[Federal Register Volume 61, Number 138 (Wednesday, July 17, 1996)]
[Notices]
[Pages 37320-37343]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 96-18000]



[[Page 37319]]


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Part II





Department of Health and Human Services





_______________________________________________________________________



Food and Drug Administration



_______________________________________________________________________



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

  Federal Register / Vol. 61, No. 138 / Wednesday, July 17, 1996 / 
Notices  

[[Page 37320]]



DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration
[Docket No. 95D-0218]


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

AGENCY: Food and Drug Administration, HHS.

ACTION: Notice.

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

SUMMARY: The Food and Drug Administration is publishing a guideline 
entitled ``Structure and Content of Clinical Study Reports.'' The 
guideline was prepared under the auspices of the International 
Conference on Harmonisation of Technical Requirements for Registration 
of Pharmaceuticals for Human Use (ICH). The guideline is intended to 
facilitate the compilation of a single worldwide core clinical study 
report acceptable to all regulatory authorities.

DATES: Effective July 17, 1996. Submit written comments at any time.

ADDRESSES: Submit written comments on the guideline to the Dockets 
Management Branch (HFA-305), Food and Drug Administration, 12420 
Parklawn Dr., rm. 1-23, Rockville, MD 20857. Copies of the guideline 
are available from the Division of Communications Management (HFD-210), 
Center for Drug Evaluation and Research, Food and Drug Administration, 
7500 Standish Pl., Rockville, MD 20855, 301-594-1012. An electronic 
version of this guideline is also available via Internet by connecting 
to the CDER file transfer protocol (FTP) server (CDVS2.CDER.FDA.GOV).

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 ICH: Janet Showalter, Office of Health Affairs (HFY-1), 
Food and Drug Administration, 5600 Fishers Lane, Rockville, MD 20857, 
301-443-1382.

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.
    In the Federal Register of August 23, 1995 (60 FR 43910), FDA 
published a draft tripartite guideline entitled ``Structure and Content 
of Clinical Study Reports.'' The notice gave interested persons an 
opportunity to submit comments by October 10, 1995.
    After consideration of the comments received and revisions to the 
guideline, a final draft of the guideline was submitted to the ICH 
Steering Committee and endorsed by the three participating regulatory 
agencies at the ICH meeting held on November 29, 1995.
    The guideline is intended to facilitate the compilation of a single 
worldwide core clinical study report acceptable to all regulatory 
authorities. The clinical study report described in this guideline is 
an integrated full report of an individual study of any therapeutic, 
prophylactic, or diagnostic agent conducted in patients. Certain 
information is contained in appendices, including the protocol, 
listings of investigators and their qualifications, trial material 
information, technical statistical documentation, related publications, 
patient data listings, case report forms, and documentation of 
statistical methods. These appendices should be prepared by sponsors, 
but may be submitted as part of an initial submission, or on request, 
at the discretion of the regulatory authority. The material in the 
appendices should be provided in submissions to the Food and Drug 
Administration unless specific agreements are reached with reviewing 
divisions/offices to retain particular appendices.
    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. It is intended to replace one section of an existing 
FDA guideline, specifically, Section III of the Guideline for the 
Format and Content of the Clinical and Statistical Sections of New Drug 
Applications.
    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). Although this 
guideline does not create or confer any rights for or on any person and 
does not operate to bind FDA, it does represent the agency's current 
thinking on structure and content of clinical study reports.
    As with all of FDA's guidelines, the public is encouraged to submit 
written comments with new data or other new information pertinent to 
this guideline. The comments in the docket will be periodically 
reviewed, and, where appropriate, the guideline will be amended. The 
public will be notified of any such amendments through a notice in the 
Federal Register.
    Interested persons may, at any time, submit written comments on the 
guideline to the Dockets Management Branch (address above). Two copies 
of any comments are to be submitted, except that individuals may submit 
one copy. Comments are to be identified with the docket number found in 
brackets in the heading of this document. The 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 guideline follows:

Structure and Content of Clinical Study Reports Table of Contents

Introduction to the Guideline

1. Title Page
2. Synopsis

[[Page 37321]]

