The Case for the Use of Patient and Caregiver Perception of Change Assessments in Rare Disease Clinical Trials: A Methodologic Overview

Abstract

IntroductionThe traditional model of evaluating treatments based primarily on primary outcome measures has stumbled in its application to rare disease. Rare disease clinical trials face the methodological challenges of small, heterogeneous patient populations and relatively few validated, disease-specific outcome measures. Incorporating qualitative research into rare disease clinical trials may help sponsors, regulators, payers, and prescribers to better understand the real-world and patient-specific impact of a potential therapy. This paper provides a methodologic overview of the use of Patient and Caregiver Perception of Change (PPC and CPC) Assessments utilizing patient and caregiver video interviews to complement the data captured by traditional endpoints in rare disease clinical trials.MethodsIncorporating qualitative patient and caregiver video interviews into clinical trials allows for the rigorous capture of patient experiences and caregiver observations. Interview guides informed by input from key stakeholders provide the opportunity to solicit structured feedback on experiences before, during, and after the clinical trial. Patients and caregivers can complete their video interviews in a study mobile application, and interview transcripts are analyzed by independent coders. Themes are summarized by the treatment group and individual patient, which adds context to the clinical outcome measures of how patients feel and function, as well as elucidates the degree of change that is meaningful to patients and caregivers. The qualitative results can be compared to the data captured in clinical trials to assess data concordance.ConclusionCapturing patient experience data with sufficient rigor allows it to contribute to the body of evidence utilized in regulatory, payer, and prescriber decision-making. Adding PPC and CPC Assessments to rare disease clinical trials offers an innovative and powerful way to tap into the unique insights of patients and their families to develop a fuller picture of the patient experience in the clinical trial.FundingStealth BioTherapeutics Inc.

Development of a Clinical Global Impression of Change (CGI-C) and a Caregiver Global Impression of Change (CaGI-C) measure for ambulant individuals with Duchenne muscular dystrophy

“…Insights were gathered from clinicians, caregivers and individuals with Duchenne to understand which symptoms and functional impacts of the disease were important and clinically meaningful. This study further confirmed the significance in obtaining the patient's perspective in rare diseases where heterogeneity exists and the concepts and level of change meaningful for patients and their families can vary [22]. Consistent with published literature, the most frequently experienced symptom reported in all three populations was muscle weakness [23][24][25][26][27][28].…”

“…the 6-Minute Walk Test and the Four-Stair Climb Velocity Test) capture relevant concepts to clinicians, patients and their families, subtle changes in physical functioning that families also find meaningful may be hard to detect [ 30 , 31 ]. Therefore, additional outcomes such as a global impression item, patient and observer-reported outcomes, or more creative methods such as patient videos of functioning or wearable devices, [ 32 ] in conjunction with motor function tests may be useful to evaluate change in an interventional setting [ 22 ].…”

The Use of Patient-Reported Outcome Measures in Rare Diseases and Implications for Health Technology Assessment

“…Can be unresponsive and miss important information for specific RDs [12,13,16,29] Use both a generic and a disease-specific instrument for RDs in a complementary way [12] Feasible with additional challenges: This could be a very valuable solution, but it depends on the specific HTA body and they type of data they are willing to accept; if an HTA agency only wants preference-based generic PROMs, the impact of adding disease-specific measures will likely be minimal It may be important to limit the scope of applicability, so that concept-specific instruments are created that could be applicable across a family of closely related RDs and not just any similar disease [14] Need for sufficient consideration of alternative sources of QoL evidence during the HTA deliberative process Substantial heterogeneity in the manifestation of the RD in question may mean it is not possible to measure distinct outcomes across the population, making application of these general disease-specific PROMs difficult [22] A multi-attribute questionnaire that poses questions most relevant for patients based on previous answers may help make the PROM more applicable across heterogeneous RD manifestations [5] Mixed-methods frameworks using qualitative and quantitative data may help maximize the applicability of the PROM to a different condition [5,7] Feasible: While using statistical software depends on resources and knowledge, using available tools to create such questionnaires would not require substantial time or structural changes Probably feasible: Mixed-methods research is a good approach to minimize potential problems but simultaneously requires time and resource investment…”

“…Mixed-methods frameworks may also be a practical approach to optimize the applicability of a PROM in a new context of use [3]. The US FDA suggests using mixed methods in clinical trials to capture patient experience qualitatively and quantitatively and gives recommendations for identifying what is important to patients [7,[43][44][45].…”

A systematic review of moral reasons on orphan drug reimbursement

“…OMPs share the characteristic of aiming to treat small populations with targeted therapies, which leads to higher costs and difficulties in obtaining clinical evidence [ 8 ]. As prices are often high and negatively correlate with disease prevalence [ 9 ], OMPs are often not cost-effective [ 10 ]. Recently approved curative OMPs have well exceeded previous pricing standards: onasemnogene abeparvovec, for instance, a gene replacement therapy attempting to cure Spinal Muscular Atrophy with a one-time treatment, costs more than 2 million US$.…”