[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  

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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.

-----------------------------------------------------------------------

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           
----------------------------------------------------------------------------------------------------------------
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         
------------------------------------------------------------------------


    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