3. Table of Contents for the Individual Clinical Study Report
4. List of Abbreviations and Definition of Terms
5. Ethics
5.1- Independent Ethics Committee (IEC) or Institutional Review 
Board (IRB)
5.2- Ethical Conduct of the Study
5.3- Patient Information and Consent
6. Investigators and Study Administrative Structure
7. Introduction
8. Study Objectives
9. Investigational Plan
9.1- Overall Study Design and Plan--Description
9.2- Discussion of Study Design, including the Choice of Control 
Groups
9.3 Selection of Study Population
9.3.1 Inclusion Criteria
9.3.2 Exclusion Criteria
9.3.3 Removal of Patients from Therapy or Assessment
9.4 Treatments
9.4.1 Treatments Administered
9.4.2 Identity of Investigational Product(s)
9.4.3 Method of Assigning Patients to Treatment Groups
9.4.4 Selection of Doses in the Study
9.4.5 Selection and Timing of Dose for Each Patient
9.4.6 Blinding
9.4.7 Prior and Concomitant Therapy
9.4.8 Treatment Compliance
9.5- Efficacy and Safety Variables
9.5.1 Efficacy and Safety Measurements Assessed and Flow Chart
9.5.2 Appropriateness of Measurements
9.5.3 Primary Efficacy Variable(s)
9.5.4 Drug Concentration Measurements
9.6 Data Quality Assurance
9.7- Statistical Methods Planned in the Protocol and Determination 
of Sample Size
9.7.1 Statistical and Analytical Plans
9.7.2 Determination of Sample Size
9.8- Changes in the Conduct of the Study or Planned Analyses
10. Study Patients
10.1 Disposition of Patients
10.2 Protocol Deviations
11.- Efficacy Evaluation
11.1 Data Sets Analyzed
11.2 Demographic and Other Baseline Characteristics
11.3 Measurements of Treatment Compliance
11.4 Efficacy Results and Tabulations of Individual Patient Data
11.4.1 Analysis of Efficacy
11.4.2 Statistical/Analytical Issues
11.4.2.1 Adjustments for Covariates
11.4.2.2 Handling of Dropouts or Missing Data
114.2.3 Interim Analyses and Data Monitoring
11.4.2.4 Multiple Studies
11.4.2.5 Multiple Comparisons/Multiplicity
11.4.2.6 Use of an ``Efficacy Subset'' of Patients
11.4.2.7 Active-Control Studies Intended to Show Equivalence
11.4.2.8 Examination of Subgroups
11.4.3 Tabulation of Individual Response Data
11.4.4 Drug Dose, Drug Concentration, and Relationships to Response
11.4.5 Drug-Drug and Drug-Disease Interactions
11.4.6 By-Patient Displays
11.4.7 Efficacy Conclusions
12.- Safety Evaluation
12.1 Extent of Exposure
12.2 Adverse Events (AE's)
12.2.1 Brief Summary of Adverse Events
12.2.2 Display of Adverse Events
12.2.3 Analysis of Adverse Events
12.2.4 Listing of Adverse Events by Patient
12.3 Deaths, Other Serious Adverse Events, and Other Significant 
Adverse Events
12.3.1 Listings of Deaths, Other Serious Adverse Events, and Other 
Significant Adverse Events
12.3.1.1 Deaths
12.3.1.2 Other Serious Adverse Events
12.3.1.3 Other Significant Adverse Events
12.3.2 Narratives of Deaths, Other Serious Adverse Events, and 
Certain Other Significant Adverse Events
12.3.3 Analysis and Discussion of Deaths, Other Serious Adverse 
Events, and Other Significant Adverse Events
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)
12.4.2 Evaluation of Each Laboratory Parameter
12.4.2.1 Laboratory Values Over Time
12.4.2.2 Individual Patient Changes
12.4.2.3 Individual Clinically Significant Abnormalities
12.5 Vital Signs, Physical Findings, and Other Observations Related 
to Safety
12.6 Safety Conclusions
13. Discussion and Overall Conclusions
14.- Tables, Figures and Graphs Referred To But Not Included in the 
Text
14.1 Demographic Data
14.2 Efficacy Data
14.3 Safety Data
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
16.- Appendices
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 EIC'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) CVS or 
equivalent summaries of training and experience relevant to the 
performance of the clinical study
16.1.5 Signatures of principal or coordinating investigator(s) or 
sponsor's responsible medical officer depending on the regulatory 
authority's requirement
16.1.6 Listing of patients receiving test drug(s)/investigational 
products from specific batches where more than one batch was used
16.1.7 Randomization scheme and codes (patient identification and 
treatment assigned)
16.1.8 Audit certificates (if available)
16.1.9 Documentation of statistical methods
16.1.10 Documentation of inter-laboratory standardization methods 
and quality assurance procedures if used
16.1.11 Publications based on the study
16.1.12 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 for deaths, other serious adverse events and 
withdrawals for AE
16.3.2 Other CRF's submitted
16.4 Individual Patient Data Listings (U.S. Archival Listings)
Annex I Synopsis (Example)
Annex II Principal or Coordinating Investigator(s) or Sponsor's 
responsible medical officer (Example)
Annex IIIa Study Design and Schedule of Assessments (Example)
Annex IIIb Study Design and Schedule of Assessments (Example)
Annex IVa Disposition of patients (Example)
Annex IVb Disposition of patients (Example)
Annex V Listing of patients Who Discontinued Therapy (Example)
Annex VI Listing of Patients and Observations Excluded from Efficacy 
Analysis (Example)
Annex VII Number of Patients Excluded from Efficacy Analysis 
(Example)
Annex VIII Guidance for Section 11.4.2 - Statistical/Analytical 
Issues and Appendix 16.1.9

