September 26, 2014
In response to growing clinical, technical and economic challenges to bring to market drugs and diagnostic products for pediatric rare disease (PRD) patients, the FDA conducted a public workshop in January 2014 to discuss issues with academics, researchers, patients, advocacy groups, industry and regulators. Based on their contributions, the US Food and Drug Administration (FDA) published a strategic plan last July, Accelerating the Development of Therapies for Pediatric Rare Diseases, proposing four objectives to improve children’s access to orphan drugs and devices.
The first objective is to improve basic and translational science on pediatric rare diseases. Regulators call for a better understanding of rare disease natural history, i.e. disease evolution if left untreated. Progression of rare diseases is often poorly understood due to small numbers of cases. Knowledge gaps are particularly marked in pediatric groups, in which diseases evolve in an age-dependent mode. The FDA proposes applying modelling techniques to predict orphan product performance in different age and patient groups.
The second objective is to initiate and reinforce interaction, partnerships and collaboration between stakeholders (researchers, industry, regulators, patients, advocates and physicians). Inter- and intra-regulatory agency communication contributes towards harmonizing standards for rare disease classification and therapeutic development. The FDA and the European Medicines Agency (EMA), for instance, hold regular discussions to coordinate international research and clinical protocols. The FDA recommends strengthening international collaborations to pool resources and accelerate product development plans for rare diseases.
The third objective is to further develop standards and methods to monitor the safety and efficacy of orphan products. This is particularly relevant to long term treatments for patients with chronic rare diseases. The FDA recommends guidance documents and investigator training to improve product development efficiency and age-specific product safety, suitability and effectiveness under the Best Pharmaceuticals for Children’s Act (BPCA) of 2002 and the Pediatric Research Equity Act (PREA) of 2003. Dose-dependent safety assessments are essential to treat pediatric rare disease patients effectively. The FDA recommends using biomarkers, for instance, to help find appropriate doses and measure dose responses.
The fourth objective is to enrich the FDA’s PRD evaluation process by involving patients, patient advocates and caregivers in clinical trial designs early on. Criteria such as patient benefit-risk preferences, clinical outcome measures and feedback on quality of life should constitute part of the drug assessment process more systematically and appropriately. The FDA recommends greater flexibility and adaptability in orphan product evaluation processes, building on existing evidence, to overcome the limiting effect of small patient numbers in rare disease clinical trials. This objective builds on the agency’s Rare Pediatric Disease Priority Review Voucher (PRV) program of 2012, to further accelerate the development of pediatric orphan products.
While orphan medicinal product development is challenging at the best of times, developing orphan products for children with rare diseases is all the more complex due to age-related factors and ethical considerations. Information and clinical evidence on medical product safety and efficacy in children with rare diseases is generally inadequate as a result of small patient numbers, age-specific physiology and responses to treatment. The FDA’s recommendations to increase collaboration and transparency aim to draw attention to the need for additional and improved pediatric rare disease care.