OBJECTIVES: In 2017/2018, we concluded a study on risk tolerance for gene therapy (GT) for Duchenne muscular dystrophy (Duchenne). Duchenne is a progressive, fatal condition. GTs under trial could be disease modifying, not curative. GT has serious risks, including risk of death. In our prior study we assessed maximum acceptable risk (MAR) of death in U.S.-based adults with Duchenne and parents. In GT trials over the past 5 years there were serious adverse events, clinical holds, and one death in late 2021. We initiated a second study to assess current MAR in the U.S., United Kingdom, and to explore experiences and attitudes of clinicians. Here we report on qualitative research with adults and parents in the U.K., clinicians in the U.K. and U.S., and the implications for revising our 2017/2018 MAR instrument.

METHODS: We conducted three focus groups (n=12 total) and clinician interviews (n=8 U.K., 6 U.S.). Experienced researchers employed semi-structured guides. Data were coded using a matrix-based approach. Experts and a multidisciplinary expert advisory committee are also advising.

RESULTS: Analysis is ongoing. Most adults/parents expect slowing/stopping progression of muscle, cardiac, and pulmonary decline—benefits considered highly meaningful. Adults/parents described considerable uncertainty about risks and benefits. Death was not the worst risk for some. Limited benefit duration and potential one-time dosing were important limitations. Clinician responses varied regarding potential benefits (spanning modest to curative) and duration (spanning 1 year to lifelong). Many described patient/family over-expectations of GT benefit. Clinicians referenced organ failure as the greatest risk. Across all respondents, most indicated acceptability of risk of death given the progressive nature of Duchenne.

CONCLUSIONS: Our 2017/2018 instrument is appropriate for re-use with minimal updates to state-of-science. We anticipate assessing tolerance for additional lifelong disability and adding measures of knowledge, therapeutic optimism, and risk aversion. Assessing MAR of clinicians is also important.