title: Quantifying benefit-risk preferences for new medicines in rare disease patients and caregivers.
abstract: Rare disease patients and caregivers face uncommon, serious, debilitating conditions often characterised by poor prognosis and limited treatment options. This study aimed to explore what they consider of value when choosing between hypothetical therapeutic options and to quantify both their benefit-risk preferences and the influence of disease context.
  
  
  
  A mixed-methods survey with patients and caregivers was conducted in the United Kingdom across a range of rare diseases. Discrete-choice experiments that compared hypothetical treatment profiles of benefits and risks were used to measure respondent preferences across a set of seven attributes related to health outcomes, safety, and process of care. Bespoke questions on current disease management and the joint use of the 12-item WHODAS 2.0 questionnaire and of two Likert scales capturing self- and proxy-assessed disease-induced threat to life and impairment were implemented to describe disease context. Additionally, qualitative insights on the definitions of value and risk were collected from respondents.
  
  
  
  Final study sample included 721 patients and 152 informal caregivers, across 52 rare diseases. When choosing between hypothetical novel treatments for rare diseases, respondents attributed most importance to drug response, risk of serious side effects, and the ability to conduct usual activities while on treatment. In contrast, attributes related to treatment modalities were the least important. Respondents expressed a willingness to accept risks in hopes of finding some benefit, such as a higher chance of drug response or greater health improvement potential. Increasing disease severity, impairment or disability, and the lack of effective therapeutic options were shown to raise significantly the willingness to gain benefit through increased risk.
  
  
  
  This is the first study performing a quantitative discrete choice experiment amongst patients and caregivers across 52 rare conditions. It enables a more detailed understanding of the relationship between disease context, treatment attributes and the degree of risk respondents are willing to take to gain a specific degree of benefit. Researchers of novel therapeutics for rare diseases should be encouraged to invest in preference elicitation studies to generate rigorous patient evidence and specific regulatory guidance should be issued to acknowledge their importance and their use in marketing authorisations.
authors.affiliation: KU Leuven Department of Pharmaceutical and Pharmacological Sciences, Leuven, Belgium. thomas.morel@kuleuven.be.
authors.forename: T
authors.initials: T
authors.lastname: Morel
authors.affiliation: INSERM, US14, Paris, France.
authors.forename: S
authors.initials: S
authors.lastname: Aymé
authors.affiliation: Hepatology Department, Department of Metabolic Diseases, University Hospital Leuven, Leuven, Belgium.
authors.forename: D
authors.initials: D
authors.lastname: Cassiman
authors.affiliation: KU Leuven Department of Pharmaceutical and Pharmacological Sciences, Herestraat 49, 3000, Leuven, Belgium.
authors.forename: S
authors.initials: S
authors.lastname: Simoens
authors.affiliation: Institute of Pharmaceutical Science, Faculty of Life Sciences & Medicine, King's College London, London, UK.
authors.forename: M
authors.initials: M
authors.lastname: Morgan
authors.affiliation: KU Leuven Faculty of Economics and Business and Leuven Statistics Research Centre, Leuven, Belgium.
authors.forename: M
authors.initials: M
authors.lastname: Vandebroek
mesh_terms: D017028:Caregivers / Q000523:psychology* / Q000706:statistics & numerical data*; D002755:Choice Behavior; D005260:Female; D006801:Humans; D008297:Male; D010342:Patient Acceptance of Health Care / Q000523:psychology / Q000706:statistics & numerical data; D057240:Patient Preference / Q000523:psychology* / Q000706:statistics & numerical data*; D035583:Rare Diseases / Q000188:drug therapy*; D018570:Risk Assessment
keywords: Benefit-risk; Caregivers; Disability; Discrete choice experiment; Drug development; Patient-centered outcomes; Patient-reported outcomes; Patients; Preferences; Qualitative survey; Rare diseases; Risk tolerance; Trade-offs; Values