[Federal Register Volume 62, Number 242 (Wednesday, December 17, 1997)]
[Notices]
[Pages 66113-66119]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 97-32877]
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DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
[Docket No. 97D-0188]
International Conference on Harmonisation; Guidance on General
Considerations for Clinical Trials
AGENCY: Food and Drug Administration, HHS.
ACTION: Notice.
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SUMMARY: The Food and Drug Administration (FDA) is publishing a
guidance entitled ``E8 General Considerations for Clinical Trials.''
The guidance was prepared under the auspices of the International
Conference on Harmonisation of Technical Requirements for Registration
of Pharmaceuticals for Human Use (ICH). The guidance sets forth general
scientific principles for the conduct, performance, and control of
clinical trials.
DATES: Effective December 17, 1997. Submit written comments at any
time.
ADDRESSES: Submit written comments on the guidance to the Dockets
Management Branch (HFA-305), Food and Drug Administration, 12420
Parklawn Dr., rm. 1-23, Rockville, MD 20857. Copies of the guidance 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 guidance
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 guidance: G. Alexander Fleming, Center for Drug
Evaluation and Research (HFD-510), Food and Drug Administration, 5600
Fishers Lane, Rockville, MD 20857, 301-827-6391.
Regarding 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 (CDER) and CBER, 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).
[[Page 66114]]
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.
In the Federal Register of May 30, 1997 (62 FR 29540), FDA
published a draft tripartite guideline entitled ``General
Considerations for Clinical Trials.'' The notice gave interested
persons an opportunity to submit comments by July 1, 1997.
After consideration of the comments received and revisions to the
guidance, a final draft of the guidance was submitted to the ICH
Steering Committee and endorsed by the three participating regulatory
agencies on July 17, 1997.
In accordance with FDA's Good Guidance Practices (62 FR 8961,
February 27, 1997), this document has been designated a guidance,
rather than a guideline.
The guidance describes internationally accepted principles and
practices in the conduct of clinical trials and development strategy
for new drug products. It is intended to facilitate the evaluation and
acceptance of foreign clinical trial data by promoting a common
understanding of general principles and approaches. The guidance also
presents an overview of ICH clinical safety and efficacy documents.
This guidance 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.
The public is encouraged to submit written comments with new data
or other new information pertinent to this guidance. The comments in
the docket will be periodically reviewed, and, where appropriate, the
guidance 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
guidance 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 guidance 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 guidance is
available on the Internet (http://www.fda.gov/cder/guidance/index.htm)
or at CBER's World Wide Web site at ``http://www.fda.gov/cber/
publications.htm''.
The text of the guidance follows:
E8 General Considerations for Clinical Trials\1\
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\1\ This guidance 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.
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1. Objectives of This Document
In the three ICH regions, the evolution of drug development
strategies and evaluation processes has led to the establishment of
regional guidances on general considerations for clinical trials and
the process of clinical development of pharmaceuticals for human
use. This harmonized guidance is derived from those regional
documents as well as from ICH guidances.
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 separate glossary of terms used in the ICH
clinical safety and efficacy related documents that pertain to
clinical trials and indicate which documents contain these.
For the sake of brevity, the term ``drug'' has been used in this
document. It should be considered synonymous with ``investigational
(medicinal) product,'' ``medicinal product,'' and
``pharmaceutical,'' including vaccines and other biological
products. The principles established in this guidance may also be
applied to other clinical investigations (e.g., radiotherapy,
psychotherapy, surgery, medical devices and alternative therapies).
2. General Principles
2.1 Protection of Clinical Trial Subjects
The principles and practices concerning protection of trial
subjects are stated in the ICH guidance 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 acceptably 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 qualified 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 important questions and answer
them with appropriate studies. The primary objectives of any study
should be clear and explicitly stated.
Clinical studies can be classified according to when the study
occurs during clinical development or, as shown in Table 1, by their
objectives. (The illustrative examples are not intended to be
exhaustive.) 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 a therapeutic confirmatory study may suggest a need for
additional human pharmacology studies.
The availability of foreign clinical data should obviate the
need to generate similar data in an ICH region if the ICH E5 and ICH
E6 guidances are followed (see ICH E5).
