New Codification as per November 2005 (Click here for more details)

E1: The Extent of Population Exposure to Assess Clinical Safety for Drugs Intended for Long-Term Treatment of Non-Life-Threatening Conditions

The tripartite harmonised ICH guideline was finalised (Step 4) in October 1994. This document gives recommendations on the numbers of patients and duration of exposure for the safety evaluation of drugs intended for the long-term treatment of non-life-threatening conditions.

EU : Adopted by CPMP, November 94, issued as CPMP/ICH/375/95
MHLW : Adopted May 95, PAB/PCD Notification No.592
FDA : Published in the Federal Register, Vol. 60, March 1, 1995, pages 11270

E2A: Clinical Safety Data Management : Definitions and Standards for Expedited Reporting

The tripartite harmonised ICH guideline was finalised (Step 4) in October 1994. This document gives standard definitions and terminology for key aspects of clinical safety reporting. It also gives guidance on mechanisms for handling expedited (rapid) reporting of adverse drug reactions in the investigational phase of drug development.

EU : Adopted by CPMP, November 94, issued as CPMP/ICH/377/95
MHLW : Adopted March 95, PAB/PCD Notification No.227
FDA : Published in the Federal Register, Vol.60, No. 40, March 1, 1995, pages 11284- 11287

E2B(R3): Revision of the E2B(R2) ICH Guideline (previously coded E2B(M)) on Clinical Safety Data Management
Data Elements for Transmission of Individual Case Safety Reports

This guideline provides additional information and clarification as well as some modifications to the ICH E2B guideline signed-off on July 17, 1997 and modified as E2B(R1) guideline in November 2000 (see E2B(R2) below). It incorporates adjustments based on the experience gained after the implementation of the guideline in the three regions. It is recommended that the reader reviews this document as well as the companion document : M2 ICSR Message Specification.

E2B(R3) Final Concept Paper, November 2003 (revision of E2B(R2))

EU: Transmission to CHMP and Interested Parties in May 2005. Issued as EMEA/CHMP/ICH/166783/2005. Deadline for comments : September 2005.
http://www.emea.europa.eu/pdfs/human/ich/16678305en.pdf 
MHLW: Released for consultation on 21st July 2005, PFSB/SD, deadline for comments 16th September 2005
FDA: Published in Federal Register, Vol. 70, N° 190, October 3, 2005, pages 57610-57611. Deadline for comments by October 28, 2005.

E2B(R2) (previously coded E2B(M)): Maintenance of the Clinical Safety Data Management including
Data Elements for Transmission of Individual Case Safety Reports

The tripartite harmonised ICH guideline was finalised as E2B (Step 4) in July 1997 and amended for Maintenance as E2B(R1) on 10 November 2000. 
Post Step 4 editorial corrections were given on 5 February 2001 (second revision) and the guideline renamed E2B(R2).

EU: First adopted by CPMP, September 97, issued as CPMP/ICH/287/95 - Amended Guideline : November 2000, CPMP/ICH/287/95 correction - ICH E2B(M)
MHLW: Amended guideline : Adopted March 30, 2001, PMSB/SA Notification no. 30 & PMSB/ELD Notification no. 334.
FDA: Posted on the FDA website : http://www.fda.gov/cder/guidance/index.htm on April 4, 2002.

E2B Q&As (R5): Questions and Answers

Since reaching Step 4 and publication within the ICH regions as E2B(R1) in November 2000, experiences by all parties with the implementation of the First Revision of the E2B Guideline have resulted in the need for some clarification. This supplementary Questions and Answers document intends to clarify key issues.

Please note that the Implementation Working Group has been discontinued in November 2004. Therefore, all technical questions should now be addressed to the regional Regulatory Authorities.

E2B(R5) Questions and Answers

Updated March 2005
(mistyping correction described on page i)

EU: Transmission to CHPM January 2005 and released for information in January 2005 as 
CPMP/ICH/3943/03
MHLW: Adopted 13 April 2005, PFSB/ELD Notification & PFSB/SD Notification.
FDA: Posted on FDA website at : http://www.fda.gov/cder/guidance/6675fnl.pdf, March 16, 2005.

E2C(R1): Clinical Safety Data Management : Periodic Safety Update Reports for Marketed Drugs

The tripartite core harmonised ICH guideline was finalised (Step 4) in November 1996. This document gives guidance on the format and content of safety updates, which need to be provided at intervals to regulatory authorities after products have been marketed. The guideline is intended to ensure that the worldwide safety experience is provided to authorities at defined times after marketing with maximum efficiency and avoiding duplication of effort.
E2C Final Concept Paper, October 1994

Addendum to E2C : Periodic Safety Update Reports for Marketed Drugs

Based on the comments made by the members of the Expert Working Group on CIOMS V recommendations and the PhRMA-EFPIA working document, this guideline has been finalised and reached Step 4 in February 2003. This Addendum should always be used in conjunction with the E2C Guideline.

