M03 PDF 2.3 Luis Veloso

Clinical Trial

Documentation

CHAIRPERSON

Helena Beaumont, BSc

WORKSHOP #02

13-12-2012 M03 1

Clinical Trial Report

Luís Veloso, BSc

Medical Writing Unit, Eurotrials

2.3

Describe basic concepts and practical aspects

related to the planning and structuring of Clinical

Trial/Study Reports.

Objective

Clinical Study Report

“an integrated full report of an individual study of any therapeutic,

prophylactic or diagnostic agent conducted in patients, in which the clinical

and statistical description presentations, and analyses are integrated into a

single report, incorporating tables and figures into the main text of the

report, or at the end of the text, and with appendices…”

Clinical Study Report (CSR) - Definition

Reference: CPMP/ICH. 137/95. ICH topic E3. Structure and Content

of Clinical Study Reports. London: European Medicines Agency; 1996.

“The integrated full report of a study should not be derived by simply joining a separate clinical and statistical report”

• CSRs tell the full “story” of a trial

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CSR Definition

Scientific Publication (e.g. CSR)

How it was carried out?

Why the trial was conducted? 1. Introduction/Rationale

2. Objectives

3. Methodology

4. Ethical and Regulatory considerations

5. Results

6. Discussion/Conclusion

What was observed?

What do these findings mean?

Why CSRs are required?

Clinical Study Report is the masterpiece of a marketing authorization application, as it represents the integrated full report of efficacy and safety data for an individual study of a therapeutic or diagnostic agent

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CSR Purpose

Efficacy and safety pivotal clinical trials and human pharmacology investigations

• proposed indication • support information included in product labeling

Contribute

CSR

Reported as

CSRs constitute one module of the Common Technical Document (CTD)

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• CSRs are included in CTD

• CTD is a common format for the organization of technical reports for submissions to regulatory authorities

• CTD is organized in 5 Modules

• CSR is included in Module 5

CSR as part of CTD

Reference: Organisation of the Common Technical Document for the Registration of Pharmaceuticals for Human Use - M4. Current Step 4 version, dated January 13, 2004

Placement of CSRs within CTD structure

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CSR as part of CTD

5.3.5 – Indication Z

5.3.5.1 - Study Reports of Controlled Clinical Trials Pertinent to the Claimed Indication

5.3.5.1.1 - Indication Z - Placebo Controlled Trials

5.3.5.1.2 - Indication Z - Active Controlled Trials

Study XXX - Integrated CSR

Study YYY - Integrated CSR…

5.3.5 – Indication Q

5.3.5.1 - Study Reports of Controlled Clinical Trials Pertinent to the Claimed Indication

5.3.5.1.1 - Indication Q - Placebo Controlled Trials

5.3.5.1.2 - Indication Q - Active Controlled Trials

Study ZZZ - Integrated CSR…

Study FFF - Integrated CSR

CTDs have strict formatting and layout requirements for documents

• Margins that allow printing on both A4 and 8.5 x 11” (Letter Size US) paper

• Fonts for text and tables should be of a style and size that are large enough to be easily legible, even after photocopying - Times New Roman, 12-point font is recommended for narrative text.

• References should be cited in accordance with the current edition of the Uniform Requirements for Manuscripts Submitted to Biomedical Journals, International Committee of Medical Journal Editors (ICMJE)

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CSR as part of CTD

Also impacts on CSR formatting and layout

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[Sponsor]

CSR as part of CTD

CSR as part of electronic CTD (eCTD)

- Up until recently regulatory applications to Health Authorities were paper-based.

- In 2005 Medicine Agencies agreed to receive electronic-only submissions (eCTD) starting from the end of 2009.

- A transition period when a mixed process could be followed (Non-eCTD electronic submissions - NeeS) until full adoption of eCTD.

- From 1st January 2012 new market applications would only be accepted in

eCTD format (Portugal)

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CSR as part of eCTD

Electronic format submissions involve additional requisites comparing to paper.

- Granularity (one document = one e-file [PDF])

- e-file placing and naming conventions

- PDF conversion (size, dots per inches when scanned)

- Navigational aids (bookmarks and hypertext links).

Guidance for Industry on Providing Regulatory Information in Electronic Format:

eCTD electronic Submissions, Version 1, may 2009

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Use of word macros Use of PDF software that allow legibility

with Acrobat Reader (v5.0 or higher) Facilitate compliance!

Structure of full-integrated CSR

CSR Structure

Appendix 16.1

Appendix 16.2

Appendix 16.3

Appendix 16.4



Core CSR +

Structure of Full-integrated CSR

CSR Structure - Core

1. TITLE PAGE 2. SYNOPSIS 3. TABLE OF CONTENTS 4. LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 5. ETHICS 6. INVESTIGATORS AND STUDY ADMINISTRATIVE STRUCTURE 7. INTRODUCTION 8. STUDY OBJECTIVES 9. INVESTIGATIONAL PLAN (Design, Treatments, Variables, Quality Assurance, Statistical Methods and Changes in Study Conduct) 10. STUDY PATIENTS 11. EFFICACY EVALUATION 12. SAFETY EVALUATION 13. DISCUSSION AND OVERALL CONCLUSIONS 14. END-OF-TEXT TABLES AND FIGURES 15. REFERENCE LIST 16. APPENDICES

Core CSR

(Body of

report)


Original plan

Differences from original plan

Interpretation

Findings

Background/Rationale

CSR CONTENT

Objectives

Investigational Plan

Changes in study conduct and analyses

Study Patients

Discussion & Overall Conclusions

Efficacy Evaluation

Safety Evaluation


Current version of Study Protocol

MAIN SOURCES OF INFORMATION

Protocol Amendments

Statistical Analysis Plan (SAP)

Project management-related

Statistical Output/Report

Patient data listings

Statistical Output End-of-text tables and Figures

Original plan

Differences from original plan

Interpretation

Findings

Relevant literature

CSR Structure – Statistical Outputs

Statistical outputs (examples)

Patient Disposition Adverse Events

Efficacy

CSR Structure – Statistical Outputs

Statistical outputs (examples)

Help!... I need support from Statistician for interpretation of results!

