International Conference on Harmonisation; Draft Guideline on Structure and Content of Clinical Study Reports; Availability

SUMMARY: The Food and Drug Administration (FDA) is publishing a draft

guideline entitled ``Structure and Content of Clinical Study Reports.''

This 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 is intended

to facilitate the compilation of a single worldwide core clinical study

report acceptable to all regulatory authorities.

DATES: Written comments by October 10, 1995.

ADDRESSES: Submit written comments on the draft guideline to the

Dockets Management Branch (HFA-305), Food and Drug Administration, rm.

1-23, 12420 Parklawn Dr., Rockville, MD 20857. Copies of the draft

guideline are available from the CDER Executive Secretariat Staff (HFD-

8), Center for Drug Evaluation and Research, Food and Drug

Administration, 7500 Standish Pl., Rockville, MD 20855.

FOR FURTHER INFORMATION CONTACT:

Regarding the guideline: Robert Temple, Center for Drug Evaluation

and Research (HFD-100), Food and Drug Administration, 5600 Fishers

Lane, Rockville, MD 20857, 301-594-6758.

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 March 29, 1995, the ICH Steering Committee

agreed that a draft guideline entitled ``Structure and Content of

Clinical Study Reports'' should be made available for public comment.

The draft guideline is the product of the Efficacy Expert Working Group

of the ICH. Comments about this draft will be considered by FDA and the

Expert Working Group. Ultimately, FDA intends to adopt the ICH Steering

Committee's final guideline.

The draft guideline is intended to facilitate the compilation of a

single worldwide core clinical study report acceptable to all

regulatory authorities. In general, once the guideline is in use, the

only differences between submissions to various authorities should be

in the amount of data submitted initially in tabular listings, in the

number of case report forms submitted, and in specific supplemental

analyses requested for particular cases by an authority, if any. The

clinical study report described in this draft guideline is an

integrated full report of an individual study of any therapeutic,

prophylactic, or diagnostic agent conducted in patients. The clinical

and statistical description, presentations, and analyses should be

integrated into a single report, incorporating tables and figures into

the main text of the report, or at the end of the text. Appendices

should contain the protocol, sample case report forms, investigator

information, trial material information, technical statistical

documentation, related publications, patient data listings, and

technical statistical details such as derivations, computations,

analyses, and computer output, and so on. The draft guideline is

intended to assist sponsors in the development of a report that is

complete, free from ambiguity, well organized, and easy to review.

In the past, guidelines have generally been issued under

Sec. 10.90(b) (21 CFR 10.90(b)), which provides for the use of

guidelines to state procedures or standards of general applicability

that are not legal requirements but are acceptable to FDA. The agency

is now in the process of revising Sec. 10.90(b). Therefore, this

guideline is not being issued under the authority of Sec. 10.90(b), and

it does not create or confer any rights, privileges, or benefits for or

on any person, nor does it operate to bind FDA in any way.

Interested persons may, on or before October 10, 1995, submit

written comments to the Dockets Management Branch (address above) 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.

The text of the draft guideline follows:

Structure and Content of Clinical Study Reports

Introduction to the Guideline

The objective of this guideline is to allow the compilation of a

single worldwide core clinical study report acceptable to all

regulatory authorities. The regulatory authority specific additions

will consist of modules to be considered as appendices, available

upon request.

The clinical study report described in this guideline is an

``integrated'' full report of an individual study of any

therapeutic, prophylactic, or diagnostic agent (referred to herein

as drug or treatment) conducted in patients, in which the clinical

and statistical description, presentations, and analyses are

integrated into a single report, incorporating tables and figures

into the main text of the report, or at the end of the text, and

with appendices containing the protocol, sample case report forms,

investigator information, trial material information, technical

statistical documentation, related publications, patient data

listings, and technical statistical details such as derivations,

computations, analyses, and computer output. The integrated full

report

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of a study should not be derived by simply joining a separate clinical

and statistical report. Although this guideline is mainly aimed at

efficacy and safety trials, the basic principles and structure

described can be applied to other kinds of trials, such as clinical

pharmacology studies.

The guideline is intended to assist sponsors in the development

of a report that is complete, free from ambiguity, well organized,

and easy to review. The report should provide a clear explanation of

how the critical design features of the study were chosen and enough

information on the plan, methods, and conduct of the study so that

there is no ambiguity in how the study was carried out. The report

with its appendices should also provide enough individual patient

data, including the demographic and baseline data, and details of

analytical methods, to allow replication of the critical analyses

when authorities wish to do so. It is also particularly important

that all analyses, tables, and figures carry, in text or as part of

the table, clear identification of the set of patients from which

they were generated.

Depending on the regulatory authority's review policy,

abbreviated reports using summarized data or with some sections

deleted may be acceptable for uncontrolled studies or other studies

not designed to establish efficacy (but a controlled safety study

should be reported in full), for seriously flawed or aborted

studies, or for controlled studies which examine conditions clearly

unrelated to those for which a claim is made. However, a full

description of safety aspects should be included in these cases. If

an abbreviated report is submitted, there should be enough detail of

design and results to allow the regulatory authority to determine

whether a full report is needed. If there is any question regarding

whether the reports are needed, it may be useful to consult the

regulatory authority.

In presenting the detailed description of how the study was

carried out, it may be possible simply to restate the description in

the initial protocol. Often, however, it is possible to present the

methodology of the study more concisely in a separate document. In

each section describing the design and conduct of the study, it is

particularly important to clarify features of the study that are not

well-described in the protocol and identify ways in which the study

as conducted differed from the protocol, and to discuss the

statistical methods and analyses used to account for these

deviations from the planned protocol.

The full integrated report of the individual study should

include the most detailed discussion of individual adverse events or

laboratory abnormalities, but these should usually also be

reexamined as part of an overall safety analysis of all available

data in any application.

The report should describe demographic characteristics of the

study population and, where the study is large enough to permit

this, present data for demographic (e.g., age, sex, race, weight)

and other (e.g., renal or hepatic function) subgroups so that

possible differences in efficacy or safety can be identified.

Usually, however, subgroup responses should be examined in the

larger data base used in the overall analysis.

The data listings requested as part of the report (usually in an

appendix) are those needed to support critical analyses, not the

more comprehensive archival data listings required by some

regulatory authorities. Data listings which are part of the report

should be readily usable by the reviewer. Thus, although it may be

desirable to include many variables in a single listing to limit

size, this should not be at the expense of clarity. An excess of

data should not be allowed to lead, for example, to overuse of

symbols instead of words or easily understood abbreviations or to

too small displays. In this case, it is preferable to produce

several listings.

Data should be presented in the report at different levels of

detail: overall summary figures, and tables for important

demographic, efficacy, and safety variables may be placed in the

text to illustrate important points; other summary figures, tables,

and listings for demographic, efficacy, and safety variables should

be provided in section 14; individual patient data for specified

groups of patients should be provided as listings in Appendix 16.2;

and all individual patient data (U.S. archival listings) should be

provided in Appendix 16.4.

In any table, figure, or data listing, estimated or derived

values, if used, should be identified in a conspicuous fashion.

Detailed explanations should be provided as to how such values were

estimated or derived and what underlying assumptions were made.

The guidance provided below is detailed and is intended to

notify the applicant of virtually all of the information that should

routinely be provided so that postsubmission requests for further

data clarification and analyses can be reduced as much as possible.

Nonetheless, specific requirements for data presentation and/or

analysis may depend on specific situations, may evolve over time,

may vary from drug class to drug class, may differ among regions,

and cannot be described in general terms. It is therefore important

to refer to specific clinical guidelines and to discuss data

presentation and analyses with the reviewing authority, whenever

possible. Detailed written guidance on statistical approaches is

available from some authorities.

Each report should consider all of the topics described (unless

clearly not relevant) although the specific sequence and grouping of

topics may be changed if alternatives are more logical for a

particular study. Some data in the appendices are specific

requirements of individual regulatory authorities and should be

submitted as appropriate. The numbering should then be adapted

accordingly.

In the case of very large trials, some of the provisions of this

guideline may be impractical or inappropriate. When planning and

when reporting such trials, contact with regulatory authorities to

discuss an appropriate report format is encouraged.

The provisions of this guideline should be used in conjunction

with other ICH guidelines.

Structure and Content of Clinical Study Reports

1. Title Page

The title page should contain the following information:

- Report title

- Name of drug

- Indication studied

- If not apparent from the title, a brief (one to two sentences)

description giving design (parallel, cross-over, blinding,

randomized) comparison (placebo, active, dose/response), duration,

dose, and patient population

- Name of the sponsor

- Protocol identification

- Drug development phase

- Study initiation date (first patient enrolled, or any other

verifiable definition)

- Date of early study termination, if any

- Study completion date (last patient completed)

- Name and affiliation of signatory (principal) investigator(s)

or responsible medical officer

- Name of company signatory (the person responsible for the

study report within the company.) The name, telephone number, and

fax number of the company contact persons for questions arising

during review of the study report should be indicated on this page

or in the letter of application.

