Table 1 Determining whether to initiate early-phase gene therapy (GT) trials.
From: Ethical challenges for a new generation of early-phase pediatric gene therapy trials
Step | Guiding question | Assessment |
1. Form preliminary expectation for GT’s risk–benefit profile | What is the study intervention’s expected risk–benefit profile for participants? | • Determine the type, magnitude, and likelihood of harms and benefits observed in preclinical studies • Evaluate the balance of benefits and harms |
2. Gauge uncertainty in the GT’s risk–benefit profile by evaluating preclinical evidence quality | Do preclinical studies support a causal relationship between the GT and observed outcomes (internal validity)? | • Check whether design features support a causal relationship (e.g., controls, randomization, blinding) |
Do preclinical studies accurately represent the clinical conditions in which the GT will be tested (construct validity)? | • Look for similarity between preclinical models and human patients (e.g., clinical presentation, age- and sex-matching for animal models) • Check whether preclinical GT was delivered in an analogous way to the intended delivery in humans (e.g., same volume-adjusted dose between animals and humans) | |
How generalizable are preclinical results (external validity)? | • Determine whether preclinical safety and efficacy findings have been validated in multiple models and/or species | |
Overall, what is the uncertainty in the risk–benefit profile? | • Judge overall preclinical study quality (internal, construct, and external validity): the higher the quality, the lower the uncertainty | |
3. Refine judgment of the GT’s expected risk–benefit profile by considering evidence on similar GTs | Can data on similar interventions refine or complement the above estimates about harms, benefits, and uncertainty? | • Consider whether similar interventions (e.g., similar vectors and/or delivery routes) have demonstrated safety and efficacy: the more therapeutic and better-characterized any similar interventions, the lower the uncertainty surrounding a favorable risk–benefit judgment |
4. Evaluate whether contextual factors influence the ethical acceptability of initiating early-phase trials | Do contextual factors suggest that it is more or less acceptable to begin early-phase trials? | • Evaluate relevant contextual factors: the more serious and rapidly progressive the disease, the more limited the alternatives, and the higher the support by the patient community, the more acceptable early-phase trial initiation may be |
5. Judge whether initiating early-phase trials is ethically justified | Is it ethically acceptable to begin early-phase trials in the target population? | • Make all-things-considered judgment, given the GT’s expected risk–benefit profile, its associated uncertainty, and relevant contextual factors |
