New Approach Methodologies: Opportunities and Challenges for Non-Clinical Development
Author:
Dr Rebbecca Wilcox
Principal Consultant
Introduction
Before entering clinical trials in humans, new drugs and devices must undergo nonclinical testing to evaluate their safety and efficacy. There is no fixed roadmap for nonclinical studies required for such assessments – regulatory authorities assess applications in a case-by-case manner – however, traditional approaches are outlined in FDA, EMA and ICH guidance documents. Historically, safety testing has involved a standardised battery of in vitro (laboratory-bench) assays, complemented by in vivo (whole animal) testing methods (Andrade et al., 2016).
However, in keeping with technological advancements and societal expectations, the ethical principles of Russell and Burch’s ‘3Rs’ are to be applied at all stages of drug and device development (Hubrecht and Carter, 2019). Specifically, where a valid non-animal alternative exists, we must Replace animals used in research, and where animals cannot be replaced, we must design studies to Reduce of the numbers used while still having robust and reproducible experiments and Refine study protocols to minimise the cumulative burden on individual animals and safeguard animal welfare.
All models, encompassing traditional nonclinical animal studies, and nonanimal methods have both utility, and limitations. Whilst animal models may predict clinical efficacy and safety, there are notable exceptions, and more accurate, sensitive and human-centric methods are urgently needed. With the advent of innovative Advanced Therapeutic Medicinal Products (ATMPs) and for many biopharmaceuticals, animal models may not be relevant test systems. They may lack the drug’s human-specific target, and for many complex and novel therapies, including small molecules, metabolism in humans may be unique, limiting the sensitivity and specificity of efficacy and safety assessment using animals.
The scientific and ethical benefits of shifting from animal to human-based methods are of increasing interest, with their inclusion in drug development and regulatory roadmaps across global regulatory agencies and stakeholder organisations. The limitations of animal models, such as lack of relevant targets for some biologics, or enzymatic pathways for drug metabolism and toxicity prediction, are well recognised, and they are no longer considered the gold standard for all aspects of nonclinical testing. Instead, New Approach Methodology (NAM) tests, sometimes in concert with human data from clinical trials and real-world evidence, are being applied, increasingly, to accurately predict the activity and safety of new or repurposed drugs (Ram et al., 2022).
For the purposes of this paper, acknowledging their imperative in reducing reliance on and complementing animal testing, the term new approach methodologies (NAMs) will be used interchangeably with ‘non-animal models’ and ‘novel alternative models’…