Safety Guidelines

CH 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.

The ICH Harmonised Guideline was finalised under 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.

  • S1A_Guideline Pdf
  • The ICH Harmonised Guideline was finalised under Step 4 in July 1997. This document provides guidance on approaches for evaluating the carcinogenic potential of pharmaceuticals. The Guideline embraces all pharmaceutical agents that need carcinogenicity testing as indicated in Guideline S1A. 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.

  • S1B Guideline Pdf
  • 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. The Addendum on "Addition of a Limit Dose and Related Notes", finalised in July 1997, has been incorporated into the core Guideline in November 2005, which was then renamed S1C(R1).

    The second revision has been approved by the ICH Steering Committee under Step 4 in March 2008 (S1C(R2)). In the 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, e.g., reducing the pain or discomfort of the animals at the maximally tolerated dose (MTD).

    Guideline

  • S1C_R2 Guideline Pdf

  • Endorsed Document

  • S1C_R2 Concept Paper Pdf

  • WG Presentations/ Trainings

  • S1C_R2 Presentation Pdf
  • 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 Steering Committee 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. In August 2013, the S1(R1) EWG finalised the Regulatory Notice that specifies the agreed upon details of the prospective trial data collection period. In April 2015, the Regulatory Notice Document was amended to include Health Canada, Canada as one of the Drug Regulatory Agencies that will begin receiving and reviewing Carcinogenicity Assessment Documents and Summary Study Reports in accordance with the process described in the document.

    In January 2016, an update to the Regulatory Notice Document (RND) has been posted on January 21, 2016 following discussions by the S1 Expert Working Group at the ICH Meeting held Dec 7-10, 2015. The changes to the RND are intended: a) to further clarify and improve the procedures for review by DRAs of Carcinogenicity Assessment Document (CAD) and final 2 years rat carcinogenicity study reports, b) to catalyze the numbers and quality of submissions by sponsors of CADs and final study reports, c) to improve alignment on CAD category decisions between sponsors and DRAs, and among DRAs, and d) to clarify expectations for the successful completion of the Prospective Evaluation Period (PEP). The specific changes made to the RND are as follows: 1) Swissmedic has been added as a DRA member along with the address for CAD submissions; 2) the Prospective Evaluation Period for submission of CADs has been extended for 2 years with the expectation for continuation through the end of Dec, 2017 (with the final study report expected to be submitted by Nov, 2019); 3) this extension is expected to allow for the target number of at least 20 Category 3 CADs along with the matching final study reports, that will be needed to consider revision of S1 Guidance; 4) sponsors are given opportunity to respond to requests from DRAs for clarification to CADs, or to provide additional information that may be deemed necessary by DRAs to make decisions on sponsor proposals for Category 3 submissions; 5) the longest duration of ongoing 2 years rat carcinogenicity studies allowable for CADs to be submitted has been reduced from 18 months in the original RND to 14 months effective June 1, 2016; 6) the content and format for executive summary 2 years rat study reports has been clarified.

    In April 2016 and December 2017, the S1(R1) EWG completed Prospective Evaluation Period Status Reports. These Status Report provide a brief overview of the study’s progress and actions taken by the EWG to ensure successful completion of the study.

    Endorsed Document

  • S1-R1 EWG Concept Paper Pdf
  • S1-R1 EWG Business Plan Pdf
  • S1-R1 EWG WorkPlan Pdf

  • Deliverables

  • S1 Status Report Pdf
  • S1(R1) EWG Status Report 2017 Pdf
  • S1(R1) EWG Status Report 2016 Pdf
  • S1(R1) EWG RND Pdf
  • The ICH Harmonised Guideline was finalised under Step 4 in November 2011. It replaces and combines the ICH S2A and S2B Guidelines.

    The S2A Guideline on Guidance on Specific Aspects of Regulatory Genotoxicity Tests for Pharmaceuticals 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.

    The S2B Guideline on Genotoxicity: A Standard Battery for Genotoxicity Testing for Pharmaceuticals 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 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.

