[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]]
_______________________________________________________________________
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)
BILLING CODE 4160-01-F
[[Page 37332]]
[GRAPHIC] [TIFF OMITTED] TN17JY96.000
[[Page 37333]]
[GRAPHIC] [TIFF OMITTED] TN17JY96.001
[[Page 37334]]
[GRAPHIC] [TIFF OMITTED] TN17JY96.002
[[Page 37335]]
[GRAPHIC] [TIFF OMITTED] TN17JY96.003
[[Page 37336]]
[GRAPHIC] [TIFF OMITTED] TN17JY96.004
[[Page 37337]]
[GRAPHIC] [TIFF OMITTED] TN17JY96.005
[[Page 37338]]
[GRAPHIC] [TIFF OMITTED] TN17JY96.006
[[Page 37339]]
[GRAPHIC] [TIFF OMITTED] TN17JY96.007
[[Page 37340]]
[GRAPHIC] [TIFF OMITTED] TN17JY96.008
[[Page 37341]]
[GRAPHIC] [TIFF OMITTED] TN17JY96.009
[[Page 37342]]
[GRAPHIC] [TIFF OMITTED] TN17JY96.010
BILLING CODE 4160-01-C
[[Page 37343]]
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