- Statement indicating whether the study was performed in

compliance with good clinical practices (GCP's), including the

archiving of essential documents

- Date of the report (identify any earlier reports from the same

study by title and date)

2. Synopsis

A brief synopsis (maximum: three pages) that summarizes the

study should be provided (see Annex I of the guideline for an

example). The synopsis should include numerical data to illustrate

results, not just text or p-values.

3. Table of Contents for the Individual Clinical Study Report

The table of contents should include:

- The page number or other locating information of each section,

including summary tables, figures, and graphs;

- A list and the locations of appendices, tabulations, and any

case report forms provided.

4. List of Abbreviations and Definitions of Terms

A list of the abbreviations and definitions of unusual or

specialized terms or measurements units used in the report should be

provided. In addition, abbreviated terms should be spelled out and

the abbreviation indicated at first appearance in the text.

5. Ethics

5.1 Independent Ethics Committee (IEC) or Institutional Review Board

(IRB)

It should be confirmed that the study and any amendments were

reviewed by an independent ethics committee or institutional review

board. A list of all IEC's or IRB's consulted should be given in

Appendix 16.1.3 and, if required by the regulatory authority, the

name of the committee Chair should be provided.

[[Page 43912]]

5.2 Ethical Conduct of the Study

It should be confirmed that the study was conducted in

accordance with the ethical principles that have their origins in

the Declaration of Helsinki.

5.3 Patient Information and Consent

How and when informed consent was obtained in relation to

patient enrollment (e.g., at allocation, prescreening) should be

described.

Representative written information for the patient (if any) and

a sample patient consent form should be provided in Appendix 16.1.3.

6. Investigators and Study Administrative Structure

The administrative structure of the study (e.g., principal

investigator, coordinating investigator, controller, steering

committee, administration, monitoring and evaluation committees,

institutions, statistician, central laboratory facilities, clinical

research organization, clinical trial supply management) should be

described briefly.

A list of the investigators with their affiliations, their role

in the study, and their qualifications (curriculum vitae or

equivalent), and a similar list for other persons whose

participation materially affected the conduct of the study should be

provided in Appendix 16.1.4. In the case of very large trials with

many investigators, the above information may be abbreviated to

consist of general statements of qualifications for persons carrying

out particular roles in the study with only the name, degree, and

institutional affiliation and roles of each investigator or other

participant.

The listing should include:

(a) Investigators.

(b) Any person carrying out important study observations, such

as a nurse, physician's assistant, clinical psychologist, clinical

pharmacist, or house staff physician. It is not necessary to include

in this list a person with only an occasional role, e.g., an on-call

physician who dealt with a possible adverse effect or a temporary

substitute for any of the above.

(c) The author(s) of the report, including the responsible

biostatistician(s).

Where signatures of the principal investigators are required by

regulatory authorities, these should be included in Appendix 16.1.5

(see Annex II for a sample form). Where these are not required, the

signature of the responsible medical officer should be provided in

Appendix 16.1.5.

7. Introduction

The introduction should contain a brief statement (maximum: one

page) placing the study in the context of the drug's development,

relating the critical features of the study (e.g., rationale and

aims, target population, treatment, duration, primary endpoints) to

that development. Any guidelines which were followed in the

development of the protocol or any other agreements/meetings between

the Company and regulatory authorities which are relevant to the

particular study should be identified or described.

8. Study Objectives

A statement describing the overall purpose(s) of the study

should be provided.

9. Investigational Plan

9.1 Overall Study Design and Plan - Description

The overall study plan and design (configuration) of the study

(e.g., parallel, cross-over) should be described briefly but clearly

using charts and diagram as needed. If other studies used a very

similar protocol, it may be useful to note this and describe any

important differences. The actual protocol and any changes should be

included as Appendix 16.1.1 and a sample case report form (unique

pages only; i.e., it is not necessary to include identical pages

from forms for different evaluations or visits) as Appendix 16.1.2.

If any of the information in this section comes from sources other

than the protocol, these should be identified.

The information provided should include:

- Treatments studied (specific drugs, doses, and procedures).

- Patient population studied and the number of patients to be

included.

- Level and method of blinding/masking (e.g., open, double-

blind, single-blind, blinded evaluators, and unblinded patients and/

or investigators).

- Kind of control(s) (e.g., placebo, no treatment, active drug,

dose-response, historical) and study configuration (parallel, cross-

over).

- Method of assignment to treatment (randomization,

stratification).

- Sequence and duration of all study periods, including

prerandomization and post-treatment periods, therapy withdrawal

periods, and single- and double-blind treatment periods. The timing

of randomization should be specified. It is usually helpful to

display the design graphically with a flow chart which includes

timing of assessments (see Annexes IIIa and IIIb for an example).

- Any safety, data monitoring, or special steering or evaluation

committees.

- Any interim analyses.

9.2 Discussion of Study Design, Including the Choice of Control

Groups

The specific control chosen and the study design used should be

discussed, as necessary. Examples of design issues meriting

discussion follow.

Generally, the control (comparison) groups that are recognized

are placebo concurrent control, no treatment concurrent control,

active treatment concurrent control, dose comparison concurrent

control, and historical control. In addition to the type of control,

other critical design features that may need discussion are use of a

cross-over design and selection of patients with particular prior

history, such as response or nonresponse to a specific drug or

member of a drug class. If randomization was not used, it is

important to explain how other techniques, if any, guarded against

systematic selection bias.

Known or potential problems associated with the study design or

control group chosen should be discussed in light of the specific

disease and therapies being studied. For a cross-over design, for

example, there should be consideration, among other things, of the

likelihood of spontaneous change in the disease and of carry-over

effects of treatment during the study.

If efficacy was to be demonstrated by showing equivalence, i.e.,

the absence of a specified degree of inferiority of the new

treatment compared to an established treatment, problems associated

with such study designs should be addressed. Specifically there

should be provided a basis for considering the study capable of

distinguishing active from inactive therapy. Support may be provided

by an analysis of previous studies similar to the present study with

respect to important design characteristics (e.g., patient

selection, study endpoints, duration, dose of active control,

concomitant therapy) showing a consistent ability to demonstrate

superiority of the active control to placebo. How to assess the

ability of the present study to distinguish effective from

ineffective therapy should also be discussed. For example, it may be

possible to identify a treatment response (based on past studies)

that would clearly distinguish between the treated population and an

untreated group. Such a response could be the change of a measure

from baseline or some other specified outcome like healing rate or

survival rate. Attainment of such a response would support the

expectation that the study could have distinguished the active drug

from an inactive drug. There should also be a discussion of the

degree of inferiority of the therapy (often referred to as the delta

value) the study was intended to show was not exceeded.

The limitations of historical controls are well known (e.g.,

difficulty of assuring comparability of treated groups, inability to

blind investigators to treatment, change in therapy/disease,

difference due to placebo effect) and deserve particular attention.

Other specific features of the design may also deserve

discussion, including presence or absence of washout periods and the

duration of the treatment period, especially for a chronic illness.

The rationale for dose and dose-interval selection should be

explained, if it is not obvious. For example, once daily dosing with

a short half-life drug whose effect is closely related in time to

blood level is not usually effective; if the study design uses such

dosing, this should be explained, e.g., by pointing to

pharmacodynamic evidence that effect is prolonged compared to blood

levels. The procedures used to seek evidence of ``escape'' from drug

effect at the end of the dose-interval, such as measurements of

effect just prior to dosing, should be described. Similarly, in a

parallel design dose-response study, the choice of doses should be

explained.

9.3 Selection of Study Population

9.3.1 Inclusion Criteria

The patient population and the selection criteria used to enter

the patients into the study should be described, and the suitability

of the population for the purposes of the study discussed. Specific

diagnostic criteria used, as well as specific disease requirements

(e.g., disease of a particular severity or duration, results of a

particular test or physical examination, particular features of

clinical history, such as failure or success on prior therapy, or

other potential prognostic factors, and any age, sex, or ethnic

factors) should be presented.

[[Page 43913]]

Screening criteria and any additional criteria for randomization

or entry into the drug treatment part of the trial should be

described. If there is reason to believe that there were additional

entry criteria, not defined in the protocol, the implications of

these should be discussed. For example, some investigators may have

excluded, or entered into other studies, patients who were

particularly ill or who had particular baseline characteristics.

9.3.2 Exclusion Criteria

The criteria for exclusion at entry into the study should be

specified and the rationale (e.g., safety concerns, administrative

reasons, or lack of suitability for the trial) provided. The impact

of exclusions on the generalisability of the study should be

discussed in the study report or in an overview of safety and

effectiveness.

9.3.3 Removal of Patients From Therapy or Assessment

The predetermined reasons for removing patients from therapy or

assessment observation, if any, should be described, as should the

nature and duration of any planned followup observations in those

patients.

