ICH Safety Guidelines

DOCUMENT TITLE

DESCRIPTION

S1

Rodent Carcinogenicity Studies for Human

Pharmaceuticals

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.

In April 2015, the Regulatory Notice Document was amended to include Health 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 catalyse 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) Swiss medic 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, the S1 EWG has completed a Prospective Evaluation Period Status Report. This Status Report provides a brief overview of the study’s progress and actions taken by the EWG to ensure successful completion of the study. 

S1A

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.

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.

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.

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).

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).

S2 (R1)

Guidance on Genotoxicity Testing and Data Interpretation for Pharmaceuticals intended for Human Use

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.

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.

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.

S4

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

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).

S5 (R2)

S5A, S5B (M)

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 4in 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.

S6 (R1)

Preclinical Safety Evaluation of Biotechnology-Derived Pharmaceuticals

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).

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.

S7B

The Non-Clinical 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.

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 toxicological 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 tumours.

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.

S9

NonClinical Evaluation for Anticancer Pharmaceuticals

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.

S10

Photosafety Evaluation of Pharmaceuticals

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.

S11

Nonclinical Safety Testing in Support of Development of Paediatric Medicines

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 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.

Cross-Cutting Guidelines

Some ICH Products do not fit uniquely into one of the Quality, Safety or Efficacy categories. Those Products can be found under the Multidisciplinary Section.