Measuring Meaningful Benefit-Risk Tradeoffs to Promote Patient-Focused Drug Development in Prader-Willi Syndrome: A Discrete-Choice Experiment

Abstract

Background. Prader-Willi syndrome (PWS) is a rare neurodevelopmental disorder causing quality of life impairments such as insatiable hunger (hyperphagia) and obesity. We explored caregivers’ willingness to assume treatment risk in exchange for reduced hyperphagia according to a PWS-validated observer-reported outcome measure. Methods. We partnered with PWS patient organizations to develop a discrete-choice experiment exploring caregivers’ benefit-risk tradeoffs for emerging PWS treatments. The treatment benefit was a reduction in hyperphagia (as measured by a 0-, 5-, or 10-point change on the Hyperphagia Questionnaire for Clinical Trials [HQ-CT]). Treatment risks included weight gain (none, 5%, 10%), added risk of skin rash (none, 10%, 20%), and risk of liver damage (none, 1 in 1000, 10 in 1000). Preference models were estimated using mixed logistic regression and maximum acceptable risk. We explored differences in preferences across familial caregivers of patients with and without hyperphagia. Results. Four hundred sixty-eight caregivers completed the online survey. The majority of caregivers reported that patients experienced hyperphagia (68%) and half of patients experienced obesity (52%). Caregivers of patients without hyperphagia were willing to accept greater weight gain (16.4% v. 8.1%, P = 0.004) and a higher risk of skin rash (11.7% v. 6.2% P = 0.008) as compared to caregivers of patients with hyperphagia. Caregivers of patients with hyperphagia would accept a higher risk of liver damage as compared to caregivers of patients without hyperphagia (11.9 out of 1000 v. 6.4 out of 1000, P = 0.04). Conclusions. This research demonstrates that caregivers are willing to accept risk in exchange for a five-point improvement on the HQ-CT, a smaller marginal improvement than had been previously classified as meaningful. Patient experience with hyperphagia is a modifier in how much risk caregivers will accept.

Incorporation of patient and family values and preferences for health‐related outcomes in paediatric obesity management: A systematic review

“…Our search identified 11 010 unique studies, eight of which met our eligibility criteria (see Figure 1). One study reported on values and preferences of obesity management related to outcomes of benefits and harms specific to interventions, 30 while the other seven explored general attitudes, beliefs, and perceptions around obesity managment. [31][32][33][34][35][36][37]…”

“…The lack of published data highlights the need for rigorous studies including discrete choice experiments that engage children, adolescents, and families with lived experiences of paediatric obesity to elicit their values and preferences related to the estimated benefits and harms for behavioural, psychological, pharmacological, and surgical treatment modalities. 20,30,46,47 As behavioural and psychological treatment is most commonly recommended as first-line management, the lack of studies that examined values and preferences for outcomes related to this treatment modality highlights the need for prioritizing primary studies in this area. [8][9][10] Such studies could also examine how different developmental stages (e.g.…”

A Comparison of Caregiver and Patient Preferences for Treating Duchenne Muscular Dystrophy

“…There is a push to include rare disease communities in the development of care standards to ensure they are realistic and promote treatments and interventions that are worthwhile to patients [8]. Caregiver and patient input can inform patient-centered clinical trials, such as by informing the selection of relevant outcome measures [9][10][11]. Caregiver and patient preference information is also increasingly integrated into regulatory decision making in the USA and internationally [12][13][14].…”

Authors’ Response to Comment on “Assessing the Appropriateness of the EQ-5D for Duchenne Muscular Dystrophy: A Patient-Centered Study”

“…Other recent work published by members of our group has shown that QALYs generated using the time-tradeoff method (and not derived from the EQ-5D) can also effectively document meaningful differences in specific symptoms of a pediatric rare condition. 10,11 Finally, we are pleased to hear of the success of other measures such as the DMD-QoL, 12 which the comment authors assert are better able to document what matters to the Duchenne community. We would be further interested in understanding how the responsiveness of such measures compares to that of the EQ-5D in Duchenne.…”

“…Other recent work published by members of our group has shown that QALYs generated using the time-tradeoff method (and not derived from the EQ-5D) can also effectively document meaningful differences in specific symptoms of a pediatric rare condition. 10,11…”