9.4 Treatments

9.4.1 Treatments Administered

The precise treatments or diagnostic agents to be administered

(active drug(s), placebo(s), procedures) in each arm of the study,

and for each period of the study, should be fully described by name

of drug(s), marketing formulation, route and mode of administration,

dose, and dosage schedule.

9.4.2 Identity of Investigational Product(s)

In the text of the report, a brief description of the

investigational product(s) (formulation, batch number) should be

given.

In Appendix 16.1.6 of the report, the batch/serial number(s) of

treatment(s) administered and a description of their formulation,

content, external appearance (manufacturing and packaging batch

records) should be provided. If more than one batch of test drug was

used, patients receiving each batch should be identified.

The source of placebos and active control drugs should be

provided. Any modification of active control drugs from their usual

commercial state should be noted, and the steps taken to assure that

their bioavailability was unaltered should be described.

For long-duration trials of investigational products with

limited shelf-lives or incomplete stability data, the logistics of

resupply of the materials should be described. Any use of test

materials past their expiry date should be noted, and patients

receiving them identified. If there were specific storage

requirements, these should also be described.

9.4.3 Method of Assigning Patients to Treatment Groups

The specific methods used to assign patients to treatment

groups, e.g., centralized allocation, allocation within sites,

adaptive allocation (that is, assignment on the basis of earlier

assignment or outcome), should be described in the text of the

report, including any stratification or blocking procedures. Any

unusual features should be explained.

A detailed description of the randomization method, including

how it was executed, should be given in Appendix 16.1.7 with

references cited if necessary. A table exhibiting the randomization

codes, patient identifier, and treatment assigned should also be

presented in the appendix. For a multicenter study, the information

should be given by center. The method of generating random numbers

should be explained.

For a historically controlled trial, it is important to explain

how the particular control was selected and what other historical

experiences were examined, if any, and how their results compared to

the control used.

9.4.4 Selection of Doses in the Study

The doses or dose ranges used in the study should be given and

the basis for choosing them described (e.g., prior experience in

humans, animal data).

9.4.5 Selection and Timing of Dose for Each Patient

Procedures for selecting each patient's dose of test drug and

control agent should be described. These procedures can vary from

simple random assignment to a selected fixed drug/dose regimen, to

some specified titration procedure, to more elaborate response-

determined selection procedures, e.g., where dose is titrated upward

at intervals until intolerance or some specified endpoint is

achieved. Procedures for back-titration, if any, should also be

described.

The timing (time of day, interval) of dosing and the relation of

dosing to meals should be described, and if it was not specified,

this should be noted.

Any specific instructions to patients about when or how to take

the dose(s) should be described.

9.4.6 Blinding

A description of the specific procedures used to carry out

blinding should be provided (e.g., how bottles were labeled, double

dummy techniques), including the circumstances in which the blind

would be broken for an individual or all patients, the procedures

used, and who had access to patient codes. If the study allowed for

some investigators to remain unblinded (e.g., to allow them to

adjust medication), the means of shielding other investigators

should be explained. Measures taken to ensure that drug and placebo

were indistinguishable and evidence that they were

indistinguishable, should be described, as should the appearance,

shape, smell, and taste of the test material. Measures to prevent

unblinding by laboratory measurements, if used, should be described.

If blinding was considered unnecessary to reduce bias for some

or all of the observations, this should be explained; e.g., use of a

random-zero sphygmomanometer eliminates possible observer bias in

reading blood pressure and Holter tapes are often read by automated

systems that are presumably immune to observer bias. If blinding was

considered desirable, but not feasible, the reasons and implications

should be discussed. Sometimes blinding is attempted but is known to

be imperfect because of obvious drug effects in at least some

patients (dry mouth, bradycardia, fever, injection site reactions,

changes in laboratory data). Such problems or potential problems

should be identified and if there were any attempts to assess the

magnitude of the problem or manage it (e.g., by having some end

point measurements carried out by people shielded from information

that might reveal treatment assignment), they should be described.

A description of any packaging and labeling techniques used for

blinding, e.g., double dummy techniques, special labels that reveal

blind-breakage, sealed code lists/envelopes, etc., should be

provided in Appendix 16.1.7.

9.4.7 Prior and Concomitant Therapy

Which drugs or procedures were allowed before and during the

study, whether and how their use was recorded, and any other

specific rules and procedures related to permitted or forbidden

concomitant therapy should be described. How allowed concomitant

therapy might affect the outcome due either to drug-drug interaction

or to direct effects on the study endpoints should be discussed, and

how the independent effects of concomitant and study therapies could

be ascertained should be explained.

9.4.8 Treatment Compliance

The measures taken to ensure and document treatment compliance

should be described, e.g., drug accountability, diary cards, blood,

urine, or other body fluid drug level measurements, or medication

event monitoring.

9.5 Efficacy and Safety Variables

9.5.1 Efficacy and Safety Measurements Assessed and Flow Chart

The specific efficacy and safety variables to be assessed and

laboratory tests to be conducted, their schedule (days of study,

time of day, relation to meals, and the timing of critical measures

in relation to test drug administration, e.g., just prior to next

dose, 2 hours after dose), the methods for measuring them, and the

persons responsible for the measurements should be described. If

there were changes in personnel carrying out critical measurements,

these should be reported.

It is usually helpful to display graphically in a flow chart

(see Annex III of the guideline) the frequency and timing of

efficacy and safety measurements; visit numbers and times should be

shown, or, alternatively, times alone can be used (visit numbers

alone are more difficult to interpret). Any specific instructions

(e.g., guidance or use of a diary) to the patients should also be

noted.

Any definitions used to characterize outcome (e.g., criteria for

determining occurrence of acute myocardial infarction, designation

of the location of the infarction, characterization of a stroke as

thrombotic or hemorrhagic, distinction between TIA and stroke,

assignment of cause of death) should be explained in full. Any

techniques used to standardize or compare results of laboratory

tests or other clinical measurements (e.g., ECG, chest X-ray) should

also be described. This is particularly important in multicenter

studies.

If anyone other than the investigator was responsible for

evaluation of clinical outcomes (e.g., the sponsor or an external

committee to review X-rays or ECG's or to

[[Page 43914]]

determine whether the patient had a stroke, acute infarction, or sudden

death) the person or group should be identified. The procedures,

including means of maintaining blindness, and centralizing readings

and measurements, should be described fully.

The means of obtaining adverse event data should be described

(volunteered, checklist, questioning), as should any specifically

planned followup procedures for adverse events or any planned

rechallenge procedure.

Any rating of adverse events by the investigator, sponsor, or

external group (e.g., severity rating, likelihood of drug causation)

should be described and criteria for such ratings, if any, given. If

efficacy or safety was to be assessed in terms of categorical

ratings or numerical scores, the criteria used for point assignment

(e.g., definitions of point scores) should be provided. For

multicenter studies, how methods were standardized should be

indicated.

9.5.2 Appropriateness of Measurements

If any of the efficacy or safety assessments were not standard,

i.e., widely used and generally recognized as reliable, accurate,

and relevant (able to discriminate between effective and ineffective

agents), its reliability, accuracy, and relevance should be

documented. It may be helpful to describe alternatives considered

but rejected.

If a surrogate end point (a laboratory measurement or physical

measurement or sign that is not a direct measure of clinical

benefit) was used as a study end point, this should be justified,

e.g., by reference to clinical data publications, guidelines, or

previous actions by regulatory authorities.

9.5.3 Primary Efficacy Variable(s)

The primary measurements and end points used to determine

efficacy should be clearly specified. Although the critical efficacy

measurements may seem obvious, when there are multiple variables, or

when variables are measured repeatedly, the protocol should identify

the primary ones, with an explanation of why they were chosen, or

designate the pattern of significant findings or other method of

combining information that would be interpreted as supporting

efficacy. If the protocol did not identify the primary variables,

the study report should explain how these critical variables were

selected (e.g., by reference to publications, guidelines, or

previous actions by regulatory authorities) and when they were

identified (i.e., before or after the study was completed and

unblinded). If an efficacy threshold was defined in the protocol,

this should be described.

9.5.4 Drug Concentration Measurements

Any drug concentrations to be measured, and the sample

collection times and periods in relation to the timing of drug

administration, should be described. Any relation of drug

administration and sampling to ingestion of food, posture, and the

possible effects of concomitant medication/alcohol/caffeine/nicotine

should also be addressed. The biological sample measured and the

method of measurement used should be described, referring to

published and/or internal assay validation documentation for

methodological details. Where other factors are believed important

in assessing pharmacokinetics (e.g., soluble circulating receptors,

renal or hepatic function), the timing and plans to measure these

factors should also be specified.

9.6 Data Quality Assurance - Audit Certificate

The quality assurance and quality control systems implemented to

assure the quality of the data should be described in brief. If none

were used, this should be stated.

