Download (BE) Study Reports

2.1
ToC of the CTD
(Mod 2,3,4,5)
Module 1
1.1
ToC of Module 1
or overall ToC,
including Module 1
2.1
2.2
Module 2
2.4
2.5
2.3
2.6
Module 3
3.1
ToC for Module 3
Last Update June 13 '02
Module 4
4.1
ToC for Module 4
2.7
Module 5
5.1
ToC for Module 5
4) Numbering System
Module 1
Module 2
1.0 Regional Administrative Information
1.1 ToC of Module 1 or overall ToC,
including Module 1
1.0
2.1 ToC of the CTD (Mod 2,3,4,5)
2.1
2.2 Introduction
2.2
2.3 Quality Overall Summary
2.4 Nonclinical Overview
2.4
2.5
2.3
2.6
Module 3
Quality
Last Update June 13 '02
Module 4
Nonclinical
Study Reports
2.5 Clinical Overview
2.7
2.6 Nonclinical Written and
Tabulated Summaries
Module 5
2.7 Clinical Summary
Clinical
Study Reports
4) Numbering System: Module 2
Module 2
2.1
2.2
2.3
2.3.S
2.3.S.1
2.3.S.2
2.3.S.3
2.3.S.4
2.3.S.5
2.3.S.6
OVERALL CTD TABLE OF CONTENTS OF MODULES 2, 3, 4, AND 5
INTRODUCTION
QUALITY OVERALL SUMMARY
DRUG SUBSTANCE
General Information
Manufacture
Characterization
Control of Drug Substance
Reference Standards or Materials
Container Closure System
2.3.S.7
2.3.P
2.3.P.1
2.3.P.2
2.3.P.3
2.3.P.4
2.3.P.5
2.3.P.6
2.3.P.7
2.3.P.8
Stability
DRUG PRODUCT
Description and Composition of the Drug Product
Pharmaceutical Development
Manufacture
Control of Excipients
Control of Drug Product
Reference Standards or Materials
Container Closure System
Stability
Last Update June 13 '02
4) Numbering System: Module 2
Module 2 (Cont.)
Module 2 (Cont.)
2.3.A
APPENDICES
2.3.A.1
Facilities and Equipment
2.3.A.2
Adventitious Agents Safety Evaluation
2.3.A.3
Novel Excipients
2.3.R
REGIONAL INFORMATION
2.4
NONCLINICAL OVERVIEW
2.4.1
Overview of the Nonclinical Testing Strategy
2.4.2
Pharmacology
2.4.3
Pharmacokinetics
2.4.4
Toxicology
2.4.5
Integrated Overview and Conclusions
2.4.6
List of Literature Citations
2.5
CLINICAL OVERVIEW
2.5.1
Product Development Rationale
2.5.2
Overview of Biopharmaceutics
2.5.3
Overview of Clinical Pharmacology
2.5.4
Overview of Efficacy
2.5.5
Overview of Safety
2.5.6
Benefits and Risks Conclusions
2.5.7
References
Last
Update June
13 '02
2.6
2.6.1
2.6.2
2.6.3
2.6.4
2.6.5
2.6.6
2.6.7
2.7
2.7.1
2.7.2
2.7.3
2.7.4
2.7.5
2.7.6
CONTENT OF NONCLINICAL WRITTEN AND
TABULATED SUMMARIES
Introduction
Pharmacology Written Summary
Pharmacology Tabulated Summary
(Appendix B)
Pharmacokinetics Written Summary
Pharmacokinetics Tabulated Summary
(Appendix B)
Toxicology Written Summary
Toxicology Tabulated Summary (Appendix B)
CLINICAL SUMMARY
Summary of Biopharmaceutics and
Associated Analytical Methods
Summary of Clinical Pharmacology Studies
Summary of Clinical Efficacy
Summary of Clinical Safety
References
Synopses of Individual Studies
4) Numbering System: Module 3
Module 3
3.1
3.2
3.2.S
3.2.S.1
3.2.S.2
3.2.S.3
3.2.S.4
3.2.S.5
3.2.S.6
3.2.S.7
3.2.P
3.2.P.1
MODULE 3 TABLE OF CONTENTS
BODY OF DATA
DRUG SUBSTANCE
General Information
Manufacture
Characterisation
Control of Drug Substance
Reference Standards or Materials
Container Closure System
Stability
DRUG PRODUCT
Description and Composition of the Drug
Product
3.2.P.2
Pharmaceutical Development
3.2.P.3
Manufacture
3.2.P.4
Control of Excipients
3.2.P.5
Control of Drug Product
3.2.P.6
Reference Standards or Materials
3.2.P.7
Container Closure System
3.2.P.8
Stability
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Module 3 (Cont.)
3.2.A
APPENDICES
3.2.A.1
Facilities and Equipment
3.2.A.2
Adventitious Agents Safety Evaluation
3.2.A.3
Novel Excipients
3.2.R
REGIONAL INFORMATION
3.3
LITERATURE REFERENCES
4) Numbering System: Module 4
4.1
4.2
4.2.1
4.2.2
4.2.3
4.3
Module 4
MODULE 4 TABLE OF CONTENTS
STUDY REPORTS
Pharmacology
Pharmacokinetics
Toxicology
LITERATURE REFERENCES
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4.1 Table of Contents of Module 4