The Addendum  intends to provide further clarification and guidance in the preparation of PSURs as specified in E2C. Additionally, the document addresses some new concepts not in E2C but reflecting current pharmacovigilance practice needs, including Proprietary Information (Confidentiality), Executive Summary, Summary Bridging Report, Addendum Reports, Risk Management Program and Benefit-Risk Analysis.

E2C Addendum Final Concept Paper, February 2002

The Addendum has been incorporated into the core guideline in November 2005.

EU : Adopted by CPMP, December 96, issued as CPMP/ICH/288/95
MHLW : Adopted March 97, PAB/PSD Notification No.32
FDA : Published in the Federal Register, Vol. 62, No. 96, May 19, 1997, pages 27469-27476

EU : Adopted by CPMP, March 2003, issued as CPMP/ICH/4679/02
MHLW : Adopted April 25, 2003, PFSB/ELD Notification No. 0425001 and PFSB/SA Notification No. 0425001
FDA : Published in the Federal Register, Vol. 69, No. 24, February 5, 2004, pages 5551-5552

E2D: Post-Approval Safety Data Management: Definitions and Standards for Expedited Reporting

The Guideline was finalised, under Step 4 of the ICH process, on November 12, 2003. This document provides a standardized procedure for post-approval safety data management including expedited reporting to relevant authority. The definitions of the terms and concept specific to post-approval phase are also provided. E2A definitions in clinical safety data management was maintained in this document as post-approval safety data management, such as seriousness definition. The practices of the data management were standardized in such cases obtained from consumers, literatures, internets which are all specific to post-approval data management. Good case management practice was focused and recommended for expedited reporting with clear definitions.
E2D Final Concept Paper, February 2002

EU : Adopted by CPMP, 20 November 2003, issued as CPMP/ICH/3945/03
MHLW : Adopted 28th March 2005, PFSB/SD Notification n° 0328007
FDA : Published in the Federal Register, September 15, 2003, Volume 68, Number 178, pages 53983-53984.

E2E: Pharmacovigilance Planning

The tripartite harmonised ICH guideline was finalised (Step 4) in November 2004. This guideline is intended to aid in planning pharmacovigilance activities, especially in preparation for the early postmarketing period of a new drug (in this guideline, the term "drug" denotes chemical entities, biotechnology-derived products, and vaccines). The main focus of this guideline is on a Safety Specification and Pharmacovigilance Plan that might be submitted at the time of licence application.
E2E Final Concept Paper, September 2002

EU : Adopted by CHMP, 1 December 2004, issued as CPMP/ICH/5716/03, date for coming into operation : June 2005
MHLW : Adopted 16th September 2005, PFSB/ELD Notification n° 0916001 & PFSB/SD Notification n° 0916001
FDA : Published in the Federal Register, April 1, 2005, Volume 70, Number 62, Pages 16827-16828

E2F: Development Safety Update Report

This guideline has been released for consultation under Step 2 of the ICH process on 5 June 2008.
The main focus of the DSUR is data from interventional clinical trials (referred to in this document as "clinical trials") of investigational drugs including biologicals, with or without a marketing approval, whether conducted by commercial or non-commercial sponsors.
E2F Final Concept Paper / E2F Final Business Plan, September 2006

EU : Transmitted to CHMP and Interested Parties in June 2008. Issued as EMEA/CHMP/ICH/309348/2208). Deadline for comments : December 2008
MHLW : To be notified
FDA : To be notified

E3: Structure and Content of Clinical Study Reports

The tripartite harmonised ICH guideline was finalised (Step 4) in November 1995. This document describes the format and content of a study report that will be acceptable in all three ICH regions. It consists of a core report suitable for all submissions and appendices that need to be available but will not be submitted in all cases.

EU : Adopted by CPMP, December 95, issued as CPMP/ICH/137/95
MHLW : Adopted May 96, PAB/PCD Notification No.335
FDA : Published in the Federal Register, Vol. 61, July 17, 1996, page 37320

E4: Dose-Response Information to Support Drug Registration

The tripartite harmonised ICH guideline was finalised (Step 4) in March 1994. This document gives recommendations on the design and conduct of studies to assess the relationship between doses, blood levels and clinical response throughout the clinical development of a new drug.

