International Council for Harmonisation (ICH) Safety Guideline Updates

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1 International Council for Harmonisation (ICH) Safety Guideline Updates ICH Regional Public Meeting Canada-U.S. Regulatory Cooperation Council November 12, 2015 Alisa Vespa, Ph.D. Health Canada

2 Active ICH S Guidelines S1A, B & C Guidelines on rodent carcinogenicity testing S3A Assessment of systemic exposure in toxicity studies S5 Guideline on reproductive toxicity testing & toxicity to male fertility S9 Guideline on non-clinical evaluation of anti-cancer drugs S11 Guideline on non-clinical safety testing in support of development of pediatric medicines M7 Assessment and control of DNA reactive (mutagenic) impurities to limit potential carcinogenic risk (Addendum)

3 S1A, B & C Guidelines on rodent carcinogenicity testing ICH S1A, B and C finalized as Step 4 in 1995, 1997 and 2008 respectively. Provides guidance on the need for carcinogenicity studies, testing procedures and dose selection. Most pharmaceuticals require a 2-year rat carcinogenicity study for regulatory approval. Change to the ICH S1 guideline(s) is being considered to introduce a risk-based framework and define criteria for when a 2-year rat carcinogenicity study would add value for human risk assessment.

4 S1A, B & C Guidelines on rodent carcinogenicity testing Retrospective evaluation of datasets indicate that a negative 2- year rat carcinogenicity study may be predicted when: No pharmacologic risk factors, Not genotoxic, No histopathological risk factors in the chronic rat study, No hormonal perturbation. Can the outcome of the 2-year rat study can be prospectively predicted based the weight of evidence (WoE)? WoE criteria defined ( WoE and prediction discussed in a carcinogenicity assessment document (CAD) reviewed by regulators.

5 S1A, B & C Guidelines on rodent carcinogenicity testing The current pace of CAD submissions is slow. Step 2b guideline was anticipated in November Step 2b guideline may be delayed to 2019 to accommodate a greater number of CAD submissions. ICH S1 expert working group (EWG) will meet face-to-face in December 2015.

6 S3A Assessment of systemic exposure in toxicity studies ICH S3A was finalized as Step 4 in Guideline provides recommendations for the assessment of pharmacokinetic parameters within toxicology studies (i.e., toxicokinetics). Toxicokinetic parameters typically evaluated in satellite animals. Microsampling techniques may obviate the need for satellite animals. Reduce number of animals required for toxicity studies. Directly link toxicological effects to drug exposure in main study animals.

7 S3A Assessment of systemic exposure in toxicity studies Implementation working group (IWG) formed to generate a Q&A document with a focus on microsampling methods: Comparison of methods across animal species and test materials. Use of microsampling techniques for pivotal regulatory studies. Step 2b document expected in 1Q2016. Q&A document will then be open for public comments.

8 S5 Guideline on reproductive toxicity testing & toxicity to male fertility ICH S5 was finalized as Step 4 in Primarily focused on study design. Over the past 20 years there have been significant scientific, technical and regulatory advances in the field. Need to modernize the S5 guideline. Other benefits: Potentially reduce animal use. Alignment with other ICH guidelines (e.g., ICH S9).

9 S5 Guideline on reproductive toxicity testing & toxicity to male fertility The EWG has divided work into 6 work packages: Scope of the guideline, Species selection, Dose selection, Other test systems (e.g., in vivo, ex vivo and non-mammalian in vivo embryo-fetal development assays) and principles for possible regulatory acceptance of such studies, Options for combining reproductive toxicity studies, Human reproductive risk assessment. ICH S5 IWG will meet face-to-face in December 2015.

10 S9 Guideline on non-clinical evaluation of anti-cancer drugs ICH S9 was finalized as Step 4 in November Important guideline for the development of anti-cancer drugs Describes an accelerated pathway to develop pharmaceuticals for patients with serious and life threatening malignancies. Several aspects of ICH S9 require clarification: Scope, Use of recovery groups in general toxicology studies, Antibody-drug conjugates, Impurities, Need for carcinogenicity studies. IWG formed in 4Q2014 to develop a Q&A document.

11 S9 Guideline on non-clinical evaluation of anti-cancer drugs Examples of questions: Scope: The ICH S9 guideline provides information for pharmaceuticals that are intended to treat cancer in patients with serious and life-threatening malignancies. Can the meaning of serious and life-threatening malignancies be clarified? Use of recovery groups: Should recovery groups be included in toxicology studies supporting first in human studies? Phase III studies? ICH S9 IWG will meet face-to-face in December Q&A document expected to be completed in 4Q2016.

12 S11 Guideline on non-clinical safety testing in support of development of pediatric medicines ICH S11 is a new safety guideline in development. Three regional guidelines on juvenile animal testing for pediatric indications exist (United States, Europe, Japan). Lack of harmonization regarding the need for studies, study designs and timing, which leads to: Default conduct of a study, Repeating the conduct of a study, Unnecessary use of animals, Delaying access to medicines.

13 S11 Guideline on non-clinical safety testing in support of development of pediatric medicines FDA is retrospectively evaluating the rationale for when juvenile animal studies have or have not been recommended. For submitted juvenile animal studies, a high level summary of the data and any regulatory recommendations are being captured. EMA is retrospectively evaluating concordance of results between juvenile animal studies and adult toxicity studies. Regulated industry will conduct a survey to capture all juvenile animal studies conducted and to determine if and how the results affected the design of clinical studies. ICH S11 EWG will meet face-to-face in December 2015.

14 M7 addendum Application of the principles of ICH M7 guideline to calculation of compoundspecific acceptable intakes ICH M7 Assessment and control of DNA reactive (mutagenic) impurities in pharmaceutical to limit potential carcinogenic risk finalized as Step 4 in Utilizes a generically derived threshold of toxicological concern to control mutagenic impurities of unknown carcinogenic potential. Indicates that compound-specific acceptable intakes should be derived in cases where sufficient carcinogenicity data exist or for mutagenic impurities that have a threshold dose-response curve.

15 M7 addendum Application of the principles of ICH M7 guideline to calculation of compoundspecific acceptable intakes Addendum containing monographs and acceptable daily intake values for 15 mutagenic/carcinogenic compounds developed. Commonly used in pharmaceutical manufacturing. Illustrate the principles for deriving compound-specific intakes per M7. ICH M7 addendum reached Step 2b in June Currently undergoing regulatory consultation in the regions. Step 4 document expected in Q1/Q2 of ICH M7 EWG will meet not meet in December 2015.

16 Conclusion ICH EWGs involved in safety guidelines are active: New guidelines in development. Finalized guidelines modernized and/or clarified. ICH safety guidelines facilitate drug development, regulatory approval and the efficient use of animal resources. Questions?