Development of a Concept-Driven Disease Impact Instrument from Patients with Hemophilia (Pediatric and Adult) and Caregivers

Introduction. Hemophilia has wide-reaching impacts on function, feeling, and risk perception for patients and caregivers. Fit-for-purpose patient or caregiver-reported outcome instruments are required to better inform clinical research and practice. Although there is a myriad of hemophilia disease-specific instruments, none have been constructed using both a conceptual framework of impact and a mathematical model aimed at securing scientifically sound, linearized measures. The main objective of this study is to develop a hemophilia disease-specific instrument with versions for pediatric patients, adult patients, and caregivers that, 1) covers the key components of the impact of hemophilia and its treatment on patients (pediatric and adult) and caregivers; and 2) reflects clinically interpretable score change in magnitude to better inform treatment decisions in both clinical research and clinical practice.

Methods. Participants included patients with hemophilia A or B of any severity, with or without inhibitors, or caregivers of patients aged 2-17 years who were recruited through patient advocacy and market research groups (LA Kelley and Rare Patient Voice). Each participant completed a one-hour interview by phone or in-person (if age <10 years). The interview was completed in two parts: 1) open-ended, semi-structured concept elicitation to understand the impact of disease on daily life; and 2) completion of a draft questionnaire and cognitive debriefing of the questionnaire to assess understanding, relevance, and ease of completion. Interviews were conducted in multiple stages; changes were made to the interview guide and items to reflect participant feedback between the stages. Mixed-methods qualitative and quantitative analyses were conducted to inform instrument development.

Results. Participants included 54 pediatric patients (mean age=13 years; range 6-17), 55 adult patients (mean age=39 years, range 19-72), and 19 caregivers. Most patients (79%) had hemophilia A; 15% had inhibitors. A wide range of impacts was reported. For pediatric patients, the focus was on treatment rather than bleeds as a primary impact and duration of infusions and needing to infuse before activities were major burdens. Limitations on sports in pediatric patients were very bothersome; although sports participation varied greatly. Among adults, preoccupation with the disease was common. Some adults reported chronic joint damage, while others reported only acute pain around bleeds. Bleed locations and bleed impact varied across participants. Treatment burden included frequency, mode of administration, and adherence. Caregivers reported enforcement of activity restrictions as a significant burden, as were venous access for infusion and continuously thinking about the disease.

Using patient and caregiver-generated concepts and feedback from various stakeholders (including clinicians, patient advocacy, and payer), a framework based on the grouping and comparison of the thematic content was designed. The final conceptual framework for hemophilia impact includes a range of daily activities, perceived risk, pre-occupation, treatment burden, and pain. Items were generated to form electronic instruments for pediatric patients, adult patients, and caregivers; these instruments include skip patterns for faster completion.

Conclusions. The newly-proposed concept-driven instruments focus on important areas from current hemophilia patients and caregivers. Future large-scale validation studies are warranted to confirm scoring and measurement properties. This work will form a basis to construct stable linear measures to assess the wider disease impact of hemophilia and the benefit of new therapies.