The U.S. Food and Drug Administration (FDA) has recently launched the Rare Disease Innovation Hub, a groundbreaking initiative aimed at accelerating the development of therapeutic products for rare diseases, hot on the heels of another major clinical trial innovation initiative. Dedicated workstreams within the new hub will advance regulatory science, with a particular focus on innovative trial design, novel endpoints, biomarker development, real-world evidence, and advanced statistical methods. This development holds significant promise for clinical research in rare disease and for various industry sectors that develop therapeutic products for rare diseases (e.g. pharmaceutical and medical devices). Here, we explore what the new hub might mean for clinical research and industry as well as the tangible impact it will have on patients. We will also explore the substantial impact N of 1 trial designs can have in the field of rare disease research.
Benefits for Clinical Research
For clinical research organisations (CROs), clinicians and academic researchers, the FDA Rare Disease Innovation Hub will offer a wealth of resources and support to conduct cutting-edge research in various rare diseases. In rare disease research, data is often fragmented and isolated within specific organisations or studies, making it difficult to aggregate and analyse large datasets that are crucial for making meaningful scientific advances. The hub will help to overcome the data siloing that has plagued rare disease research to date (Denton et al, 2021) by facilitating greater collaboration, data sharing, and integration across different research groups and institutions. Furthermore, the hub's focus on leveraging big data and advanced analytics will enable researchers to identify novel biomarkers and therapeutic approaches, significantly accelerating the pace of discovery.
Navigating the requirements of domestic Institutional Review Boards, international ethics boards, and the U.S. HIPAA regulations can be daunting for both new and experienced investigators working with rare disease. The complexity of adherence to HIPAA regulations is amplified when conducting clinical trials in rare diseases because of factors like maintaining the anonymity of participants (a particular challenge due to inherently smaller affected populations), and the need for institutional collaboration and data sharing, all of which adds a layer of complexity to the process (Griggs et al, 2009). The FDA Rare Disease Innovation Hub will significantly reduce this complexity. It is anticipated that it will foster a more cohesive environment for institutional collaboration and data sharing, thereby reducing administrative burdens, accelerating the approval process and ultimately facilitating a more efficient pathway for investigators (Griggs et al., 2009). Through these efforts, the FDA’s Hub will enhance researchers' capacity to conduct rigorous, ethically sound clinical trials that meet both U.S. and international standards.
Impact on Commercial Industry
For the pharmaceutical and medical device industries, the FDA Rare Disease Innovation Hub will offer a structured pathway to bring novel treatments to market more efficiently. The Hub will focus on products intended for smaller populations and for rare diseases where the natural history is variable and not fully understood, as it is recognised that developing therapies for these conditions can be particularly challenging. The Hub's focus on innovative endpoints and real-world data utilisation, as seen in the Rare Disease Endpoint Advancement Pilot Program (RDEA), will facilitate development of precise and effective therapies tailored to people with rare disease. The RDEA Program aims to provide sponsors with ongoing FDA collaboration throughout the efficacy endpoint development process, promoting scientific innovation and regulatory advancements.
The FDA Rare Disease Innovation Hub will help the larger rare disease community navigate important intersections across the FDA that affect people with rare diseases, including medical devices, diagnostic tests, and combination products (two or more different types of medical products, such as drugs, devices, and biological products). The Accelerating Rare Disease Cures Program (ARC) is another crucial component of the Hub designed to expedite the development of safe and effective treatments. This initiative is different from RDEA as the ARC Program focuses on expediting the development of treatments for rare diseases through strategic partnerships and innovative approaches. In contrast, the Rare Disease Endpoint Advancement (RDEA) Pilot Program aims to refine and validate clinical endpoints specific to rare diseases, enhancing the reliability of outcome measures in clinical trials. Building on these initiatives, the Hub also seeks to enhance cross-collaboration to address common scientific, clinical, and policy issues related to rare disease product development.
Implications for Patients
Clinical trials in rare diseases have traditionally been very challenging to conduct for several reasons including the inherently limited patient population, complex and heterogeneous symptoms, regulatory hurdles, and substantial patient and caregiver burden. All of these factors complicate the development and testing of new therapies for these patients. Importantly, the Rare Disease Innovation Hub plans to integrate patient perspectives by engaging with patients, caregivers, and patient advocacy groups. This will ensure that rare disease trials are aligned with the actual needs and experiences of those living with rare diseases.
The Role of N of 1 Trial Methodology
An N of 1 trial is a type of clinical trial that focuses on determining individual treatment responses. N of 1 trials are particularly relevant in the context of rare diseases, where patient populations are small and often heterogeneous. Griggs et al. (2009) show how N of 1 trials can be used to establish efficacy and to support regulatory approval of new treatments for rare diseases. A recent systematic review highlighted the importance of N of 1 trials in providing tailored therapeutic strategies for people with rare disease, demonstrating their potential to significantly improve treatment outcomes (Müller et al, 2021). N of 1 trials are one type of single-case design; there are other types of single-case experimental design that may be valuable and suitable for the field of rare disease.
We hope to see N of 1 trials feature among the innovative clinical trial designs considered in the work carried out by the new hub. N-of-1 Hub is uniquely positioned to leverage these advancements, because of our expertise in design, conduct, and analysis of clinical trials for rare diseases using N of 1 trial methodology. Our work aligns with the Rare Disease Innovation Hub’s aim to ensure that people with rare disease receive the most tailored and effective treatments possible.
N-of-1 Hub is a consulting company that specialises in designing, conducting and analysing personalised clinical trials using single-case designs. N-of-1 Hub provides consulting services and training for companies, clinicians, researchers, and healthcare consumers who wish to conduct personalised clinical trials. N-of-1 Hub also offers data management and analysis services and customised workshops and courses. For further information about N-of-1 Hub, and to discuss your study needs, please contact us.
References
Denton, N., Molloy, M., Charleston, S., Lipset, C., Hirsch, J., Mulberg, A. E., ... & Marsh, E. D. (2021). Data silos are undermining drug development and failing rare disease patients. Orphanet Journal of Rare Diseases, 16, 1-4. https://doi.org/10.1186/s13023-021-01806-4
Griggs, R. C., Batshaw, M., Dunkle, M., Gopal-Srivastava, R., Kaye, E., Krischer, J., ... & Merkel, P. A. (2009). Clinical research for rare disease: opportunities, challenges, and solutions. Molecular genetics and metabolism, 96(1), 20-26. https://doi.org/10.1016/j.ymgme.2008.10.003
Müller, A. R., Brands, M. M., van de Ven, P. M., Roes, K. C., Cornel, M. C., van Karnebeek, C. D., ... & van Eeghen, A. M. (2021). Systematic review of N-of-1 studies in rare genetic neurodevelopmental disorders: the power of 1. Neurology, 96(11), 529-540. doi:10.1212/WNL.0000000000011597