[[Page 66115]]
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 Pharmacology Assess Dose-
tolerance tolerance studies
Define/ Single and
describe PK\1\ and multiple dose PK and/
PD\2\ or PD studies
Explore drug Drug
metabolism and drug interaction studies
interactions
Estimate
activity
Therapeutic Exploratory Explore use Earliest
for the targeted trials of relatively
indication short duration in
Estimate well-defined narrow
dosage for subsequent patient populations,
studies using surrogate or
Provide basis pharmacological
for confirmatory study endpoints or clinical
design, endpoints, measures
methodologies Dose-response
exploration studies
Therapeutic Demonstrate/ Adequate, and
Confirmatory confirm efficacy well controlled
Establish studies to establish
safety profile efficacy
Provide an Randomized
adequate basis for parallel dose-
assessing the benefit/ response studies
risk relationship to Clinical
support licensing safety studies
Establish dose- Studies of
response relationship mortality/morbidity
outcomes
Large simple
trials
Comparative
studies
Therapeutic Use Refine Comparative
understanding of effectiveness studies
benefit/risk Studies of
relationship in mortality/morbidity
general or special outcomes
populations and/or Studies of
environments additional endpoints
Identify less Large simple
common adverse trials
reactions Pharmacoecono
Refine dosing mic studies
recommendation
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\1\ Pharmacokinetics
\2\ Pharmacodynamics
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 the first studies in humans, the dose
that is administered should be determined by careful examination of
the prerequisite nonclinical pharmacokinetic, 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 and pharmacokinetic studies. The basis and
direction of the clinical exploration and development rests on the
nonclinical pharmacokinetic and 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.
(e) Studies of absorption, distribution, metabolism, and
excretion.
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 may be 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
Clinical drug development is often described as consisting of
four temporal phases (Phases I-IV). It is important to recognize
that the phase of development provides an inadequate basis for
classification of clinical trials because one type of trial may
occur in several phases (see Figure 1). A classification system
using study objectives as discussed in section 2.2 is preferable. It
is important to appreciate that the phase concept is a description,
not a set of requirements. It is also important to realize that the
temporal phases do not imply a fixed order of studies since for some
drugs in a development plan the typical sequence will not be
appropriate or necessary. For example, although human pharmacology
studies are typically conducted during Phase I, many such studies
are conducted at each of the other three stages, but nonetheless are
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.
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\1\ This matrix graph illustrates the relationship between the
phases of development and types of study by objective that may be
conducted during each 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 that phase of
development but are less usual. Each circle represents an individual
study. To illustrate the development of a single study, one circle
is joined by a dotted line to an inset column that depicts the
elements and sequence of an individual study.
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BILLING CODE 4160-01-F
[[Page 66116]]
Figure 1.--Correlation Between Development Phases and Types of Study\1\
[GRAPHIC] [TIFF OMITTED] TN17DE97.000
BILLING CODE 4160-01-C
Drug development is ideally a logical, 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 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 efficacy 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. In addition, to support a new
marketing application approval for the same drug, e.g., for a new
indication, pharmacokinetic or therapeutic exploratory studies are
considered to be in Phase I or Phase II of development.
3.1.3.1 Phase I (Most typical kind of study: Human pharmacology).
Phase I starts with the initial administration of an investigational
new drug into humans.
Although 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 and
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 is usually intended to determine the
tolerability of the dose range expected to be needed for later
clinical studies and to determine the nature of adverse reactions
that can be expected. These studies typically include both single
and multiple dose administration.
(b) Pharmacokinetics
Characterization of a drug's absorption, distribution,
metabolism, and excretion continues throughout the development plan.
Their preliminary characterization is an important goal of Phase I.
Pharmacokinetics may be assessed via separate studies or as a part
of efficacy, safety and tolerance studies. Pharmacokinetic studies
are particularly important to assess the clearance of the drug and
to anticipate possible accumulation of parent drug or metabolites
and potential drug-drug interactions. 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; these are generally performed in phases beyond Phase I, but
studies in animals and in vitro studies of metabolism and potential
interactions may lead to doing such studies earlier.
(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 efficacy and may guide the
dosage and dose regimen in later studies.
(d) Early measurement of drug activity
Preliminary studies of activity or potential therapeutic benefit
may be conducted in Phase I as a secondary objective. Such studies
are generally performed in later phases but may be appropriate when
drug activity is readily measurable with a short duration of drug
exposure in patients at this early stage.
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 efficacy in patients.
Initial therapeutic exploratory studies may use a variety of
study designs, including concurrent controls and comparisons with
baseline status. Subsequent trials are usually randomized and
concurrently 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
relatively narrow criteria, leading to a relatively homogeneous
population, and who are closely monitored.
An important goal for this phase is to determine the dose(s) and
regimen for Phase III trials. Early studies in this phase often
utilize dose escalation designs (see ICH E4) to give an early
estimate of dose response and later studies may confirm the dose
response relationship for the indication in question by using
recognized parallel dose-response designs (could also be deferred to
phase III). Confirmatory dose response studies may be conducted in
Phase II or 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.
[[Page 66117]]
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
demonstrate, or confirm therapeutic benefit.
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
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 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. These studies carried out in
Phase III complete the information needed to support adequate
instructions for use of the drug (official product information).
3.1.3.4 Phase IV (Variety of studies: Therapeutic use). Phase IV
begins after drug approval. Therapeutic use studies go beyond the
prior demonstration of the drug's safety, efficacy 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 studies that were 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 use under the approved indication, e.g., mortality/
morbidity studies, epidemiological studies.
3.1.3.5 Development of an application unrelated to original approved
use. After initial approval, drug development may continue with
studies 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, necessitating a new
development plan.
The need for some studies may be obviated by the availability of
data from the original development plan or from therapeutic use.
