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

S1A: Guideline on the Need for Carcinogenicity Studies of Pharmaceuticals

The tripartite harmonised ICH guideline was finalised (Step 4) in November 1995. This document provides a consistent definition of the circumstances under which it is necessary to undertake carcinogenicity studies on new drugs. These recommendations take into account the known risk factors as well as the intended indications and duration of exposure.

EU : Adopted by CPMP, December 95, issued as CPMP/ICH/140/95
MHLW : Adopted April 97, PAB/PCD Notification No.315
FDA : Published in the Federal Register, Vol. 61, March 1, 1996, pages 8153

S1B: Testing for Carcinogenicity of Pharmaceuticals

The tripartite harmonised ICH guideline was finalised (Step 4) in July 1997. This document provides guidance on the need to carry out carcinogenicity studies in both mice and rats, and guidance is also given on alternative testing procedures which may be applied without jeopardizing safety.

EU : Adopted by CPMP, September 97, issued as CPMP/ICH/299/95
MHLW : Adopted July 1998, PMSB/ELD Notification No.548
FDA : Published in the Federal Register, Vol. 63, February 23, 1998, page 8983

S1C(R2): Dose Selection for Carcinogenicity Studies of Pharmaceuticals

This second revision has been approved by the ICH Steering Committee directly under Step 4 without further public consultation in March 2008.

Note 2 of the parent guideline has been deleted, and the text referring to the Notes has been revised. The title has been changed by deleting "& Limit Dose". 
The Addendum has been integrated in the text.

This document addresses the criteria for the selection of the high dose to be used in carcinogenicity studies on new therapeutic agents to harmonise current practices and improve the design of studies. 

In this revision, the pharmacokinetic endpoint of 25 is declared to be applicable also for pharmaceuticals with positive genotoxicity signals. This change has implications on "Refinement" (one of the 3R's) in enhancing the welfare, i.e., reducing the pain or discomfort of the animals at the MTD.
S1C(R2) Final Concept Paper, June 2006 (revision of S1C(R1)

EU : Core guideline adopted by CPMP (CPMP/ICH/383/95), November 94, Addendum adopted, September 97, issued as CPMP/ICH/366/96. 
Second revision: Final approval by CHMP in April 2008 (CHMP/ICH/383/1995). Date for coming into operation: October 2008.
MHLW : Core guideline adopted August 96, PAB/PCD Notification No.544, Addendum adopted July 1998, PMSB/ELD Notification No.551. 
Second revision: PFSB/ELD Notification n° 1127001 on November 27, 2008.
FDA : Core guideline published in the Federal Register, Vol. 60, No.40, March 1, 1995, pages 11278- 11281, Addendum published in the FR, Vol. 62, No. 233, December 4, 1997, page 64260. 
Second revision: To be Notified

S2(R1): Guidance on Genotoxicity Testing and Data Interpretation for Pharmaceuticals Intended for Human Use

This guideline has been released for consultation under Step 2 of the ICH process on 6 March 2008. 
This guidance replaces and combines the ICH S2A* and S2B* guidelines. The purpose of the revision is to optimize the standard genetic toxicology battery for prediction of potential human risks, and to provide guidance on interpretation of results, with the ultimate goal of improving risk characterization for carcinogenic effects that have their basis in changes in the genetic material. The revised guidance describes internationally agreed upon standards for follow-up testing and interpretation of positive results in vitro and in vivo in the standard genetic toxicology battery, including assessment of non-relevant findings.
S2(R1) Final Concept Paper, September 2006 (revision of S2A and S2B)

EU : Transmitted to CHMP and Interested Parties in March 2008, issued as EMEA/CHMP/ICH/126642/2008. Deadline for comments : May 2008
MHLW : Released for consultation 1 April 2008, PFSB/ELD, deadline for comments 30 April 2008.
FDA : Published in the Federal Register, March 26, 2008, Volume 73, Number 59, Page 16024-16025, deadline for comments: May 10, 2008.

S2A: Guidance on Specific Aspects of Regulatory Genotoxicity Tests for Pharmaceuticals

The tripartite harmonised ICH guideline was finalised (Step 4) in July 1995. This document provides specific guidance and recommendations for in vitro and in vivo tests and on the evaluation of test results. It  includes a glossary of terms related to genotoxicity tests to improve consistency in applications.
S2(R1) Final Concept Paper, September 2006 (revision of S2A and S2B)

EU : Adopted by CPMP, September 95, issued as CPMP/ICH/141/95
MHLW : Adopted July 96, PAB/PCD Notification No.444
FDA : Published in the Federal Register, Vol. 61, April 24, 1996, page 18199

S2B: Genotoxicity: A Standard Battery for Genotoxicity Testing for Pharmaceuticals

The tripartite harmonised ICH guideline was finalised (Step 4) in July 1997. This document addresses two fundamental areas of genotoxicity testing: the identification of a standard set of assays to be conducted for registration, and the extent of confirmatory experimentation in any particular genotoxicity assay in the standard battery.
S2(R1) Final Concept Paper, September 2006 (revision of S2A and S2B)

EU : Adopted by CPMP, September 97, issued as CPMP/ICH/174/95
MHLW : Adopted July 1998, PMSB/ELD Notification No.554
FDA : Published in the Federal Register 21 November 1997

S3A: Note for Guidance on Toxicokinetics: The Assessment of Systemic Exposure in Toxicity Studies

The tripartite harmonised ICH guideline was finalised (Step 4) in October 1994. This document gives guidance on developing test strategies in toxicokinetics and the need to integrate pharmacokinetics into toxicity testing, in order to aid in the interpretation of the toxicology findings and promote rational study design development.

