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Table 1 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]

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

Main challenges to RD research
Disease characteristics
Target population • Small number of patients
• Eligible patients often geographically dispersed
Heterogeneity of disease and diseased study cohort • Many genotypes and phenotypes; inconsistent genotype-phenotype correlations; improper diagnostics
• Soft inclusion criteria to foster recruitment
• Enhanced degree of random imbalance in covariates in small study samples ➔ limited generalizability and applicability of RD clinical trial results for real life
Ethical issues • Concerns to conduct research in children who, however, are predominantly affected and at risk to develop early, potentially irreversible complications, thus benefit most from preventive therapeutics
Patient perspectives
Travel burden • Limited number of trial sites, complex medical problems, disease burden and health condition affecting transportability
Financial burden for patients • Travel, accommodation, dependent care, off-work time, family/caregivers‘commitments
Time consuming • Daily routine for (additional) dressing changes, patient diaries, photo documentation
• Study visits at short intervals in addition to standard/routine clinical appointments
Additional clinical tests • Invasive interventions on vulnerable skin e.g. blood tests, biopsies, additional dressing changes
Higher risks • Generated evidence on safety and/or efficacy from clinical trials in small (adult) populations limited;
• Attempts to reduce risks may increase complexity of clinical trials with coincident declining numbers of eligible and recruited patients per site
Trial design/planning, study protocol
Limited data • Limited knowledge on pathogenic disease traits, potential therapeutic targets and natural course; lack of knowledge on types and timing of outcomes; little background research to support clinical trial planning ➔
• Difficulties to identify key milestones; estimate expected effect size; calculate number of probands; define appropriate study length, clinical rating scales and suitable clinical trial endpoints
Small sample size • Restricted replication and limited statistical power; limited acceptable evidence of efficacy; especially slight or moderate changes hardly reach statistical significance
Outcome measures, endpoints • Determination of feasible, appropriate, well-defined, reliably measurable parameters that are relevant to patient, observable within a reasonable timeframe, sensitive to intervention
• Complex endpoints reduce number of centers able to participate in trial
Restrictive inclusion/exclusion criteria • Stringency usually enables a more uniform group of participants which is especially relevant in highly heterogeneous diseases/disease populations like in EB
• Account for reduced variability and increased validity/statistical power/significance in trials with a small number of participants
• Stringency may create (younger and healthier) trial population that is not representative of the population with the given disease (real life data)
Complex safety testing • Required for cellular and molecular therapies
• Needed to be tailored to particular types of individual patients
Longer study periods • Slower enrollment due to fewer patients; more time necessary to capture meaningful data; lack of precedent, often “first in class” drugs; increased development costs, not expected to make huge revenues once drugs come to market due to small consumer base
Concurrently recruiting trials • (Internal) competition for a small number of eligible patients
Administrative burden / costs
Administrative and logistical efforts • Small number of geographically dispersed patients and specialist centres
• Multinational trials logistically difficult to conduct and costly (differences in regulatory and ethical requirements; hurdles of international contracting, insurance and liability laws; additional means of communication and translation; national cost variation; language and cultural barriers, inherent differences in healthcare systems, different standards for diagnostics and of care; variable availability of treatment options, funding and research culture; risk of increased heterogeneity of patient population due to genetic (subsets) or environmental factors
Approaches to overcome obstacles in RD research
Addressing disease characteristics
Disease registries • Encourage and facilitate clinical research (correlation of complex genotype/phenotype relationships; determination of epidemiological and prognostic markers to identify and comprehensively characterize disease traits; enable accurate prenatal/preimplantation/predictive diagnosis, prognostication and determination of recurrence risks)
Natural history / observational studies • Increase knowledge about pathogenic disease traits and natural course
Addressing trial design/planning, study protocol
Statistical analysis plans • Rigorous sample size planning and statistical analysis to precisely define probabilities of a false positive and false negative error in conclusions
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
Alternative clinical trial designs • May decrease necessary sample size; increase information obtained from each enrolled subject, trial acceptability and enhance patient enrollment
Regulatory and legal issues • Global regulatory strategy and global operational execution; harmonization of regulatory and funder requirements and institutional policies to reduce complexity
Addressing patient perspectives / recruitment
Electronic patient recruitment • 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. allocation ratio)
Site support • Concierge service; minimal waiting time; all assessments within local facility; comfortable environment
Transparency • Transparent practices: availability and communication of clinical trial results for/to patients
Patient education • Comprehensible, age-adapted patient education and information material, clear consent forms
• Use of various media formats to provide key messages and outreach materials: videos, workshops/webinars, websites, newsletters, paper-handouts
• Education on reliable sources that demonstrate a close collaboration between medical experts, sponsors, academia, regulatory agencies, patient groups
• Layperson’s summaries on ongoing and scheduled trials via homepage, emails and press releases
• Explaining thoroughly and objectively informed consent procedures; giving realistic expectations on the basis of preclinical safety and toxicity testing to address therapeutic misconceptions (“new is not always better”; misconstruction of research as therapy); clarification about the study purpose including production of generalizable knowledge with potentially no direct benefit
• Involvement of trial experienced patients serving as authentic promoters
Travel burden
Facilitated travelling • Comfortable lodgings and logistical support (concierge-level service for transportation and booking)
Home healthcare services • Home-based support and delivery of study medication carried out by homecare health practitioners, if applicable (e.g. for drug infusions, blood draws, minimally-invasive tests including pharmacokinetic sampling)
Flexible study design • Critical review of study protocols for feasible frequency of on-site visits; flexible slots for on-site visits (including assessment schedules with early, late or weekend appointments); alternate assignment of participants to data collection time points to reduce sample collection burden
Alternative clinical trial designs • e.g. shared care sites, “hub and spoke” trial design (major procedures performed at the main study site; minor procedures happen on local sites); cross-over design, series of n-of-trials; response-adaptive study design; factorial designs, etc.
Cost reduction • Upfront payments or reimbursement from study account of trial-related added expenses, especially travel costs and accommodation for patients and caregivers
Mobile and web-based technology • For data collection