ICH Public MeetingJanuary 21, 2003

5630 Fishers Lane, Room 1066

FDA PERSPECTIVEIMPLEMENTATION

STATUS OF THE CTD

Justina A. Molzon, M.S. Pharm., J.D.Associate Director for International Programs

Center for Drug Evaluation and Research/USFDACDER ICH Steering Committee Representative

Practical Issues of Implementation

Finalized CTD presented at ICH-59-11 November 2000, San Diego

Three separate groups working in isolation to get the documents done on time

Had to edit for consistencyNumbering systemsStyleFormat

Reality of Implementation

Once regulators started preparing documents for publication, realized how complicated they are

Faced with the enormous task of making them consistent

Regulators have different systemsNo matter how closely we work

together will still have some minor inconsistencies

I C HINTERNATIONALCONFERENCE ON

HARMONIS/ZATIONof

Technical Requirements for the Registration of

Pharmaceuticals for Human Use

Reality of Implementation

Complications and minor inconsistencies don’t detract from the enormous work that has been done

We want the CTD to be the best it can be

Must work hard to do away with ambiguities and inconsistencies

An evolving process

The CTD Triangle

Module 1

RegionalAdmin

Information

Module 3

Quality

Module 4

NonclinicalStudy Reports

Module 5

ClinicalStudy Reports

QualityOverall

SummaryNonclinicalSummary

NonclinicalOverview

ClinicalSummary

ClinicalOverview

Module 2

NOT Part of the CTD

The CTD

Numbering System

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 Information1.1 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

May 2001 Steering Committee

Practical Issues of Implementation

Need to work with other regionsNeed experience with documentsMeetings a big help in pointing out

areas which can be improvedSubmissions will help industry and

regulators gain familiarity with the new format

Reason voluntary submission phase extended from 2002 to July 2003

An Overview of the CTDThe CTD is not a “Global Dossier”!

Content different for US, EU and Japan based on individual regulations

Some regulations never covered in ICH

It is an agreed upon common format for the “modular” presentation of summaries, reports and data

Incorporates relevant ICH guidelines as building blocks and puts them in the same order for submission to ICH regions

CTD General Questions and Answers

Question #1Will a dossier using the CTD format

(Modules 2 to 5) be identical for all regions?

Answer #1Not necessarily

Answer

The CTD provides a common format for the submission of information to regulatory authorities in the three ICH regions.

However, the CTD does not address the content of submissions. Regional requirementsApplicants preferences

DRAFT Guidance PublicationSubmitting Marketing Applications

According to the ICH/CTD Format: General Considerations (DRAFT)Posted September 5, 2001Comment period until November 5, 200112 sets of comments submittedComments always welcomeIn process of reopening docket

Will incorporate comments from SC/EWG and outreach meetings into final draft this spring

CTDGeneral Considerations

GuidanceWhat we expect to be submitted

Description of Module 1Administrative/Prescribing Information

Physical description of submission CTD requirements addressedObsolete guidances listedLogistics of submission describedTimeframe for submission

Electronic Submission

The General Considerations Guidance describes the organization of an application provided entirely in paper

Also describes how to adapt the CTD to our current process for electronic submissions

May provide documents electronically (in PDF format) instead of on paper

CTD Guidance PublicationM4: Common Technical

Document for the Registration of Pharmaceuticals for Human UsePosted October 15, 2001Kept in review discipline format for ease

of printing and navigatingSafety appendices split off because of

sizePosted in WORD so companies can populate

tables with data

CTD Guidance PublicationM4: Organization of the CTD

M4: The CTD -- Quality M4: The CTD -- Efficacy M4: The CTD -- Safety M4: The CTD -- Safety Appendices

POSTED ON CDER WEB http://www.fda.gov/cder/guidance/index.htm

CDER CTD Submissions11 submissions in CTD Format7 different Review DivisionsAll 5 Offices (ODE 1-->5)Several CTDs for new dosage formsSeveral rolling submissionsHybrids (Safety or Quality Modules)Paper and electronic submissions

Office of Drug Evaluation I Division of Oncology Drug Products

Received: August 1, 2001

CTD: Pharmtox section submitted electronically

Fast track rolling submission

Office of Drug Evaluation IV Division of Special Pathogen and

Immunologic Drug Products

Received: October 22, 2001

CTD: Uses CTD table of contents

Structure is not as recommended but close

Office of Drug Evaluation VDivision of Anti-Inflammatory Analgesic, and

Ophthalmologic Drug Products

Received: Dec 27, 2001

Different dosage form

CTD: Pharmtox, presubmission in CTD format

The application consists of a paper copy and electronic copy

Office of Drug Evaluation III Division of Reproductive and Urologic

Drug Products

Received: December 31, 2001

CTD: Only the chemistry section is in the CTD format

Submitted on paperElectronic sections not in CTD

format.