I. Introduction

    The objective of this guideline is to facilitate the compilation 
of a single core clinical study report acceptable to all regulatory 
authorities of the ICH regions. The regulatory authority-specific 
additions will consist of modules to be considered as appendices, 
available upon request according to regional regulatory 
requirements.
    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. 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, with appendices 
containing such information as the protocol, sample case report 
forms, investigator-related information, information related to the 
test drugs/investigational products including active control/
comparators, technical statistical documentation, related 
publications, patient data listings, and technical statistical 
details such as derivations, computations, analyses,

[[Page 37322]]

and computer output. The integrated full report 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. Depending on the nature and importance of such studies, a 
less detailed report might be appropriate.
    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, for seriously flawed or aborted 
studies, or for controlled studies that examine conditions clearly 
unrelated to those for which a claim is made. A controlled safety 
study, however, should be reported in full. If an abbreviated report 
is provided, a full description of safety aspects should be included 
in all 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 be reexamined as 
part of an overall safety analysis of all available data in any 
application.
    The report should describe demographic and other potentially 
predictive 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. Data 
listings that 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 to, for example, 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 (archival listings requested only in 
the United States) 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:
    - Study title.
    - Name of test drug/investigational product.
    - 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 (code or number).
    - Development phase of study.
    - 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 principal or coordinating 
investigator(s) or sponsor's responsible medical officer.
    - Name of company/sponsor signatory (the person responsible for 
the study report within the company/sponsor). The name, telephone 
number, and fax number of the company/sponsor 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 practice (GCP), 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 (usually limited to three pages) that 
summarizes the study should be provided (see Annex I of the 
guideline for an example of a synopsis format used in Europe). 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 lists and definitions of 
specialized or unusual terms or measurement units used in the report 
should be provided. Abbreviated terms should be spelled out and the 
abbreviation indicated in parentheses 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 IEC or IRB. 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

[[Page 37323]]

name of the committee Chair should be provided.
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 of the patient consent form used 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, steering committee, 
administration, monitoring and evaluation committees, institutions, 
statistician, central laboratory facilities, contract research 
organization (C.R.O.), clinical trial supply management) should be 
described briefly in the body of the report.
    There should be provided in Appendix 16.1.4 a list of the 
investigators with their affiliations, their role in the study, and 
their qualifications (curriculum vitae or equivalent). A similar 
list for other persons whose participation materially affected the 
conduct of the study should also be provided in Appendix 16.1.4. In 
the case of 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 other person carrying out observations of primary or 
other major efficacy variables, 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 or coordinating 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 sponsor's 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 development of the 
test drug/investigational product, relating the critical features of 
the study (e.g., rationale and aims, target population, treatment, 
duration, primary endpoints) to that development. Any guidelines 
that were followed in the development of the protocol or any other 
agreements/meetings between the sponsor/company and regulatory 
authorities that 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 diagrams 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. When 
patients were randomized should be specified. It is usually helpful 
to display the design graphically with a flow chart that 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 before 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

[[Page 37324]]

