The patient’s view on rare disease trial design – a qualitative study

Abstract

BackgroundClinical trials in rare diseases are more challenging than trials in frequent diseases. Small numbers of eligible trial participants, often complicated by heterogeneity among rare disease patients, hamper the design and conduct of a ‘classical’ Randomized Controlled Trial. Therefore, novel designs are developed by statisticians. However, it is important to be aware of possible design aspects that may jeopardize the feasibility of trial conduct. If the burden of participation is considered out of proportion by patients or parents, recruitment may fail or participants may drop out before trial completion. In order to maximize the chance of success of trials in small populations, it is important to know which aspects of trial design are considered important by patients.ResultsWe have interviewed all ten members of the Patient Think Tank (PTT) of the ASTERIX project, a European research consortium on methodology for clinical trials in small populations. The PTT members are rare disease patient representatives who have completed extensive training in clinical trial methodology. We have analyzed the interviews qualitatively according to Grounded Theory using a thematic analysis, and we structured the topics in four chronologically ordered themes: 1. Involvement in trial design; 2. Opinions on trial design; 3. Trial participation; 4. Phase after the trial. Our main findings are that the PTT-members recommend that patients are involved in trial design from an early stage on, and have influence on the outcomes and measurement instruments that are chosen in the trial, the length of the study, the choice of participants, and the information that is sent to potential participants. Also, according to the PTT-members, patient groups should consider setting up disease registries, placebo groups should be minimized, and more education on clinical trials is advised.ConclusionsRare disease patient representatives who have been educated about clinical trial methodology think it is important to involve patient representatives in research at an early stage. They can be of advice in trial design in such a way that the ratio of potential benefit and burden of trial participation as well as the chosen outcome measures and in- and exclusion criteria are optimized.Electronic supplementary materialThe online version of this article (10.1186/s13023-019-1002-z) contains supplementary material, which is available to authorized users.

Patient and clinician opinions of patient reported outcome measures (PROMs) in the management of patients with rare diseases: a qualitative study

“…One of limitations of this study was the difficulty of recruiting a sufficient number of participants to ensure that data saturation was achieved. However, this is not unique to our study as other studies involving patients with rare diseases have encountered similar difficulties [39,61,62]. The small sample sizes makes it difficult to preserve the anonymity of participants hence the decision not to provide a detailed socio-demographic description of the participants [63].…”

Profiling trial burden and patients’ attitudes to improve clinical research in epidermolysis bullosa

“…Example of challenges and solution approaches for RD trials[8][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23][24][25][26][27] …”

“…Example of challenges and solution approaches for RD trials[8][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23][24][25][26][27] (Continued) Multi-centre trials • Increase sample size through (international) recruiting, collaboration and networking • For lower costs and tighter timelines, prevalence of an illness should determine where a site is activated Research networks • Identification and cross-linking of specialized centers and disease specific registries • Data/knowledge/expertise sharing, dissemination of information among experts (standardized registries with international interoperability, inventories, partnership with patient organizations) to boost recruitment, trial feasibility and international research collaboration Protocol discussion • Assembly of a study review panel comprising patients, EB physicians, nurses, researchers, statisticians with assessment of appropriate/feasible rationale, methodology, endpoints/outcome measures, inclusion/exclusion criteria Patient centricity • Patients to co-decide on clinically meaningful endpoints, patient-relevant outcome measures, surmountable trial burden, study portfolio and amendments to meet patients' demands and priorities, thereby fostering faster recruiting/enrollment, reduced complexity and drop out rates, faster drugs marketing • Costs of gathering such patient input on protocol design are additionally reported to be relatively low compared to the potential benefits Ethical principles • Distinct consideration of disease severity and adequacy of alternative treatments especially in paediatric population Pharmacovigilance regulations • Evaluation and discussion of acceptable trial burden for patients with authorities and sponsors Exploit impact of social media; patient communities homepage; messaging or telephone reminders to increase awareness • Access to registry data and referral networks Placebo control • Allowing standard of care treatment instead of placebo control; alternative clinical trial designs (e.g. cross-over); minimize the use of placebo (e.g.…”

Impact of rarity on Canadian oncology health technology assessment and funding

“…Although some of these end points are validated, International Journal of Technology Assessment in Health Care they do not always translate into a survival advantage. Advocates for these trial designs note that it is important for patient advocates to be consulted early in the design process, such that they are able to provide input to maximize participation and optimize trial criteria (24). In contrast, others argue that rare indications should not be accommodated by lowering the bar for the type and design of supporting evidence that is required, as patients do not benefit from sub-optimal evidence and may fall under false pretenses of cure or improved quality of life (25).…”