[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 ``<a href="http://www.fda.gov/cber/
publications.htm">http://www.fda.gov/cber/
publications.htm</a>''.
    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    
------------------------------------------------------------------------
Human Pharmacology       <bullet> Assess          <bullet> Dose-        
                          tolerance                tolerance studies    
                         <bullet> Define/         <bullet> Single and   
                          describe PK\1\ and       multiple dose PK and/
                          PD\2\                    or PD studies        
                         <bullet> Explore drug    <bullet> Drug         
                          metabolism and drug      interaction studies  
                          interactions                                  
                         <bullet> Estimate                              
                          activity                                      
Therapeutic Exploratory  <bullet> Explore use     <bullet> Earliest     
                          for the targeted         trials of relatively 
                          indication               short duration in    
                         <bullet> Estimate         well-defined narrow  
                          dosage for subsequent    patient populations, 
                          studies                  using surrogate or   
                         <bullet> Provide basis    pharmacological      
                          for confirmatory study   endpoints or clinical
                          design, endpoints,       measures             
                          methodologies           <bullet> Dose-response
                                                   exploration studies  
Therapeutic              <bullet> Demonstrate/    <bullet> Adequate, and
 Confirmatory             confirm efficacy         well controlled      
                         <bullet> Establish        studies to establish 
                          safety profile           efficacy             
                         <bullet> Provide an      <bullet> Randomized   
                          adequate basis for       parallel dose-       
                          assessing the benefit/   response studies     
                          risk relationship to    <bullet> Clinical     
                          support licensing        safety studies       
                         <bullet> Establish dose- <bullet> Studies of   
                          response relationship    mortality/morbidity  
                                                   outcomes             
                                                  <bullet> Large simple 
                                                   trials               
                                                  <bullet> Comparative  
                                                   studies              
Therapeutic Use          <bullet> Refine          <bullet> Comparative  
                          understanding of         effectiveness studies
                          benefit/risk            <bullet> Studies of   
                          relationship in          mortality/morbidity  
                          general or special       outcomes             
                          populations and/or      <bullet> Studies of   
                          environments             additional endpoints 
                         <bullet> Identify less   <bullet> Large simple 
                          common adverse           trials               
                          reactions               <bullet> Pharmacoecono
                         <bullet> Refine dosing    mic studies          
                          recommendation                                
------------------------------------------------------------------------
\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