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Training Workshop on Pharmaceutical Development with a Focus on Paediatric Medicines / 15-19 October 20071 |

Regulatory Requirement on Dossier of Medicinal Products

WHO Workshop, October 2007

Regulatory Requirement on Dossier of Medicinal Products

WHO Workshop, October 2007

Sultan Ghani, DirectorBureau of Pharmaceutical Sciences

Therapeutic Products Directorate, Health Canada


OutlineOutline

Common Technical Document (CTD – ICH)

Quality Overall Summary (QOS)


An Overview of the CTDAn Overview of the CTD

The CTD is not a “Global Dossier” !

It is an agreed-upon common format for the “modular” presentation of summaries, reports and data

Incorporates relevant ICH guidelines

It is organized into five sections: All “modules” harmonized except Module 1 – regional specific

Raw data per regional requirements


Module 1

Regional Administrative

Information

NonclinicalOverviewQuality

OverallSummary Clinical

Summary

Module 3

Quality

Module 4

NonclinicalStudy Reports

Module 5

ClinicalStudy Reports

ClinicalOverview

NonclinicalSummaries

Not Part of CTD

CTD

Module 2NDS

Result was the CTD Triangle


CTD StructureCTD Structure

Full dossier contains 5 “Modules” - -

- Only Modules 2-5 are “CTD”

Module 1 – region-specific but always included in complete CTD structure

Module 2- All summaries / overviews

Module 3 – CMC (“Quality”)

Module 4 – Preclinical

Module 5 - Clinical


Module 2 - CTD SummariesModule 2 - CTD Summaries

2.1 Overall CTD ToC

2.2 CTD Introduction

2.3 Quality Overall Summary

2.4 Non-Clinical Overview

2.5 Clinical Overview

2.6 Non-Clinical Written and Tabulated Summaries

2.7 Clinical Summary


2.2 CTD Introduction2.2 CTD Introduction

General introduction to the pharmaceutical, including Pharmacologic class

Mode of action

Proposed clinical use

Typically 1 page


2.3 Quality Overall Summary - Content2.3 Quality Overall Summary - Content

A Summary that follows the scope and outline of the Body of Data in Module 3

Emphasize and discuss critical key parameters of the product

Discuss key issues to integrate information from Module 3 and other modules

Typically 40 pages, excluding tables, figures


2.3 Quality Overall Summary - Format2.3 Quality Overall Summary - Format

2.3 Introduction

2.3.S Drug Substance

2.3.P Drug Product

2.3.A Appendices

2.3.R Regional Information


2.4 Nonclinical Overview - Content2.4 Nonclinical Overview - Content

An integrated and critical assessment of the pharmacologic, pharmacokinetic, and toxicologic evaluation

Discuss relevant guidance; any deviations from guidance should be discussed and justified

Nonclinical testing strategy should be justified, including GLP status of submitted studies

Discuss associations with quality characteristics, clinical trial results, effects with related products

Typically 30 pages


2.4 Nonclinical Overview - Format2.4 Nonclinical Overview - Format

2.4.1 Overview of 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 - Content2.5 Clinical Overview - Content

Highest level summary and analysis of clinical data and overall clinical development plan

Overview of the clinical part of the dossier with succinct discussion and interpretation

Critical analysis of clinical data for efficacy and safety, as well as other relevant information (e.g. pertinent animal data or quality issues)

Typically 30 pages


2.5 Clinical Overview - Format2.5 Clinical Overview - Format

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


2.6 Nonclinical Written and Tabulated Summaries - Content

2.6 Nonclinical Written and Tabulated Summaries - Content

Integrate information across studies and across species

Primarily text, with examples of tables and figures

Exposure in test animals should be related to exposure in humans given maximum intended doses

Age, gender, and metabolite-related effects

In vitro studies first, then in vivo

Ordered by species, route, duration

Typically 100-150 pages


2.6 Nonclinical Written and Tabulated Summaries - Format

2.6 Nonclinical Written and Tabulated Summaries - Format

2.6.1 Introduction

2.6.2 Written Summary of Pharmacology

2.6.3 Tabulated Summary of Pharmacology

2.6.4 Written Summary of Pharmacokinetics

2.6.5 Tabulated Summary of Pharmacokinetics

2.6.6 Written Summary of Toxicology

2.6.7 Tabulated Summary of Toxicology


2.7 Clinical Summary - Content2.7 Clinical Summary - Content

Provides factual summary and support for conclusions and critical issues identified in the Clinical Overview

Comparison of results across studies with integration of clinical information

Analysis of all relevant information for dosing recommendations

Typically 50-400 pages (excluding tables)


2.7 Clinical Summary - Format2.7 Clinical Summary - Format

2.7.1 Summary of biopharmaceutic studies and associated analytical methods

2.7.2 Summary of clinical pharmacology (including clin micro characterization studies)

2.7.3 Summary of clinical efficacy

2.7.4 Summary of clinical safety

2.7.5 References

2.7.6 Synopses of individual studies


Submission of CMC Information in CTD Format


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

DRUG SUBSTANCE

General Information

Manufacture

Characterization

Control of Drug Substance

Reference Standards or Materials

Container Closure System

Stability


Submission of CMC Information in CTD Format (cont’d)


3.2.P

3.2.P.1

3.2.P.2

3.2.P.3

3.2.P.4

3.2.P.5

3.2.P.6

3.2.P.7

3.2.P.8

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




3.2.A

3.2.A.1

3.2.A.2

3.2.A.3

3.2.R

APPENDICES

Facilities and Equipment

Adventitious Agents Safety Evaluation

Excipients

REGIONAL INFORMATION




The CTD Quality Module is unique in that it is a combination of historical development and future commitments that apply to the commercial, post-approval production period.


Impact of the CTDImpact of the CTD

The ICH CTD represents one of the most ambitious and successful international harmonization activities undertaken

It will significantly reduce time and resources needed by industry to compile applications for global registration


Benefits of the CTDBenefits of the CTD

More “reviewable” applications

Complete, well-organized submissions

More predictable format

More consistent reviews

Easier analysis across applications

Easier exchange of information

Facilitates electronic submissions


Quality Overall Summary (QOS)Quality Overall Summary (QOS)

U.S.

information source not used for decision

Module M3 reviewed serves as a basis for decision and action

EU

Same as above

Can be used for reviews



Japan

Primary review document

Canada

Basis for review template



The Quality Overall Summary (QOS):

Is part of a drug submission organized according to ICH’s Common Technical Document (CTD) Guideline (i.e., Module 2.3)

ICH’s CTD-Q structure (including the QOS) has been formally adopted by Canada for various drug submission types, e.g.: Clinical Trial Applications (CTAs)

• Phase I, Phase II/III, BA Studies



The Quality Overall Summary (QOS) (cont’d):

New Drug Submissions (NDSs)

Abbreviated New Drug Submissions (ANDSs)

Drug Master Files (DMFs) Provided the ‘Open’/‘Closed’ portions are submitted in separately

bound dossiers


Quality Overall Summary – Chemical Entities (QOS-CE) Template

Quality Overall Summary – Chemical Entities (QOS-CE) Template

Health Canada’s (QOS-CE) Template:

Was developed to manage the submission workload and to assist sponsors in the preparation of the Quality Summary

Promotes efficiencies in submission preparation and in the review process

Available for various submissions types (CTAs x3, NDSs and ANDSs, etc.)

Entirely compatible with ICH’s QOS (e.g., can be considered an acceptable replacement for the QOS as defined by the CTD-Q)


Thank youThank you

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