A Table of Contents should be provided that lists all
of the nonclinical study reports and gives the
location of each study report in the Common
Technical Document.
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4.2 Study Reports

The study reports should be presented in the
following order:
4.2.1
 4.2.1.1
Pharmacology
Primary Pharmacodynamics
 4.2.1.2 Secondary Pharmacodynamics
 4.2.1.3 Safety Pharmacology
 4.2.1.4 Pharmacodynamic Drug Interactions
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Species should be ordered as follows:
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• Mouse
• Rat
• Hamster
• Other rodent
• Rabbit
• Dog
• Non-human primate
• Other non-rodent mammal
• Non-mammals
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Routes of administration should be ordered as follows :
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• The intended route for human use
• Oral
• Intravenous
• Intramuscular
• Intraperitoneal
• Subcutaneous
• Inhalation
• Topical
• Other
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4.2.2 Pharmacokinetics
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4.2.2.1 Analytical Methods and Validation Reports (if separate
reports are available)
4.2.2.2 Absorption
4.2.2.3 Distribution
4.2.2.4 Metabolism
4 2.2.5 Excretion
4.2.2.6 Pharmacokinetic Drug Interactions (nonclinical)
4.2.2.7 Other Pharmacokinetic Studies
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4.2.3 Toxicology
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4.2.3.1 Single-Dose Toxicity (in order by species, by route)
4.2.3.2 Repeat-Dose Toxicity (in order by species, by route, by
duration; including supportive toxicokinetics evaluations)
4.2.3.3 Genotoxicity
4.2.3.3.1 In vitro
4.2.3.3.2 In vivo (including supportive toxicokinetics
evaluations)
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4.2.3 Toxicology

4.2.3.4 Carcinogenicity (including supportive toxicokinetics
evaluations)

4.2.3.4.1 Long-term studies (in order by species; including
range-finding studies that cannot appropriately be included
under repeat-dose toxicity or pharmacokinetics)

4.2.3.4.2 Short- or medium-term studies (including rangefinding studies that cannot appropriately be included under
repeat-dose toxicity or pharmacokinetics)

