Common Technical Document (CTD)

Dr Pravina

ICRI

What is the CTD?

The CTD refers to an application format and not to an application type

The CTD is a prescribed organization of the information required to be submitted.

CTD is a DOSSIER/RESEARCH BINDER for regulatory submission for marketing approval of a drug

CTD helps in

CTD does not indicate the studies required to support the application; it merely indicates an appropriate format for the representation of chemical-pharmaceutical, nonclinical and clinical data that have been acquired.

CTD Objectives

1) To provide a common format for the preparation of technical documentation to support a Marketing Authorization Application (i.e. a new drug application) that will be submitted to the regulatory authorities.

2) Possibility of simultaneous filings in the ICH regions

3) Reduce the time and resources needed to compile i.e. Eliminates the extensive work of rewriting/converting a dossier for different regulatory submissions

CTD Objectives

4) Regulatory reviews and communication

with the applicant will be facilitated by a

standard document of common elements.

5) Exchange of regulatory information between Regulatory Authorities will be simplified.

What is the current status of the CTD?

Nov 2000 meeting of the ICH Steering Committee in San Diego – Step 4 status of CTD guidelineDeficiency of formatting and integration of the components (modules) of the CTD

May 2001 ICH meeting in Tokyo, agreement was reached on a set of principles for the uniform formatting of the CTD.

Sept 2002 - Inclusion of the Granularity Document as Annex.

What is the current status of the CTD?

Current Step 4 version M4 (R3)

January 2004

Applications for all new pharmaceuticals (including biotechnology-derived products)

Functionality of CTD

The CTD does not harmonise the technical content of the submission it simply provides a common format in which the data must be submitted. Therefore it is necessary to complete development programs that address regional requirements and include those within the CTD format.

Is CTD format mandatory?

Implementation within the three ICH regions

Yes : Europe

Japan

(July 2003)

USFDA & CTD

On October 16, 2001, FDA electronically published the CTD as formatted in May (Notice of Availability published in FR), after having been reviewed for compliance with GGPs.

FDA publishes the document as a guidance in the Federal Register per Good Guidance Practices (GGPs) and thereby formally adopts the ICH guideline as an FDA guidance

USFDA

CDER --------- NDA

CBER ---------BLA

Form 356h

BLA

No final CTD format

no regulatory impediment to accepting a BLA that follows the CTD format, as long as the content meets CBER's requirements.

CTD guidance document

No of documents:

M4O - OrganizationM4Q - QualityM4S - SafetyM4E - Efficacy

eCTD – electronic version of CTD

Total pages 200

CTD Modules

No. of modules : 5

* Module 1 - Regional Information * Module 2 – Quality overall summary

Nonclinical overview Clinical overview Nonclinical written

summaries Clinical summaries

* Module 3 - Quality * Module 4 – Safety (Nonclinical)* Module 5 – Efficacy (Clinical)

Module 1

Module 1 contains the administrative and prescribing information documents specific to each regional regulatory agency.

application form, application feesNeed to do the studylabelling and package leaflet detailsSummary of product characteristics (SPC)Foreign clinical data

Module 2

2.1 Table of Contents2.2 Introduction2.3 Quality overall summary 2.4 Nonclinical overview2.5 Clinical overview2.6 Nonclinical written summaries2.7 Clinical summary.

A one-page introduction of the pharmaceutical description should be provided

Comment on GMP

2.3 Quality overall summary

an overview of Module 3emphasize the critical key parameters of the productprovide justification in cases where guidelines are not followed.discussion of key issues that integrate information from other modules (e.g. qualification of impurities via toxicological studies) with cross reference to the other modules in CTDMax pages: 40; The summary may be longer for biotechnology products and should not exceed 80 pages (excluding tables and figures).

2.4 Non-clinical overview Comprehensive factual synopsis of the non-clinical data

with interpretation of the data, the clinical relevance of the findingscross-linking with the quality aspects of the pharmaceutical and the implications of the nonclinical findings for the safe use of the product (i.e. as applicable to the labelling).

