1. Justina A. Molzon, MS Pharm, JD
The Evolution of ICH Shift From Input to Output-- The Influence of the CTD
Justina A. Molzon, MS Pharm, JD
Associate Director for International Programs
Center for Drug Evaluation and Research
US Food and Drug Administration

2. 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

3. Information Flow Shift in Center of Gravity
ICH
Guidelines
CTD
REVIEW
Initial
Current

4. ICH and the CTD

5. I C H
INTERNATIONAL CONFERENCE ON HARMONIS/ZATION of Technical Requirements for the Registration of Pharmaceuticals for Human Use
Hosted by ICH Secretariat
IFPMA-Geneva, Switzerland

6. 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

7. ICH Harmonized Guidelines
Efficacy - 15 topic headings/16 guidelines
Safety 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

9. 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

10. 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

11. Survey Results Conversion Times
Months
Company

12. Survey Results Number of Staff Needed to Convert

13. 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

14. ICH CTD 1.0 Regional Administrative Information
1.1 ToC of Module 1 or overall ToC,
including Module 1
Module 1
1.0
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
2.1
Module 2
2.2
2.4
2.5
One of the integrating uniform numbering system for the entire CTD.
measures that was agreed to in May was a Here we have a “refinement” of the CTD pyramid reflecting that system.
2.3
2.6
2.7
Module 3
Module 4
Module 5
Clinical
Study Reports
5.0
Quality
3.0
Nonclinical
Study Reports
4.0
Source: ICH Implementation Coordination Group 14

15. 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

17. Electronic Submissions
The equivalent of 50,000 paper pages of data..

18. Electronic Submission Receipt
System creates submission record & notifies document room. (Submission identified by Document ID)
Document control clerk completes coding, assigns review staff, notifies Project Manager
FDA Gateway
Sponsor
DARRTS
ASR
COMIS
ECH
EDR
Submission received at Gateway (ESG), Sponsor notified
CDER Inbound
If validation fails, ASR s Document room for manual handling.
ASR s Project Manager

19. 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

21. eCTD Format Flows Through the Review Process
ICH
Guidelines
CTD
eReview
Easier to Develop Standardized Reviewer eTemplates
Promotes eSubmission and eReview tools

22. 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

23. 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

24. 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

25. Thank you for your attention