Training Workshop on Pharmaceutical Development

with a Focus on Paediatric Medicines / 15-19 October 2007

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

Training Workshop on Pharmaceutical Development
with a Focus on Paediatric Medicines / 15-19 October 2007
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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
Training Workshop on Pharmaceutical Development
with a Focus on Paediatric Medicines / 15-19 October 2007
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Module 1

Regional
Administrative
Information
Nonclinical
Overview
Quality
Overall
Summary
Clinical
Summary
Module 3

Quality
Module 4

Nonclinical
Study Reports
Module 5

Clinical
Study Reports
Clinical
Overview
Nonclinical
Summaries
Not Part of
CTD
CTD
Module 2
NDS
Result was the CTD Triangle
Training Workshop on Pharmaceutical Development
with a Focus on Paediatric Medicines / 15-19 October 2007
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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
Training Workshop on Pharmaceutical Development
with a Focus on Paediatric Medicines / 15-19 October 2007
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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

Training Workshop on Pharmaceutical Development
with a Focus on Paediatric Medicines / 15-19 October 2007
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2.2 CTD Introduction
General introduction to the pharmaceutical, including
Pharmacologic class
Mode of action
Proposed clinical use
Typically 1 page


Training Workshop on Pharmaceutical Development
with a Focus on Paediatric Medicines / 15-19 October 2007
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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
Training Workshop on Pharmaceutical Development
with a Focus on Paediatric Medicines / 15-19 October 2007
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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
Training Workshop on Pharmaceutical Development
with a Focus on Paediatric Medicines / 15-19 October 2007
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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
Training Workshop on Pharmaceutical Development
with a Focus on Paediatric Medicines / 15-19 October 2007
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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
Training Workshop on Pharmaceutical Development
with a Focus on Paediatric Medicines / 15-19 October 2007
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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
Training Workshop on Pharmaceutical Development
with a Focus on Paediatric Medicines / 15-19 October 2007
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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
Training Workshop on Pharmaceutical Development
with a Focus on Paediatric Medicines / 15-19 October 2007
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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
Training Workshop on Pharmaceutical Development
with a Focus on Paediatric Medicines / 15-19 October 2007
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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
Training Workshop on Pharmaceutical Development
with a Focus on Paediatric Medicines / 15-19 October 2007
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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)
Training Workshop on Pharmaceutical Development
with a Focus on Paediatric Medicines / 15-19 October 2007
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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
Training Workshop on Pharmaceutical Development
with a Focus on Paediatric Medicines / 15-19 October 2007
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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
Training Workshop on Pharmaceutical Development
with a Focus on Paediatric Medicines / 15-19 October 2007
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Submission of CMC Information in CTD
Format (contd)
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
Training Workshop on Pharmaceutical Development
with a Focus on Paediatric Medicines / 15-19 October 2007
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Submission of CMC Information in CTD
Format (contd)
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
Training Workshop on Pharmaceutical Development
with a Focus on Paediatric Medicines / 15-19 October 2007
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Submission of CMC Information in CTD
Format
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.
Training Workshop on Pharmaceutical Development
with a Focus on Paediatric Medicines / 15-19 October 2007
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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
Training Workshop on Pharmaceutical Development
with a Focus on Paediatric Medicines / 15-19 October 2007
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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
Training Workshop on Pharmaceutical Development
with a Focus on Paediatric Medicines / 15-19 October 2007
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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

Training Workshop on Pharmaceutical Development
with a Focus on Paediatric Medicines / 15-19 October 2007
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Quality Overall Summary (QOS)
Japan
Primary review document
Canada
Basis for review template
Training Workshop on Pharmaceutical Development
with a Focus on Paediatric Medicines / 15-19 October 2007
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Quality Overall Summary (QOS)
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
Training Workshop on Pharmaceutical Development
with a Focus on Paediatric Medicines / 15-19 October 2007
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Quality Overall Summary (QOS)
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

Training Workshop on Pharmaceutical Development
with a Focus on Paediatric Medicines / 15-19 October 2007
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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)
Training Workshop on Pharmaceutical Development
with a Focus on Paediatric Medicines / 15-19 October 2007
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Thank you