Status of Safety Topics

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. R2 was posted on the FDA website on September 17, 2008.

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: 
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 provided 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. 
S2B: Genotoxicity: A Standard Battery for Genotoxicity Testing for Pharmaceuticals ; The tripartite harmonised ICH guideline was finalised (Step 4) in July 1997. This document addressed 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.

The purpose of the revision of this guideline 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.

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

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

S6(R1): Preclinical Safety Evaluation of Biotechnology-Derived Pharmaceuticals

This guideline has been released for consultation under Step 2 of the ICH process on 29 October 2009. 
The purpose of the addendum is to provide clarification on S6 and an update of the following topics discussed in the original ICH S6 guidance: species selection, study design, immunogenicity, reproductive and developmental toxicity and assessment of carcinogenic potential. Scientific advances and experience gained since publication of the original ICH S6 guidance call for this addendum.
This harmonised addendum will provide further complementary guidance to the S6 guideline and will help to define the current recommendations and reduce the likelihood that substantial differences will exist among regions.

S6(R1) Concept Paper, June 2008 

EU : Transmission to CHMP and Interested Parties in November 2009. Deadline for comments: February 2010. Issued as CPMP/ICH/302/95
MHLW : Released for consultation 8 January 2010, deadline for comments 8 March 2010
FDA : Published in the Federal Register, Vol. 74, No 241, Docket No. FDA-2009-D-0573, page 66980, 17 December 2009. Deadline for comments by February 1, 2010

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 : Adopted 23 October 2009, PFSB/ELD Notification n° 1023-4
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
The Guideline reached Step 4 of the ICH process on 29 October 2009.
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.
 S9 Final Concept Paper, April 2007
S9 Final Business Plan, May 2007

EU : Adopted by CHMP November 2009, issued as CHMP/ICH/646107/2008, Date for coming into operation: May 2010
MHLW : Adopted 4 June 2010, PFSB/ELD Notification n°0604-1
FDA : Published in the Federal Register, Vol. 75, No 44, Docket No. FDA?2009?D?0006, page 10487, 8 March 2010

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

The recommendations of this revised guidance further harmonise the nonclinical safety studies to support the various stages of clinical development among the regions of European Union (EU), Japan, and the United States. The present guidance represents the consensus that exists regarding the type and duration of nonclinical safety studies and their timing 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 : Approved by CHMP June 2009, issued as CPMP/ICH/286/95. Date for coming into operation: December 2009
MHLW : Adopted on February 19, 2010, PFSB/ELD notification No. 0219-4
FDA : Published in the Federal Register, Vol. 75, No 13, Docket No. FDA?2008?D?0470, page 3471, 21 January 2010