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Title: ICH and CTD

The Common Technical Document
  • November 19, 2002
  • Kimberly Stranick, Ph.D.
  • Worldwide Regulatory Affairs

  • 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

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

ICH Mission (International Conference on
  • 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.

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

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

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
  • M Multidisciplinary Topics

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

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

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

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.

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
  • Content guidelines distinct from CTD

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

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)

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
  • Step 5 Implementation
  • Ongoing in ICH regions

Implementation of CTD(ICH Step 5)
  • July, 2001 Optional EU
  • Japan
  • US
  • July, 2003 Mandatory EU
  • Japan
  • Highly Recom. US

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

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
  • Does not affect common understanding by the
    parties of the ICH CTD.
  • However, some region-specific expectations and
    requirements exist.

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
  • 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

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,
  • SPRI example Ezetimibe
  • After July 03, CTD is mandatory for all initial
    submissions under MRP.

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
  • DP in CTD format
  • EU Variation
  • All new data in CTD format
  • US Supplement
  • Follow format of original NDA

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

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

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

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
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
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
  • 2.7 Clinical Summary

2.2 CTD Introduction
  • General introduction to the pharmaceutical,
  • 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
  • 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

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 -
  • Integrate information across studies and across
  • Primarily text, with examples of tables and
  • 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 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
  • 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

Clinical Overview vs Clinical Summary
  • Clinical Overview (2.5)
  • critical analyses of efficacy, safety, and
  • 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

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

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

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

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,

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

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

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

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
  • Facilitate electronic viewing, navigation,
    searching, updating

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

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

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

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

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

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
  • Communicate with subsidiaries to identify
    additional support/processes required with CTD
    dossiers (including regional and module 1

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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