The journey of developing effective treatments for rare diseases, particularly in a pediatric population, has its own unique challenges, including (but not limited to), a small population size, disease heterogeneity, and the absence of established endpoints to support regulatory decisionmaking. While regulatory authorities have special programs and various initiatives to foster novel treatment development for rare diseases, ultimately, authorities and sponsors still need to satisfy statutory requirements for determining the safety and effectiveness of a product prior to its marketing approval. Therefore, it is essential, particularly due to the limited number of patients with a given rare disease, that careful consideration be given to the potential complexities and challenges faced when planning the development path for a rare disease treatment. 

Challenges and complexities

Rare diseases, by definition, affect a small percentage of the population, making it challenging to recruit enough participants with which to generate statistically significant data. It also doesn’t help that the natural history of many rare diseases is not well understood. This scarcity in both knowledge and patients is even more pronounced when the rare disease occurs primarily in a pediatric population where additional ethical considerations further limit the pool of eligible participants in trials. In many cases, finding enough patients to participate in even a single trial could be challenging. 

Identifying a safe and effective dose for registrational trials is one of the most critical and complex aspects of early-stage drug development for rare diseases. This process is especially challenging due to the limited number of patients available for study. Traditionally, early drug development focuses on ensuring the safety of clinical doses, with regulatory authorities prioritizing patient protection. They often favor establishing a drug as safe—even if later proven ineffective—over approving an effective drug that carries significant safety risks. 

However, in rare and ultra-rare diseases, patients and caregivers often have a different perspective of acceptable risk. With few or no existing treatment options, these communities may be more willing to accept a different benefit:risk balance in the hope of a breakthrough therapy. Despite this, drug developers must still meet regulatory requirements. Engaging early and actively with regulators, leveraging incentive programs, and discussing the benefit:risk balance—especially for severe diseases with no available treatments—are key strategies for advancing novel therapies in rare diseases. 

In addition to the different perspective on “setpoint” for the benefit:risk ratio, potential ethical and/or patient enrollment and participation issues beyond the commonly held concepts for clinical trial conduct may also need to be considered for rare disease trials. The wide variety of technology platforms, cell and gene therapies, and classes of molecules used in the treatment of rare diseases may themselves introduce additional complexity to decisions regarding patient enrollment and participation. 

Potential challenges may arise from the unique aspects of a novel therapeutic modality (e.g., cell and gene). Some treatments and conditions may preclude patients that are first exposed to an investigational therapy in the dose finding phase of the development program from receiving another dose within the confines of a future trial (due to the restrictions placed by inclusion and exclusion criteria). In addition, certain viral vector-based therapies that carry a significant risk of forming neutralizing antibodies may also prevent multiple patient exposures to an investigative therapy. Given the low patient numbers in rare diseases, sponsors may find themselves forced to consider specifically when, and for what purpose, patients can best be utilized in the clinical development program. 

Innovative approaches and FDA initiatives

In addition to the special designations available (e.g., orphan, breakthrough therapy, fast track, etc.) and accelerated pathways that the FDA has defined to inspire innovative drug development, the FDA encourages sponsors (particularly in rare disease drug development) to consider the use of novel trial designs with use of alternative statistical theories. These approaches are discussed in multiple workshops held by the Agency and its partners (e.g., Regulatory Science Accelerator: Computational Modeling & Simulation (CM&S) in FDA-Regulated products | Reagan-Udall Foundation). Importantly, exploring the use of novel trial designs with the goal of determining the safe and effective dose of a product and/or to advance assessments of effectiveness, requires a true interdisciplinary collaboration between scientific and regulatory experts as well as the patient and their caregivers, who are in many instances, the true experts in rare diseases.   

Some innovative approaches that sponsors should consider include: 

• Pharmacokinetic studies using an N-of-1 or single-case experimental design. 

• The use of mathematical modeling and simulation (i.e., in silico trials) for informing dose selection. 

In particular, the use of in silico trials should not be underestimated as a viable approach given its already successful application in rare disease drug development. Decentralized trials, when designed and used properly, can provide an irreplaceable level of comfort to patients and allow for increased participation in trials while yet, ensuring the quality of data required for regulatory decision-making. Further, various innovative approaches using a combination of dose ranging and efficacy assessments in a single trial using innovative designs (e.g., adaptive designs, randomized withdrawal designs, and randomized delayed-start designs) should also be considered with a recognition of the complexity and unique challenges for each rare disease.  

Ultimately, each investigational drug product needs a detailed and specific multi-faceted assessment to optimally choose a combination of in vitro, in vivo, in silico, and innovative trial design approaches to make the most of the rare disease patient’s involvement in the dose selection and efficacy assessment process. Sponsors should consider all scientifically relevant and regulatorily acceptable study/testing options available (e.g., microphysiologic systems, relevant animal models, etc.) to diminish both the time and number of participants required at all stages of the clinical program.  

Navigating the regulatory landscape is another significant challenge in rare disease drug development. Each rare disease presents unique hurdles, and a one-size-fits-all approach is rarely effective. A multidisciplinary team, including clinicians, pharmacologists, and regulatory experts, is essential to successfully navigating these hurdles. The FDA has recognized the challenges faced by sponsors and has launched several initiatives to support drug development for rare diseases. The Accelerating Rare disease Cures (ARC) Program and the Rare Disease Endpoint Advancement (RDEA) Pilot Program are examples of efforts to simplify the development process and provide clearer guidance to sponsors. 

In a significant move to further support the development of treatments for rare diseases, the FDA recently inaugurated the Rare Disease Innovation Hub. This initiative aims to facilitate multidisciplinary, cross-center information sharing and collaboration among various divisions and offices across the Center for Drug Evaluation and Research (CDER) and the Center for Biologics Evaluation and Research (CBER) at the FDA. The Hub is designed to enhance the development of therapies by integrating knowledge and expertise from different sources (both internal and external to the Agency) with the ultimate goal of improving outcomes for patients with rare diseases. By fostering a collaborative environment, the Hub will help refine the regulatory process, address scientific and policy issues, and engage with patients and patient advocacy groups to ensure that the unique needs of rare disease patients are met. 

Navigating the landscape

Early-stage drug development for rare diseases is inherently complex and requires a tailored approach for each condition. A multidisciplinary team is essential to navigating regulatory challenges and ensuring new treatments reach patients in need. Sponsors should leverage FDA initiatives, such as the newly launched Rare Disease Hub, which offers valuable support and resources. Additionally, early and well-planned meetings with the FDA can help clarify development stages, endpoints, and regulatory requirements—ultimately improving and potentially accelerating the development of critical rare disease therapies. 

Premier’s multidisciplinary team approach to rare disease drug development leverages expertise from an array of disciplines to streamline the development pathway. Our teams are here to help sponsors navigate the challenges in this space with an eye toward the unique aspects of each product, the specifics of each disease population, the sponsor’s specific goals, and the needs of the waiting patient(s).  

For support with your rare disease development program, contact us.