    Guideline

  • S2_R1 Guideline Pdf

  • Endorsed Document

  • S2_R1 Concept Paper Pdf

  • WG Presentations/ Trainings

  • S2(R1) step 4 Presentation Pdf
  • The ICH Harmonised Guideline was finalised under Step 4 in October 1994. This document gives guidance on developing test strategies in toxicokinetics and highlights 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.

  • S3A Guideline Pdf
  • This S3A 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.

    Questions and Answers

  • S3A_Q&As_Q&As Pdf

  • Endorsed Document

  • S3A_Q&As Concept Paper Pdf
  • S3A_Q&As Business Plan Pdf

  • WG Presentations/ Trainings

  • S3A_Q&As Step2 Presentation Pdf
  • The ICH Harmonised Guideline was finalised under Step 4 in October 1994. This document gives guidance on circumstances when repeated dose tissue distribution studies should be considered (e.g., when appropriate data cannot be derived from other sources). It also gives recommendations on the conduct of such studies.

    Guideline

  • S3B_Guideline Pdf
  • The ICH Harmonised ICH Guideline was finalised under Step 4 in September 1998. This guidance has been prepared for the development of medicinal products with the exception of those already covered by the ICH Guideline on Safety Studies for Biotechnological Products, e.g., Monoclonal antibodies, recombinant DNA proteins. The text incorporates the guidance for repeat-dose toxicity tests that was agreed during the first ICH meeting in 1991 (reduction of the duration of repeat dose toxicity studies in the rat from 12 to 6 months).

  • S4 Guideline Pdf
  • The core ICH Harmonised Guideline was finalised under 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 under Step 4 in November 1995. The Guideline has been amended in November 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.

  • S5_R2 Guideline Pdf
  • This topic was endorsed by the ICH Steering Committee in March 2015 and the ICH S5(R3) Guideline on Detection of Toxicity to Reproductions for Human Pharmaceuticals reached Step 4 of the ICH Process in February 2020. This third revision of the ICH S5 Guideline incorporates experience gained with the testing of pharmaceuticals using the current and novel testing paradigms as well as the advances of scientific, technological and regulatory knowledge over the past years. The ICH S5(R3) provides human safety assurance at least equivalent to that provided by current testing paradigms. In addition, this revision intends to provide greater clarity and alignment with other ICH Guidelines including ICH M3(R2), ICH S6(R1) as well as ICH S9.

    Guideline

  • S5-R3 Step4 Guideline Pdf

  • Endorsed Documents

  • S5-R3 EWG Concept Paper Pdf

  • WG Presentations/ Trainings

  • S5-R3 Step4 Presentation Pdf
  • The ICH Harmonised Guideline was finalised under Step 4 in July 1997. This document covers the preclinical 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. 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).

    Guideline

  • S6_R1 Guideline Pdf

  • Endorsed Document

  • S6_R1 Concept Paper Pdf
  • S6_R1 Concept Paper Addendum Pdf
  • The ICH Harmonised Guideline was adopted under Step 4 in November 2000. This document provides a definition, general principles and recommendations for safety pharmacology studies. This Guideline generally applies to new chemical entities and biotechnology-derived products for human use. It can be applied to marketed pharmaceuticals when appropriate (e.g., when adverse clinical events, a new patient population, or a new route of administration raises concerns not previously addressed).

    Guideline

  • S7A Guideline Pdf

  • WG Presentations/ Trainings

  • S7A_Step4 Presentation Pdf
  • The ICH Harmonised Guideline was adopted under Step 4 in 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.

