Regulatory strategies for rare diseases under current global regulatory statutes: a discussion with stakeholders

Abstract

Rare or orphan diseases often are inherited and overwhelmingly affect children. Many of these diseases have no treatments, are incurable, and have a devastating impact on patients and their families. Regulatory standards for drug approval for rare diseases must ensure that patients receive safe and efficacious treatments. However, regulatory bodies have shown flexibility in applying these standards to drug development in rare diseases, given the unique challenges that hinder efficient and effective traditional clinical trials, including low patient numbers, limited understanding of disease pathology and progression, variability in disease presentation, and a lack of established endpoints.To take steps toward improving rare disease clinical development strategies under current global regulatory statutes, Amicus Therapeutics, Inc. and BioNJ convened a 1-day meeting that included representatives from the Food and Drug Administration (FDA), biopharmaceutical industry, and not-for-profit agencies. The meeting focused on orphan diseases in pediatric and adult patients and was intended to identify potential strategies to overcome regulatory hurdles through open collaboration.During this meeting, several strategies were identified to minimize the limitations associated with low patient numbers in rare diseases, including the use of natural history to generate historical control data in comparisons, simulations, and identifying inclusion/exclusion criteria and appropriate endpoints. Novel approaches to clinical trial design were discussed to minimize patient exposure to placebo and to reduce the numbers of patients and clinical trials needed for providing substantial evidence. Novel statistical analysis approaches were also discussed to address the inherent challenges of small patient numbers. Areas of urgent unmet need were identified, including the need to develop registries that protect patient identities, to establish close collaboration and communication between the sponsor and regulatory bodies to address methodological and statistical challenges, to collaborate in pre-competitive opportunities within multiple sponsors and in conjunction with academia and disease-specific patient advocacy groups for optimal data sharing, and to develop harmonized guidelines for data extrapolation from source to target pediatric populations. Ultimately, these innovations will help in solving many regulatory challenges in rare disease drug development and encourage the availability of new treatments for patients with rare diseases.

Randomized Controlled Trials Versus Real World Evidence: Neither Magic Nor Myth

“… Extrapolation based on experience with broadly similar treatment modalities, in vitro experiments, animal models of efficacy, and pharmacokinetic/pharmacodynamic (PK/PD) modelling, as well as modelling of disease progression based on natural history data 20 .…”

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.…”

Ethics framework for treatment use of investigational drugs

“…There are different situations in which no authorized treatment can be satisfactorily used. For instance, in some orphan diseases there is no authorized treatment at all [ 20 ]. In other cases, a doctor may consider treatment with IDs due to the development of resistance to authorized drugs.…”