Abstract
BackgroundDemonstrating treatment benefits within clinical trials in the context of rare diseases is often methodologically and practically challenging. Mixed methods research offers an approach to overcome these challenges by combining quantitative and qualitative data, thus providing a better understanding of the research question. A convergent mixed methods design in the context of Merkel cell carcinoma, a rare skin cancer, was used during the JAVELIN Merkel 200 trial (NCT02155647).MethodsNine patients receiving avelumab in the JAVELIN Merkel 200 trial were interviewed at baseline prior to receiving study treatment, and at 13 weeks and 25 weeks after first avelumab administration. Key concepts of interest identified from the baseline interviews were physical functioning, fatigue/energy, and pain. Patient perceptions of the overall change in their cancer-related health status since starting study treatment were also recorded. During qualitative analysis, at each time-point, each concept of interest was assigned a category describing the trend in change (e.g. newly emerged, no change/stable, improved, worsened, ceased/disappeared). In parallel, patients’ tumour status was determined by the clinical overall response status as per the clinical trial protocol.ResultsA high concordance between patient-reported qualitative data and assessed tumour response was observed. All eight patients who clinically improved had perceived a subjective improvement in their disease since the beginning of the study; the single patient whose disease worsened had a perceived deterioration. Patient perceived benefit in physical functioning, fatigue/energy and pain was subsequent to the measured change in clinical status as assessed by tumour response. This suggests that patient-reported assessment should be examined over the long term in order to optimally capture meaningful treatment effect.ConclusionEmbedding qualitative research in clinical trials to complement the quantitative data is an innovative approach to characterise meaningful treatment effect. This application of mixed methods research has the potential to overcome the hurdles associated with clinical outcomes assessment in rare diseases.
Highlights
Demonstrating treatment benefits within clinical trials in the context of rare diseases is often methodologically and practically challenging
The standardized procedures for patient-reported outcome (PRO) questionnaire development to support labelling claims, and the qualification for drug development tools recently released by the Food and drug administration (FDA) [2] are hardly feasible in the context of rare diseases; and the FDA roadmap is difficult to apply to orphan drugs [3]
Patient population Of the 88 patients with metastatic Merkel cell carcinoma (MCC) whose disease progressed after latest chemotherapy and who were enrolled in the JAVELIN Merkel 200 clinical trial Part A, 19 accepted to be interviewed at baseline prior to receiving study treatment; of those 19 patients, 12 were interviewed at Week 13, and 10 at Week 25
Summary
Demonstrating treatment benefits within clinical trials in the context of rare diseases is often methodologically and practically challenging. The best candidates for concepts of interest used to show a meaningful treatment effect are often not known at the time of start of the clinical trial due to the lack of knowledge of natural history of these diseases and the novelty of the drugs being assessed. This is especially true for rare diseases where randomized controlled clinical trials are usually not possible, preventing comparison of PRO data within and across trials. Conventional PRO methods used to demonstrate a meaningful treatment benefits-risks assessment and support labelling claims may be challenged in the context of rare diseases
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