    Guideline

  • S7B Guideline Pdf

  • Endorsed Document

  • S7B Concept Paper Pdf
  • In November 2018, the Assembly endorsed the establishment of the E14/S7B Implementation Working Group (IWG) for the development of Q&As for the ICH E14 and ICH S7B Guidelines. ICH S7B and ICH E14 describe non-clinical and clinical risk assessment strategies to inform the potential risk for proarrhythmia of a test substance and contribute to the design of clinical investigations. Emergent data over the past several years demonstrate that different experimental results can arise for the same compound as a function of the study conditions used in non-clinical assays. The E14/S7B IWG will build on work done by the former E14/S7B Discussion Group (DG) which discussed the advances in science and methods related to the clinical assessment of QT prolongation and worked on the Comprehensive in vitro Proarrhythmia Assessment (CiPA) initiative.

    The E14/S7B IWG will provide guidance regarding best practices for the design, conduct, analysis, interpretation and reporting of in vitro, in silico and in vivo non-clinical assays in order for these assays to influence non-clinical and clinical evaluations. The Q&As will be developed in two stages to allow for more rapid impact of novel approaches on S7B and subsequently E14 for evolving drug candidates, enabling a more efficient, comprehensive and mechanism-driven process. The objective of the first stage of the proposed harmonisation work is to provide clarity on how to standardise assays such as multi-ion channel assays, in silico models, in vitro human primary and induced pluripotent cardiomyocyte assays and in vivo evaluation, and apply these learnings to guide predictions and subsequent clinical assessment. These efforts will provide a customisable non-clinical strategy that is more informative for clinical development.

    Endorsed Document

  • E14S7B IWG Concept Paper Pdf
  • E14-S7BIWG WorkPlan Pdf
  • The ICH Harmonised Guideline was adopted under Step 4 in September 2005. This Guideline provides recommendations on nonclinical testing approaches to identify compounds which have the potential to be immunotoxic, and guidance on a weight-of-evidence decision making approach for immunotoxicity testing It applies to new pharmaceuticals intended for use in humans, as well as to marketed pharmaceuticals proposed for different indications or other variations on the current product label in which the change could result in unaddressed and relevant immunotoxicity issues.

    In addition, the Guideline might also apply to drugs in which clinical signs of immunotoxicity are observed during clinical trials and following approval to market.

    Guideline

  • S8 Guideline Pdf

  • Endorsed Document

  • S8 Concept Paper Pdf
  • The ICH Harmonised Guideline was adopted under Step 4 in October 2009. This Guideline provides information for pharmaceuticals that are 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.

    Guideline

  • S9 Guideline Pdf

  • Endorsed Document

  • S9 Concept Paper Pdf
  • S9 Business Plan Pdf

  • WG Presentations/ Trainings

  • S9 Step4 Presentation Pdf
  • The document was adopted under Step 4 in June 2018. 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 its scope as well as its interpretation and implementation.

    Question And Answers

  • S9 Q&As Q&As Pdf

  • Endorsed Document

  • S9 Q&As Concept Paper Pdf

  • WG Presentations / Trainings

  • S9 Q&As Step4 Presentations Pdf
  • The ICH Harmonised Guideline was finalised under Step 4 in 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.

    Guideline

  • S10 Guideline Pdf

  • Endorsed Document

  • S10 Concept Paper Pdf
  • S10 Business Plan Pdf
  • 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 paediatric development programme. 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.

    Guideline

  • S11 EWG Draft Guideline Pdf

  • Endorsed Document

  • S11_EWG Concept Paper Pdf
  • S11 Business Plan Pdf
  • S11EWG WorkPlan Pdf

  • WG Presentations/ Trainings

  • S11_EWG Step2 Presentation Pdf
  • This topic was endorsed by the ICH Assembly in June 2019. The S12 EWG is working on the development of a new S12 Guideline on “Nonclinical Biodistribution Considerations for Gene Therapy Products”, with a view to providing recommendations on the elements of nonclinical studies performed that include Biodistribution assessment, and will contribute to the streamlined development of the Gene Therapy products, while maintaining scientific rigor and minimising the unnecessary use of animals.

    Endorsed Documents

  • S12_Final Concept Paper Pdf
  • S12_Final BusinessPlan Pdf
  • S12 EWG WorkPlan Pdf