The rare disease landscape poses myriad challenges for researchers, policymakers, and CROs, particularly in navigating its intricate regulatory environment. Rare diseases, which affect only a small portion of the population, make it especially challenging to develop effective treatments because there are so few patients available for research and clinical trials. In addition, the high costs associated with developing treatments for rare diseases are exacerbated by the need for specialized manufacturing processes and logistical complexities. These factors can deter pharmaceutical companies from investing in rare disease research altogether.
The landscape faced by rare disease researchers is, therefore, a challenging one. Policymakers are acutely aware of the difficulties of surmounting evidence thresholds amid tiny patient populations but continue to run into hurdles when it comes to helping sponsors navigate them.
What is a rare disease?
While the classification of a disease as “rare” varies by region, The World Health Organization (WHO) recognizes rare diseases as affecting 0.065%-0.1% of the total population, with around 70% of these conditions starting in childhood. Globally, rare diseases affect around 300 million people[i].
Featuring small patient populations not only makes it difficult to gather sufficient clinical data but also raises unique regulatory questions regarding the evidence required for drug approval. Policymakers are aware of these challenges and acknowledge that traditional evidence thresholds may not be suitable for the unique context of rare diseases. However, despite this understanding, significant hurdles remain in guiding sponsors through the regulatory maze.
The integration of advanced technologies, such as AI and big data analytics, have the potential to streamline clinical trials and improve data collection, yet they also introduce new regulatory considerations regarding data privacy and security. In addition, high therapy costs and complex reimbursement plans remain major barriers to patient access, highlighting the need for new pricing and access models in the rare disease market.
As stakeholders continue to advocate for greater awareness and resources, the need for a cohesive regulatory strategy that addresses the unique challenges of rare diseases becomes increasingly vital.
The Rare Pediatric Disease Designation (RPDD) program is winding down
The FDA’s RPDD program has been a pivotal initiative in addressing the unique challenges faced in developing treatments for rare pediatric conditions.[ii] This programme provided a priority review voucher (PRV) to sponsors of approved drugs, expediting the review process for future drug applications. However, as the programme began winding down in late 2024, it has raised significant concerns about the future landscape of pediatric rare disease treatment, with the final vouchers to be issued ‘not later than September 30, 2026.’[iii]
Established in 2012 as a financial incentive to encourage drug development for rare pediatric diseases, the RPDD programme has been instrumental in incentivising pharmaceutical companies to invest in treatments for rare pediatric diseases, which often affect fewer than 200,000 individuals in the US. The PRV was a valuable asset, allowing companies to accelerate the FDA review process for other drugs, thereby potentially bringing new treatments to market more swiftly.
The winding down of RPDD could lead to a reduction in the number of new treatments being developed, as the financial and logistical challenges of bringing pediatric rare disease drugs to market remain significantly high. Its winding down poses challenges that require innovative solutions to ensure that children with rare conditions continue to receive the attention and resources necessary for effective treatment development.
Introducing the Rare Disease Evidence Principles (RDEP)
Orphan drug designation is a special regulatory status granted to medicines for rare diseases affecting small patient populations – conferring incentives like reduced fees, additional scientific support and periods of market exclusivity to encourage development. In response to the winding down of RPDD, the FDA launched the Rare Disease Evidence Principles (RDEP)[iv] to expedite and clarify the review of therapies for rare diseases with very small patient populations and significant unmet needs – particularly those caused by known genetic defects. RDEP aims to offer sponsors clearer guidance on acceptable evidence to demonstrate a treatment’s effectiveness, recognizing the challenges of conducting traditional clinical trials in rare disease contexts.
