M4 (R3): Organisation

Including the Granularity document that provides guidance on document location and paginations.

Re-edited with Numbering and Section Headers changes, September 2002

The Common Technical Document provides for a harmonised structure and format for new product applications. The Common Technical Document was agreed upon in November 2000, in San Diego, USA. This Common Technical Document is divided into four separate sections. The four sections address the application organisation (M4 : Organisation), the Quality section (M4Q), the Safety section (M4S) and the Efficacy section (M4E) of the harmonised application. The agreed upon implementation date for the Common Technical Document in the three regions was July 2003.

EU : Adopted by CPMP, November 2003, issued as CPMP/ICH/2887/99 rev.2 Organisation CTD (including the revised Granularity)
MHLW : Adopted May 25, 2004, PFSB/ELD Notification n°. 0525003 (including the revised Granularity)
FDA : The revised M4 Granularity Annex is available from: http://www.fda.gov/cder/guidance/7042fnl.pdf

EU:  Released for information as CHMP/ICH/5552/02, June 2004.
MHLW: Adopted 24 November 2004, PFSB/ELD Notification
FDA: Posted on the FDA website at http://www.fda.gov/cder/guidance/6674fnl.pdf, December 22, 2004

M4Q (R1): Quality

Module 2 : Quality Overall Summary (QOS)

Module 3 : Quality

The section of the application covering chemical and pharmaceutical data including data for biological/ biotechnological products.

Re-edited with Numbering and Section Headers changes, September 2002

The Quality section of the Common Technical Document (M4Q) provides a harmonised structure and format for presenting CMC (Chemistry, Manufacturing and Controls) information in a registration dossier. The table of contents includes sections on Drug Substance and Drug Product. There are also sections for regional specific information as well as some appendices. Due to the fact that many CMC topics have not yet been the subject of ICH guidelines (e.g. drug substance synthesis, drug product manufacture, container closure), the content of  M4Q is not totally harmonised. A new section on Pharmaceutical Development has been included to replace the Development Pharmaceutics Report (currently a part of the EU submission requirements). Also, a new CMC summary document, the Quality Overall Summary, has been developed.

EU:  Adopted by CPMP, March 2003, issued as CPMP/ICH/2887/99 rev.1 Quality
MHLW: Adopted on July 1, 2003, PFSB/ELD Notification No. 0701004
FDA: To be notified

EU:  Adopted by CPMP, August 2003, issued as Location Issues Quality CPMP/ICH/4680/02
MHLW: Questions and Answers / Location Issues adopted on 5 November 2003, PFSB/ELD Notification
FDA: Quality Questions and Answers /Location Issues [Word] or [PDF] or [HTML] (Issued 6/2004, Posted 6/8/2004) http://www.fda.gov/cder/guidance/5951fnl.pdf

M4S (R2) SAFETY

Nonclinical Summaries and Organisation of Module 4

The non-clinical section of the application.

Re-edited with Numbering and Section Headers changes, September 2002

The CTD Safety (M4S) Guideline delineates the structure and format of the nonclinical summaries in Module 2 of the Common Technical Document, and provides the organisation of Module 4, the Nonclinical Study Reports. The Nonclinical Overview should present an integrated and critical assessment of the pharmacologic, pharmacokinetic, and toxicologic evaluation of the pharmaceutical, and generally should not exceed 30 pages.

The Nonclinical Written Summaries (100 - 150 pages) are recommended to provide more extensive summaries and discussion of the nonclinical information on pharmacology, pharmacokinetics and toxicology. Thirty-four templates are provided for the preparation of the Nonclincal Tabulated Summaries, and 31 example tables are provided. Finally, the organisation of the Nonclinical Study Reports in Module 4 is described. Preparation of the nonclinical sections of the Common Technical Document according to the M4S Guideline results in a single harmonised dossier of the nonclinical information that is acceptable in all three ICH regions.

  Please note that a small typing mistake has been corrected on page 46.  Read point 2.6.7.3 Toxicokinetics (instead of 2.7.7.3) 

EU:  Adopted by CPMP, March 2003, issued as CPMP/ICH/2887/99 rev.1 Safety
MHLW: Adopted on July 1, 2003, PFSB/ELD Notification No. 0701004
FDA: To be notified

EU:  Adopted by CPMP, 20 November 2003, issued as CPMP/ICH/5549/02
MHLW: Adopted May 24, 2004, PFSB/ELD Notification
FDA: To be notified

M4E (R1):  EFFICACY

Module 2 : Clinical Overview and Clinical Summary 

Module 5 : Clinical Study Reports

The clinical section of the Application.

Re-edited with Numbering and Section Headers changes, September 2002

CTD-Efficacy (M4E) describes the structure and format of the clinical data in an application, including summaries and detailed study reports. There are two high level clinical summaries in Module 2 of the CTD : the Clinical Overview, a short document that provides a critical assessment of the clinical data; and the Clinical Summary, a longer document that focuses on data summarisation and integration. Clinical Study Reports and raw data (where applicable) are included in Module 5 of the CTD.

EU:  Adopted by CPMP, March 2003, issued as CPMP/ICH/2887/99 rev.1 Efficacy
MHLW: Adopted on July 1, 2003, PFSB/ELD Notification No. 0701004
FDA: To be notified

EU:  Released for information as CHMP/ICH/5551/02, June 2004.
MHLW: Adopted 24 November 2004, PFSB/ELD Notification
FDA: Posted on the FDA website at http://www.fda.gov/cder/guidance/6673fnl.pdf December 22, 2004

NEW ! : Posted on the FDA website, September 12, 2006
Clarification for Q&A 10 on submitting integrated summaries of safety and effectiveness (ISS/ISE) in the eCTD format (esrs/eCTD page).
http://www.fda.gov/cder/regulatory/ersr/ISS_ISE_clarification.htm

eCTD

The electronic CTD

This specification has been developed by the ICH M2 Expert Working Group and maintained by the eCTD Implementation Working Group in accordance with the ICH Process as pertains to the M2 EWG and eCTD change control as it pertains to the eCTD IWG.

 eCTD Specs.v.3.2

Implementation (Step 5):

EU: Published on the EMEA eSubmission website
MHLW: Adopted May 27, 2004, PFSB/ELD Notification n° 0527001
FDA: Posted on the FDA website at http://www.fda.gov/cder/guidance/6339fnl.pdf March 14, 2005

Status : Step 5
November 2003

Open the complete eCTD page from here