Recent years have seen an increasing surge in the development of novel biotherapeutics. Preclinical safety evaluation plays a crucial role in drug development and the highly diverse modalities and complexity of biotherapeutics poses several development challenges, such as identifying relevant species, dose selection, pharmacokinetic and pharmacodynamic profile, managing immunogenicity, etc.
The first speaker Jorg Blumel, PhD, ERT, Genentech, shared a broad overview about biotherapeutic development strategies including relevant regulatory guidelines, study design, pharmacologically-relevant species, study requirements, and development timeline considerations based on differences between small molecules and biotherapeutics. The talk also addressed alternative development strategies in the absence of a cross reactive/relevant species. In addition, the few examples shared by Dr. Blumel suggested that these biotherapeutics have a complex safety profile and require adaptive, flexible study designs and diligent species selection to mitigate development challenges.
Appropriately, the next talk by Maggie Dempster, PhD, GlaxoSmithKline, focused in detail on species selection considerations due to target biology and molecular attributes. Dr. Dempster discussed the various factors that play a key role in species selection, such as target expression, specificity, potency, physiological role, etc. The second part of the presentation provided details on several experimental (in vitro potency, tissue cross reactivity assay, and receptor affinity) and alternative approaches (surrogate proteins, transgenic animals, and disease models) that may help in overcoming these challenges. To put this concept in context, specific examples where alternative approaches were employed due to lack of relevant preclinical test system were discussed.
Robert Caldwell, PhD, Abbvie, described factors influencing immunogenicity, such as anti-drug antibody (ADA) formation, in a preclinical phase, their unpredictability, and the clinical impact of preclinical ADA. In this talk, the speaker highlighted the lack of regulatory guidelines for preclinical ADA analytical techniques and how the foundation of current testing strategies is based on clinically-focused US Food and Drug Administration (US FDA) Guidance for Immunogenicity Assessment. He explained drug interference and immune complex kinetics and considerations when designing toxicology studies with ADA timepoints and interpreting ADA data. Lastly, he discussed case studies of preclinical immune complex formation, how to describe it in toxicology study, and its impact on clinical translatability and dose selection.
Christopher Ellis, PhD, US FDA, presented a regulatory perspective on the development of biotherapeutics, reemphasizing the scientific and regulatory diversity of biologics and the goals of nonclinical safety evaluation of biotherapeutics. The detailed overview about ICH guidelines, specifically ICH S6 (R1), and the type of studies corresponding to the development timeline (to initiate a clinical trial and then for clinical development and licensing) were discussed. In addition, several case studies were presented that highlighted the complexity in challenges encountered in development of biotherapeutics and the diverse approaches that may be considered to address it. In conclusion, the speaker encouraged initiating an early discussion with the regulatory agency and providing complete justification for study design and study plan, and he emphasized a need for a “case-by-case approach” for safety evaluation of biologics.
Overall, this excellent session covered key principles and provided an overview of relevant regulatory guidelines for nonclinical safety assessment of biotherapeutics. In addition, the session encompassed a case study-based approach to understand how to mitigate specific challenges frequently encountered in executing nonclinical development strategies for biotherapeutics.
Editor's Note: This Continuing Education course was recorded and will be available as part of CEd-Tox, the SOT online Continuing Education program, in May 2018.
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