4.2.3.4.3 Other studies

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4.2.3 Toxicology
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4.2.3.5 Reproductive and Developmental Toxicity (including
range-finding studies and supportive toxicokinetics
evaluations) (If modified study designs are used, the
following sub-headings should be modified accordingly.)
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4.2.3.5.1 Fertility and early embryonic development
4.2.3.5.2 Embryo-fetal development
4.2.3.5.3 Prenatal and postnatal development, including
maternal function
4.2.3.5.4 Studies in which the offspring (juvenile animals) are
dosed and/or further evaluated.
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4.2.3 Toxicology
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4.2.3.6 Local Tolerance
4.2.3.7 Other Toxicity Studies (if available)
4.2.3.7.1 Antigenicity
4.2.3.7.2 Immunotoxicity
4.2.3.7.3 Mechanistic studies (if not included elsewhere)
4.2.3.7.4 Dependence
4.2.3.7.5 Metabolites
4.2.3.7.6 Impurities
4.2.3.7.7 Other
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4.3 Literature References
4) Numbering System: Module 5
Module 5
5.1
5.2
5.3
5.3.1
5.3.2
5.3.3
5.3.4
5.3.5
5.3.6
5.3.7
5.4
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MODULE 5 TABLE OF CONTENTS
TABULAR LISTINGS OF ALL CLINICAL STUDIES
CLINICAL STUDY REPORTS
Reports of Biopharmaceutic Studies
Reports of Studies Pertinent to Pharmacokinetics
using Human Biomaterials
Reports of Human Pharmacokinetic (PK) Studies
Reports of Human Pharmacodynamic (PD) Studies
Reports of Efficacy and Safety Studies
Reports of Post-Marketing Experience
Case Report Forms and Individual Patient Listings
LITERATURE REFERENCES
5.1 Table of Contents of Module 5

A Table of Contents for study reports should be
provided.
5.2 Tabular Listing of All Clinical Studies
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5.3 Clinical Study Reports

5.3.1 Reports of Biopharmaceutic Studies

5.3.1.1 Bioavailability (BA) Study Reports
BA studies in this section should include

• studies comparing the release and systemic availability
of a drug substance from a solid oral dosage form to
the systemic availability of the drug substance given
intravenously or as an oral liquid dosage form
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• dosage form proportionality studies, and
• food-effect studies.
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5.3.1.2 Comparative BA and Bioequivalence
(BE) Study Reports
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Comparative BA or BE studies may include
comparisons between :
the drug product used in clinical studies supporting
effectiveness and the to-be-marketed drug product,
• the drug product used in clinical studies supporting
effectiveness and the drug product used in stability
batches, and
• similar drug products from different manufacturers.
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5.3.1.3 In vitro-In vivo Correlation Study Reports
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5.3.1.4 Reports of Bioanalytical and Analytical
Methods for Human Studies
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5.3 Clinical Study Reports
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5.3.2 Reports of Studies Pertinent to Pharmacokinetics using Human
Biomaterials
5.3.2.1 Plasma Protein Binding Study Reports
5.3.2.2 Reports of Hepatic Metabolism and Drug Interaction Studies
5.3.2.3 Reports of Studies Using Other Human Biomaterials
5.3.3 Reports of Human Pharmacokinetic (PK) Studies
5.3.3.1 Healthy Subject PK and Initial Tolerability Study Reports
5.3.3.2 Patient PK and Initial Tolerability Study Reports
5.3.3.3 Intrinsic Factor PK Study Reports
5.3.3.4 Extrinsic Factor PK Study Reports
5.3.3.5 Population PK Study Reports
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5.3 Clinical Study Reports
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5.3.4 Reports of Human Pharmacodynamic (PD) Studies
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5.3.4.1 Healthy Subject PD and PK/PD Study Reports
5.3.4.2 Patient PD and PK/PD Study Reports
5.3.5 Reports of Efficacy and Safety Studies
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5.3.5.1 Study Reports of Controlled Clinical Studies Pertinent to the Claimed
Indication
5.3.5.2 Study Reports of Uncontrolled Clinical Studies
5.3.5.3 Reports of Analyses of Data from More Than One Study
5.3.5.4 Other Clinical Study Reports
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5.3.5.1 Study Reports of Controlled Clinical Studies Pertinent to the
Claimed Indication

The controlled clinical study reports should be
sequenced by type of control:
Placebo control (could include other control groups,
such as an active comparator or other doses)
 No-treatment control
 Dose-response (without placebo)
 Active control (without placebo)
 External (Historical) control, regardless of the control
treatment

