Platform-based opportunities to streamline animal use in support of the 3Rs – recommendations from an antibody-drug conjugate analysis

Abstract

The field of antibody drug conjugates (ADCs) continues to be an active area of development which has greatly evolved over the past 25 years since the first approved ADC in 2000 (Mylotarg). Simultaneously, increasing attention is being given to the use of animals, particularly large animal species, in biopharmaceutical drug development in the wake of the global COVID-19 pandemic and legislation implemented/pending in the US Congress (the FDA Modernization Act). A recent publication summarizing data from an analysis of 14 antibody-drug conjugates (ADCs) provides a springboard for the recommendation of best practices to streamline nonclinical toxicology evaluation for these molecules. Additionally, key principles from the ADC molecule class may be applied to other biologic platforms, such as CD3 bispecific antibodies and possibly cell and gene therapy. Widespread adoption of modernized program strategies should lead both to a reduction in the use of animals in nonclinical toxicology evaluation and to more rapid delivery of new medicines to patients with unmet medical needs.

The primary goal of nonclinical toxicology evaluation in the pharmaceutical industry is the identification of hazards and characterization of their monitorability, manageability, and reversibility in support of clinical trials and the eventual marketing of new drugs. An additional key deliverable of a toxicology program is the determination of appropriate dose levels to be evaluated in clinical trials. To accomplish these goals, nonclinical toxicology studies have traditionally utilized animal models in keeping with recommendations of global health authorities (e.g., ICH M3 for small molecule drugs and ICH S6 for biologic drugs). Although the 3Rs of ethical animal use (reduce, refine, replace) have been recognized since the late 1950s (Russell and Burch, 1959), increasing attention is being given to the use of animals in pharmaceutical research. The COVID-19 pandemic and accompanying ban on the export of non-human primates (NHPs) from China highlighted the dependence of nonclinical safety evaluation on NHPs, particularly for biologics and other modalities that have limited cross-reactivity. This realization contributed to the passage of the FDA Modernization Act 2.0 and the drafting of additional legislation (FDA Modernization Act 3.0) and the recent ‘Roadmap to Reducing Animal Testing in Preclinical Safety Studies’ which codify support in the US for the refinement of nonclinical toxicology programs and signal an opportunity for decreased reliance on animal models for safety evaluation. Similarly, the European Federation of Pharmaceutical Industries and Associations (EFPIA) recently released ‘EFPIA Recommendations on Phasing Out Animal Testing for Chemical Safety Assessments’ with comparable assessments and recommendations aimed at the evolution of pharmaceutical toxicity testing away from animal studies.