Any steps taken at the investigation site or centrally to ensure

the use of standard terminology and the collection of accurate,

consistent, complete, and reliable data, such as training sessions,

monitoring of investigators by sponsor personnel, instruction

manuals, data verification, cross-checking, use of a central

laboratory for certain tests, centralized ECG reading, or data

audits, should be described. It should be noted whether investigator

meetings or other steps were taken to prepare investigators and

standardize performance.

If the sponsor used an independent internal or external auditing

procedure, it should be mentioned here and described in Appendix

16.1.8 and audit certificates (if available; see Annexes IVa and IVb

for descriptions) provided in the same appendix.

9.7 Statistical Methods Planned in The Protocol and Determination of

Sample Size

9.7.1 Statistical and Analytical Plans

The statistical analyses planned in the protocol and any changes

made before outcome results were available should be described. In

this section emphasis should be on which analyses, comparisons, and

statistical tests were planned, not on which ones were actually

used. If critical measurements were made more than once, the

particular measurements (e.g., average of several measurements over

the entire study, values at particular times, values only from study

completers, or last on-therapy value) planned as the basis for

comparison of drug and control should be specified. Similarly, if

more than one analytical approach is plausible, e.g., changes from

baseline response, slope analysis, life table analysis, the planned

approach should be identified. Also, whether the primary analysis is

to include adjustment for covariates should be specified.

If there were any planned reasons for excluding from analysis

patients for whom data are available, these should be described. If

there were any subgroups whose results were to be examined

separately, these should be identified. If categorical responses

(global scales, severity scores, responses of a certain size) were

to be used in analyzing responses, they should be clearly defined.

Planned monitoring of the results of the study should be

described. If there was a data monitoring committee, either within

or outside the sponsor's control, its composition and operating

procedures should be described and procedures to maintain study

blinding should be given. The frequency and nature of any planned

interim analysis, any specified circumstances in which the study

would be terminated, and any statistical adjustments to be employed

because of interim analyses should be described.

9.7.2 Determination of Sample Size

The planned sample size and the basis for it, such as

statistical considerations or practical limitations, should be

provided. Formulae for sample size and power calculation should be

given together with their derivations or source of reference.

Estimates used in the formulae should be given and explanations

provided as to how they were obtained. For a positive control study

intended to show that a new therapy is at least as effective as the

standard therapy, the sample size determination should specify a

``delta value'' (a difference between treatments that would be

considered unacceptably large) and therefore the difference the

study is designed to be able to exclude.

9.8 Changes in the Conduct of the Study or Planned Analyses

Any change in the conduct of the study or planned analyses

(e.g., dropping a treatment group, changing the entry criteria or

drug dosages, adjusting the sample size, etc.) instituted after the

start of the study should be described. The time(s) and reason(s)

for the change(s), the procedure used to decide on the change(s),

the person(s) or group(s) responsible for the change(s), and the

nature and content of the data available (and to whom they were

available) when the change was made should also be described,

whether the change was documented as a formal protocol amendment or

not. (Personnel changes need not be included.) Any possible

implications of the change(s) for the interpretation of the study

should be discussed briefly in this section and more fully in other

appropriate sections of the report. In every section of the report,

a clear distinction between conditions (procedures) planned in the

protocol and amendments or additions should be made.

10. Study Patients

10.1 Disposition of Patients

There should be a clear accounting of all patients who entered

the study, using figures or tables in the text of the report. The

numbers of patients who were screened, were randomized, and who

entered and completed each phase of the study (or each week/month of

the study) should be provided, as well as the reasons for all

postrandomization discontinuations, grouped by treatment and by

major reason (e.g., lost to followup, adverse event, poor

compliance). In some cases, it may also be relevant to provide a

breakdown of the reasons for excluding patients during screening, if

this could help clarify the appropriate patient population for

eventual drug use. A flow chart is often helpful (see Annexes Va and

Vb of the guideline). Whether patients are followed for the duration

of the study, even if drug is discontinued, should be made clear.

In Appendix 16.2.1, there should also be a listing of all

patients discontinued from the study after enrollment, broken down

by center and treatment group, giving a patient identifier, the

specific reason for discontinuation, the treatment (drug and dose),

cumulative dose (where appropriate), and the duration of treatment

before discontinuation. Whether or not the blind for the patient was

broken at the time of discontinuation should be noted. It may also

be useful to include other information, such as critical demographic

data (e.g., age, sex, race), concomitant medication, and the major

[[Page 43915]]

response variable(s) at termination. See Annex VI for an example of

such a listing.

10.2 Protocol Deviations

All important deviations related to study inclusion or exclusion

criteria, conduct of the trial, patient management, or patient

assessment should be described.

In the body of the text, protocol deviations should be

appropriately summarized by center and grouped into different

categories, such as:

- Those who entered the study even though they did not satisfy

the entry criteria.

- Those who developed withdrawal criteria during the study but

were not withdrawn.

- Those who received the wrong treatment or incorrect dose.

- Those who received an excluded concomitant treatment.

In Appendix 16.2.2, individual patients with these protocol

deviations should be listed, broken down by center for multicenter

studies.

11. Efficacy Evaluation

11.1 Data Sets Analyzed

Exactly which patients were included in each efficacy analysis

should be precisely defined, e.g., all patients receiving any drug,

all patients with any efficacy observation or with a certain minimum

number of observations, only patients completing the trial, all

patients with an observation during a particular time window, only

patients with a specified degree of compliance, etc. It should be

clear, if not defined in the study protocol, when (relative to study

unblinding), and how inclusion/exclusion criteria for the data sets

analyzed were developed. As a general rule, even if the applicant's

proposed primary analysis is based on a reduced subset of the

patients with data, there should also be for any trial intended to

establish efficacy an additional analysis using all randomized (or

otherwise entered) patients with any on-treatment data.

There should be a tabular listing of all patients, visits, and

observations excluded from the efficacy analysis provided in

Appendix 16.2.3 (see Annex VII of the guideline for an example). The

reasons for exclusions should also be analyzed for the whole

treatment group over time (see Annex VIII of the guideline for an

example).

11.2 Demographic and Other Baseline Characteristics

Group data for the critical demographic and baseline

characteristics of the patients, as well as other factors arising

during the study that could affect response, should be presented in

this section and comparability of the treatment groups for all

relevant characteristics should be displayed by use of tables or

graphs in section 14.1. The data for the patient sample included in

the ``all patients with data'' analysis should be given first. This

can then be followed by data on other groups used in principal

analyses, such as the ``per-protocol'' analysis or other analyses,

e.g., groups defined by compliance, concomitant disease/therapy, or

demographic/baseline characteristics. When such groups are used,

data for the complementary excluded group should also be shown. In a

multicenter study, comparability should be assessed by center, and

centers should be compared.

A diagram showing the relationship between the entire sample and

any other analysis groups should be provided.

The critical variables will depend on the specific nature of the

disease but will usually include:

Demographic variables

- Age

- Sex

- Race

Disease factors

- Specific entry criteria (if not uniform), duration, stage, and

severity of disease and other clinical classifications and

subgroupings in common usage or of known prognostic significance.

- Baseline values for critical clinical measurements carried out

during the study or identified as important indicators of prognosis

or response to therapy.

- Concomitant illness at trial initiation such as renal disease,

diabetes, heart failure.

- Relevant previous illness.

- Relevant previous treatment for illness treated in the study.

- Concomitant treatment maintained, even if the dose was changed

during the study, including oral contraceptive and hormone

replacement therapy; treatments stopped at entry into the study

period (or changed at study initiation).

Other factors that might affect response to therapy

(e.g., weight, renin status, antibody levels, metabolic status).

Other possibly relevant variables (e.g., smoking,

alcohol intake, special diets) and, for women, menstrual status and

date of last menstrual period, if pertinent for the study.

In addition to tables and graphs giving group data for these

baseline variables, relevant individual patient demographic and

baseline data, including laboratory values, and all concomitant

medication for all individual patients randomized (broken down by

treatment and by center for multicenter studies) should be presented

in by-patient tabular listings in Appendix 16.2.4. Although some

regulatory authorities will require all baseline data to be

presented elsewhere in tabular listings, the appendix to the study

report should be limited to only the most relevant data, generally

the variables listed above.

11.3 Measurements of Treatment Compliance

Any measurements of compliance of individual patients with the

treatment regimen under study and drug concentrations in body fluids

should be summarized, analyzed by treatment group and time interval,

and tabulated in Appendix 16.2.5.

11.4 Efficacy Results and Tabulations of Individual Patient Data

11.4.1 Analysis of Efficacy

Treatment groups should be compared for all critical measures of

efficacy (primary and secondary end points; pharmacodynamics), as

well as benefit/risk assessment measured in each patient where these

are utilized. In general, the results of all analyses contemplated

in the protocol and an analysis including all patients with on-study

data should be performed in studies intended to establish efficacy.

