The critical role of symptom experience on risk tolerance for gene therapy

TO THE EDITOR:

We are greatly encouraged by the attention our publication has garnered from fellow researchers and are thankful for the chance to address the commentary by Johnson et al.¹ We share the belief that a rigorous and transparent presentation of potential benefits and risks associated with treatments is crucial in a decision-making process that involves patients with sickle-cell disease (SCD) and the caregivers of these patients. In continuing this important dialogue, we wish to highlight 2 key elements of our study that can help contextualize the concerns raised by Johnson et al.

First, our team went to great lengths to explain the many outcomes associated with gene therapy in the survey instrument, including side effects associated with pretreatment conditioning and long-term adverse event risks such as stunted growth, organ damage, fertility issues, and future potential childbirth complications. However, we assumed that these outcomes did not vary across gene therapy options. Consequently, when participants were shown alternative gene therapy options with different levels of risks and benefits in the discrete-choice experiment (DCE), these “background” risks were not repeated in each DCE question. Respondents’ understanding and consideration of these factors were assessed during qualitative interviews to review the survey instrument before implementation. Given the uncertainty around the risk of malignancy and the importance of 1-year mortality in early evaluations of gene therapy in patients with SCD, our DCE focused on these 2 significant risks to understand what would constitute acceptable levels of these risks in future clinical studies.

The second factor to highlight is that we evaluated both respondents’ willingness to accept gene therapy at the patients’ current health baseline and under the assumption that they had developed more severe symptoms typical of those considered for gene therapy. Consistent with the work outlined by Johnson et al,¹ we found that respondents had misgivings about accepting gene therapy given current symptoms, particularly when SCD symptoms were considered mild and the chance of eliminating symptoms with gene therapy was relatively low. However, our aim was not just to evaluate what benefit-risk tradeoffs patients or caregivers would accept at present, but also to understand how preferences might change in the context of more severe SCD symptoms. This consideration, more than any other factor, significantly increased respondents’ preference for gene therapy.

The essence of our work, and the work shared by Johnson et al,¹ is that patient centricity may require suspending our own preconceptions about what constitutes acceptable tradeoffs. We believe our study compellingly demonstrates that variations in patient and caregiver perspectives may stem in part from differences in the patients’ experience with SCD symptoms and associated events. Awareness of the strengths and limitations of the various approaches available to assess patient preferences is warranted. This applies to both quantitative and qualitative evidence. The significant contributions of Johnson et al and our findings show that the degree of acceptability of tradeoffs associated with gene therapy is not universal, and that assuming that 1 answer is right for everyone is not in the best interest of patients.

Contribution: J.M.G.S., S.D.R., and M.T. drafted the manuscript.

Conflict-of-interest disclosure: M.T. is an unpaid member of the National Institutes of Health Cure Sickle Cell Initiative Executive Committee. The remaining authors declare no competing financial interests.

Correspondence: Juan Marcos Gonzalez Sepulveda, Population Health Sciences, Duke University, 300 West Morgan St, Durham, NC 27701; email: jm.gonzalez@duke.edu.