ICH and CTD

1
ICH and CTD
The Common Technical Document

• November 19, 2002
• Kimberly Stranick, Ph.D.
• Worldwide Regulatory Affairs

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Topics

• What is ICH?
• Who is ICH?
• ICH Guidelines
• What is CTD?
• Applicability and Implementation of CTD
• CTD Structure
• Whats New with CTD?
• FDA Experience with CTD
• What is e-CTD?
• WRAs CTD Initiatives

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What is ICH?

• Agreement between EU, Japan, and US
• Joint Initiative between HA Regulators and
  Industry
• System of Steering Committee and Expert Working
  Groups
• Defined Process for Implementation of agreements
  in ICH regions

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ICH Mission (International Conference on
Harmonization)

• A more economical use of human, animal and
  material resources, and the elimination of
  unnecessary delay in the global development and
  availability of new medicines whilst maintaining
  safeguards on quality, safety and efficacy, and
  regulatory obligations to protect public health.

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ICH Parties

• European Commission - European Union
• European Federation of Pharmaceutical Industries
  and Associations (EFPIA)
• Ministry of Health, Labor and Welfare (MHLW) -
  Japan
• Japan Pharmaceutical Manufacturers Association
  (JPMA)
• US FDA
• Pharmaceutical Research and Manufacturers of
  America (PhRMA)

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ICH Observers

• WHO
• European Free Trade Area (EFTA)
• represented at ICH by Switzerland
• Canada
• represented at ICH by Health Canada
• ICH Secretariat managed by International
  Federation of Pharmaceutical Manufacturers
  Associations (IFPMA) to ensure contact with
  industry outside ICH region

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ICH Topics

• Q QUALITY Topics
• those relating to chemical and pharmaceutical
  Quality Assurance
• S SAFETY Topics
• those relating to in vitro and in vivo
  preclinical studies
• E EFFICACY Topics
• those relating to clinical studies in human
  subjects
• M Multidisciplinary Topics

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Multidisciplinary ICH Topics

• M1 Medical Terminology
• M2 Electronic Standards for Transmission of
  Regulatory Information
• M3 Timing of Preclinical Studies in Relation to
  Clinical Trials
• M4 The Common Technical Document

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ICH Guidelines

• E1 The Extent of Population Exposure to Assess
  Clinical Safety
• E3 Structure and Content of Clinical Study
  Reports
• E5 Ethnic Factors in the Acceptability of
  Foreign Clinical Data
• E6 Good Clinical Practice (GCP)
• Q7 GMP for Active Pharmaceutical Ingredients

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ICH Process

• Step 1 - Consensus Building
• Sign off by Expert Working Group members
• Step 2 - Start of Regulatory Action (and testing)
• Step 3 - Regulatory Consultation (Draft guidance)
• Step 4 - Adoption of a Tripartite Harmonized Text
• Step 5 - Implementation

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What is the Common Technical Document?

• CTD is
• an agreed format for common organization of
  documents in regulatory applications.
• CTD is not
• a common content for all markets.
• As always, content is data and label driven for a
  given market.

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What does CTD specify?

• The intention of the CTD format is to save time
  and resources and to facilitated regulatory
  review and communication
• CTD guidance gives no information about the
  content of a dossier and does not indicate which
  studies and data are required for a successful
  application.
• Content guidelines distinct from CTD

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Why a common format?

• CTD concept provides a common format to
• allow each HA to find supporting information they
  need for their assessment (consistency of
  scientific content)
• show approach to scientific development plan and
  assess quality of design, study performance, and
  compliance

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Applicability of CTD

• The CTD was designed to apply to all categories
  of medicinal products, including
• drugs
• biologics
• generics
• herbals
• radiopharmaceuticals
• vaccines
• Applies to all types of applications (stand alone
  and abridged)

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CTD through the ICH Process

• Step 1 Consensus Building
• presented to ICH Steering Committee March 1996
• Step 4 Adoption
• Endorsed by the ICH Steering Committee October
  2000
• Step 5 Implementation
• Ongoing in ICH regions

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Implementation of CTD(ICH Step 5)

• July, 2001 Optional EU
• Japan
• US
• July, 2003 Mandatory EU
• Japan
• Highly Recom. US

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US Requirement for CTD

• CTD is highly recommended in US after July 03,
  not required
• Likely CTD will never be mandatory in US
• Would require change in US law
• FDA expects rather than requires

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CTD Implementation Issues

• At national level for each ICH party, a local
  version of ICH approved guidance is published.
• Wording in the core CTD may be slightly different
  among regions due to specific editing for local
  regulations.
• Does not affect common understanding by the
  parties of the ICH CTD.
• However, some region-specific expectations and
  requirements exist.

