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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