Analyses based on continuous variables (e.g., mean blood

pressure or depression scale score) and categorical responses (e.g.,

cure of an infection) can be equally valid; ordinarily both should

be presented if both were planned and are available. If categories

are newly created (i.e., not in the statistical plan), the basis for

them should be explained. Even if one variable receives primary

attention (e.g., in a blood pressure study, supine blood pressure at

week x), other reasonable measures (e.g., standing blood pressure

and blood pressures at other particular times) should be assessed,

at least briefly. In addition, the time course of response should be

described, if possible. For a multicenter study, data display and

analysis of individual centers should be included to give a clear

picture of the results at each site, especially the larger sites.

If any critical measurements or assessments of efficacy or

safety outcomes were made by more than one party (e.g., both the

investigator and an expert committee may offer an opinion on whether

a patient had an acute infarction), overall differences between the

ratings should be shown, and each patient having disparate

assessments should be identified. The assessments used should be

clear in all analyses.

In many cases, efficacy and safety end points are difficult to

distinguish (e.g., stroke in a thrombolytic trial, deaths in a fatal

disease study). Many of the principles addressed below should be

adopted for critical safety measures as well.

11.4.2 Statistical/Analytical Issues

The statistical analysis used should be described for clinical

and statistical reviewers in the text of the report, with detailed

documentation of statistical methods (see section Annex IX)

presented in Appendix 16.1.9. Important features of the analysis,

including the particular tests used, adjustments made for

demographic or baseline measurements or concomitant therapy,

handling of dropouts and missing data, adjustments for multiple

comparisons, special analyses of multicenter studies, and

adjustments for interim analyses, should be discussed. Any changes

in the analysis made after blind-breaking should be identified.

In addition to the general discussion, the following specific

issues should be addressed (unless not applicable):

11.4.2.1 Adjustments for Covariates

Selection of, and adjustments for, demographic or baseline

measurements, concomitant therapy, or any other covariate or

prognostic factor should be explained in the report, and methods of

adjustment, results of analyses, and supportive information (e.g.,

ANCOVA or Cox regression output) should be included in the detailed

documentation of statistical methods. If the covariates or methods

used in these analyses differed from those planned in the protocol,

the differences should be explained and where possible and relevant,

the results of planned analyses should also be presented. Although

not part of the individual study report, comparisons of covariate

adjustments and prognostic factors across individual studies may be

an informative analysis in a summary of clinical efficacy data.

11.4.2.2 Handling of Dropouts or Missing Data

There are several factors that may affect dropout rates. These

include the duration of

[[Page 43916]]

the study, the nature of the disease, the efficacy and toxicity of the

drug under study, and other factors that are not therapy related.

Ignoring the patients who dropped out of the study and drawing

conclusions based only on patients who completed the study can be

misleading. A large number of dropouts, however, even if included in

an analysis, may introduce bias, particularly if there are more

early dropouts in one treatment group or the reasons for dropping

out are treatment or outcome related. Although the effects of early

dropouts, and sometimes even the direction of bias, can be difficult

to determine, possible effects should be explored as fully as

possible. It may be helpful to examine the observed cases at various

time points or, if dropouts were very frequent, to concentrate on

analyses at time points when most of the patients were still under

observation and when the full effect of the drug was realized. It

may also be helpful to examine modeling approaches to the evaluation

of such incomplete data sets.

The results of a clinical trial should be assessed not only for

the subset of patients who completed the study, but also for the

entire patient population as randomized (the intent-to-treat

analysis) or at least for all those with any on-study measurements.

Several factors should be considered and compared for the treatment

groups in analyzing the effects of dropouts: the reasons for the

dropouts, the time to dropout, and the proportion of dropouts among

treatment groups at various time points.

Procedures for dealing with missing data, e.g., use of estimated

or derived data, should be described. Detailed explanation should be

provided as to how such estimations or derivations were done and

what underlying assumptions were made.

11.4.2.3 Interim Analyses and Data Monitoring

The process of examining and analyzing data accumulating in a

clinical trial, either formally or informally, can introduce bias

and/or increase type I error. Therefore, all interim analyses,

formal or informal, preplanned or ad hoc, by any study participant,

sponsor staff member, or data monitoring group should be described

in full, even if the treatment groups were not identified. The need

for statistical adjustment because of such analyses should be

addressed. Any operating instructions or procedures used for such

analyses should be described. The minutes of meetings of any data

monitoring group and any data reports reviewed at those meetings,

particularly a meeting that led to a change in the protocol or early

termination of the study, may be helpful and should be provided in

Appendix 16.1.9. Data monitoring without code-breaking should also

be described, even if this kind of monitoring is considered to cause

no increase in type I error.

11.4.2.4 Multicenter Studies

A multicenter study is a single study under a common protocol,

involving several centers (e.g., clinics, practices, hospitals)

where the data collected are intended to be analyzed as a whole (as

opposed to a post-hoc decision to combine data or results from

separate studies). Individual center results should be presented,

however, and statistical tests for homogeneity across centers, i.e.,

for detecting treatment-by center interaction, should be provided,

if feasible. The significance level used to declare the significance

of a given test for treatment-by-center interaction should be

considered in light of the sample sizes involved. Any extreme or

opposite results among centers should be noted and discussed,

considering such possibilities as differences in study conduct,

patient characteristics, or clinical settings. As mentioned in

previous sections, demographic, baseline, and postbaseline data, as

well as efficacy data, should be presented by center, even though

the combined analysis is the primary one.

11.4.2.5 Multiple Comparisons

False positive findings increase in number as the number of

significance tests (number of comparisons) performed increases. If

there was more than one primary endpoint (outcome variable), or if

there were multiple treatment groups, or subsets of the patient

population being examined, the statistical analysis should reflect

awareness of this and either explain the statistical adjustment used

for type I error criteria or give reasons why it was considered

unnecessary.

11.4.2.6 Use of an ``Efficacy Subset'' of Patients

Particular attention should be devoted to the effects of

dropping patients with available data from analyses because of poor

compliance, missed visits, ineligibility, or any other reason. As

noted above, an analysis using all available data should be carried

out for all studies intended to establish efficacy, even if it is

not the analysis proposed as the primary analysis by the applicant.

11.4.2.7 Active-Control Studies Intended to Show Equivalence

If an active control study is intended to show equivalence

(i.e., lack of a difference greater than a specified size) between a

new drug and a control, the analysis should show the confidence

interval for the comparison between the two agents for critical end

points and the relation of that interval to the prespecified degree

of inferiority that would be considered unacceptable. (See 9.2, for

important considerations when using the active control equivalence

design.)

11.4.2.8 Examination of Subgroups

If the size of the study permits, important demographic or

baseline value-defined subgroups should be examined for unusually

large or small responses and the results presented, e.g., comparison

of effects by age, sex, or race, by severity or prognostic groups,

by history of prior treatment with a drug of the same class. If

these analyses were not carried out because the study was too small,

it should be noted. These analyses are not intended to ``salvage''

an otherwise nonsupportive study but may suggest hypotheses worth

examining in other studies or be helpful in refining, for example,

labeling information, patient selection, or dose selection. Where

there is a prior hypothesis of a differential effect in a particular

subgroup, this hypothesis and its assessment should be part of the

planned statistical analysis.

11.4.3 Tabulation of Individual Response Data

In addition to tables and graphs representing group data,

individual response data and other relevant study information should

be presented in tables. Some regulatory authorities may require all

individual data in archival case report tabulations. What needs to

be included in the report will vary from study to study and from one

drug class to another and the applicant should decide, if possible

after consultation with the regulatory authority, what to include in

an appendix to the study report. The study report should indicate

what material is included as an appendix, what is in the more

extensive archival case report tabulations, if required by the

regulatory authority, and what is available on request.

For a controlled study in which critical efficacy measurements

or assessments (e.g., blood or urine cultures, pulmonary function

tests, angina frequency, or global evaluations) are repeated at

intervals, the data listings accompanying the report should include,

for each patient, a patient identifier, all measured or observed

values of critical measurements, including baseline measurements,

with notation of the time during the study (e.g., days on therapy

and time of day, if relevant) when the measurements were made, the

drug/dose at the time (if useful, given as milligrams per kilogram

(mg/kg)), any measurements of compliance, and any concomitant

medications at the time of, or close to the time of, measurement or

assessment. If, aside from repeated assessments, the study included

some overall responder versus nonresponder evaluation(s)

(bacteriologic cure or failure), it should also be included. In

addition to critical measurements, the tabulation should note

whether the patient was included in the efficacy evaluation (and

which evaluation, if more than one), provide patient compliance

information, if collected, and a reference to the location of the

case report form, if included. Critical baseline information such as

age, sex, weight, disease being treated (if more than one in study),

and disease stage or severity, is also helpful. The baseline values

for critical measurements would ordinarily be included as zero time

values for each efficacy measurement.

The tabulation described should usually be included in Appendix

16.2.6 of the study report, rather than in the more extensive case

report tabulations required by some regulatory authorities, because

it represents the basic efficacy data supporting summary tables.