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5.3.5.4 Other Clinical Study Reports
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Reports of interim analyses of studies pertinent to the claimed
indications
− Reports of controlled safety studies not reported elsewhere
− Reports of controlled or uncontrolled studies not related to
the claimed indication
Published reports of clinical experiences with the medicinal
product that are not included in Section 5.3.5.1. However,
when literature is important to the demonstration or
substantiation of efficacy, it should be included in Section
5.3.5.1
− Reports of ongoing studies
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5.3 Clinical Study Reports
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5.3.6 Reports of Post-Marketing Experience
5.3.7 Case Report Forms and Individual Patient
Listings
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5.4 Literature References
THE EXTENT OF POPULATION EXPOSURE
 TO ASSESS CLINICAL SAFETY
 FOR DRUGS INTENDED FOR LONG-TERM
TREATMENT OF
 NON-LIFE-THREATENING CONDITIONS
 E1

Last Update June 13 '02

The objective of this guideline is to present an accepted set of
principles for the safety evaluation of drugs intended for the
long-term treatment (chronic or repeated intermittent use for
longer than 6 months) of non-life-threatening diseases. The
safety evaluation during clinical drug development is expected
to characterise and quantify the safety profile of a drug over a
reasonable duration of time consistent with the intended longterm use of the drug. Thus, duration of drug exposure and its
relationship to both time and magnitude of occurrence of
adverse events are important considerations in determining the
size of the data base necessary to achieve such goals.
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CLINICAL SAFETY DATA MANAGEMENT:

DEFINITIONS AND STANDARDS FOR
 EXPEDITED REPORTING
 E2A
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There are two issues within the broad subject of
clinical safety data management that are appropriate
for harmonisation at this time:
(1) the development of standard definitions and
terminology for key aspects of clinical safety reporting,
and
(2) the appropriate mechanism for handling expedited
(rapid) reporting, in the investigational (i.e., preapproval) phase.
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KEY DATA ELEMENTS FOR INCLUSION IN
EXPEDITED

REPORTS OF SERIOUS ADVERSE DRUG
REACTIONS
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1. Patient Details
Initials
 Other relevant identifier (clinical investigation number,
for example)
 Gender
 Age and/or date of birth
 Weight
 Height
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2. Suspected Medicinal Product(s)
Brand name as reported
International Non-Proprietary Name (INN)
Batch number
Indication(s) for which suspect medicinal product was
prescribed or tested
Dosage form and strength
Daily dose and regimen (specify units - e.g., mg, ml, mg/kg)
Route of administration
Starting date and time of day
Stopping date and time, or duration of treatment
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3. Other Treatment (s)
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Details of Suspected Adverse Drug Reaction(s)
Full description of reaction(s) including body site and severity,
as well as the criterion (or criteria) for regarding the report as
serious should be given. In addition to a description of the
reported signs and symptoms, whenever possible, attempts
should be made to establish a specific diagnosis for the
reaction.
Start date (and time) of onset of reaction
Stop date (and time) or duration of reaction
Dechallenge and rechallenge information
Setting (e.g., hospital, out-patient clinic, home, nursing home)
Outcome:
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Details on Reporter of Event (Suspected ADR)
Name
Address
Telephone number
Profession (speciality)
Administrative and Sponsor/Company Details
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CLINICAL SAFETY DATA MANAGEMENT:
PERIODIC SAFETY UPDATE REPORTS FOR
MARKETED DRUGS
 E2C(R1)
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Last Update June 13 '02
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The current situation for periodic safety reports on marketed drugs is
different among the three ICH regions. For example:
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− The US regulations require quarterly reports during the first 3 years, then
annual reports. The FDA has recently published proposed rules1 which take into
account the CIOMS Working Group II proposals2.
− In the EU, Council Directive 93/39/EEC and Council Regulation 2309/93
require reports with a periodicity of 6 months for two years, annually for the
three following years and then every five years, at time of renewal of registration.
− In Japan, the authorities require a survey on a cohort of a few thousand
patients established by a certain number of identified institutions during the 6
years following authorization. Systematic information on this cohort, taking into
account a precise denominator, must be reported annually. Regarding other
marketing experience, adverse reactions which are non-serious, but both mild in
severity and unlabeled must be reported every 6 months for 3 years and annually
thereafter.
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SAMPLE TITLE PAGE
 PERIODIC SAFETY UPDATE REPORT FOR:
(PRODUCT)
 MAHs NAME AND ADDRESS (Corporate headquarters or
other company entity responsible for report preparation)
 PERIOD COVERED BY THIS REPORT: (dates)
 INTERNATIONAL BIRTH DATE: Date (Country of IBD)
 DATE OF REPORT
 (Other identifying information at the option of MAH, such as
report number)

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TABLE OF CONTENTS FOR MODEL PSUR

Introduction .........................................................................................................
World-wide market authorization status...........................................................................
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Update of regulatory authority or MAH actions taken for safety reasons .....................