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Region-specific requirements

• Module 1 (all)
• regional administrative information (forms),
  labeling, Environmental Risk Assessment,
  signature of experts...
• Module 3 (3.2R and 2.3R summary)
• US Method validation package, comparability
  protocols
• US and Canada Executed batch records
• EU Process validation scheme for drug product,
  medical device
• Module 5 (no location specified)
• ISE, ISS and case report forms if required by FDA
  
• tabulated list of trial subjects if required by
  MHLW

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Implementation in EU for MRPs

• CPMP has clarified CTD implementation
  requirements for ongoing MRPs.
• For submissions made to RMS in old format before
  July 03, where MRP starts after July 03, the
  CMSs will accept old EU format until Dec 31,
  2004.
• SPRI example Ezetimibe
• After July 03, CTD is mandatory for all initial
  submissions under MRP.

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SPRIs CTD Implementation recommendations for
ongoing procedures

• Line extensions
• EU DS reformatted to CTD with identical content
• US cross reference to approved DS application IF
  electronic
• DP in CTD format
• EU Variation
• All new data in CTD format
• US Supplement
• Follow format of original NDA

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CTD Implementation by SPRI Source Areas

• DevOps
• Document Quality Initiative for report templates
  and sample reports according to CTD
• DSM
• Tabular formats and summary document templates
  revised for CTD
• Clinical
• No content change required to CSRs
• Different summary documents required

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Making a CTD Submission

• Submission format as defined by M4 is paper
• Electronic applications before July 03 must be
  hybrid based on old electronic guidelines with
  CTD pieces mapped in
• Electronic CTD guidance is separate and lags
  behind CTD for definition and implementation

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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

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Non-clinicalSummary
1.1 Overall ToC inc. Mod 1-5
Not part ofthe CTD
Module 1 Regional Administrative Information
2.1 ToC of the CTD (Mod 2, 3, 4, 5)
2.2 CTD Introduction
Module 2
Non-clinicalOverview
ClinicalOverview
2.3
2.4
2.5
QualityOverallSummary
CTD
ClinicalSummary
2.6
2.7
4.0
5.0
3.0
Module 3 Quality
Module 4 Non-clinicalStudyReports
Module 5 ClinicalStudyReports
3.1 ToC for Mod 3
5.1 ToC for Mod 5
4.1 ToC for Mod 4
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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

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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

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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

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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

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2. 4 Nonclinical Overview - Content

• An integrated and critical assessment of the
  pharmacologic, pharmacokinetic, and toxicologic
  evaluation
• Discuss relevant guidance, and 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

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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

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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

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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

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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

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2.6 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

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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)

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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

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Clinical Overview vs Clinical Summary

• Clinical Overview (2.5)
• critical analyses of efficacy, safety, and
  benefit/risk
• links the dossier with the label
• links all aspects of the development program
• Clinical Summary (2.7)
• comprehensive factual summary of all relevant
  data, including cross study analyses and
  post-marketing experience
• includes references and synopses of clinical
  studies

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Whats New with CTD?

