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

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

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

ICH and the CTD

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

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

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

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

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

Survey Results Conversion Times Months Company

Survey Results Number of Staff Needed to Convert

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

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

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

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

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 emails Document room for manual handling. ASR e-mails Project Manager

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

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

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

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

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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