Changes to Reference Product Information.......................................................................
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Patient exposure..................................................................................................................
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Presentation of individual case histories............................................................................
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Studies .......................................................................................................................
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Other information................................................................................................................
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Overall safety evaluation....................................................................................................
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Conclusion .......................................................................................................................
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APPENDIX: COMPANY CORE DATA SHEET.................................................................

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3. GLOSSARY OF SPECIAL TERMS
Company Core Data Sheet (CCDS)
A document prepared by the MAH containing, in
addition to safety information, material relating to
indications, dosing, pharmacology and other
information concerning the product.
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Company Core Safety Information (CCSI)
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Data Lock-Point (Data Cut-off Date)
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International Birth Date IBD
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Listed Adverse Drug Reaction
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Spontaneous Report or Spontaneous Notification

Unlisted Adverse Drug Reaction
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ADDENDUM TO ICH E2C
 CLINICAL SAFETY DATA MANAGEMENT
PERIODIC SAFETY UPDATE REPORTS FOR
MARKETED DRUGS
 ICH Harmonised Tripartite Guideline
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Summary Bridging Report
Addendum Report
Proprietary information
Executive Summary
Risk management programme
Benefit-risk analysis
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POST-APPROVAL SAFETY DATA
MANAGEMENT: DEFINITIONS AND
STANDARDS FOR EXPEDITED REPORTING
 E2D
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Last Update June 13 '02
PHARMACOVIGILANCE PLANNING
 E2E
This guideline is intended to aid in planning pharmacovigilance
activities, especially in preparation for the early postmarketing
period of a new drug
The guideline describes a method for summarising the
important identified risks of a drug, important potential
risks, and important missing information, including the
potentially at-risk populations and situations where the
product is likely to be used that have not been studied preapproval.
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STRUCTURE AND CONTENT OF CLINICAL
STUDY REPORTS
 E3
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1. TITLE PAGE
The title page should contain the following information:
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− study title
− name of test drug/ investigational product
− indication studied
− if not apparent from the title, a brief (1 to 2 sentences) description giving design (parallel,
cross-over, blinding, randomised) 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
Practices (GCP), including the archiving of essential documents
− date of the report (identify any earlier reports from the same study by title and date).
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2. SYNOPSIS
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3. TABLE OF CONTENTS FOR THE
INDIVIDUAL CLINICAL STUDY REPORT
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
DEFINITION OF TERMS
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5. ETHICS
5.1 INDEPENDENT ETHICS COMMITTEE
(IEC) OR INSTITUTIONAL REVIEW BOARD
(IRB)
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5.2 ETHICAL CONDUCT OF THE STUDY
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5.3 PATIENT INFORMATION AND CONSENT
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6. INVESTIGATORS AND STUDY ADMINISTRATIVE
STRUCTURE
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7. INTRODUCTION
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8. STUDY OBJECTIVES
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9. INVESTIGATIONAL PLAN
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9.1 OVERALL STUDY DESIGN AND PLAN DESCRIPTION
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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, doseresponse, historical) and study configuration (parallel, cross-over);
 − method of assignment to treatment (randomisation, stratification);
 − sequence and duration of all study periods, including prerandomisation and post-treatment periods, therapy withdrawal
periods and single- and double-blind treatment periods. When
patients are randomised should be specified.
It is usually helpful to display the design graphically with a flow chart
which includes timing of assessments (see Annexes IIIa and IIIb for an
example);
− any safety, data monitoring or special steering or evaluation
committees;
− any interim analyses.
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9.2 DISCUSSION OF STUDY DESIGN,
INCLUDING THE CHOICE OF CONTROL
GROUPS
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9.3 SELECTION OF STUDY POPULATION
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9.3.1 Inclusion Criteria
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9.3.2 Exclusion Criteria
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9.3.3 Removal of Patients from Therapy or
Assessment
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9.4 TREATMENTS
9.4.1 Treatments Administered
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9.4.2 Identity of Investigational Product(s)
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9.4.3 Method of Assigning Patients to Treatment Groups
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9.4.4 Selection of Doses in the Study
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9.4.5 Selection and Timing of Dose for each Patient
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9.4.6 Blinding
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9.4.7 Prior and Concomitant Therapy
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9.4.8 Treatment Compliance
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9.5 EFFICACY AND SAFETY VARIABLES
9.5.1 Efficacy and Safety Measurements
Assessed and Flow Chart
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9.5.2 Appropriateness of Measurements
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9.5.3 Primary Efficacy Variable(s)
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9.5.4 Drug Concentration Measurements
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9.6 DATA QUALITY ASSURANCE
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9.7 STATISTICAL METHODS PLANNED IN
THE PROTOCOL AND DETERMINATION OF
SAMPLE SIZE

