, additional human
pharmacology studies may be indicated.
3.1.4 Special considerations
A number of special circumstances and populations require
separate consideration when they are part of the development plan.
3.1.4.1 Studies of drug metabolites. Major active metabolite(s)
should be identified and
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receive detailed pharmacokinetic study when feasible. The rate of
formation and elimination should be determined whenever possible.
Timing of the metabolic assessment studies within the development
plan depends on the characteristics of the individual drug.
3.1.4.2 Drug-drug interactions. If a potential for drug-drug
interaction is suggested by metabolic profile, by the results of
nonclinical studies, or by information on similar drugs, studies on
drug interaction during clinical development are highly desirable.
For drugs that are frequently coadministered, it is important that
drug-drug interaction studies should be performed in nonclinical
and/or in human studies, if appropriate. This is particularly true
for drugs that are known to alter the absorption or metabolism of
other drugs (see ICH E7), or to be susceptible to effects by other
drugs.
3.1.4.3 Special populations. Some groups in the general
population may require special study because they have unique risk/
benefit considerations to take into account during drug development,
or because they can be anticipated to need modification of use of
the dose or schedule of a drug compared to general adult use.
Pharmacokinetic studies in patients with renal and hepatic
dysfunction are important to assess the impact of potentially
altered drug metabolism or excretion. Other ICH documents address
such issues for geriatric patients (ICH E7) and patients from
different ethnic groups (ICH E5). The need for nonclinical safety
studies to support human clinical trials in special populations is
addressed in the ICH M3 document.
(a) Investigations in pregnant women
In general, pregnant women should be excluded from clinical
trials where the drug is not intended for use in pregnancy. If a
patient becomes pregnant during administration of the drug,
treatment should generally be discontinued if this can be done
safely. A followup study of the pregnancy, fetus, and child is very
important. For clinical trials of a medicinal product for use during
pregnancy a followup study of the pregnancy, fetus, and child is
important.
(b) Investigations in nursing women
Excretion of the drug or its metabolites into human milk should
be examined where applicable. When nursing mothers are enrolled in
clinical studies their babies should be monitored for the effects of
the drug.
(c) Investigations in children
The extent of the studies needed depends on the current
knowledge of the drug and the possibility of extrapolation from
adults and children of other age groups. Some drugs may be used in
children from the early stages of drug development (see ICH M3).
For a drug expected to be used in children, evaluation should be
made in the appropriate age group. When clinical development is to
include studies in children, it is usually desirable to begin with
older children before extending the trial to younger children and
then infants.
3.2 Considerations for individual clinical trials
The following important principles should be followed in
planning the objectives, design, conduct, analysis, and reporting of
a clinical trial (see ICH guidelines in Annex 1). Each part should
be defined in a written protocol before the study starts (see ICH
E6).
3.2.1 Objectives
The objective(s) of the study should be clearly stated and may
include exploratory or confirmatory characterization of safety and/
or effectiveness and/or assessment of pharmacological,
physiological, biochemical, or clinical effects.
3.2.2 Design
The appropriate study design should be chosen to provide the
desired information. Examples include parallel group, crossover,
factorial, dose escalation, and historical controlled designs (see
ICH E4, E6, E9, and E10). Appropriate comparators should be utilized
and adequate numbers of subjects included to achieve the study
objectives. Primary and secondary endpoints and plans for their
analyses should be clearly stated. The methods of monitoring adverse
events by changes in clinical signs and symptoms and laboratory
studies should be described (see ICH E3). The protocol should
specify procedures for the followup of patients who stop treatment
prematurely.
3.2.2.1 Selection of subjects. The selection of the subject
population will depend on the indication to be studied and should
take account of the prior nonclinical and clinical knowledge. The
variability of groups of patients or healthy volunteers studied in
early trials may be limited to a narrow range by strict selection
criteria, but as drug development proceeds, the populations tested
should be broadened to reflect the target population.
Depending on the stage of development and level of concern for
safety, it may be necessary to conduct studies in a closely
monitored (i.e., inpatient) environment.
Subjects should not be enrolled repetitively in clinical trials
without time off treatment adequate to protect safety and minimize
carryover effects.
In general, women of childbearing potential should be using
highly effective contraception to participate in clinical trials
(see ICH M3).
For male subjects, potential hazards of drug exposure in the
trial to their sexual partners or resulting progeny should be
considered. When indicated (e.g., trials involving drugs which are
potentially mutagenic, or toxic to the reproductive system), an
appropriate contraception provision should be included in the trial.
3.2.2.2 Selection of control group. Trials should be adequately
controlled. Comparators may be placebo, active controls, or of
different doses of the same compound. The choice of the comparator
depends on, among other things, the objective of the trial (see ICH
E9 and E10). Historical or observational (external) controls may be
employed when justified but additional care is important to minimize
the likelihood of erroneous inference.
3.2.2.3 Number of subjects. The trial size should be based on
consideration of the magnitude of the treatment effect, the disease
to be investigated, the objective of the study, the endpoint
criteria, and the number of trial sites (see ICH E9). In some
circumstances a larger database may be necessary to establish the
safety of the drug. ICH E1 and ICH E7 suggest a minimum experience
to assess safety for a registrational database for a new indication.
