ICH and CTD

November 19, 2002

Kimberly Stranick, Ph.D.

Worldwide Regulatory Affairs

The Common Technical Document

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

IndustrySystem of Steering Committee and Expert

Working GroupsDefined 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 ObserversWHOEuropean 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 TerminologyM2 = Electronic Standards for

Transmission of Regulatory InformationM3 = Timing of Preclinical Studies in

Relation to Clinical TrialsM4 = 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

TextStep 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 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 lawFDA “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/overviewsModule 3 - CMC (“Quality”)Module 4 - PreclinicalModule 5 - Clinical

Non-clinicalSummary

Module 1

RegionalAdministrative

Information

Non-clinicalOverviewQuality

OverallSummary Clinical

Summary

ClinicalOvervie

w

Module 2

Not part ofthe CTD

CTD

Module 3Quality

Module 4Non-clinical

StudyReports

Module 5ClinicalStudy

Reports

2.1 ToC of the CTD (Mod 2, 3, 4, 5)

2.2 CTD Introduction

1.1 Overall ToC inc. Mod 1-5

3.1 ToC for Mod 3

4.1 ToC for Mod 4

5.1 ToC for Mod 5

2.3 2.4 2.5

4.0 5.03.0

2.6 2.7

Module 2 - CTD Summaries

2.1 Overall CTD ToC2.2 CTD Introduction2.3 Quality Overall Summary2.4 Non-Clinical Overview2.5 Clinical Overview2.6 Non-Clinical Written and Tabulated

Summaries2.7 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 Introduction2.3.S Drug Substance2.3.P Drug Product2.3.A Appendices2.3.RRegional 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 rationale2.5.2 Overview of Biopharmaceutics2.5.3 Overview of Clinical Pharmacology2.5.4 Overview of Efficacy2.5.5 Overview of Safety2.5.6 Benefits and Risks Conclusions2.5.7 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 efficacy2.7.4 Summary of clinical safety2.7.5 References2.7.6 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 modulesConfusion 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 ongoing10 CTD submissions to CDER (across 7

review divisions)No RTFsMost have been supplements, not full NDAsSeveral rolling submissions in CTDSeveral 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 moduleAdvise 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, 2002Step 5 - To be Implemented in all regionsUnder 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?