EU : Adopted by CPMP, November 94, issued as CPMP/ICH/384/95
MHLW : Adopted July 96, PAB/PCD Notification No.443
FDA : Published in the Federal Register, Vol. 60, No. 40, March 1, 1995, pages 11264-11268

S3B: Pharmacokinetics: Guidance for Repeated Dose Tissue Distribution Studies

The tripartite harmonised ICH guideline was finalised (Step 4) in October 1994. This document gives guidance on circumstances when repeated dose tissue distribution studies should be considered (i.e., when appropriate data cannot be derived from other sources). It also gives recommendations on the conduct of such studies.

EU : Adopted by CPMP, November 94, issued as CPMP/ICH/385/95
MHLW : Adopted July 96, PAB/PCD Notification No.442
FDA : Published in the Federal Register, Vol. 60, No. 40, March 1, 1995, pages 11274-11275

S4:  Single Dose Toxicity Tests

Agreement was reached, at the time of ICH 1, in 1991, that the LD₅₀ determination should be abandoned for pharmaceuticals. The recommendation was published in the Proceedings of the First International Conference on Harmonisation, page 184.

S4:  Duration of Chronic Toxicity Testing in Animals (Rodent and Non-Rodent Toxicity Testing)

A tripartite, harmonised ICH guideline was finalised (Step 4) in September 1998. The recommendations are unchanged from those in the consultation draft issued in July 1997. The text incorporates the guidance for repeat-dose toxicity tests that was agreed at the time of ICH 1, in 1991 (reduction of the duration of repeat dose toxicity studies in the rat from 12 to 6 months).

EU : Adopted by CPMP, November 98 issued as CPMP/ICH/300/95
MHLW : Adopted on 5 April 1999, lyaku-sin No. 655
FDA : Published in the Federal Register, June 25, 1999 : 64FR Page 34259

S5(R2): Detection of Toxicity to Reproduction for Medicinal Products & Toxicity to Male Fertility

The core tripartite harmonised ICH guideline was finalised (Step 4) in June 1993. This document provides guidance on tests for reproductive toxicity. It defines the periods of treatment to be used in animals to better reflect human exposure to medical products and allow more specific identification of stages at risk.

The addendum to the core ICH guideline above with respect to male fertility studies was finalised (Step 4) in November 1995. The guideline has been amended on November 9, 2000, under the Maintenance Process.

The amendments provide a better description of the testing concept and recommendations, especially those addressing flexibility, pre-mating treatment duration, and observations.

EU : Adopted by CPMP, September 93, issued as CPMP/ICH/386/95
MHLW : Adopted July 94, PAB/PCD Notification No.470
FDA : Published in the Federal Register, Vol. 59, No.183, September 22, 1994, pages 48746-48752

EU : Adopted by CPMP, December 95, issued as CPMP/ICH/136/95 - Amended guideline : CPMP/ICH136/95 modification
MHLW : Adopted April 97, PAB/PCD Notification No.316 - Amended guideline : Adopted December 27, 2000, PMSB/ELD Notification No. 1834
FDA : Published in the Federal Register, Vol. 61, No. 67, April 5, 1996, pages 15360 - Amended guideline : To be notified

S6: Preclinical Safety Evaluation of Biotechnology-Derived Pharmaceuticals

The tripartite harmonised ICH guideline was finalised (Step 4) in July 1997. This document covers the pre-clinical safety testing requirements for biotechnological products. It addresses the use of animal models of disease, determination of when genotoxicity assays and carcinogenicity studies should be performed, and the impact of antibody formation on duration of toxicology studies.
S6 Final Concept Paper, October 1994

Revision of S6 Guideline: S6(R1) Concept Paper, June 2008 

EU : Adopted by CPMP, September 97, issued as CPMP/ICH/302/95
MHLW : Published, PAB/PCD, Notification n° 326, 22 February 2000
FDA : Published in the Federal Register, Vol. 62, No. 222, November 18, 1997, pages 61515

S7A: Safety Pharmacology Studies for Human Pharmaceuticals

The ICH guideline reached Step 4 of the ICH process in November 2000. This document addresses the definition, objectives and scope of safety pharmacology studies. It also addresses which studies are needed before initiation of Phase 1 clinical studies as well as information needed for marketing.