These numbers should not be considered as absolute.
3.2.2.4 Efficacy and safety variables. Response variables should
be defined prospectively, giving descriptions of methods of
observation and quantification. Objective methods of observation
should be used where possible and when appropriate (see ICH E9).
Study endpoints are the response variables, usually relating to
efficacy, that are chosen to assess drug effects. A primary
endpoint(s) represents clinically relevant changes and is typically
selected based on the principal objective of the study. Secondary
endpoints assess other drug effects which may or may not be related
to the primary endpoint. Endpoints and the plan for their analysis
should be prospectively specified in the protocol.
A validated surrogate endpoint is an endpoint which allows
prediction of a clinically important outcome but in itself does not
measure a clinical benefit. When appropriate, surrogate outcomes may
be used as primary endpoints.
The methods used to make the measurements of the endpoints, both
subjective and objective, should meet accepted standards for
accuracy, precision, reproducibility, reliability, validity, and
responsiveness (sensitivity to change over time).
3.2.2.5 Methods to minimize bias. The protocol should specify
methods of allocation to treatment groups and blinding (see ICH E9
and E10).
(a) Randomization
In conducting a controlled trial, randomized allocation is
usually the preferred means of assuring comparability of test groups
and minimizing the possibility of selection bias.
(b) Blinding
Blinding is an important means of reducing or minimizing the
risk of biased study outcomes. A trial where the treatment
assignment is not known by the study participant because of the use
of placebo or other methods of masking the intervention, is referred
to as a single blind study. When the study clinician is also unaware
of treatment assignment the study is double blind.
(c) Compliance
Methods used to survey patient usage of the test drug should be
specified in the protocol and the actual usage documented.
3.2.3 Conduct
The study should be conducted according to the principles
described in this guideline and in accordance with other pertinent
elements outlined in ICH E6 and other relevant ICH guidelines (see
Annex 1). Adherence to the study protocol is essential. If
modification of the protocol becomes necessary, a clear description
of the rationale for the modification should be provided in a
protocol amendment. Timely adverse event reporting during a study is
essential and should be documented. Guidance is available on
expedited reporting of safety data to
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appropriate officials and on the content of safety reports (see ICH
E2A and E2B).
3.2.4 Analysis
The study protocol should have a specified analysis plan that is
appropriate for the objectives and design of the study taking into
account the method of subject allocation, the measurement methods of
outcome variables, specific hypotheses to be tested, and analytical
approaches to common problems including early study withdrawal and
protocol violations. The plan for analyzing primary and secondary
endpoints should be stated in the protocol.
The results of a clinical trial should be analyzed in accordance
with the plan prospectively stated in the protocol and all
deviations from the plan should be indicated in the study report.
Detailed guidance is available in other ICH guidelines on planning
of the protocol (ICH E6), statistical analysis of results (ICH E9),
and on study reports (ICH E3).
Studies are normally expected to run to completion although in
some studies the possibility of early stopping is formally
recognized. In such cases this should be clearly described in the
protocol with due statistical attention to the overall levels of
statistical significance and to the need to adjust the estimates of
the size of treatment effects.
Safety data should be collected for all clinical trials,
appropriately tabulated, and, with adverse events, classified
according to their seriousness and their likely causal relationship.
3.2.5 Reporting
Clinical study reports should be adequately documented following
the approaches outlined in other ICH guidelines (see E3 and E6).
4. Annex 1
List of Relevant ICH Guidelines and Topics
------------------------------------------------------------------------
Code Topic
------------------------------------------------------------------------
E1.......... The Extent of Population Exposure to Assess Clinical
Safety for Drugs Intended for Long-Term Treatment of Non-
Life-Threatening Conditions
E2A......... Clinical Safety Data Management: Definitions and Standards
for Expedited Reporting
E2B......... Clinical Safety Data Management: Data Elements for
Transmission of Individual Case Safety Reports
E2C......... Clinical Safety Data Management: Periodic Safety Update
Reports for Marketed Drugs
E3.......... Structure and Content of Clinical Study Reports
E4.......... Dose-Response Information to Support Drug Registration
E5.......... Ethnic Factors in the Acceptability of Foreign Clinical
Data
E6.......... Good Clinical Practice: Consolidated Guideline
E7.......... Studies in Support of Special Populations: Geriatrics
E8.......... General Considerations for Clinical Trials
E9.......... Statistical Considerations in the Design of Clinical
Trials
E10......... Choice of Control Group in Clinical Trials
M1.......... International Medical Terminology
M2.......... Electronic Standards for the Transfer of Regulatory
Information (ESTRI)
M3.......... Nonclinical Safety Studies for the Conduct of Human
Clinical Trials for Pharmaceuticals
S6.......... Safety Studies for Biotechnology-Derived Products
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Dated: May 15, 1997.
William K. Hubbard,
Associate Commissioner for Policy Coordination.
[FR Doc. 97-14139 Filed 5-29-97; 8:45 am]
BILLING CODE 4160-01-F