Regulatory Requirement On Dossier of Medicinal Products: WHO Workshop, October 2007

Regulatory Requirement on Dossier
of Medicinal Products
WHO Workshop, October 2007
Sultan Ghani, Director
Bureau of Pharmaceutical Sciences
Therapeutic Products Directorate, Health Canada
Training Workshop on Pharmaceutical Development

1 | with a Focus on Paediatric Medicines / 15-19 October 2007
Outline
Common Technical Document (CTD ICH)
Quality Overall Summary (QOS)

An 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

Result was the CTD Triangle

Module 1
Not Part of
CTD
Regional
Administrative
Information
Module 2
Quality
Overall
Summary
Nonclinical
Overview
Clinical
Overview
NDS
Nonclinical
Summaries
Clinical
Summary
CTD
Module 3
Module 4
Module 5
Quality
Nonclinical
Study Reports
Clinical
Study Reports

CTD 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 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 Introduction

General introduction to the pharmaceutical, including
Pharmacologic class
Mode of action
Proposed clinical use
Typically 1 page

2.3 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 - 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 - 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 - 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 - 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 - 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
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
2.6.1
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 - 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 - 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
DRUG SUBSTANCE
3.2.S.1
General Information
3.2.S.2
Manufacture
3.2.S.3
Characterization
3.2.S.4
Control of Drug Substance
3.2.S.5
Reference Standards or Materials
3.2.S.6
Container Closure System
3.2.S.7
Stability


Format (contd)
3.2.P
DRUG PRODUCT
3.2.P.1
Description and Composition of the Drug Product

Pharmaceutical Development
3.2.P.2
Manufacture
3.2.P.3
Control of Excipients
3.2.P.4
Control of Drug Product
3.2.P.5
Reference Standards or Materials
3.2.P.6
Container Closure System
3.2.P.7
Stability
3.2.P.8

Format (contd)
3.2.A
APPENDICES
3.2.A.1
Facilities and Equipment
3.2.A.2
Adventitious Agents Safety Evaluation
3.2.A.3
Excipients
3.2.R
REGIONAL INFORMATION


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

Impact 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 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


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 ICHs
Common Technical Document (CTD) Guideline (i.e.,
Module 2.3)
ICHs 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)
(contd)
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
Health Canadas (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 ICHs QOS (e.g., can be considered
an acceptable replacement for the QOS as defined by the
CTD-Q)
Thank you


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Regulatory Requirement on Dossier

Training Workshop on Pharmaceutical Development

Training Workshop on Pharmaceutical Development

An Overview of the CTD

Training Workshop on Pharmaceutical Development

Result was the CTD Triangle

Training Workshop on Pharmaceutical Development

Training Workshop on Pharmaceutical Development

Module 2 - CTD Summaries

Training Workshop on Pharmaceutical Development

2.2 CTD Introduction

Training Workshop on Pharmaceutical Development

2.3 Quality Overall Summary - Content

Training Workshop on Pharmaceutical Development

2.3 Quality Overall Summary - Format

Training Workshop on Pharmaceutical Development

2.4 Nonclinical Overview - Content

2.4 Nonclinical Overview - Format

Overview of Nonclinical Testing Strategy

Integrated Overview and Conclusions

List of Literature Citations

Training Workshop on Pharmaceutical Development

2.5 Clinical Overview - Content

Training Workshop on Pharmaceutical Development

2.5 Clinical Overview - Format

Product development rationale

Overview of Clinical Pharmacology

Benefits and Risks Conclusions

Training Workshop on Pharmaceutical Development

2.6 Nonclinical Written and Tabulated

2.6 Nonclinical Written and Tabulated

Written Summary of Pharmacology

Tabulated Summary of Pharmacology

Written Summary of Pharmacokinetics

Tabulated Summary of Pharmacokinetics

Written Summary of Toxicology

Tabulated Summary of Toxicology

Training Workshop on Pharmaceutical Development

2.7 Clinical Summary - Content

Training Workshop on Pharmaceutical Development

2.7 Clinical Summary - Format

Summary of biopharmaceutic studies and

Summary of clinical pharmacology (including

Summary of clinical efficacy

Summary of clinical safety

Synopses of individual studies

Training Workshop on Pharmaceutical Development

Submission of CMC Information in CTD

Control of Drug Substance

Reference Standards or Materials

Container Closure System

Training Workshop on Pharmaceutical Development

Submission of CMC Information in CTD

Description and Composition of the Drug Product

Control of Drug Product

Reference Standards or Materials

Container Closure System

Submission of CMC Information in CTD

Facilities and Equipment

Adventitious Agents Safety Evaluation

Training Workshop on Pharmaceutical Development

Submission of CMC Information in CTD

Training Workshop on Pharmaceutical Development