The treatment landscape for SMA has undergone tremendous changes with three FDA approved therapies becoming available in the last few years. It is therefore critically important to understand how patients and caregivers view treatment choices. This study is the first-ever discrete choice experiment to characterize decision-making and benefit-risk trade-offs for SMA treatment characteristics. These findings can inform the perceptions and preferences of SMA patients and their caregivers to stakeholders including regulators, patients, patient advocacy group such as CureSMA, and providers.
Across patient-centered treatment attributes to address the variety and severity of impairments and disabilities that accompany SMA, findings from this study identified the overall preferred treatment attributes including improvement in motor function, breathing function, oral administration, broad indication without age limits, and minimal risk. Overall, the preference on treatment characteristics were quite robust across demographic groups and clinical subgroups. Respondents’ age, sex, SMA type and associated characteristics (e.g., age of diagnosis<=18 months), did not show a difference in direction of conditional logit estimates for patient preference.
Not surprisingly, improvement in motor and breathing function were highly valued over stabilization of each function, regardless of subgroup. For breathing function, the strength in preference for improvement over stabilization was the greatest among patients with the greatest severity of disease. One-time IV infusion and oral daily are preferred frequency of treatments vs. repeated IT administration across all SMA patients (β=0.80). The preference is even stronger for oral daily among very young patients (β=1.01), adult patients (β=0.92), and patients with previous spinal surgeries (β=1.12). Those not currently under an IT injection treatment, were less likely to prefer the one-time IV infusion rather than the IT spinal injection that is done 3-6 times per year (RC: -0.65, p-value <0.05). This finding warrants further research.
The route of administration is an important treatment attribute because of the challenges of IT administration for SMA patients, particularly for those with severe scoliosis and spinal surgeries. The challenge of IT treatment may be further complicated by its treatment burden (travel, time from school/work) to receive IT injection among adults which may provide reasoning as to why oral route of administration was preferred. It is surprising that respondents expressed a stronger preference for oral daily administration than the one-time IV infusion except for those who were treated with gene replacement therapy. One possible explanation might be that although all treatment profiles are hypothetical in this experimental design, patients and caregivers would have naturally associated treatment attributes to actual approved treatments, as such one-time treatment may have suggested gene replacement therapy for some patients, which may have influenced treatment preference. Moreover, broad indication is strongly preferred for all patients except those ≤ 2 years of age, which currently have an effective gene replacement therapy available for this age group.
In using this DCE methodology, it is important to evaluate the preferences in the context of other features, examining the relative size of those preferences compared to other preferences. In doing so, the cross-attribute results found that for most patients (e.g., very young patients, adult patients, or patients with spinal surgeries), there may be willingness to trade off higher efficacy for less invasive, less risk, and more convenient route and frequency of treatment. When reducing side effect severity from ‘moderate risk’ to ‘mild risk’ the utility was 20% more than utility of moving from stabilization to better improvement in motor function. When reducing side effect severity from ‘serious, life-threatening’ to ‘mild risk’, this ratio was more than 5 times greater yielding 2.9 (1.86/0.65) times as much utility, as increasing efficacy from stabilization to improvement, suggesting a stronger preference for risk minimization over additional efficacy gain.
Likewise, the utility of changing from repeated IT injections to oral daily medication was 20% more than the utility of moving from stabilization to improvement; for adults, this ratio was about 50% more. These findings are consistent with previous research that has found stabilization in treatment to be highly meaningful (39), and although improvement in treatment is obviously preferred if given in comparison alone, patients would prefer to maintain stabilization if that means other treatment attributes would be prioritized (i.e. route of administration, side-effect severity, etc.). In a European SMA survey conducted by Rouault et al. (2017), the authors found that 96.5% of respondents believed that “stabilization of their current clinical state through treatment would represent progress.”(39) These findings demonstrate that SMA patients and caregivers deem stabilization as a very meaningful marker for their quality of life. This should be taken into consideration by clinicians and drug manufacturers, when developing new drugs and understanding benefits and risks associated with such treatments.
