Transcript CTD - MJoTA.org

The Common Technical Document
ICH and CTD
November 19, 2002
Kimberly Stranick, Ph.D.
Worldwide Regulatory Affairs
Topics
 What is ICH?
 Who is ICH?
 ICH Guidelines
 What is CTD?
 Applicability and Implementation of CTD
 CTD Structure
 What’s New with CTD?
 FDA Experience with CTD
 What is e-CTD?
 WRA’s CTD Initiatives
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
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.”
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)
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 subjects
 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
Reports
 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 application.
 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 compliance
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 2000
 Step 5: Implementation
– Ongoing in ICH regions
Implementation of CTD
(ICH Step 5)
 July, 2001
 July, 2003
Optional
EU
Japan
US
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
regulations.
 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 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
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.
SPRI’s 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
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 of
the CTD
Module 1
Regional
Administrative
Information
2.1 ToC of the CTD (Mod 2, 3, 4, 5)
Module 2
2.2 CTD Introduction
2.3
Quality
Overall
Summary
3.0
Module 3
Quality
3.1 ToC for Mod 3
2.4 Non-clinical
Overview
Clinical 2.5
Overview
Clinical
Summary 2.7
2.6
Non-clinical
Summary
4.0
Module 4
Non-clinical
Study
Reports
4.1 ToC for Mod 4
5.0
Module 5
Clinical
Study 5.1 ToC for Mod 5
Reports
CTD
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
 2.3.S
 2.3.P
 2.3.A
 2.3.R
Introduction
Drug Substance
Drug Product
Appendices
Regional Information
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
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 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
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
What’s 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,
excipients
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 divisions)
 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 won’t 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
submission
 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
WRA’s 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 needs
– Communicate with subsidiaries to identify additional
support/processes required with CTD dossiers (including
regional and module 1 requirements)
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
QUESTIONS?