3.1.4 Special Considerations
A number of special circumstances and populations require
consideration on their own when they are part of the development
plan.
3.1.4.1 Studies of drug metabolites. Major active metabolite(s)
should be identified and deserve detailed pharmacokinetic study.
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 recommended.
For drugs that are frequently coadministered, it is usually
important that drug-drug interaction studies be performed in
nonclinical and, if appropriate, in human studies. This is
particularly true for drugs that are known to alter the absorption
or metabolism of other drugs (see ICH E7), or whose metabolism or
excretion can be altered by effects of 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 that need to be taken 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.
Particular attention should be paid to the ethical
considerations related to informed consent from vulnerable
populations and the procedures scrupulously followed (see ICH E6).
(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. Followup evaluation of the pregnancy, fetus, and child is
very important. Similarly, for clinical trials that include pregnant
women because the medicinal product is intended for use during
pregnancy, followup of the pregnancy, fetus, and child is very
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 appropriate 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 guidances 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 efficacy and/or assessment of pharmacokinetic parameters and
pharmacological, physiological, or biochemical effects.
3.2.2 Design
The appropriate study design should be chosen to provide the
desired information. Examples of study design include parallel
group, crossover, factorial, dose escalation, and fixed dose-dose
response (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 (see ICH E9). 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 stage of development and the
indication to be studied should be taken into account in selecting
the subject population (e.g., normal healthy subjects, cancer
patients or other special populations in early phase development) as
should 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.
As a general principle, trial subjects should not participate
concurrently in more than one clinical trial but there can be
justified exceptions. Subjects should not be enrolled repetitively
in clinical trials without time off treatment adequate to protect
safety and exclude 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 that 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 have an adequate
control group. Comparisons may be made with placebo, no treatment,
active controls, or of different doses of the drug under
investigation. The choice of the comparator depends on, among other
things, the objective of the trial (see ICH E9 and E10). Historical
(external) controls can be justified in some cases, but particular
care is important to minimize the likelihood of erroneous inference.
[[Page 66118]]
3.2.2.3 Number of subjects. The size of a trial is influenced by the
disease to be investigated, the objective of the study, and the
study endpoints. Statistical assessments of sample size should be
based on the expected magnitude of the treatment effect, the
variability of the data, the specified (small) probability of error
(see ICH E9), and the desire for information on subsets of the
population or secondary endpoints. In some circumstances, a larger
database may be needed to establish the safety of a 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 and may be insufficient in some cases
(e.g., where long-term use in healthy individuals is expected).
3.2.2.4 Response 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 that are chosen to
assess drug effects that are related to pharmacokinetic parameters,
pharmacodynamic measures, efficacy and safety. A primary endpoint(s)
should reflect clinically relevant effects and is typically selected
based on the principal objective of the study. Secondary endpoints
assess other drug effects that 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 surrogate endpoint is an endpoint that is intended to relate
to a clinically important outcome but does not in itself measure a
clinical benefit. Surrogate endpoints may be used as primary
endpoints when appropriate (when the surrogate is reasonably likely
or well known to predict clinical outcome).
The methods used to make the measurements of the endpoints, both
subjective and objective, should be validated and meet appropriate
standards for accuracy, precision, reproducibility, reliability, and
responsiveness (sensitivity to change over time).
3.2.2.5 Methods to minimize or assess 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 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 investigator and sponsor staff
who are involved in the treatment or clinical evaluation of the
subjects and analysis of data are also unaware of the treatment
assignments, the study is double blind.
(c) Compliance
Methods used to evaluate 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 guidance and in accordance with other pertinent elements
outlined in ICH E6 and other relevant ICH guidances (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 (see ICH
E6). Timely adverse event reporting during a study is essential and
should be documented. Guidance is available on expedited reporting of
safety data to appropriate officials, on the content of safety reports,
and on privacy and confidentiality of data (see ICH E2A, E2B, and E6).
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
response variables, specific hypotheses to be tested, and analytical
approaches to common problems including early study withdrawal and
protocol violations. A description of the statistical methods to be
employed, including timing of any planned interim analysis(es),
should be included in the protocol (see ICH E3, E6, and E9).
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 guidances on planning of
the protocol (ICH E6), on the analysis plan and 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 (ICH E9).
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 (see ICH
E2A).
3.2.5 Reporting
Clinical study reports should be adequately documented following
the approaches outlined in other ICH guidances (see E3 and E6).
4. Annex 1
Table 2.--List of Relevant ICH Guidances 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
M3 Nonclinical Safety Studies for the Conduct of
Human Clinical Trials for Pharmaceuticals
S6 Safety Studies for Biotechnology-Derived
Products
------------------------------------------------------------------------
[[Page 66119]]
Dated: December 10, 1997.
William K. Hubbard,
Associate Commissioner for Policy Coordination.
[FR Doc. 97-32877 Filed 12-16-97; 8:45 am]
BILLING CODE 4160-01-F