A previous study assessing patients’ perceptions of benefit-risk decision-making for SMA therapies found no strong correlations between risk tolerance and patient/disease attributes.(40) However, this was before the approval of any therapeutic options. Now that new treatment options are available to patients, the benefit-risk decision making we observed in this study found that patients had a lower willingness for high risk therapies even if the benefit trade-off was higher.
Evaluating patient preferences in our study should be interpreted in the context of two innovative treatments used by some of the study respondents as two important subgroups (i.e. onasemnogene abeparvovec-xioi and nusinersen), although the use of gene replacement therapy in our study only represents a small sample size. A comparison on the conditional logit estimates found that the preferences between nusinersen users and non-users were quite similar, except for the strong preference for oral daily administration among those receiving nusinersen (repeated IT spinal injection). The Pacione et al. (2019) qualitative study on the perspectives of nusinersen treatment, characterized the patients/caregivers with SMA who did not want or were unsure about nusinersen and found that their decision about pursuing nusinersen treatment was quite nuanced, challenging and context-specific.(41)
It is important to note that all treatments presented to patients and caregivers in this study are hypothetical and were automatically generated by computers. As such, one is supposed to not associate the preference (or lack of) for certain treatment attributes to actually approved treatments and treatments currently being developed. We recognized that it may be inevitable that a distinct treatment attribute may be linked to a specific treatment and/or patient experience with such a treatment, which may have influenced treatment choices. For example, the actual 10 gene-replacement therapy users did not appear to prefer the oral daily administration, and instead had a strong preference for the one-time IV administration, which may suggest the experience of one-time IV gene transfer is well tolerated and could be appealing for patients who are eligible.
With new treatments potentially turning a life-threatening disease into a chronic disease, clinicians may need to conform to a patient-centered care model that prioritizes a patient’s/family’s values, goals, and knowledge as well as patient’s self-awareness. The attention to the values and priorities from clinicians may create a shared decision making between patients and providers.
There were several limitations in the study. First, the survey sample was drawn from a SMA patient organization membership database, representing a highly informed and engaged patient population, and therefore the results may not represent all SMA patients in the United States. In particular, our sample only had one patient with type 4 SMA. Second, SMA type, motor function, and treatment status were self- or caregiver-reported. No attempts were undertaken to verify such information. Third, although affordability was a concern for many patients and caregivers, patient out-of-pocket cost was not included in the treatment profile due to administration burden and sample size limitation. Furthermore, a number of factors beyond the efficacy and side effects of treatment may influence perception and preferences on treatment characteristics among patients with SMA including disease knowledge, transportation needs, and functional status as well as insurance approval or financial assistance for very expensive SMA treatments. These factors may also interact with each other with large scope of complexity and difficulty involved in the treatment decisions for patients with SMA.
In regard to availability of actual treatments on the market, preference of one attribute may be confounded by related attributes based on actual, approved SMA treatments on the market (e.g. association of one-time infusion with gene therapy). Additionally, treatments were not explicitly described during the interview process in terms of scientific facts of effects and adverse effects of these treatments. Information about the purpose of the survey and directions for completing the survey were provided but information about specific SMA treatments and their effects were not provided. Patients only made responses based on their own personal knowledge, which limited the chance of interviewer bias. This is because the DCE study design was hypothetical and the purpose of this study was not to explicitly describe SMA treatments but rather common treatment attributes and characteristics. Thus, allowing us to understand a patient’s desired treatment in a hypothetical scenario to provide insight as to whether patients would be interested or prefer an option over the others if it was available.
Lastly, the hypothetical treatment attributes and levels may over-simplify any treatment in the real world; treatment decision has to be made in clinical context and tailored to patient specific needs. Nonetheless, these hypothetical scenarios provide insight into patient and caregiver preferences that can inform future drug development and drive the implications for future research of this highly rare, complicated, and expensive disease.