Integrated and critical assessment of *pharmacological*pharmacokinetic*toxicological information

Max pages: 30A comment on the GLP status of the studies

2.5 clinical overview

A high-level summary and analysis of the clinical data in the CTD. critical assessment of the clinical development and clinical efficacy with regard to the safety data, supporting the SPC and the benefit/risk assessment.Assess the quality of the design and performance of all the studies and include a statement regarding GCP compliance.a brief overview of the clinical findings including important limitations e.g. lack of comparisons with an especially relevant active comparator, absence of information on some patient populations.

evaluation of benefits and risks based on the conclusions of the relevant clinical studies.Max pages: 30

2.6 Non-clinical summaryDocument as written (text) and tabulated summaries a summary of the pharmacological, pharmacokinetic and toxicology studies performed ordered by in vitro, in vivo, species, route and then durationage and gender related effects (if applicable)Integrated information - across studies and across species exposure in the test animals should be related to exposure in humans given the maximum tolerated dose. Max pages : 100 -150

2.7 clinical summary

Document as written (text) and tabulated summaries

detailed, factual summarization of the clinical information in Module 5 and any post marketing data for products that have been marketed in other regions.

The comparison and analyses of results across studies should focus on factual observations

Pages : 50 – 400 (excluding tables).

Module 3

Chemical-pharmaceutical and biological information for both chemically active substances and biological medicinal products.

Table of contents to direct the reviewer around the document

Body of text on information

Adherence to the principle of GMP All analytical test procedures must be described in sufficient detail for

reproducibilityAll procedures need to be validated and the results of the validation

studies must be provided.

Module 3 sections :SPARCSection S - drug substance

• Section P - drug product • Section A - appendices which includes

information referenced in the core dossier and adventitious agents safety evaluation i.e. transmissible spongiform encephalopathy agents.

• Section R - any regional information e.g. executed batch records (USA only) and the process validation scheme for the drug product (EU only).

• Section C - key literature references, if applicable.

Module 4

nonclinical study reports

ToC

Detailed reports of each study

appendices containing information referenced in the module

key references

Module 5

clinical study reports

ToC

Detailed reports of each study

appendices containing information referenced in the module

key references

Electronic Common Technical Document (eCTD)

ICH Multidisciplinary 2 Expert Working Group

(M2 EWG)

In May 2001, step 2 of the eCTD process was agreed by ICH

eCTD

Role of the eCTD: to provide the ability to transfer the CTD from industry to a regulatory authority.

The eCTD is an XML (Extensible Markup Language) catalogue with links to the actual files in the CTD submission.

The elements defined in the specification of the "Step 2 eCTD for testing"

1. XML based backbone - defines the overall structure of the submission.

2. Directory Structure - defines the physical folder of the files and follows the

hierarchy of CTD. 3. File formats

- Portable Document Format (PDF) and XML. - JPEG, PNG or GIF may be used for higher resolution

eCTD: XML based backbone

- defines the overall structure- manages the metadata for the entire submission and for each document within the submission.- provides the logical structure for the entire eCTD- allows the eCTD submission to be viewed via a web browser and can be loaded on a Web server.

(Metadata is descriptive data about the submission or file)

ANNEX : Granularity Document

Ganularity of the paper and electronic submissions should be equivalent

Document as per CTD

Document – paper submission

File -----------Electronic submission

Display of information

Scientific aspects

Text format

Margins

Paper size

Numbering of pages

Acronyms & Abbreviations in each modules

References

Display of informationClarity in scientific informationNo ambiguityTransparencyFlow of information in order - to facilitate the review of the basic data

- to help a reviewer become quickly oriented to the application contents

margins that allow the document to be printed on both A4 paper (E.U. and Japan) and 8.5 x 11” paper (U.S.)

Left hand margin – gutter for bindingFont: Times New Roman, 12-point for narrative text. Reference citation - in accordance with the current edition

of the Uniform Requirements for Manuscripts Submitted to Biomedical Journals, International Committee of Medical Journal Editors (ICMJE)