9.7.1 Statistical and Analytical Plans
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9.7.2 Determination of Sample Size
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9.8 CHANGES IN THE CONDUCT OF THE
STUDY OR PLANNED ANALYSES
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10. STUDY PATIENTS
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10.1 DISPOSITION OF PATIENTS
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10.2 PROTOCOL DEVIATIONS
those who entered the study even though they did criteria;
− those who developed withdrawal criteria during the
withdrawn;
− those who received the wrong treatment or incorrect dose;
− those who received an excluded concomitant treatment.
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11. EFFICACY EVALUATION
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11.1 DATA SETS ANALYSED
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11.2 DEMOGRAPHIC AND OTHER BASELINE
CHARACTERISTICS
demographic variables
− age
 − sex
 − race
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disease factors
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− 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)
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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.
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11.3 MEASUREMENTS OF TREATMENT COMPLIANCE
11.4 EFFICACY RESULTS AND TABULATIONS OF INDIVIDUAL
PATIENT DATA
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11.4.1 Analysis of Efficacy
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11.4.2 Statistical/Analytical Issues
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11.4.2.1 Adjustments for Covariates
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11.4.2.2 Handling of Dropouts or Missing Data
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11.4.2.3 Interim Analyses and Data Monitoring
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11.4.2.4 Multicentre Studies
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11.4.2.5 Multiple Comparison/Multiplicity
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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
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12. SAFETY EVALUATION
12.1 EXTENT OF EXPOSURE
12.2 ADVERSE EVENTS (AEs)
12.2.1 Brief Summary of Adverse Events
12.2.2 Display of Adverse Events ( should be displayed in
summary tables (section 14.3.1))
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12.2.3 Analysis of Adverse Events
12.2.4 Listing of Adverse Events by Patient (should be
listed in appendix 16.2.7 )
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12.3 DEATHS, OTHER SERIOUS ADVERSE EVENTS,
AND OTHER SIGNIFICANT ADVERSE EVENTS
12.3.1 Listing of Deaths, other Serious Adverse Events
and Other Significant Adverse Events
12.3.1.1 Deaths ( should be listed by patient in section
14.3.2. )
12.3.1.2 Other Serious Adverse Events (should be listed
in section 14.3.2.)
12.3.1.3 Other Significant Adverse Events (should be
listed in section 14.3.2. )
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12.3.2 Narratives of Deaths, Other Serious
Adverse Events and Certain Other Significant
Adverse Events( These narratives can be placed
either in the text of the report or in section 14.3.3,
depending on their number.)
12.3.3 Analysis and Discussion of Deaths,
Other Serious Adverse Events and Other
Significant Adverse Events
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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)
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12.4.2 Evaluation of Each Laboratory Parameter
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12.4.2.1 Laboratory Values Over Time
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12.4.2.2 Individual Patient Changes
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12.4.2.3 Individual Clinically Significant
Abnormalities
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12.5 VITAL SIGNS, PHYSICAL FINDINGS
AND OTHER OBSERVATIONS RELATED TO
SAFETY
12.6 SAFETY CONCLUSIONS
13. DISCUSSION AND OVERALL
CONCLUSIONS
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14. TABLES, FIGURES AND GRAPHS REFERRED TO BUT NOT
INCLUDED IN THE TEXT
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14.1 DEMOGRAPHIC DATA
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14.2 EFFICACY DATA
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14.3 SAFETY DATA
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14.3.1 Displays of Adverse Events
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14.3.2 Listings of Deaths, Other Serious and Significant Adverse Events
