ICH has produced a comprehensive set of safety Guidelines to uncover potential risks like carcinogenicity, genotoxicity and reprotoxicity.  A recent breakthrough has been a non-clinical testing strategy for assessing the QT interval prolongation liability: the single most important cause of drug withdrawals in recent years.
Zip file with all ICH Safety Guidelines in Word format

  • S1A - S1C Carcinogenicity Studies

    Code Document Title Previously coded
    • Description :

      This topic was endorsed by the ICH Steering Committee in April 2012.

      A change to the current S1 harmonised Guidelines on rodent carcinogenicity testing is proposed to introduce a more comprehensive and integrated approach to addressing the risk of human carcinogenicity of pharmaceuticals, clarify and update, without compromising safety, the criteria for deciding whether the conduct of a two-year rodent carcinogenicity study of a given pharmaceutical would add value to this risk assessment.

      In November 2012, the SC endorsed the revision of both the S1 Concept Paper and Business Plan to provide clarification concerning how the prospective data gathering period should be integrated in the normal ICH Step process. The revised S1 Concept Paper and Business Plan describe the S1 strategy which consists of first preparing a draft "Regulatory Notice for Public Input" which would be issued by each ICH regulatory health authority to solicit comments from the public to the proposal, the procedure, and the specific weight-of-evidence criteria. A final “Regulatory Notice" is planned to be published in June 2014 and will mark the beginning of the prospective data collection period. After collecting and incorporating results from the prospective analyses, a Step 2 document is planned to be published in November 2016, and a Step 4 document finalised in November 2017.

      In August 2013, the S1 EWG finalised the Regulatory Notice that specifies the agreed upon details of the prospective trial data collection period.

      Status :

      Prospective data Collection Period

      EU :

      To be notified

      MHLW :

      RND posted on the PMDA website on 25 October 2013

      FDA :

      To be notified

    • Finalised Guideline:
      November 1995

      Description :

      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.

      Implementation :

      Step 5

      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, p. 8153, 1 March 1996

    • Finalised Guideline:
      July 1997

      Description :

      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.

      Implementation :

      Step 5

      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, p. 8983, 23 February 1998

    • Finalised Guideline:
      March 2008

      Description :

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

      The Addendum on "Addition of a Limit Dose and Related Notes", finalised in July 1997, has been incorporated into the core Gudeline in November 2005, which was then renamed S1C(R1).

      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 second 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 maximally tolerated dose (MTD).

      Implementation :

      Step 5

      EU :

      Adopted by CHMP, April 2008, issued as CHMP/ICH/383/1995

      MHLW :

      Adopted 27 November 2008, PFSB/ELD Notification No. 1127001

      FDA :

      Published in the Federal Register, Vol. 62, No. 233, 4 December 1997, p. 64260. R2 was posted on the FDA website on 17 September 2008

  • S2 Genotoxicity Studies

    Code Document Title Previously coded
    • Finalised Guideline:
      November 2011

      Description :

      The tripartite harmonised ICH Guideline was finalised under Step 4 in November 2011. It 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 under 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 under 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 combined Guideline is to optimise 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 characterisation 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.

      Implementation :

      Step 5

      EU :

      Adopted by CHMP, December 2011, issued as EMA/CHMP/ICH/126642/2008

      MHLW :

      Adopted 20 September 2012, PFSB/ELD Notification No. 0920-2

      FDA :

      Published in the Federal Register, 7 June 2012, Vol. 77, No. 110, p. 33748-9

  • S3A - S3B Toxicokinetics and Pharmacokinetics

    Code Document Title Previously coded
    • Finalised Guideline:
      October 1994

      Description :

      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.

      Implementation :

      Step 5

      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, p. 11264-11268, 1 March 1995

    • Description :

      This Implementation Working Group (IWG) was endorsed by the ICH Steering Committee in October 2014.

      Since reaching Step 4 and publication within the ICH regions, experiences by all parties with the implementation of the S3A Guideline on toxicokinetics have resulted in the need for some clarification. The Questions and Answers developed by the S3A Implementation Working Group (IWG) are intended to facilitate the implementation of the S3A Guideline and especially to address the benefit and use of microsampling techniques in main study animals.

      Status :

      Step 1

    • Finalised Guideline:
      October 1994

      Description :

      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.

      Implementation :

      Step 5

      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, p. 11274-11275, 1 March 1995

  • S4 Toxicity Testing

    Code Document Title Previously coded
    • Finalised Guideline:
      September 1998

      Description :

      A tripartite, harmonised ICH Guideline was finalised under  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).

      Implementation :

      Step 5

      EU :

      Adopted by CPMP, November 1998 issued as CPMP/ICH/300/95

      MHLW :

      Adopted 5 April 1999, lyaku-sin No. 655

      FDA :

      Published in the Federal Register, 25 June 1999, Vol. 64, p. 34259

  • S5 Reproductive Toxicology

    Code Document Title Previously coded
    • Finalised Guideline:
      November 2000

      Description :

      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.

      Implementation :

      Step 5

      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, p. 48746-48752, 22 September 1994

      Addendum: Toxicity to Male Fertility (incorporated in S5(R2))

      Implementation :

      Step 5

      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 27 December 2000, PMSB/ELD Notification No. 1834

      FDA :

      Published in the Federal Register, Vol. 61, No. 67, April 5, 1996, p. 15360 - Amended Guideline : To be notified

  • S6 Biotechnological Products

    Code Document Title Previously coded
    • Finalised Guideline:
      June 2011

      Description :

      The tripartite harmonised ICH Guideline was finalised under 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.