Such a thorough tabulation can be unwieldy for review purposes,

however, and more targeted displays should be developed as well. For

example, if there are many measurements reported, tabulations of the

most critical measurements for each patient (e.g., the blood

pressure value at certain visits might be more important than

others) will be useful in providing an overview of each individual's

results in a study, with each patient's response summarized on a

single line or small number of lines.

11.4.4 Drug Dose, Drug Concentration, and Relationships to Response

When the dose in each patient can vary, the actual doses

received by patients should be shown and individual patient's doses

should be tabulated. Although studies not designed as dose-response

studies may have limited ability to contribute dose-response

[[Page 43917]]

information, the available data should be examined for whatever

information they can yield. In examining the dose response, it may

be helpful to calculate dose as mg/kg body weight or milligrams per

meter squared (mg/m2) body surface.

Drug concentration information, if available, should also be

tabulated (Appendix 16.2.5), analyzed in pharmacokinetic terms and,

if possible, related to response.

Further guidance on the design and analysis of studies exploring

dose-response or concentration response can be found in the ICH

Guideline ``Dose-Response Information to Support Drug

Registration.''

11.4.5 Drug-Drug and Drug Disease Interactions

Any apparent relationship between response and concomitant

therapy and between response and past and/or concurrent illness

should be described.

11.4.6 By-Patient Displays

While individual patient data ordinarily can be displayed in

tabular listings, it has on occasion been helpful to construct

individual patient profiles in other formats, such as graphic

displays. These might, for example, show the value of (a) particular

parameter(s) over time, the drug dose over the same period, and the

times of particular events (e.g., an adverse event or change in

concomitant therapy). Where group mean data represent the principal

analyses, this kind of ``case report extract'' may offer little

advantage; it may be helpful, however, if overall evaluation of

individual responses is a critical part of the analysis.

11.4.7 Efficacy Conclusions

The important conclusions concerning efficacy should be

concisely described, considering primary and secondary endpoints,

prespecified and alternative statistical approaches, and results of

exploratory analyses.

12. Safety Evaluation

Analysis of safety-related data can be considered at three

levels. First, the amount of exposure (dose, duration) should be

examined to determine the extent to which safety can be assessed

from the study. Second, the more common adverse events, e.g.,

laboratory test changes, should be identified, classified in some

reasonable way, compared for treatment groups, and analyzed, as

appropriate, for that may affect the frequency of adverse reactions,

such as time dependence, relation to demographic characteristics,

relation to dose or drug concentration. Finally, serious adverse

events and other significant adverse events should be identified,

usually by close examination of patients who left the study

prematurely because of an adverse event, whether or not identified

as drug related, or who died.

The ICH Guideline on Clinical Safety Data Management,

Definitions and Standards for Expedited Reporting defines serious

adverse events as follows: A ``serious adverse event'' (experience)

or reaction is any untoward medical occurrence that at any dose:

results in death, is life-threatening, requires inpatient or

prolongation of existing hospitalization, results in persistent or

significant disability/incapacity, or is a congenital anomaly/birth

defect.

For the purpose of this guideline, ``other significant adverse

events'' are marked hematological and other laboratory abnormalities

and any medical events that led to an intervention, including

withdrawal of drug treatment, dose reduction, or significant

additional concomitant therapy.

In the following sections, three kinds of analysis and display

are suggested:

(1) Summarized data, often using tables and graphical

presentations presented in the main body of the report;

(2) Listings of individual patient data; and

(3) Narrative statements of events of particular interest.

In all tabulations and analyses, events associated with both

test drug and control treatment should be displayed.

12.1 Extent of Exposure

The extent of exposure to study drugs (and to active control and

placebo) should be characterized according to the number of patients

exposed, the duration of exposure, and the dose to which they were

exposed.

Duration: Duration of exposure to any dose can be

expressed as a median or mean, but it is also helpful to describe

the number of patients exposed for specified periods of time, such

as for 1 day or less, 2 days to 1 week, more than 1 week to 1 month,

more than 1 month to 6 months. The numbers exposed to drug for the

various durations should also be broken down into age, sex, and

racial subgroups, and any other pertinent subgroups, such as disease

(if more than one is represented), disease severity, concurrent

illness.

Dose: The mean or median dose used and the number of

patients exposed to specified daily dose levels should be given; the

daily dose levels used could be the maximum dose for each patient,

the dose with longest exposure for each patient, or the mean daily

dose. It is often useful to provide combined dose-duration

information, such as the numbers exposed for a given duration (e.g.,

at least 1 month) to the most common dose, the highest dose, the

maximum recommended dose. In some cases, cumulative dose might be

pertinent. Dosage may be given as the actual daily dose or on a mg/

kg or mg/m2 basis as appropriate. The numbers of patients

exposed to various doses should be broken down into age, sex, and

racial subgroups, and any other pertinent subgroups.

Drug concentration: If available, drug concentration

data (e.g., concentration at the time of an event, maximum plasma

concentration, area under curve) may be helpful in individual

patients for correlation with adverse events or changes in

laboratory variables. (Appendix 16.2.5.)

It is assumed that all patients entered into treatment who

received at least one dose of the treatment are included in the

safety analysis; if that is not so, an explanation should be

provided.

12.2 Adverse Events (AE's)

12.2.1 Brief Summary of Adverse Events

The overall adverse event experience in the study should be

described in a brief narrative, supported by the following more

detailed tabulations and analyses. In these tabulations and

analyses, events associated with both the test drug and control

treatment should be displayed.

12.2.2 Display of Adverse Events

All adverse events (including events likely to be related to the

underlying disease or likely to represent concomitant illness,

unless there is a prior agreement with the regulatory authority to

consider specified events as disease related) should be displayed in

summary tables (section 14.3.1). The tables should include changes

in vital signs and any laboratory changes that were considered

serious adverse events or that resulted in withdrawal of treatment.

In most cases, it will also be useful to describe in such

tables, ``treatment emergent signs and symptoms'' (TESS; those not

seen at baseline, and those which worsened even if present at

baseline).

The tables should list each adverse event, the number of

patients in each treatment group in whom the event occurred, and the

rate of occurrence. Adverse events should be grouped by body system.

Each event may then be divided into defined severity categories

(e.g., mild, moderate, severe) if these were used. The tables may

also divide the adverse events into those considered at least

possibly related to drug use and those considered not related, or

use some other causality (e.g., unrelated or possibly, probably, or

definitely related). For any such categorization, the categories

should be defined and the person(s) responsible for classification

of each event identified. Even when such a causality assessment is

used, the tables should include all adverse events, whether or not

considered drug related, including events thought to represent

intercurrent illnesses. Subsequent analyses of the study or of the

overall safety data base may help to distinguish between adverse

events that are, or are not, considered drug related. So that it is

possible to analyze and evaluate the data in these tables, it is

important to identify each patient having each adverse event. An

example of such a tabular presentation is shown below.

BILLING CODE 4160-01-F

[[Page 43918]]

[GRAPHIC][TIFF OMITTED]TN23AU95.010

BILLING CODE 4160-01-C

[[Page 43919]]

In addition to these complete tables provided in 14.3.1, an

additional summary table comparing treatment and control groups,

without the patient identifying numbers limited to relatively common

adverse events (e.g., those in at least 1 percent of the treated

group), should be provided in the body of the report.

In presenting adverse events, it is important both to display

the original terms used by the investigator and to attempt to group

related events (i.e., events that probably represent the same

phenomena) so that the true occurrence rate is not obscured. One way

to do this is with a standard adverse reaction dictionary.

12.2.3 Analysis of Adverse Events

The basic display of adverse event rates described in section

12.2.2 (and located in section 14.3.1) of the report should be used

to compare rates in treatment and control groups. For this analysis

it may be helpful to combine the event severity categories and the

causality categories, leading to a simpler side-by-side comparison

of treatment groups. In addition, if study size and design permit,

it may be useful to examine the more common adverse events that seem

to be drug related for relationship to dosage and to mg/kg or mg/

m2 dose, to dose regimen, to duration of treatment, to total

dose, to demographic characteristics, such as age, sex, race, to

other baseline features, such as renal status to effectiveness

outcomes, and to drug concentration, if data are available. It may

also be useful to examine time of onset and duration of adverse

events. A variety of additional analyses may be suggested by the

study results or by the pharmacology of the drug.

It is not intended that every adverse event be subjected to

rigorous statistical evaluation. It may be apparent from initial

display and inspection of the data that a significant relation to

demographic or other baseline features is not present. If the

studies are small and if the number of events is relatively small,

it may be sufficient to limit analyses to a comparison of treatment

and control.

Under certain circumstances, life table or similar analyses may

be more useful than reporting of crude adverse event rates.

12.2.4 Listing of Adverse Events by Patient

All adverse events for each patient, including the same event on

several occasions, should be listed in Appendix 16.2.7, giving both

preferred term and the original term used by the investigator. The

listing should be by investigator and by treatment group and should

include:

- Patient identifier

- Age, race, sex, weight (height, if relevant)

- Location of case report forms (CRF's), if provided.