• Granularity and pagination of documents within
  modules and study reports
• Definition of discrete header information for
  documents within modules
• Cross referencing between modules
• Confusion about ISS requirement for US

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Cross references between modules

• Quality and Nonclinical/Clinical
• Quality module should include appropriate
  reference to modules 4 and 5 for drug substance
  and drug product batch information and
  formulation development issues
• Process change information should cross reference
  reports in modules 4 or 5 that demonstrate
  comparability after the process changes

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Cross references between modules

• Nonclinical and Quality
• Nonclinical overview should address
• relevance of analytical methods used
• quality characteristics of human drug as relates
  to nonclinical findings
• impurities and degradants present in drug
  substance and product and what is known of their
  potential pharmacologic and toxicologic effects

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Cross references between modules

• Nonclinical and Clinical
• Nonclinical overview should include
• Assessment of limitations and utility of
  nonclinical studies for prediction of potential
  AEs in humans
• associations between nonclinical data and results
  of clinical trials
• relevance of pharmacokinetic and nonclinical
  models, including derived parameters
• effects seen with related products, metabolites,
  excipients

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US Need for ISS?

• FDA to reissue guideline to clarify what should
  be included as ISS for CTD submissions
• ISS should be integrated analysis, not summary
• Lengthy integrated analyses unlikely to be fully
  captured in shorter Module 2 documents
• Integrated safety analysis in Module 5 for US
• FDA recommends early discussion with review
  division for agreement or questions

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FDA Experience with CTD

• FDA reviewer training ongoing
• 10 CTD submissions to CDER (across 7 review
  divisions)
• No RTFs
• Most have been supplements, not full NDAs
• Several rolling submissions in CTD
• Several hybrids (CTD/NDA, paper/elec)

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Problems noted by FDA

• Deletion or renumbering/renaming of CTD sections
• Additional decimal points in numbering - wont
  match e-CTD structure
• Incorrect regional sections in Quality module
• Advise to strictly follow guidance and examples

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Next step What is e-CTD?

• Guidelines and technical specifications for
  submission of CTD dossier electronically
• Reached step 4 (adoption of final) Sept 12, 2002
• Designed to support full life cycle of regulatory
  submission
• Facilitate electronic viewing, navigation,
  searching, updating

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eCTD Impact

• Technological
• XML format for identifying individual files and
  creating ToC
• requires new tools to create, manage, review
• Procedural
• eCTD specification will have significant impact
  on company processes from authoring to archiving
• Document granularity and metadata must be defined
  up front

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eCTD Implementation Activities

• Step 4 - September, 2002
• Step 5 - To be Implemented in all regions
• Under development
• eCTD Viewer for review
• XML tools
• Training, Training, Training

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21 CFR Part 11 Considerations

• Electronic submissions include electronic records
• Electronic records are subject to 21 CFR Part 11
  according to predicate rules
• Examples of impact
• Versions of documents included in submissions and
  xml attributes assigned to each submission file
  must include audit trail for changes
• Lifecycle management tool(s) and strategy must
  comply with records requirements

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WRAs CTD Initiatives

• CTD Task Force established within WRA
• Identify and track submissions that will be in
  CTD format
• Establish Cross Functional Task Force with
  representatives from across SPRI to advise and
  coordinate CTD implementation issues
• Initiate Scoping Project for new technology and
  processes required to support eCTD
• Establish Working Groups to ensure implementation
  of CTD format submissions in a timely and
  efficient manner

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CTD Working Groups in WRA

• CTD Publishing Working Group
• Purpose define publishing/template standards and
  processes for CTD submissions, including future
  electronic CTD requirements
• Representatives from WRA, Source areas,
  Publishing groups, RIS
• WRA Implementation Working Group
• Purpose provide communication and training on
  CTD guidance and SPRI implementation strategies
• Communication teams available using WRA
  representatives and experts

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CTD Working Groups in WRA

• Subsidiary Communication
• Purpose provide communication to subsidiaries on
  SPRI's implementation of CTD guidance
• Periodic communications as information becomes
  available, including e-CTD information
• Global Dossier Support
• Purpose define requirements and processes
  necessary to ensure SPRI's CTD format submissions
  will be adequate for global subsidiary submission
  needs
• Communicate with subsidiaries to identify
  additional support/processes required with CTD
  dossiers (including regional and module 1
  requirements)

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CTD Working Groups in WRA

• Frequently Asked Questions Working Group
• Purpose provide coordinated responses to CTD
  related questions from members of WRA and SPRI,
  as well as subsidiaries
• Q As on WRA CTD web site for reference

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• QUESTIONS?