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14.3.3 Narratives of Deaths, Other Serious and Certain Other
Significant Adverse Events
14.3.4 Abnormal Laboratory Value Listing (Each Patient)
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15. REFERENCE LIST
A list of articles from the literature pertinent to the
evaluation of the study should be provided. Copies
of important publications should be attached in an
appendix (16.1.11 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".
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16. APPENDICES
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16.1 STUDY INFORMATION
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16.1.1 Protocol and protocol amendments
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16.1.2 Sample case report form (unique pages only)
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16.1.3 List of IECs or IRBs (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 product(s)
from specific batches, where more than one batch was used
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16.1.7 Randomisation scheme and codes (patient
identification and treatment assigned)
16.1.8 Audit certificates (if available) (see Annex IVa and
IVb of the guideline)
16.1.9 Documentation of statistical methods
16.1.10 Documentation of inter-laboratory standardisation
methods and quality assurance procedures if used
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16.1.11 Publications based on the study
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16.1.12 Important publications referenced in the report
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16.2. PATIENT DATA LISTINGS
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16.2.1 Discontinued patients
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16.2.2 Protocol deviations
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16.2.3 Patients excluded from the efficacy analysis
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16.2.4 Demographic data
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16.2.5 Compliance and/or drug concentration data (if available)
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16.2.6 Individual efficacy response data
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16.2.7 Adverse event listings (each patient)
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16.2.8. Listing of individual laboratory measurements by patient, when
required by regulatory authorities
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16.3 CASE REPORT FORMS
16.3.1 CRFs for deaths, other serious adverse
events and withdrawals for AE
16.3.2 Other CRFs submitted
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16.4. INDIVIDUAL PATIENT DATA LISTINGS
(US ARCHIVAL LISTINGS)
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DOSE-RESPONSE INFORMATION TO
SUPPORT DRUG REGISTRATION
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E4
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ETHNIC FACTORS IN THE ACCEPTABILITY
OF FOREIGN CLINICAL DATA
 E5(R1)
ASSESSMENT OF THE CLINICAL DATA
PACKAGE INCLUDING FOREIGN CLINICAL
DATA
FOR
ITS
FULFILMENT
OF
REGULATORY REQUIREMENTS IN THE
NEW REGION
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Additional Studies to Meet the New Region’s
Regulatory Requirements
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ASSESSMENT OF THE FOREIGN CLINICAL
DATA FOR EXTRAPOLATION TO THE NEW
REGION
Characterization of the Medicine’s Sensitivity
to Ethnic Factors
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Bridging Data Package
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Bridging Study
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GUIDELINE FOR GOOD CLINICAL
PRACTICE
 E6(R1)
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STUDIES IN SUPPORT OF
SPECIAL POPULATIONS:
 GERIATRICS
 E7
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GENERAL CONSIDERATIONS FOR CLINICAL
TRIALS
 E8
STATISTICAL PRINCIPLES FOR CLINICAL TRIALS
 E9
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CHOICE OF CONTROL GROUP AND RELATED
 ISSUES IN CLINICAL TRIALS
 E10
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CLINICAL INVESTIGATION OF MEDICINAL PRODUCTS IN
THE PEDIATRIC POPULATION
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E11
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PRINCIPLES FOR CLINICAL EVALUATION OF NEW
ANTIHYPERTENSIVE DRUGS
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E12A
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THE CLINICAL EVALUATION OF QT/QTC INTERVAL
PROLONGATION AND PROARRHYTHMIC POTENTIAL FOR
NON-ANTIARRHYTHMIC DRUGS

E14
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