EU : Adopted by CPMP, November 2000, issued as CPMP/ICH/539/00 - ICH S7A
MHLW : Adopted on 21 June 2001, PFSB/ELD Notification n° 902
FDA : Published in the Federal Register, Vol. 66, No. 135; July 13, 2001, page 36791-92

S7B : The Nonclinical Evaluation of the Potential for Delayed Ventricular Repolarization
(QT Interval Prolongation)
By Human Pharmaceuticals

The Guideline reached Step 4 of the ICH process on 12 May 2005.

This guideline describes a non-clinical testing strategy for assessing the potential of a test substance to delay ventricular repolarization.

This guideline includes information concerning non-clinical assays and integrated risk assessments.
S7B Final Concept Paper, May 2001

Implementation (Step 5) :

EU : Adopted by CHMP May 2005, issued as CHMP/ICH/423/02. Date for coming into operation : November 2005.
MHLW : To be notified
FDA : Published in the Federal Register, Vol. 70, N° 202, pages 61133-61134; October 20, 2005

S8 : Immunotoxicity Studies for Human Pharmaceuticals

The Guideline reached Step 4 of the ICH process on 15 September 2005.

This guideline addresses the recommendations on nonclinical testing for immunosuppression induced by low molecular weight drugs (non-biologicals). It applies to new pharmaceuticals intended for use in humans, as well as to marketed drug products proposed for different indications or other variations on the current product label in which the change could result in unaddressed and relevant toxicologic issues. In addition, the guideline might also apply to drugs in which clinical signs of immunosuppression are observed during clinical trials and following approval to market. The term immunotoxicity in this guideline will primarily refer to immunosuppression, i.e. a state of increased susceptibility to infections or the development of tumors.
It is beyond the scope of this guideline to provide specific guidance on how each immunotoxicity study should be performed. 
General guidance is provided in Appendix 1.
S8 Final Concept Paper, November 2003

EU : Adopted by CHMP October 2005, issued as EMEA/CHMP/167235/2004-ICH, Date for coming into operation: April 2006.
MHLW : Adopted 18 April 2006, PFSB/ELD Notification n° 0418001
FDA : Published in the Federal Register, Vol. 71, n° 71, pages 19193 - 19194; April 13, 2006

S9: Nonclinical Evaluation for Anticancer Pharmaceuticals
This guideline has been released for consultation under Step 2 of the ICH process on 13 November 2008. 
This guideline provides information for pharmaceuticals that are only intended to treat cancer in patients with late stage or advanced disease regardless of the route of administration, including both small molecule and biotechnology-derived pharmaceuticals. It describes the type and timing of nonclinical studies in relation to the development of anticancer pharmaceuticals and references other guidance as appropriate.

EU : Transmission to CHMP and Interested Parties in December 2008. Issued as CHMP/ICH/646107/08. Deadline for comments: March 2009.
MHLW : Released for consultation 9 January 2009, PFSB/ELD, deadline for comments 9 March 2009.
FDA : Published in the Federal Register on February 17, 2009, Volume 74, Number 30. Deadline for comments by April 20, 2009.

M3(R2): Guidance on Nonclinical Safety Studies for the Conduct of Human Clinical Trials and Marketing Authorization for Pharmaceuticals

This guideline has been released for consultation under Step 2 of the ICH process on 15 July 2008. 

The recommendations of this revised guidance further harmonise the nonclinical safety studies to support the various stages of clinical development among the regions of Europe, USA and Japan. The present guideline represents the consensus that exists regarding the scope and duration of nonclinical safety studies to support the conduct of human clinical trials and marketing authorization for pharmaceuticals.

M3(R2) Final Concept Paper, September 2006 (revision of M3(R1))

EU : Transmission to CHMP and Interested Parties in July 2008. Issued as CPMP/ICH/286/95. Deadline for comments: October 2008.
MHLW : Released for consultation in July 2008, deadline for comments by August 29, 2008.
FDA : Published in the Federal Register on September 3, 2008, Volume 73, Number 171, pages 51491-51492. Deadline for comments by October 20, 2008

M3(R1): Maintenance of the ICH Guideline on Non-Clinical Safety Studies for the Conduct of Human Clinical Trials for Pharmaceuticals

The tripartite harmonised ICH guideline was finalised (Step 4) in July 1997. 

This multidisciplinary document addresses principles for the development of non-clinical strategies on the timing of toxicity studies in relation to the conduct of clinical trials. The guideline represents an important step forward on requirements for the different phases of clinical development but it is recognised that there remain some further important issues yet to be resolved.
The Guideline has been amended on November 9, 2000, under the Maintenance process.
M3(R2) Final Concept Paper, September 2006 (revision of M3(R1))

EU : Adopted by CPMP, September 97, issued as CPMP/ICH/286/95 - Amended Guideline : Adopted in November 2000, CPMP/ICH286/95 modification
MHLW : Adopted November 1998, PMSB/ELD Notification No. 1019 - Amended Guideline : Adopted December 27, 2000, PMSB/ELD, Notification No. 1831
FDA : Published in the Federal Register, Vol 62, November 25, 1997, pages 62922