Annual Meeting of the Japanese Society of Toxicology

Evasion of immune surveillance represents a major mechanism limiting the effectiveness of traditional therapies against tumor cells. However, an increasing number of approaches designed to stimulate or directly utilize the immune system in overcoming this limitation are currently undergoing preclinical and clinical testing, including immunotherapies utilizing autoreactive effector cells. The relatively recent expansion in the understanding of basic mechanisms in T cell biology, combined with continuously improving molecular biology techniques, have made possible an explosion of clinical trials involving the adoptive transfer of genetically engineered T cells for the treatment of both hematological and solid malignancies. However, one significant factor potentially limiting the widespread use of T cell therapies for a variety of cancer types includes the expression of target antigens on cancer cells as well as on other normal, and essential, tissues. This presentation will review the field of adoptive T cell therapies, with a particular focus on chimeric antigen receptor T cells, highlight experimentally-verified and theoretical safety concerns for such therapies, and review current thinking concerning non-clinical safety assessment approaches for such therapies.

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Biomarkers are invaluable drug development tools to assess and monitor safety in early clinical trials especially when exposure margins are limiting for promising therapeutics. Although progress is made towards identifying and implementing translational safety biomarkers for a number of organ toxicities such as kidney and liver, significant gaps still exist to monitor toxicities for testis, pancreas, etc. Several precompetitive consortia (eg., PSTC, IMI) are working with industry, academia, government, patient advocacy groups and foundations with a goal to qualify biomarkers such that they can be used in preclinical studies and clinical trials to accelerate drug development. This talk will provide examples of how unique miRNA (miRNA profiling), protein (eg, gastrin) and low molecular weight molecules/metabolite (eg, bile acids, hyaluronic acid, norepinephrine) biomarkers are used as exploratory biomarker tools to understand mechanistic aspects of organ toxicity. In addition, the talk will also provide examples to demonstrate the complexities of biomarker discovery, validation and regulatory qualification intended for clinical trial applications. Examples include 1) regulatory qualification of GLDH to address the specificity gaps of ALT and 2) efforts to qualify biomarkers for skeletal muscle injury/dystrophy for their potential use in clinical trials for Duchene muscular dystrophy. As part of the global qualification of biomarkers, there are international efforts led by PSTC Japan that include leading Japanese scientists and pharmaceutical companies to advance qualification of emerging safety biomarkers at PMDA for clinical use in Japanese population. These efforts will not only increase the contributions of Japanese scientists in biomarker working groups but also provide annotated bio specimens from Japanese subjects to bridge the biomarker data needed for qualification. These efforts will be discussed.

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Generic drugs have a major public health impact and account for increasing amounts of prescriptions dispensed in the United States. In 2012, the Generic Drug User Fee Amendments (GDUFA) were enacted to enable U.S. Food and Drug Administration's (FDA) to assess industry user fees to bring greater predictability and timeliness to the review of abbreviated new drug applications (ANDAs) in the United States. During this time, a Pharmacology/Toxicology team was formed within FDA’s Office of Generic Drugs (OGD) to review and ensure that generic drugs are as safe as their respective reference listed drug (RLD). A generic drug must have the same safety profile as the RLD but can differ from its RLD with respect to the levels of impurities (organic or elemental), excipients, solvents, and extractables and leachables. OGD has developed several guidelines specific for generic drugs to provide the generic drug industry with pathways to control or justify the safety of impurities in their proposed generic drug product. In addition, principles from various International Conference on Harmonisation (ICH) guidances are used when reviewing the safety of a generic drug formulation. This session will discuss the principles of pharmacology/toxicology review, relevant guidance, and context of use that underpin the safety assessment that is conducted by the Pharmacology/Toxicology team in OGD. The session will include the following presentations:

Overview and timing of Pharmacology/Toxicology review for generic drugs

This presentation will give an overview of “why, when, and how” the Pharmacology/Toxicology team conducts reviews of ANDAs. We will discuss key ICH, FDA and generic-specific guidances that serve as a foundation of Pharmacology/Toxicology review. This presentation will also highlight the ways in which a Pharmacology/Toxicology reviewer addresses safety questions in generic drug applications.

Safety evaluation of organic impurities in generic drugs

Drug substance and drug product impurities can change the safety profile of a generic drug when compared with its RLD. Applicants must identify, report, control and provide justification for the levels of impurities according to FDA regulations and ICH guidance to ensure that the safety of impurities in generic drugs is properly addressed. This presentation will discuss control and safety evaluation of both genotoxic and non-genotoxic organic impurities.

Safety review of excipients in generic drugs

Excipients in generic drugs may differ from the RLD, but the applicant must provide information that supports the safety of their formulation. The safety justification may include reference to levels that are in FDA-approved products (i.e., listed on the Inactive Ingredient Database), providing published literature for excipient safety, and by considering the route and context of use for the intended patient population. This presentation will outline the methods that the Pharmacology/Toxicology team uses to evaluate the safety of excipients for proposed generic drugs.

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