EU : Adopted by CPMP, May 94, issued as CPMP/ICH/378/95
MHLW : Adopted July 94, PAB/PCD Notification No.494
FDA : Published in the Federal Register, Vol. 59, No. 216, November 9, 1994, pages 55972-55976

E5(R1): Ethnic Factors in the Acceptability of Foreign Clinical Data

The tripartite harmonised ICH guideline was finalised (Step 4) in February 1998. This document addresses the intrinsic characteristics of the drug recipient and extrinsic characteristics associated with environment and culture that could affect the results of clinical studies carried out in regions and describes the concept of the "bridging study" that a new region may request to determine whether data from another region are applicable to its population.

EU : Adopted by CPMP, March 1998, issued as CPMP/ICH/289/95
MHLW : Adopted August 98, PMSB/ELD Notification No. 672, PMSB Notification No739
FDA :Published in the Federal Register, Vol. 63, No. 111, June 10, 1998, page 31790 in force September 98

E5: Ethnic Factors in the Acceptability of Foreign Clinical Data
Questions & Answers (R1)

Since reaching Step 4 and publication within the ICH regions, experiences by all parties with the implementation of the E5 guideline have resulted in the need for some clarification. This supplementary Questions and Answers document intends to clarify key issues.

EU: Adopted by CPMP, 20 November 2003, issued as CPMP/ICH/5746/03
MHLW: Adopted 5 October 2006, PFSB/ELD Notification
FDA: E5 Questions and Answers (Issued 9/27/2006; Posted 9/28/2006) http://www.fda.gov/cder/guidance/7377fnl.pdf 

E6(R1): Good Clinical Practice : Consolidated Guideline

The tripartite harmonised ICH guideline was finalised (Step 4) in May 1996. This Good Clinical Practices document describes the responsibilities and expectations of all participants in the conduct of clinical trials, including investigators, monitors, sponsors and IRBs. GCPs cover aspects of monitoring, reporting and archiving of clinical trials and incorporating addenda on the Essential Documents and on the Investigator's Brochure which had been agreed earlier through the ICH process.

EU : Adopted by CPMP, July 96, issued as CPMP/ICH/135/95/Step5, Explanatory Note and Comments to the above, issued as CPMP/768/97
MHLW : Adopted March 97, PAB Notification No.430, MHLW Ordinance No.28
FDA : Published in the Federal Register, Vol. 62, No. 90, May 9, 1997, pages 25691-25709E7

E7: Studies in Support of Special Populations : Geriatrics

The tripartite harmonised ICH guideline was finalised (Step 4) in June 1993. This document provides recommendations on the special considerations which apply in the design and conduct of clinical trials of medicines that are likely to have significant use in the elderly.

EU : Adopted by CPMP, September 93, issued as CPMP/ICH/379/95
MHLW : Adopted December 93, PAB/NDD Notification No.104
FDA : Published in the Federal Register, Vol.59, No. 102, August 2, 1994, pages 39398-39400

E8: General Considerations for Clinical Trials

The tripartite harmonised ICH guideline was finalised (Step 4) in July 1997. This document sets out the general scientific principles for the conduct, performance and control of clinical trials. The guideline addresses a wide range of subjects in the design and execution of clinical trials.

EU : Adopted by CPMP, September 97, issued as CPMP/ICH/291/95
MHLW : Adopted April 1998, PMSB/ELD Notification No.380
FDA : Published in the Federal Register, Vol. 62, No. 242, December 17, 1997, page 66113

E9: Statistical Principles for Clinical Trials 

The harmonised tripartite guideline was adopted in February 1998. This biostatistical guideline describes essential considerations on the design and analysis of clinical trials, especially the "confirmatory" (hypothesis-testing) trials that are the basis for demonstrating effectiveness.

EU : Adopted by CPMP, March 1998, issued as CPMP/ICH/363/96
MHLW : Adopted November 1998, PMBS/ELD Notification No. 1047
FDA : Published in the Federal Register, Vol. 63, No. 179, September 16, 1998, page 49583 in force September 98

E10: Choice of Control Group and Related Issues in Clinical Trials 

The harmonised tripartite guideline was finalised, having reached Step 4 in July 2000 . 
This document addresses the choice of control groups in clinical trials considering the ethical and inferential properties and limitations of different kinds of control groups. It points out the assay sensitivity problem in active control equivalence / non-inferiority trials that limits the usefulness of trial design in many circumstances.

EU : Adopted by CPMP, July 2000, issued as CPMP/ICH/364/96
MHLW : Adopted February 27, 2001, PMSB/ELD Notification No 136
FDA : Published in the Federal Register, Vol. 66, No. 93, May 14, 2001, pages 24390-91

E11: Clinical Investigation of Medicinal Products in the Pediatric Population

The harmonised tripartite guideline was finalised, having reached Step 4 in July 2000. This document addresses the conduct of clinical trials of medicines in pediatric populations. This document will facilitate the development of safe and effective use of medicinal product in pediatrics.

