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The Evolution of ICH

Shift From Input to Output--The Influence of the CTD

Justina A. Molzon, MS Pharm, JDAssociate Director for International Programs

Center for Drug Evaluation and ResearchUS Food and Drug Administration

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Topics for Discussion• Shift in focus of ICH from input by industry

to output by regulators• The influence of the CTD and eCTD in

making this shift possible • The link between the CTD/eCTD, Good

Review Practices and eReview Initiatives• The global ramifications on review and

sharing of information between drug regulatory authorities

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Information Flow Shift in Center of Gravity

ICH

Guidelines CTD

REVIEW

CurrentInitial

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ICH and the CTD

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I C HINTERNATIONAL CONFERENCE ON

HARMONIS/ZATIONof

Technical Requirements for the Registration of

Pharmaceuticals for Human Use

http://www.ich.orgHosted by ICH Secretariat

IFPMA-Geneva, Switzerland

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A Unique Approach

• ICH was created in 1990• Agreement between the EU, Japan and the USA to

harmonize different regional requirements for registration of pharmaceutical drug products– Canada, EFTA and WHO participate in ICH as observers

• Unique because joint effort by regulators and associated pharmaceutical industry trade associations

• Pharmaceutical industry aware of areas of disharmony in regulatory submission requirements

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ICH Harmonized Guidelines • Efficacy - 15 topic headings/16 guidelines

• Safety - 8 topic headings/16 guidelines• Quality - 10 topic headings/24 guidelines• Multidisciplinary (Regulatory Communications)

– Medical Dictionary - MedDRA– Electronic Standards - ESTRI, E2B

• In 1996 ICH industry representatives proposed assembling the information generated by these harmonized guidances in the same order

• Goal was to decrease the amount of time and staff needed to assemble and disassemble documents for submission to ICH regions

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Regulators

• Initially the ICH regulators were resistant to change established submission formats

• Felt it would be too disruptive to the review process

• Needed to be convinced there was value in a harmonized submission format

• Requested a resource and feasibility study

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Industry Resource Survey

• Conducted in May 1996

• Evaluated the number of weeks to convert an NDA into an EMEA submission (and the reverse)

• Evaluated the number and types of staff required for the conversion

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Survey Results Conversion Times

0

1

2

3

4

5

6

7

8

9

10

1 2 3 4 5 6 7 8

CompanyCompany

Mon

ths

Mon

ths

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Survey ResultsNumber of Staff Needed to Convert

0

10

20

30

40

50

60

TotalStaff

1 2 3 4 5 6 7 8Company

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Realization

• Lots of time and energy to rearrange paper from one ICH region submission format to another

• Caused a delay of submission to that ICH region

• Resulted in a delayed access to new innovative medicines for patients in that region

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Module 1

Module 3 Module 4 Module 5

2.1

2.2

2.32.4 2.5

2.6 2.7

1.0

Quality3.0

NonclinicalStudy Reports

4.0

ClinicalStudy Reports

5.0

1.0 Regional Administrative Information 1.1 ToC of Module 1 or overall ToC,

including Module 1

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

2.2 Introduction

2.3 Quality Overall Summary

2.4 Nonclinical Overview

2.5 Clinical Overview

2.7 Clinical Summary

2.6 Nonclinical Summary

Module 2

Source: ICH Implementation Coordination Group

ICH CTD

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Benefits of the CTD—FDA Perspective

• More reviewable applications– More logical order of presentation– Follows development scheme

• More predictable format• More consistent reviews• Easier analysis across applications• Easier exchange of information • Facilitates electronic submissions

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Electronic Submissions

The equivalent of 50,000 paper pages of data..

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Electronic Submission Receipt

SponsorFDA Gateway

ASR

EDR

System creates submission record & notifies document room. (Submission identified by Document ID)

ASR e-mails Project Manager

Document control clerk completes coding, assigns review staff, notifies Project Manager

CDER InboundSubmission received at Gateway (ESG), Sponsor notified

If validation fails, ASR emails Document room for manual handling.

DARRTS

COMIS

ECH

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Electronic Submission Gateway

• Critical to improving efficiency

• Gets submission material to the reviewer in an expedited manner

• Introduces automation into FDA processes– Use of electronically filable forms key

• Promotes paperless review

• Electronic review tools for reviewers

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eCTD Format Flows Through the Review Process

ICH

Guidelines

CTD

eReview

Easier to Develop Standardized Reviewer eTemplatesPromotes eSubmission and eReview tools

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Guidance to Industry Good Review Practices

• What we believe we should do in a review is closely tied to what data we want a sponsor to submit

• As a result there will be considerable similarity between guidance to industry and what we consider Good Review Practices

• Because ICH Regions have harmonized much of the information submitted for marketing authorization, ICH regulators could trend towards similar review practices

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Transparency and Consistent Review Process

• Because of the complexity of disciplines and specialties involved in the review process, a consistent approach to evaluating submissions and expressing conclusions is needed

• Should represent agreed upon best practices-Good Review Practices (GRPs)

• Having a common style and review format will help drug regulatory authority staff, industry and the public understand the review process from data to interpretation, to recommendations and decisions and subsequent regulatory actions

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Summary

• The CTD format of a submission influences the content of a review by imposing a consistent order of information and data provided

• The CTD shapes both the conduct of the review and the presentation of the results of the review

• Consistency of CTD format should promote consistent review practices leading to GRPs

• As more countries utilize ICH guidelines and the CTD, a common regulatory language will evolve promoting greater interaction between drug regulatory authorities

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Thank you for your attention