(e.g., disease of a particular severity or duration, results of a 
particular test or rating scale(s) 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.
    Screening criteria and any additional criteria for randomization 
or entry into the test drug/investigational product 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 provided (e.g., safety concerns, 
administrative reasons, or lack of suitability for the trial). The 
impact of exclusions on the generalizability of the study should be 
discussed in section 13 of the study report or in an overview of 
safety and efficacy.
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 
in each arm of the study, and for each period of the study, should 
be described including route and mode of administration, dose, and 
dosage schedule.
9.4.2 Identity of Investigational Products(s)
    In the text of the report, a brief description of the test 
drug(s)/investigational product(s) (formulation, strength, batch 
number(s)) should be given. If more than one batch of test drug/
investigational product was used, patients receiving each batch 
should be identified in Appendix 16.1.6.
    The source of placebos and active control/comparator product(s) 
should be provided. Any modification of comparator product(s) 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 for 
all treatments 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/ 
investigational product and active control/comparator should be 
described. These procedures can vary from simple random assignment 
to a selected fixed drug/dose regimen, to use of a specified 
titration procedure, or 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 timing 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, use of 
labels that reveal blind-breakage, sealed code list/envelopes, 
double dummy techniques), including the circumstances in which the 
blind would be broken for an individual or for all patients (e.g., 
for serious adverse events), the procedures used to do this, 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 test drug/investigational 
product 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 there was a data monitoring committee with access to 
unblinded data, procedures to ensure maintenance of overall study 
blinding should be described. The procedure used to maintain the 
blinding when interim analyses were performed should also be 
explained.
    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 endpoint 
measurements carried out by people shielded from information that 
might reveal treatment assignment), they should be described.
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 prohibited 
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.

[[Page 37325]]

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 determine whether the 
patient had a stroke, acute infarction, or sudden death), the person 
or group should be identified. The procedures used, 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, or questioning), as should any specific 
rating scale(s) used and 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., rating by severity or likelihood of drug 
causation) should be described. The criteria for such ratings, if 
any, should be given and the parties responsible for the ratings 
should be clearly identified. If efficacy or safety was to be 
assessed in terms of categorical ratings or numerical scores, the 
criteria used for point assignment should be provided (e.g., 
definitions of point scores). For multicenter studies, how methods 
were standardized should be indicated.
9.5.2 Appropriateness of Measurements
    If any of the efficacy or safety assessments was 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 endpoint (a laboratory measurement or physical 
measurement or sign that is not a direct measure of clinical 
benefit) was used as a study endpoint, 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 endpoints 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, the handling of samples 
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
    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. Documentation of inter-laboratory 
standardization methods and quality assurance procedures, if used, 
should be provided under Appendix 16.1.10.
    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; audit certificates, if available, should be 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 test drug/investigational product 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. Methods for sample size calculation should be given 
together with their derivations or source of reference. Estimates 
used in the calculations should be given, and explanations should be 
provided as to how they were obtained. For a study intended to show 
a difference between treatments, the difference the study is 
designed to detect should be specified. 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 the 
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) 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. In general, 
changes in planned analyses made prior to breaking the blind have 
limited implications for study interpretation. It is therefore 
particularly critical that the timing of changes relative to blind 
breaking and availability of outcome results be well characterized.

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 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,

[[Page 37326]]

adverse event, poor compliance). It may also be relevant to provide 
the number of patients screened for inclusion and 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 IVa and IVb for examples). 
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 
response variable(s) at termination. See Annex V 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 managements 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 test 
drugs/investigational products, 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, or only patients with a specified 
degree of compliance. 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. Generally, 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 VI for an example). The reasons for 
exclusions should also be analyzed for the whole treatment group 
over time (see Annex VII 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 
may 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, where appropriate, 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 and on the protocol 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 endpoints; any pharmacodynamic 
endpoints studied), as well as benefit/risk assessment(s) 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. The analysis should show the size (point 
estimate) of the difference between the treatments, the associated 
confidence interval, and, where utilized, the results of hypothesis 
testing.
    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, where 
appropriate, data display and analysis of individual centers should 
be included for critical variables 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 endpoints are difficult to 
distinguish (e.g., 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 Annex IX) presented in 
Appendix 16.1.9. Important features of the analysis, including the 
particular methods 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

[[Page 37327]]

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 covariates or 
prognostic factors 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 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 times or, if dropouts were 
very frequent, to concentrate on analyses at times 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 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, where appropriate, e.g., when the centers have sufficient 
numbers of patients to make such analysis potentially valuable, the 
possibility of qualitative or quantitative treatment-by-center 
interaction should be explored. 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. Treatment comparison should 
include analyses that allow for center differences with respect to 
response. If appropriate, 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/Multiplicity
    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 more 
than one analysis of particular endpoint, 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. 
In general, it is advantageous to demonstrate robustness of the 
principal trial conclusions with respect to alternative choices of 
patient populations for analysis. Any substantial differences 
resulting from the choice of patient population for analysis should 
be the subject of explicit discussion.
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 
the test drug/investigational product and the active control/
comparator, the analysis should show the confidence interval for the 
comparison between the two agents for critical endpoints and the 
relation of that interval to the prespecified degree of inferiority 
that would be considered unacceptable. (See section 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; 
and 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 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 must 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 milligram 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