Appendix 16.1

Appendix 16.2

Appendix 16.3

Appendix 16.4

Study information Protocol/amendments, CRF, List IECs, Investigators (CVs), medication batches used, Randomizations

codes, SAP, etc.

Patient Data Listings Discontinued patients, Protocol deviations,

Demographic data, etc.

Case Report Forms (Deaths, SAEs, AE withdrawals)

CSR Structure - Appendices

Individual Patient Data Listings (US)

Note for guidance on the inclusion of appendices to clinical study reports in Marketing

Authorisation Applications. CHMP/EWP/2998/03/Final, 23 June 2004

Patient Data Listings – Appendix 16.2 (Example)

Data listings are those needed to support critical analyses

CSR Structure - Appendices

CSR writing challenges

Some aspects/sections of CSR are more challenging than others

Section 9. Investigational plan: 9.2 - Discussion of Study Design, including the choice of Control Groups

9.5.2 - Appropriateness of Efficacy and Safety measurements

Both aspects are often absent from study protocols requiring discussion with protocol authors


Section 9. Investigational plan: 9.8 Changes in the Conduct of the Study or Planned Analyses

The narrative in CSR should explain the implications of the changes in the interpretation of results.

Changes in study conduct:

- e.g. Waivers/Exemptions for non-eligible patients, or any procedure conducted differently from study protocol at the site level.

Changes in planned analysis:

- e.g. Insufficient data to analyze a secondary endpoint

There are changes that are not previoulsy documented in formal documents (e.g., Amendments) - exhaustive searching will be required from the Medical Writer


Section 10. Study Patients:

- Disposition of Patients

- Protocol deviations

Review of Patient Data Listings is sometimes required to obtain a clear picture of patients disposition


Section 11. Efficacy evaluation:

Section 12. Safety evaluation:

• Description of results discussed with Statistician

• Balance between tables, graphs and listings presentation vs narrative text

Section 13. Efficacy, Safety discussion

”…Depending on the nature and importance of such studies, a less detailed

report might be appropriate.

Abbreviated CSR or a Synopsis

Safety emphasis

- ICH topic E3 is not very specific about the

content of Abbreviated CSR

CSR - Abbreviated

Reference: FDA - Center for Drug Evaluation and Research (CDER). Center for Biologics Evaluation and Research (CBER).

Guidance for Industry: submission of abbreviated reports and synopses in support of marketing applications. Rockville (MD):

Department of Health and Human Services, Food and Drug Administration, Center for mDrug Evaluation and Research; 1999.



- A guideline by the Food and Drug Administration (1999) is the only document available from a regulatory authority that recommends which sections can be included in an abbreviated CSR.

Q:Every clinical trial needs a full-lenght CSR? R: No

• uncontrolled studies or other studies not designed to establish efficacy • seriously flawed or aborted studies. • controlled studies that examine conditions clearly unrelated to those for which a

claim is made.

Full description of safety aspects



Key Message: Any question regarding whether full integrated CSR are needed consult the reviewing health authorities.

Under which circumstances may an Abbreviated CSR be submitted?

CSR - Abbreviated

Multidisciplinary activity

QUALITY ASSURANCE Audit to integrated CSR

TRIAL PROJECT MANAGER Project history Documentation Appendices

CSR - Planning the Writing

CLINICAL EXPERT Data review Clinical narratives Discussion of results

STATISTICIAN SAP Statistical outputs Results Interpretation

REGULATORY AFFAIRS Liaison with reviewing

authorities Technical input (eCTD)

DATA MANAGER Data Listings

MEDICAL WRITER (Primary author)

CSR PROJECT MANAGER

Liaison all parties

Kick-off meeting

Mock or Shell CSR 1st Draft CSR 2nd Draft CSR

• Timelines

• Parties involved

• Review flow

The writing steps for a full lenght CSR

• Plan

(derived from Protocol)

• Shells for results

(sample text, tables,

figures, listings)

• Plan (robust)

• Results (with text,

tables, figures,

listings)

Compilation of Appendices

• Plan (finalized)

• Results

(robust)

• Discussion

drafted

Final CSR

• Core CSR

• Integration of

Appendices

Technical Release of CSR Performed by Regulatory Affairs personnel


CSR 1st draft

CSR 2nd draft

Final CSR (Medical Writer)

MOCK

Compilation of Appendices

Statistics involvement

Data Management involvement

CSR - Planning the Writing Chronology of events:

How long it takes to prepare CSR? Depends on the study’s complexity: - No of patients - Study Phase - Indication - Nr of secondary efficacy variables - Complexity of Statistical Analysis

Sam Hamilton. Effective scheduling of Clinical Study Reports,

The Write Stuff, The Journal of the European Medical Writers Association.

Vol. 17, No. 3, 2008

For a moderate complexity CSR : • Phase 3 study • 200–400 subjects • 6 to 12 twelve secondary efficacy variables • some complex statistical analysis

80 working days (average)


CSR are complex and multi-component document so for an adequate planning the Primary Author should have a deep knowledge of: CSR requisites (structure, content and formatting)

Different disciplines involved, respective tasks and timings

Final Remarks

OBRIGADO

QUESTÕES?

Documents

M03 PDF 2.3 Luis Veloso