Washington, DC – Over the last few years, we’ve witnessed a significant shift in the regulatory space for rare disease therapeutics, with the FDA and other authorities making conscious efforts to implement much-needed regulatory flexibility to accommodate the practical challenges of trial design for these conditions. For small biotechs and pharma companies focusing on rare disease treatments, this presents an unprecedented opportunity to solve problems with patient access and trial design by collaborating with authorities to adapt protocols and get approved drugs to market.
In the U.S., an estimated 25 to 30 million people live with a rare disease. And yet, only 5% of these conditions have FDA-approved therapeutics, leaving countless Americans and their loved ones without adequate treatment options. Rare disease specialists and patients around the world desperately need options. The problem? These conditions don’t fit the mold, presenting several obstacles to straightforward drug development.
The main issue blocking these processes is small patient populations. By definition, a rare disease impacts fewer than 200,000 persons in the U.S., and patients are likely to be geographically dispersed. Only a select few of these patients may be eligible to join a study, and many individuals decline to participate due to the severity of their condition or distance from study sites. Consequently, preparing a conventional clinical dossier to support a New Drug Application is often impossible.
We’ve experienced these challenges and regulatory evolutions first-hand at TMC, a global full-service clinical research organization specializing in rare, orphan and oncology diseases. Now, to enable our clients to capitalize on the latest regulatory changes, our team is focused on creating and executing innovative trial designs that enable an expedited path to market. This takes careful consideration of the specific diseases and therapies involved. While the FDA can provide new frameworks, there’s no one-size-fits-all solution in the world of rare disease research. It’s ultimately up to biotechs to push the envelope in trial design.
The Evolution of Rare Disease Regulation
The FDA recognizes that rare diseases are highly diverse, with varying prevalence, rates of progression, clinical manifestations and degrees of heterogeneity. So while all trials must follow strict quality and pharmacovigilance protocols, many industry leaders advocate for more flexibility in how regulatory standards are met.
For example, Peter Marks, director of the FDA’s Center for Biologics Evaluation and Research, recently argued for non-randomized, single-arm trials when testing gene therapies for rare diseases backing adaptive biomarkers and surrogate endpoints to support approvals. U.S. regulators agree this approach could benefit specific cases. While the FDA has run an “accelerated approval” mechanism since 1992 to help green light medicines for life-threatening diseases based on surrogate endpoints, the agency is now taking more proactive steps to cater to rare conditions.
In the oncology space, there is Project Optimus, an FDA initiative to reform the dose optimization and selection paradigm in oncology drug development. In 2023, the Biden Administration also launched the Support for clinical Trials Advancing Rare disease Therapeutics (START) pilot program, which enables a limited number of sponsors to communicate more frequently with FDA staff and provides a mechanism for addressing clinical development issues.
The goal of these initiatives is simple: to compress development timelines and make rare disease studies more accessible for researchers and patients alike. However, there isn’t a universal solution that will effectively get therapies to patients.
Regulators may deem single-arm trials inappropriate for very heterogeneous disease populations or too-small sample groups, and rare disease drugs must still have substantial evidence of their effectiveness and safety in order to secure FDA approval. As a result, to successfully harness new regulatory flexibility to bring therapies to market, biopharma firms must consider the specific parameters of each disease and drug study, working to align trial design with regulatory standards.
Capitalizing on New Regulatory Opportunities
At TMC, we encourage biotechs to embrace innovative approaches to trial design. In particular, we’ve seen promising results from combining study phases to expedite marketing approvals. For example, we’re working with a biotech developing a rare disease product that’s currently in Phase I/IIa. Through early interactions with the FDA, the company expanded the existing study to incorporate the Phase IIb requirements rather than conducting a separate Phase IIb trial.
Should the current study have positive outcomes, researchers can immediately engage in future developmental steps, including planning a Phase III trial. The company has calculated that this could save them an impressive 15–18 months in the overall development timeline.
The FDA is also encouraging sponsors to evaluate the identification and use of biomarkers. Researchers must collect enough information to support each biomarker and validate assay methods to determine quality, but more flexibility in this area is driving progress. Identifying a biomarker or surrogate biomarker where possible will strengthen trial data—essential to making the most of limited rare disease patient numbers.
What’s more, many biopharmas are embracing more patient-centric studies to tackle issues with small participant groups. We believe site choice is crucial, as is engaging key opinion leaders and patient associations from the outset. By decentralizing trials and taking research to those affected by the targeted disease, biotechs can create patient-friendly studies that generate meaningful endpoints and get treatments to market quickly.
Embrace Flexibility While Avoiding Pitfalls
Although global authorities are offering new financial and regulatory incentives to accelerate rare disease drug development, this flexibility has its limits. Modifying original protocols to meet regulatory standards may be acceptable on a case-by-case basis, but some practices remain nonnegotiable.
For example, biotechs may not necessarily need to do natural history studies for every rare disease drug they develop, but they’ll still have to show that they’ve researched existing natural history studies and demonstrate an in-depth knowledge of the natural history of the condition.
From understanding the development of the disease, innovations can be made to a clinical investigation using nonstandard methods and controls, such as real-world data, historical control groups, Bayesian analysis, ‘n-of-1’ clinical investigations and master protocols—but only if the FDA approves these unconventional approaches.
The agency still expects the usual clinical and non-clinical tests to be carried out where possible, so getting its early buy-in is crucial to expediting marketing approvals. With this in mind, sponsors must work closely with regulators, skilled protocol designers and statisticians to find a suitable course of action.
Fortunately, as FDA regulators continue to advocate for flexibility in rare disease therapy trials, we expect sponsors will face fewer obstacles in this area. By collaborating with patient groups, regulatory authorities and medical specialists, even small biotechs can overcome problems with conventional trial design, ultimately helping them to deliver rare disease therapies to the people who need them most.
Carol Woodward is the chief operating officer and Catherine Moncad is the vice president of regulatory services at TMC Pharma Services Ltd, a clinical research organization that supports biotech and pharma companies to develop innovative, often lifesaving, treatments for orphan, rare and oncology diseases.