[[Page 37328]]

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, and 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 it is expected that more targeted displays will 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 
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 milligram per 
square meter (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 entitled ``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 extent of exposure (dose, duration, number of 
patients) should be examined to determine the degree to which safety 
can be assessed from the study. Second, the more common adverse 
events and laboratory test changes should be identified, classified 
in some reasonable way, compared for treatment groups, and analyzed, 
as appropriate, for factors that may affect the frequency of adverse 
reactions/events, 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 entitled ``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 
hospitalization 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 adverse 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 called for:
    (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 test drugs/investigational products 
(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 test drug(s)/
investigational product(s) for the various durations should also be 
broken down into age, sex, and racial subgroups, and any other 
pertinent subgroups, such as groups defined by disease (if more than 
one is represented), disease severity, or 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, or 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 number of patients 
exposed to various doses should be broken down into age, sex, 
racial, 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 not, an explanation should be provided.
12.2 Adverse Events
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 occurring after initiation of study 
treatments (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 other significant adverse events.
    In most cases, it will also be useful to identify in such tables 
``treatment emergent signs and symptoms'' (TESS: events not seen at 
baseline and events that 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. When treatments are cyclical, e.g., cancer 
chemotherapy, it may also be helpful to list results separately for 
each cycle. 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

[[Page 37329]]

the adverse events into those considered at least possibly related 
to drug use and those considered not related, or use another 
causality scheme (e.g., unrelated or possibly, probably, or 
definitely related). 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.

                ADVERSE EVENTS: NUMBER OBSERVED AND RATE,               
                      WITH PATIENT IDENTIFICATIONS                      
                                                                        
         Treatment Group X                                  N=50        
------------------------------------------------------------------------
               Mild        Moderate       Severe         Total     Total
         ---------------------------------------------------------------
          Related1  NR1  Related   NR  Related   NR  Related   NR   R+NR
------------------------------------------------------------------------
Body                                                                    
 System                                                                 
 A                                                                      
Event 1   6(12%)    2(4  3(6%)    1(2  3(6%)    1(2  12(24%)  4(8       
                     %)            %)            %)            %)       
                                                                        
                                                                        
                                                                        
          N112      N21  N31      N41  N51      N61                     
                                                                        
                                                                        
          N12       N22  N32           N52                              
                                                                        
                                                                        
          N13            N33           N53                              
                                                                        
                                                                        
          N14                                                           
                                                                        
                                                                        
          N15                                                           
                                                                        
                                                                        
          N16                                                           
                                                                        
                                                                        
                                                                        
                                                                        
                                                                        
Event 2                                                                 
                                                                        
                                                                        
------------------------------------------------------------------------
\1\NR = not related; related could be expanded, e.g., as definite,      
  probable, possible.                                                   
\2\Patient identification number.                                       

    In addition to these complete tables provided in section 14.3.1, 
an additional summary table comparing treatment and control groups, 
without the patient identifying numbers and 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 
phenomenon), so that the true occurrence rate is not obscured. One 
way to do this is with a standard adverse reaction/events 
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, although this is usually best done 
in an integrated analysis of safety, 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 mg/kg or 
mg/m2 dose; dose regimen; duration of treatment; total dose; 
demographic characteristics such as age, sex, race; other baseline 
features such as renal status, efficacy outcomes, and drug 
concentration. 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 test 
drug/investigational product.
    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 informative than reporting of crude adverse event rates. 
When treatments are cyclical, e.g., cancer chemotherapy, it may also 
be helpful to analyze results separately for each cycle.
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, if provided.
    - The adverse event (preferred term, 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, and so forth).
    - 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 the last 
dose of the test drug/investigational product (when applicable).
    - Study treatment at the time of event or the most recent study 
treatment taken.
    - Test drug/investigational product dose in absolute amount, mg/
kg or mg/m2, at time of event.
    - Drug concentration (if known).
    - Duration of test drug/investigational product treatment.
    - Concomitant 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 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, should be provided for the following events.
12.3.1.1 Deaths
    All deaths during the study, including the post-treatment 
followup period, and deaths that resulted from a process that began 
during the study, should be listed by patient in section 14.3.2.
12.3.1.2 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

[[Page 37330]]