- preferred term

- The adverse event -

- reported term

- Duration of the adverse event

- Severity (e.g., mild, moderate, severe)

- Seriousness (serious/nonserious)

- Action taken (none, dose reduced, treatment stopped, specific

treatment instituted, etc.)

- Outcome (e.g., CIOMS format)

- Causality assessment (e.g., related/not related). How this was

determined should be described in the table or elsewhere.

- Date of onset or date of clinic visit at which the event was

discovered

- Timing of onset of the adverse event in relation to last dose

of study drug (when applicable)

- Study treatment at time of event or most recent study

treatment taken

- Study drug dose in absolute amount, mg/kg or mg/m2 at

time of event

- Drug concentration (if known)

- Duration of study drug treatment

- Other drug treatment during study

Any abbreviations and codes should be clearly explained at the

beginning of the listing or, preferably, on each page.

12.3 Deaths, Other Serious Adverse Events, and Other Significant

Adverse Events

Deaths, other serious adverse events, and other significant

adverse events (see definition in section 12) deserve special

attention.

12.3.1 Listing of Deaths, Other Serious Adverse Events, and Other

Significant Adverse Events

Listings, containing the same information as called for in

section 12.2.4 above, should be provided for the following events.

12.3.1.1 Deaths

All deaths during the study, including the posttreatment

followup period, and deaths that resulted from a process that began

during the study, should be listed by patient in section 14.3.2.

21.3.1.2 Other Serious Adverse Events

All serious adverse events (other than death but including the

serious adverse events temporally associated with or preceding the

deaths) should be listed in section 14.3.2. The listing should

include laboratory abnormalities, abnormal vital signs, and abnormal

physical observations that were considered serious adverse events.

12.3.1.3 Other Significant Adverse Events

Marked hematological and other laboratory abnormalities (other

than those meeting the definition of serious) and any events that

led to an intervention, including withdrawal of drug treatment, dose

reduction, or significant additional concomitant therapy, other than

those reported as serious adverse events, should be listed in

section 14.3.2.

12.3.2 Narratives of Deaths, Other Serious Adverse Events, and

Certain Other Significant Adverse Events

There should be brief narratives describing each death, each

other serious adverse event, and those of the other significant

adverse events that are of special interest because of clinical

importance. These narratives can be placed either in the text of the

report or in section 14.3.3, depending on their number. Events that

were clearly unrelated to the study drug may be omitted or described

very briefly. In general, the narrative should describe:

- The nature and intensity of event, the clinical course leading

up to the event, with an indication of timing relevant to drug

administration; relevant laboratory measurements whether the drug

was stopped, and when; countermeasures; post mortem findings;

investigator's opinion on causality, and sponsor's opinion on

causality, if appropriate.

In addition, the following information should be included:

- Patient identifier

- Age and sex of patient; general clinical condition of patient,

if appropriate

- Disease being treated (if the same for all patients this is

not required) with duration of current episode of illness

- Relevant concomitant/previous illnesses with details of

occurrence/duration

- Relevant concomitant/previous medication with details of

dosage

- Study drug administered, drug dose, if this varied among

patients, and length of time administered

12.3.3 Analysis and Discussion of Deaths, Other Serious Adverse

Events, and Other Significant Adverse Events

The significance of the deaths, other serious adverse events,

and other significant adverse events leading to withdrawal, dose

reduction, or institution of concomitant therapy should be assessed

with respect to the safety of the drug. Particular attention should

be paid to whether any of these events may represent a previously

unsuspected important adverse effect of the drug. For serious

adverse events that appear of particular importance, it may be

useful to use life table or similar analyses to show their relation

to time on drug and to assess their risk over time.

12.4 Clinical Laboratory Evaluation

12.4.1 Listing of Individual Laboratory Measurements by Patient

(16.2.8) and Each Abnormal Laboratory Value (14.3.4)

When required by regulatory authorities, the results of all

safety-related laboratory tests should be available in tabular

listings, using a display similar to the following, where each row

represents a patient visit at which a laboratory study was done,

with patients grouped by investigator (if more than one) and

treatment group, and columns include critical demographic data, drug

dose data, and the results of the laboratory tests. As not all tests

can be displayed in a single table, they should be grouped logically

(e.g., hematological tests, liver chemistries, electrolytes,

urinalysis). Abnormal values should be identified, e.g., by

underlining, bracketing. These listings should be submitted as part

of the registration/marketing application, when this is required, or

may be available on request.

[[Page 43920]]

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

Laboratory Tests

Patient Time Age Sex Race Weight Dose -------------------------------------

SGOT SGPT AP.........X

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

#1 T0 70 M W 70 kg 400 mg V1* V5 V9

T1 ........ ........ ........ ......... .......... V2 V6 V10

T2 ........ ........ ........ ......... .......... V3 V7 V11

T3 ........ ........ ........ ......... .......... V4 V8 V12

......... ........ ........ ........ ......... .......... .......... ........ ..............

#2 T10 65 F B 50 kg 300 mg V13 V16 V19

T21 ........ ........ ........ ......... .......... V14 V17 V20

T32 ........ ........ ........ ......... .......... V15 V18 V21

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

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

*Vn = value of a particular test

For all regulatory authorities, there should be a by-patient

listing of all abnormal laboratory values in section 14.3.4, using

the format described above. For laboratory abnormalities of special

interest (abnormal laboratory values of potential clinical

importance), it may also be useful to provide additional data, such

as normal values before and after the abnormal value, and values of

related laboratory tests. In some cases, it may be desirable to

exclude certain abnormal values from further analysis. For example,

single, nonreplicated, small abnormalities of some tests (e.g., uric

acid or electrolytes) or occasional low values of some tests (e.g.,

transaminase, alkaline phosphatase, blood urea nitrogen (BUN)) can

probably be defined as clinically insignificant and excluded. Any

such decisions should be clearly explained, however, and the

complete list of values provided (or available to authorities on

request) should identify every abnormal value.

12.4.2 Evaluation of Each Laboratory Parameter

The necessary evaluation of laboratory values must in part be

determined by the results seen, but, in general, the following

analyses should be provided. For each analysis, comparison of the

treatment and control groups should be carried out, as appropriate,

and as compatible with study size. In addition, normal laboratory

ranges should be given for each analysis.

12.4.2.1 Laboratory Values Over Time

For each parameter at each time over the course of the study

(e.g., at each visit) the following should be described: the group

mean or median values, the range of values, and the number of

patients with abnormal values, or with abnormal values that are of a

certain size (e.g., twice the upper limit of normal, 5 times the

upper limit; choices should be explained). Graphs may be used.

12.4.2.2 Individual Patient Changes

An analysis of individual patient changes by treatment group

should be given. A variety of approaches may be used, including:

I. ``Shift tables'' - These tables show the number of patients

who are low, normal, or high at baseline and then at selected time

intervals.

II. Tables showing the number or fraction of patients who had a

change in parameter of a predetermined size at selected time

intervals. For example, for BUN, it might be decided that a change

of more than 10 mg per deciliter BUN should be noted. For this

parameter, the number of patients having a change less than this or

greater than this would be shown for one or more visits, usually

grouping patients separately depending on baseline BUN (normal or

elevated). The possible advantage of this display, compared to the

usual shift table, is that changes of a certain size are noted, even

if the value is not abnormal.

III. A graph comparing the initial value and the on-treatment

values of a laboratory measurement for each patient by locating the

point defined by the initial value on the abscissa and a subsequent

value on the ordinate. If no changes occur, the point representing

each patient will be located on the 45 deg. line. A general shift to

higher values will show a clustering of points above the 45 deg.

line. As this display can show only a single time point for a single

treatment, interpretation requires a time series of these plots for

treatment and control groups. This kind of display identifies

outliers readily (it is useful to include patient identifiers for

the outliers).

12.4.2.3 Individual Clinically Significant Abnormalities

Clinically significant changes (defined by the applicant) should

be discussed. A narrative of each patient whose laboratory

abnormality was considered a serious adverse event and, in certain

cases, considered another significant event should be provided under

section 12.3.2 or 14.3.3. When toxicity grading scales are used

(e.g., World Health Organization, National Cancer Institute),

changes graded as severe should be discussed regardless of

seriousness. An analysis of the clinically significant changes,

together with a recapitulation of discontinuations due to laboratory

measurements, should be provided for each parameter. The

significance of the changes and likely relation to the treatment

should be assessed, e.g., by analysis of such features as

relationship to dose, relationship to drug concentration,

disappearance on continued therapy, positive dechallenge, positive

rechallenge, and the nature of concomitant therapy.

12.5 Vital Signs, Physical Findings, and Other Observations Related

to Safety

Vital signs, other physical findings, and other observations

related to safety should be analyzed and presented in a way similar

to laboratory variables. If there is evidence of a drug effect, any

dose-response or drug concentration-response relationship or

relationship to patient variables (e.g., disease, demographics,

concomitant therapy) should be identified and the clinical relevance

of the observation described. Particular attention should be given

to changes not evaluated as efficacy variables and to those

considered to be adverse events.

