Assessing risk/benefit for trials using preclinical evidence: a proposal

Abstract

Moral evaluation of risk/benefit in early phase studies requires assessing the clinical promise of a candidate intervention using preclinical evidence. Yet there is little to guide ethics committees, investigators, sponsors or other stakeholders morally charged with making these assessments ("evaluators"). In what follows, we draw on published guidelines for preclinical study design to develop a structured process for assessing the clinical promise of new interventions. In the first step, evaluators gather all relevant preclinical studies, assess the magnitude of treatment effects, and determine clinical promise in light of various threats to valid clinical inference. In the second step, evaluators adjust assessments of clinical promise from preclinical studies by examining how other agents in the same reference class-and supported by similar evidence-have fared in clinical development. Assessments of clinical promise can then be fed into moral evaluation of risk and benefit in early phase trials. Though our approach has limitations, it offers a systematic and transparent method for assessing risk/benefit in early phase trials of novel interventions.

Evaluating mesenchymal stem cell therapy for sepsis with preclinical meta-analyses prior to initiating a first-in-human trial

“…construct validity) (Henderson et al, 2013; Kimmelman and Henderson, 2016). To evaluate clinical generalizability of the experimental conditions used, we performed a formal evaluation of construct validity using an eight item index that had been developed in a systematic review of preclinical sepsis (Table 4) (Lamontagne et al, 2010).…”

One Size Fits All?: Ethical Considerations for Examining Efficacy in First-in-Human Pluripotent Stem Cell Studies

“…In a second step, the outcome should be assessed by examining how similar interventions, supported by similar preclinical data, have fared in the translational process. 30 Fourth, if efficacy is tested in FIH studies, it should be transparent which aspect of efficacy is being tested: surrogate outcomes, such as successful engraftment of transplanted cells, and/or clinical outcomes, such as better eyesight. Research ethics committees do not have a common language or a common approach for assessing these benefits in human research, 31 and consent forms, as well as investigators' discussions with participants, are vague and ambiguous with respect to benefit, making this a critical issue.…”

Ethical considerations and challenges in first-in-human research

“…This new approach consists of 2 main steps: (1) evaluating clinical promise based on all relevant nonclinical efficacy evidence, taking into account various threats to valid inference, and (2) adjusting the assessments of clinical promise with reference class evidence in clinical development. 41 However, the applicability of this approach to various scenarios requires further rigorous validation as publication and reporting bias may have caused the clinical promise of the intervention under evaluation to be exaggerated. 42,43 Although rigorous assessments may provide compelling value of the intervention (aspirational benefits), justification for the conduct of FIH research based solely on this possibility may raise other concerns for responsible parties due to a novel therapy's inherent potential to cause irreversible damage to the research subjects.…”