    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 test drug/
investigational product 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 a brief narrative describing each death, other 
serious adverse event, and other significant adverse event that is 
judged to be 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 test drug/investigational product may be 
omitted or described very briefly. In general, the narrative should 
describe the following: The nature and intensity of event; the 
clinical course leading up to event, with an indication of timing 
relevant to test drug/investigational product 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 (this is not required if it is the same 
for all patients) with duration (of current episode) of illness.
    - Relevant concomitant/previous illnesses with details of 
occurrence/ duration.
    - Relevant concomitant/previous medication with details of 
dosage.
    - Test drug/investigational product 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 test drug/investigational product. 
Particular attention should be paid to whether any of these events 
may represent a previously unsuspected important adverse effect of 
the test drug/investigational product. For serious adverse events 
that appear of particular importance, it maybe useful to use life 
table or similar analyses to show their relation to time on test 
drug/investigational product and to assess their risk over time.
12.4 Clinical Laboratory Evaluation
12.4.1 Listing of Individual Laboratory Measurements by Patient 
(Appendix 16.2.8) and Each Abnormal Laboratory Value (section 
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. Because 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 or bracketing. These listings should be 
submitted as part of the registration/marketing application, when 
this is required, or may be available on request.

List of Laboratory Measurement

                                                                                                                
----------------------------------------------------------------------------------------------------------------
                                                                                          Laboratory Tests      
----------------------------------------------------------------------------------------------------------------
            Patient                Time     Age     Sex    Race    Weight    Dose    SGOT    SGPT     AP     X  
----------------------------------------------------------------------------------------------------------------
#1        .....................  T0       70      M       W       70 kg     400 mg  V1 Vn = value of 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, or 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 will 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 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 or five 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 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/dL BUN should be noted. For this parameter, the 
number of patients having a smaller or greater change 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 final 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 usually shows only a single time point for a 
single treatment, interpretation requires a time series of these 
plots for treatment and control groups. Alternatively, the display 
could show baseline and most extreme on-treatment value. These 
displays identify outliers

[[Page 37331]]

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 an ``other significant adverse event,'' should be 
provided under section 12.3.2 or 14.3.3. When toxicity grading 
scales are used (e.g., WHO, NCI), 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 test drug(s)/
investigational product(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 should be 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. Discussion and Overall Conclusions

    The efficacy and safety results of the study and the 
relationship of risks and benefits should be briefly summarized and 
discussed, 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 discussion and 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. Alternatively, such discussions 
may be reserved for summaries of safety and efficacy referring to 
the entire dossier (integrated summaries).

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 presented in this section of 
the core clinical study report:
14.1 Demographic Data 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 (Appendices 16.1.11 
and 16.1.12). 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 need not be submitted 
with the report but need to be provided only on request.
    The applicant should therefore clearly indicate those Appendices 
that are submitted with the report.
    N.B.: In order 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) and 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 (one page) CV's or 
equivalent summaries of training and experience relevant to the 
performance of the clinical study.
16.1.5 Signatures of principal or coordinating investigator(s) or 
sponsor's responsible medical officer, depending on the regulatory 
authority's requirement.
16.1.6 Listing of patients receiving test drug(s)/investigational 
product(s) from specific batches, where more than one batch was 
used.
16.1.7 Randomization scheme and codes (patient identification and 
treatment assigned).
16.1.8 Audit certificates (if available).
16.1.9 Documentation of statistical methods.
16.1.10 Documentation of inter-laboratory standardization methods 
and quality assurance procedures if used.
16.1.11 Publications based on the study.
16.1.12 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 (CRF's)
16.3.1 CRF's for deaths, other 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 VIII

Guidance for Section 11.4.2--Statistical/Analytical Issues and Appendix 
16.1.9

A. Statistical Considerations

    Details of the statistical analysis performed on each primary 
efficacy variable should be presented in Appendix 16.1.9. 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) The statistical methods applied to estimate effects, 
construct confidence intervals, etc. Literature references should be 
included where appropriate.
    (d) 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, it is essential to consider 
the extent to which the analyses were planned prior to the 
availability of data and, if they were not, how bias was avoided in 
choosing the particular analysis used as a basis for conclusions. 
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.
    (e) 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 multicenter studies analyzed 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 within 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.
    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: July 3, 1996.
William B. Schultz,
Deputy Commissioner for Policy.
[FR Doc. 96-18000 Filed 7-16-96; 8:45 am]
BILLING CODE 4160-01-F