EU : Adopted by CPMP, July 2000, issued as CPMP/ICH/2711/99
MHLW : Adopted December 15, 2000, PMSB/ELD Notification No. 1334
FDA : Published in the Federal Register, Vol. 65, No. 71, April 12, 2000, pages 19777-81

Guidelines for Clinical Evaluation by Therapeutic Category

The ICH Efficacy Guidelines to date have focused on guidance which can be applied to all therapeutic classes of drugs, but there are, in some therapeutic classes, individual drug evaluation guidelines among the three regions. Differences between guidelines can result in obstacles to the mutual use and acceptance of clinical data. At the Steering Committee meeting in September 1998, it was agreed that this should be adopted as a new area of work for ICH, with the first such guideline being undertaken as a "pilot study" to assess the feasibility of extending work in this area.

E12: Principles for Clinical Evaluation of New Antihypertensive Drugs

Consensus Draft Principle

This therapeutic area guideline considers the Clinical Evaluation of New Antihypertensive Drugs. It provides a set of "Principles" on which there is general agreement among all three ICH regions covering endpoints and trial designs. Since there are a few differences in the requirements of the three regions that have not been harmonised, this document should be considered an "ICH Principle Document" rather than an "ICH Guideline". It will not be subject to the usual procedures leading to a fully harmonized document.

EU : Released for information, June 00, issued as CPMP/ICH/541/00
MHLW : Released for consultation, PMSB/ELD, Notification n° 738, 29 May 2000, deadline for comments on 1 September 2000
FDA : Released for consultation, published in the Federal Register, Vol. 65, No. 154; August 9, 2000; pages 48720-21. Deadline for comments on November 7, 2000.

E14: The Clinical Evaluation of QT/QTc Interval Prolongation and Proarrhythmic Potential for Non-Antiarrhythmic Drugs
The harmonised tripartite guideline was finalised, having reached Step 4 on 12 May 2005 .

This document provides recommendations to sponsors concerning the design, conduct, analysis, and interpretation of clinical studies to assess the potential of a drug to delay cardiac repolarization.
This assessment should include testing the effects of new agents on the QT/QTc interval as well as the collection of cardiovascular adverse events. The investigational approach used for a particular drug should be individualized, depending on the pharmacodynamic, pharmacokinetic, and safety characteristics of the product, as well as on its proposed clinical use.
The assessment of the effects of drugs on cardiac repolarization is the subject of active investigation. When additional data (non-clinical and clinical) are accumulated in the future, this document may be reevaluated and revised.

Implementation (Step 5) :

EU : Adopted by CHMP May 2005, issued as CHMP/ICH/2/04. Date for coming into operation : November 2005.
MHLW : To be notified
FDA : Published in the Federal Register, Vol. 70, n° 202, pages: 61134-61135; October 20, 2005.

E14: The Clinical Evaluation of QT/QTc Interval Prolongation and Proarrhythmic Potential for Non-Antiarrhythmic Drugs
Questions & Answers

Since reaching Step 4 and publication within the ICH regions, experiences by all parties with the implementation of the E14 guideline have resulted in the need for some clarification. This supplementary Questions and Answers document intends to clarify key issues.

EU: To be notified
MHLW: To be notified
FDA: To be notified 

E15: Definitions for Genomic Biomarkers, Pharmacogenomics, Pharmacogenetics, Genomic Data and Sample Coding Categories
The harmonised tripartite guideline was finalised, having reached Step 4 on 1 November 2007.
This guideline contains definitions of key terms in the discipline of pharmacogenomics and pharmacogenetics, namely genomic biomarkers, pharmacogenomics, pharmacogenetics and genomic data and sample coding categories. The validation and qualification processes for genomic biomarkers, evidence for their intended use and acceptance criteria across ICH regions are outside of the scope of this guideline. As new scientific knowledge in the discipline of pharmacogenomics and pharmacogenetics emerges, the current guidance will be reviewed and expanded if appropriate.
E15 Final Concept Paper, April 2006

E15 Business Paper, April 2006

Implementation (Step 5) :

EU : Approved by CHMP in November 2007, issued as EMEA/CHMP/ICH/437986/2006, date for coming into operation : May 2008
MHLW : Adopted January 9, 2008, PFSB/ELD Notification 0109013 & PFSB/SD Notification 0109002
FDA : Published in the Federal Register, Vol. 73, n° 68, pages 19074-19076; April, 8, 2008.