      An addendum was proposed to provide clarification on S6 and an update of the following topics discussed in the original ICH S6 Guideline: 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 Guideline call for this addendum. The harmonised addendum provides further complementary guidance to the S6 Guideline and helps to define the current recommendations and reduce the likelihood that substantial differences will exist among regions.

      The addendum reached Step 4 of the harmonisation process in June 2011 and was integrated as part II in the core Guideline that was then renamed S6(R1).

      Implementation :

      Step 5

      EU :

      Adopted by CPMP, September 1997, issued as CPMP/ICH/302/95

      MHLW :

      Adopted February 2000, PAB/PCD Notification No. 326

      FDA :

      Published in the Federal Register, 18 November 1997 , Vol. 62, No. 222, p. 61515

      Addendum: Preclinical Safety Evaluation of Biotechnology-Derived Pharmaceuticals

      Implementation :

      Step 5

      EU :

      Adopted by CHMP, July 2011, issued as EMA/CHMP/ICH/731268/1998

      MHLW :

      Adopted March 2012, PFSB/ELD Notification No. 0323-1

      FDA :

      Published in the Federal Register, 18 May 2012, Vol. 77, No. 97, p. 29665-6

  • S7A - S7B Pharmacology Studies

    Code Document Title Previously coded
    • Finalised Guideline:
      November 2000

      Description :

      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.

      Implementation :

      Step 5

      EU :

      Adopted by CPMP, November 2000, issued as CPMP/ICH/539/00 - ICH S7A

      MHLW :

      Adopted on 21 June 2001, PFSB/ELD Notification no 902

      FDA :

      Published in the Federal Register, Vol. 66, No. 135, p. 36791-92, 13 July 2001

    • Finalised Gudeline:
      May 2005

      Description :

      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.

      Implementation :

      Step 5

      EU :

      Adopted by CHMP May 2005, issued as CHMP/ICH/423/02. Coming into operation in November 2005

      MHLW :

      Adopted 23 October 2009, PFSB/ELD Notification no 1023-4

      FDA :

      Published in the Federal Register, Vol. 70, No 202, p. 61133-61134, 20 October 2005

  • S8 Immunotoxicology Studies

    Code Document Title Previously coded
    • Finalised Guideline:
      September 2005

      Description :

      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.

      Implementation :

      Step 5

      EU :

      Adopted by CHMP October 2005, issued as EMEA/CHMP/167235/2004-ICH, Coming into operation in April 2006

      MHLW :

      Adopted 18 April 2006, PFSB/ELD Notification no 0418001

      FDA :

      Published in the Federal Register, Vol. 71, no 71, p. 19193 - 19194, 13 April 2006

  • S9 Nonclinical Evaluation for Anticancer Pharmaceuticals

    Code Document Title Previously coded
    • Finalised Guideline:
      October 2009

      Description :

      The tripartite harmonised ICH 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.

      Implementation :

      Step 5

      EU :

      Adopted by CHMP, November 2009, issued as CHMP/ICH/646107/2008

      MHLW :

      Adopted June 2010, PFSB/ELD Notification No. 0604-1

      FDA :

      Published in the Federal Register, 8 March 2010, Vol. 75, No. 44, Docket No. FDA/2009/D/0006, p. 10487

    • Description :

      This Implementation Working Group (IWG) was endorsed by the ICH Steering Committee in October 2014.

      Since reaching Step 4 and publication within the ICH regions, experiences by all parties with the implementation of the S9 Guideline on nonclinical evaluation for anticancer pharmaceuticals have resulted in the need for some clarification. The Questions and Answers developed by the S9 Implementation Working Group (IWG) are intended to facilitate the implementation of the S9 Guideline clarifying the scope of the S9 Guideline as well as its interpretation and implementation.

      Status :

      Step 1

  • S10 Photosafety Evaluation

    Code Document Title Previously coded
    • Finalised Guideline:
      November 2013

      Description :

      The tripartite harmonised ICH Guideline reached Step 4 of the ICH process on 13 November 2013.

      This Guideline provides international standards for photosafety assessment and harmonises such assessments supporting human clinical trials and marketing authorizations for pharmaceuticals. It includes factors for initiation of and triggers for additional photosafety assessment and should be read in conjunction with ICH M3(R2), Section 14 on Photosafety Testing.

      Implementation :

      Step 5

      EU :

      Adopted by CHMP December 2013, issued as EMA/CHMP/ICH/752211/2012

      MHLW :

      Adopted May 2014, PFSB/ELD Notification No. 0521-1

      FDA :

      To be notified

  • S11 Nonclinical Safety Testing

    Code Document Title Previously coded
    • Description :

      This topic was endorsed by the ICH Steering Committee in November 2014.

      The S11 Guideline is proposed to provide direction on the nonclinical safety studies important to support a pediatric development program. It will recommend standards for the conditions under which nonclinical juvenile animal testing is considered informative and necessary to support paediatric clinical trials, and also provide guidance on the design of the studies. A streamlined drug development and higher scientific rigor while minimizing the unnecessary use of animals will be achieved with the implementation of this new harmonised ICH Guideline.

      Status :

      Step 1

       

       

  • Cross-cutting Topics

    Code Document Title Previously coded