The use of mechanistic evidence in drug approval

Abstract

The role of mechanistic evidence tends to be under‐appreciated in current evidence‐based medicine (EBM), which focusses on clinical studies, tending to restrict attention to randomized controlled studies (RCTs) when they are available. The EBM+ programme seeks to redress this imbalance, by suggesting methods for evaluating mechanistic studies alongside clinical studies. Drug approval is a problematic case for the view that mechanistic evidence should be taken into account, because RCTs are almost always available. Nevertheless, we argue that mechanistic evidence is central to all the key tasks in the drug approval process: in drug discovery and development; assessing pharmaceutical quality; devising dosage regimens; assessing efficacy, harms, external validity, and cost‐effectiveness; evaluating adherence; and extending product licences. We recommend that, when preparing for meetings in which any aspect of drug approval is to be discussed, mechanistic evidence should be systematically analysed and presented to the committee members alongside analyses of clinical studies.

The guidelines challenge—Philosophy, practice, policy

“…Kelly revisited the traditional problems with establishing causal associations and external validity and spoke of how EBM tried to deal with these, with some but limited success . As a way towards resolution for many of the limitations of EBM, Kelly proposed a better consideration of mechanisms and mechanistic science . He reinforced previous suggestions that scientific data are not value‐neutral, and that other factors (social values, theory, clinical judgement, expert opinion, experience, observation, etc) also play important roles in the development and implementation of EBM.…”

Treating real people: Science and humanity

“…We are delighted to report that, in the year following these comments, we have received a vast amount of correspondence and submissions from some of the most insightful and influential commentators in health research and practice, taking this “great debate” forward in just the way we had hoped. This thematic edition of the Journal of Evaluation in Clinical Practice (the largest single edition of the JECP in its 24‐year history) includes over 50 papers, reviews, and reports of conferences that reflect the attention being given across the board—by practitioners, guideline developers, systematic reviewers, and philosophers—to the relationship between evidence, science, context, bias, truth, value, and methodology, with the quintessentially pragmatic goal to develop accounts of these concepts to assist decision‐making in practice. It includes specific sections consisting of papers delivered to major conferences on diagnostic categories (focussing on both their limitations and their overuse), clinical guidelines, and mechanisms in medicine .…”

“…Jeffrey Aronson and colleagues argue that, despite a dependence upon RCTs, mechanistic evidence rightly enters into every step of the drug development and approval process . While currently mechanism may implicitly or surreptitiously enter into deliberations that claim to be focused on empirical clinical research alone, the authors convincingly advocate for a more systematic and explicit incorporation of mechanistic evidence.…”

Gathering Evidence of Mechanisms

“…For instance, expert evaluations routinely take place at the International Agency for Research on Cancer (IARC), the UK Medicines and Healthcare Products Regulatory Agency (MHRA), the UK National Institute for Health and Care Excellence (NICE), and the EU Committee for Medicinal Products for Human Use (CHMP). In such cases, it may be useful to provide a list of specific mechanism hypotheses to committee members before gathering evidence, in order to give them the opportunity to suggest alterations to the list well in advance of the committee actually meeting (Aronson et al 2018). Identifying a set of specific mechanism hypotheses at the outset is a good way of proceeding in the face of a large number of mechanistic studies: it makes the process of gathering evidence more manageable by helping to restrict focus to only those published mechanistic studies potentially relevant to the mechanism hypotheses of interest.…”