12.6 Safety Conclusions

The overall safety evaluation of the study drug(s) should be

reviewed, with particular attention to events resulting in changes

of dose or need for concomitant medication, serious adverse events,

events resulting in withdrawal, and deaths. Any patients or patient

groups at increased risk should be identified and particular

attention paid to potentially vulnerable patients who may be present

in small numbers, e.g., children, pregnant women, frail elderly,

people with marked abnormalities of drug metabolism or excretion.

The implication of the safety evaluation for the possible uses of

the drug should be described.

13. Overall Conclusions

The efficacy and safety results of the study and the

relationship of risks and benefit should be briefly summarized,

referring to the tables, figures, and sections above as needed. The

presentation should not simply repeat the description of results nor

introduce new results.

The conclusions should clearly identify any new or unexpected

findings, comment on their significance, and discuss any potential

problems such as inconsistencies between related measures. The

clinical relevance and importance of the results should also be

discussed in the light of other existing data. Any specific benefits

or special precautions required for individual subjects or at-risk

groups and any implications for the conduct of future studies should

be identified.

14. Tables, Figures, and Graphs Referred to but not Included in the

Text

Figures should be used to visually summarize the important

results, or to clarify results that are not easily understood from

tables.

Important demographic, efficacy, and safety data should be

presented in summary figures or tables in the text of the report.

However, if these become obtrusive because of size or number they

should be presented here, cross-referenced to the text, along with

supportive, or additional, figures, tables, or listings.

The following information may be incorporated in this section:

14.1 Demographic Data

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Summary figures and tables

14.2 Efficacy Data

Summary figures and tables

14.3 Safety Data

Summary figures and tables

14.3.1 Displays of Adverse Events

14.3.2 Listings of Deaths, Other Serious and Significant Adverse

Events

14.3.3 Narratives of Deaths, Other Serious and Certain Other

Significant Adverse Events

14.3.4 Abnormal Laboratory Value Listing (each patient)

15. Reference List

A list of articles from the literature pertinent to the

evaluation of the study should be provided. Copies of important

publications should be attached in an appendix (16.1.10 and

16.1.11). References should be given in accordance with the

internationally accepted standards of the 1979 Vancouver Declaration

on ``Uniform Requirements for Manuscripts Submitted to Biomedical

Journals'' or the system used in ``Chemical Abstracts.''

16. Appendices

This section should be prefaced by a full list of all appendices

available for the study report. Where permitted by the regulatory

authority, some of the following appendices should not be submitted

with the report but should be provided only on request.

The applicant should therefore clearly indicate those appendices

that are submitted with the report.

N.B. To have appendices available on request, they should be

finalized by the time of filing of the submission.

16.1 Study Information

16.1.1 Protocol and protocol amendments

16.1.2 Sample case report form (unique pages only)

16.1 .3 List of IEC's or IRB's (plus the name of the committee Chair

if required by the regulatory authority) - Representative written

information for patient and sample consent forms

16.1.4 List and description of investigators and other important

participants in the study, including brief (1 page) curriculum

vitaes or equivalent summaries of training and experience relevant

to the performance of the clinical study

16.1.5 Signatures of principal investigator(s) (or coordinating

investigators) or responsible medical officer, depending on the

regulatory authority's requirement

16.1.6 Analytical documentation--batch certificate for the

investigational product(s)

16.1.7 Randomization scheme and codes (patient identification and

treatment assigned )

16.1.8 Audit certificates (if available) (see Annex IVa and IVb of

the guideline)

16.1.9 Documentation of statistical methods

16.1.10 Publications based on the study

16.1.11 Important publications referenced in the report

16.2. Patient Data Listings

16.2.1 Discontinued patients

16.2.2 Protocol deviations

16.2.3 Patients excluded from the efficacy analysis

16.2.4 Demographic data

16.2.5 Compliance and/or Drug Concentration Data (if available)

16.2.6 Individual Efficacy Response data

16.2.7 Adverse event listings (each patient)

16.2.8. Listing of individual laboratory measurements by patient,

when required by regulatory authorities

16.3 Case Report Forms

16.3.1 CRF's of serious adverse events and withdrawals for adverse

events

16.3.2 Other CRF's submitted

16.4. Individual Patient Data Listings (U.S. Archival Listings)

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ANNEX IV a

AUDIT CERTIFICATES (if available)

The audit certificate is a document indicating:

- The audit (type, identification number)

- The audited system, clinical trial, or organization

- The audit dates

- The date of release of the audit report

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The Audit Certificate should be prepared and used in accordance

with standard operating procedures. To be valid the Audit

Certificate should be signed by the responsible auditor(s) or the

head of the independent audit organization as defined in the

standard operating procedures.

Audit Certificates may be added to the clinical study report.

Since it is recognized that not every clinical study will be

subject to an independent audit, Audit Certificates for systems

audits can demonstrate the independent assessment of the systems or

part of the systems used to ensure that the trial is performed and

the data are generated in compliance with good clinical practice.

Audit Certificates pertaining to audits of systems implemented

and existing during the planning, conduct, data analysis, and

reporting of the reported clinical trial may be added to the

clinical study report together with the certificate for the audit of

the reported study, if such an audit was conducted.

The Audit Certificate should be retained in accordance with any

regulatory requirements.

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ANNEX IX

Guidance for Section 11.3.2--Statistical/Analytical Issues

A. Statistical Considerations

Details of the statistical analysis performed on each primary

efficacy measure should be presented in an appendix. Details

reported should include at least the following information:

(a) The statistical model underlying the analysis. This should

be presented precisely and completely, using references if

necessary.

(b) A statement of the clinical claim tested in precise

statistical terms, e.g., in terms of null and alternative

hypotheses.

(c) When statistically reasonable and appropriate, the power

against specific clinically meaningful alternatives for those tests

that fail to reject the null hypothesis to indicate whether the

study size was adequate.

(d) The statistical methods applied to estimate effects,

construct confidence intervals, etc. Literature references should be

included where appropriate.

(e) The assumptions underlying the statistical methods. It

should be shown, insofar as statistically reasonable, that the data

satisfy crucial assumptions, especially when necessary to confirm

the validity of an inference. When extensive statistical analyses

have been performed by the applicant, the extent to which the

analyses were planned prior to the availability of data should be

considered, and, if they were not, how bias was avoided in choosing

the particular analysis used as a basis for conclusions should be

described. This is particularly important in the case of any

subgroup analyses, because if such analyses are not preplanned, they

will ordinarily not provide an adequate basis for definitive

conclusions.

(i) In the event data transformation was performed, a rationale

for the choice of data transformation along with interpretation of

the estimates of treatment effects based on transformed data should

be provided.

(ii) A discussion of the appropriateness of the choice of

statistical procedure and the validity of statistical conclusions

will guide the regulatory authority's statistical reviewer in

determining whether reanalysis of data is needed.

(f) The test statistic, the sampling distribution of the test

statistic under the null hypothesis, the value of the test

statistic, significance level (i.e., p-value), and intermediate

summary data, in a format that enables the regulatory authority's

statistical reviewer to verify the results of the analysis quickly

and easily. The p-values should be designated as one- or two-tailed.

The rationale for using a one-tailed test should be provided.

For example, the documentation of a two-sample t-test should

consist of the value of the t-statistic, the associated degrees of

freedom, the p-value, the two sample sizes, mean and variance for

each of the samples, and the pooled estimate of variance. The

documentation of multi-center studies analysed by analysis of

variance techniques should include, at a minimum, an analysis of

variance table with terms for centers, treatments, their

interaction, error, and total. For crossover designs, the

documentation should include information regarding sequences,

patients with sequences, baselines at the start of each period,

washouts and length of washouts, dropouts during each period,

treatments, periods, treatment by period interaction error, and

total. For each source of variation, aside from the total, the table

should contain the degrees of freedom, the sum of squares, the mean

square, the appropriate F-test, the p-value, and the expected mean

square. Generally, it is recommended that regression type sums of

squares be provided in addition to any other analyses.

Intermediate summary data should display the demographic data

and response data, averaged or otherwise summarized, for each

center-by-treatment combination (or other design characteristic such

as sequence) at each observation time.

B. Format and Specifications for Submission of Data Requested by

Regulatory Authority's Statistical Reviewers

In the report of each controlled clinical study, there should be

data listings (tabulations) of patient data utilized by the sponsor

for statistical analyses and tables supporting conclusions and major

findings. These data listings are necessary for the regulatory

authority's statistical review, and the sponsor may be asked to

supply these patient data listings in a computer-readable form.

Dated: August 15, 1995.

William K. Hubbard,

Acting Deputy Commissioner for Policy.

[FR Doc. 95-20813 Filed 8-22-95; 8:45 am]

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