Developed and implemented jointly by the Center for Drug Evaluation and Research (CDER) and the Center for Biologics Evaluation and Research (CBER) the process allows approval based on a single robust study supplemented by strong confirmatory evidence, such as mechanistic or biomarker data, non-clinical models, pharmacodynamic results, or case reports.[v] Sponsors may apply before pivotal trials begin, provided the therapy targets a genetically defined, rapidly progressive rare disease affecting fewer than 1,000 US patients with no adequate alternatives. The process is distinct from orphan-drug designation, and postmarketing requirements may apply to ensure ongoing safety and efficacy.
Why does this matter?
In 2024, half of the FDA’s novel drug approvals had orphan drug designation, reflecting rapid growth in rare disease research and its appeal to innovative biotechs. However, the recent federal funding cuts and slower legislative processes have raised concerns about the future of rare disease research among stakeholders. The FDA’s Rare Disease Innovation Hub[vi], launched in July 2024, aims to support orphan drug research and foster collaboration, but currently operates with limited resources and no dedicated budget. Meanwhile, organisational changes at the FDA and the US Department of Health (HHS) as well as high-profile drug approval delays, have contributed to industry unease. Despite these challenges, there is ongoing commitment from the FDA and the rare disease community to advance research, adapt to policy shifts, and maintain momentum in developing treatments for rare diseases.
Trial designs that are kinder to families
Instead of just focusing on the data being collected companies are “putting the patients first” in Rare Disease studies. Amid ongoing difficulties expediting rare disease research, and with the RPDD boost fading, sponsors will need trial designs that are kinder to families if they are to meet legal strictures. This means fewer clinic trips, simpler schedules, and options like home visits and blood microsamples.
The traditional clinical trial model often requires frequent visits to specialised sites and is often burdensome for families dealing with rare pediatric diseases. Such families may face logistical challenges, including long-distance travel. To address these issues, trial designs must evolve to become more family friendly. This includes reducing the number of clinic visits, simplifying trial schedules, and incorporating options such as home visits and the use of new technologies.
For instance, decentralised (virtual) clinical trials offer a proven solution, leveraging digital technologies to reduce the need for physical site visits. As their expansion during the Covid-19 pandemic highlighted, it is an approach that also increases access to trials for those living in remote or underserved areas. The use of wearable technologies can further enhance the trial experience, and provide continuous health monitoring, additionally offering real-world data (RWD) that can be invaluable for trial outcomes. The result is enhanced patient retention and adherence, thereby generating more robust data and contributing to the success of clinical studies.
As the RPDD program’s influence wanes, the rare disease community must embrace these new methodologies to ensure that the momentum in pediatric research is not lost. By adopting trial designs that are kinder to families, sponsors can continue to meet regulatory requirements while also addressing the unique challenges faced by those living with rare pediatric diseases.
The vital role of CROs
The operational agility of a seasoned CRO is invaluable in overcoming the unique challenges of rare disease trials, where limited patient populations, complex logistics, and shifting regulatory landscapes demand specialised expertise. Through expert execution, the right CRO can help ensure that every participant, regardless of age, helps drive the study towards clear and meaningful outcomes.
Be sure to work with a CRO that provides bespoke teams and flexible operational models that align closely with sponsor objectives. As the orphan drug sector grows, strategic CROs like Caidya are essential partners, helping sponsors design trials with patients at the center, navigating a tricky regulatory landscape, and ultimately delivering more meaningful outcomes for the rare disease community.
[i] https://www.rarediseaseday.org/
[ii] https://www.fda.gov/industry/medical-products-rare-diseases-and-conditions/rare-pediatric-disease-designation-and-priority-review-voucher-programs
[iii] https://www.fda.gov/industry/medical-products-rare-diseases-and-conditions/rare-pediatric-disease-designation-and-priority-review-voucher-programs
[iv] https://www.fda.gov/news-events/press-announcements/fda-advances-rare-disease-drug-development-new-evidence-principles
[v] https://www.fda.gov/about-fda/fda-organization/center-biologics-evaluation-and-research-cber
[vi] https://www.fda.gov/industry/medical-products-rare-diseases-and-conditions/fda-rare-disease-innovation-hub