CDER CTD SubmissionsNo refuse to filesNot perfect submissions but could be reviewedFlexible during voluntary submission phase

Through July 2003 July 2003--Mandatory in EU, Japan,

highly recommended in US. Further training based on practical experienceEncouraged to submit in CTD formatHybrid submissions acceptable

CTD Pre-submissionExperience

Submission should exactly match CTD3.2.S.1.2 -- The structural formula, including

relative and absolute stereochemistry, the molecular formula and the relative molecular mass should be provided.

Provide all information under CTD ICH negotiated headings and numbers

Do not create new headings or numbers

CTD Pre-submissionExperience

DO NOT modifiy CTD TOC numbering system by adding additional levels3.2.S.1.2 Structure 3.2.S.1.2.1 Molecular Formula3.2.S.1.2.2 Molecular Weight

Provide all information under CTD designated headings

May use subheaders or bullets

CTD General Questions and Answers

Question #5 Sub-Heading Numbering or Numbering within SectionsHow should sub-numbering within a

document be organized? Some documents can be up to 50 pages in length with no defined CTD guideline heading and potentially no TOC entries or bookmarks

Answer

Within the document, the applicant can use section numbers at a lower level than those specified in the CTD guideline. However, there should be no other headings appearing in the overall TOC going below the numbering given in the CTD guideline

CTD Pre-submissionExperience

If you don’t have information for a section provide: ICH CTD Number and HeaderNA (not applicable) or other languageDon’t skip or delete section Never renumber sections

See CTD Safety Q&A #2

CTD Pre-submissionExperience

CTD-Q 3.2.R -- Regional information is for unique regional information

Unique=Information that does not have a general topic designation in Module 3 Adhere to examples Listed in 3.2.R

Even though requested information may be unique to FDA, insert information in appropriate CTD-Q topic section

DO NOT place in Regional Information

CTD IWG/EWG Meetings9-12 September 2002

Main topic for discussionLOCATION-LOCATION-LOCATIONEspecially for CTD-Q

Comparing to FDA DRAFT Drug Product and Drug Substance Guidances for Chemistry, Manufacturing and Controls Information

Location of information in CTD will be detailed by DRAFT Guidances

See CTD-Quality Q&A’s

CTD IWG/EWG Meetings9-12 September 2002

Revised--Organisation of the Common Technical Document for the Registration of Pharmaceuticals for Human Use

Numbering and section headers have been edited for consistency and use in the e-CTD

Granularity document provides guidance on document location and pagination

Q&A’s for each Module (S, E, Q) posted on ICH web for clarification

CTD IWG/EWG Meetings9-12 September 2002

DISCLAIMER

The final ICH CTD adopted version is published on the ICH website.

At regional level a local version is published. The wording of the core CTD may be slightly

different from one region to another due to specific editing and local regulation.

It does not affect the common understanding by the six parties of the CTD published on the ICH website.

eCTDSix months behind CTDThe eCTD will be a transport format

to be moved into an agency’s review environment

Step 4 reached in Washington DC September 2002

Biggest Payoff--eliminate controversyA4 vs. 8 by 11 inch paper

The CTD Triangle

Module 1

RegionalAdmin

Information

Module 3

Quality

Module 4

NonclinicalStudy Reports

Module 5

ClinicalStudy

Reports

QualityOverall

Summary Nonclinical

Summary

Nonclinical

Overview

ClinicalSummary

ClinicalOvervie

w

Module 2

NOT Part of the CTD

The CTD

CTD Major Issue Integrated Summary of

Safety Integrated Summary of

EfficacyThe name”summary” has caused great confusion

Not a summary but an integrated analysis

Critical components of the safety and efficacy review and expected to be part of FDA submission.

FDA’s ISS/ISEClarifying what remains of the Guideline

for the Format and Content of the Clinical and Statistical Sections of an Application, July 1988Integrated summary of safety section

page 32 to 46Integrated summary of efficacy

section page 28 to 32 Likely to be updated as part of

PDUFA-3 risk management initiative

FDA’s ISS/ISEIf what is called for in the FDA

Guidances can be incorporated into the CTD, it will be a complete substitute for the analysis

If not, it will need to be submitted as a separate document

If ISS is volumes a summaryIf ISE >200 pages a summaryConcerns should be raised with FDA

staff prior to submission

CTDNext Steps--Training

Prior to ICH-5 CDER rolled out CTD documents with review disciplines

Met with senior project managers to provide updates

Waiting for submissions for the next phase of training

Reviewers with CTD experience will provide practical training

Impact of the CTDThe ICH CTD represents one of the

most ambitious and successful international harmonization activities undertaken.

It will significantly reduce time and resources needed by industry to compile applications for global registration.

Benefits of the CTDFDA Perspective

More “reviewable” applicationsComplete, well-organized submissionsMore predictable formatMore consistent reviewsEasier analysis across applicationsEasier exchange of information Facilitates electronic submissions

BETTER DRUGS TO PATIENTS FASTER

Domo ArigatoThank You

DankeMerci