# Presentation: 808989

## FDA PERSPECTIVE

**January 21, 2003**
**5630 Fishers Lane, Room 1066**

***FDA PERSPECTIVE***
***IMPLEMENTATION***
***STATUS OF THE CTD***

**Justina A. Molzon, M.S. Pharm., J.D.**
**Associate Director for International Programs**
**Center for Drug Evaluation and Research/USFDA**
**CDER ICH Steering Committee Representative**

## Practical Issues of Implementation

- Finalized CTD presented at ICH-5
- 9-11 November 2000,** **San Diego
- Three separate groups working in isolation to get the documents done on time
- Had to edit for consistency
- Numbering systems
- Style
- Format

## 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 systems
- No matter how closely we work together will still have some minor inconsistencies

## I C HINTERNATIONALCONFERENCE ONHARMONIS/ZATIONof 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

- RegionalAdminInformation

- QualityOverallSummary

- NOT Part of the CTD

- The CTD

## May 2001 Steering Committee

**Module 1**

**Module 3**

**Module 4**

**Module 5**

**2.1**

**2.2**

**2.3**

**2.4**

**2.5**

**2.6**

**2.7**

**1.0**

**Quality**
**3.0**

**Nonclinical**
**Study Reports**
**4.0**

**Clinical**
**Study Reports **
**5.0**

**Module 2**

**Source: ICH Implementation Coordination Group**

**May 2001 Steering Committee**

**Notes:**

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. 

## Practical Issues of Implementation

- Need to work with other regions
- Need experience with documents
- Meetings a big help in pointing out areas which can be improved
- Submissions 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 CTD

- The 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 #1
- Will a dossier using the CTD format (Modules 2 to 5) be identical for all regions?
- Answer #1
- Not 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 requirements
- Applicants preferences

## DRAFT Guidance Publication

***Submitting Marketing Applications According to the ICH/CTD Format: General Considerations (DRAFT)***
- Posted September 5, 2001
- Comment period until November 5, 2001
- 12 sets of comments submitted
- Comments always welcome
- In process of reopening docket
- Will incorporate comments from SC/EWG and outreach meetings into final draft this spring

## CTDGeneral Considerations Guidance

- What we expect to be submitted
- Description of Module 1
- Administrative/Prescribing Information
- Physical description of submission
- CTD requirements addressed
- Obsolete guidances listed
- Logistics of submission described
- Timeframe 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 Publication

***M4: Common Technical Document for the Registration of Pharmaceuticals for Human Use***
- Posted October 15, 2001
- Kept in review discipline format for ease of printing  and navigating
- Safety appendices split off because of size
*Posted in WORD so companies can populate tables with data*

## CTD Guidance Publication

- M4: 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 Submissions

- 11 submissions in CTD Format
- 7 different Review Divisions
- All 5 Offices  (ODE 1-->5)
- Several CTDs for new dosage forms
- Several rolling submissions
- Hybrids (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 VDivision 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 paper**
**Electronic sections not in CTD format.**

## CDER CTD Submissions

- No refuse to files
- Not perfect submissions but could be reviewed
- Flexible during voluntary submission phase
- Through July 2003
**July 2003--Mandatory in EU, Japan, highly recommended in US**.
- Further training based on practical experience
- Encouraged to submit in CTD format
- Hybrid submissions acceptable

## CTD Pre-submissionExperience

- Submission should exactly match CTD
- 3.2.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-submissionExperience

-  DO NOT modifiy CTD TOC numbering system by adding additional levels
- 3.2.S.1.2  		Structure
- 3.2.S.1.2.1		Molecular Formula
- 3.2.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 Sections
- How 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-submissionExperience

- If you don’t have information for a section provide:
- ICH CTD Number and Header
- NA (not applicable) or other language
- Don’t skip or delete section
- Never renumber sections
- See CTD Safety Q&A #2

## CTD Pre-submissionExperience

- 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 Meetings9-12 September 2002

- Main topic for discussion
- LOCATION-LOCATION-LOCATION
- Especially 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 Meetings9-12 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 Meetings9-12 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.

## eCTD

- Six months behind CTD
- The 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 controversy
- A4 vs. 8  by 11 inch paper

## The CTD Triangle

**Module 1**

**Regional****Admin****Information**

**Quality****Overall****Summary**

- Module 2

- NOT Part of the CTD

- The CTD

## CTD Major Issue Integrated Summary of Safety Integrated Summary of Efficacy

- The 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/ISE

- Clarifying what remains of the *Guideline for the Format and Content of the Clinical and Statistical Sections of an Application, July 1988*
- Integrated summary of safety section page 32 to 46
- Integrated summary of efficacy section  page 28 to 32
-  Likely to be updated as part of PDUFA-3 risk management initiative

## FDA’s ISS/ISE

- If 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 summary
- If ISE >200 pages   a summary
- Concerns should be raised with FDA staff prior to submission

## CTDNext 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 CTD

- The 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 CTDFDA Perspective

**More “reviewable” applications**
**Complete, well-organized submissions**
**More predictable format**
**More consistent reviews**
**Easier analysis across applications**
**Easier exchange of information  **
**Facilitates electronic submissions**
**BETTER DRUGS TO PATIENTS FASTER**

## Domo ArigatoThank YouDankeMerci