Opinion: Regulatory flexibility can accelerate the development of drugs for rare diseases

In the photo: collage showing a scientist examining, DNA and glass test tubes on a cellular background/Taylor Tieden for Biospace

Over the past few years, we have witnessed significant changes in the regulatory space for drugs for rare diseases, and there has been a conscious effort by the FDA and other authorities to implement much-needed regulatory flexibility to address the practical challenges of designing clinical trials in these diseases. For small biotech and pharmaceutical companies focused on treating rare diseases, this presents an unprecedented opportunity to address patient access and clinical trial design issues by working with authorities to adapt protocols and bring approved medicines to market.

It is estimated that 25 to 30 million people in the United States live with a rare disease. Yet only 5% of these conditions have treatments approved by the FDA, leaving countless Americans and their loved ones without adequate treatment options. Rare disease specialists and patients around the world desperately need alternative solutions. Problem? These conditions do not fit the mold, which creates several obstacles to simple drug development.

The main problem blocking these processes are small patient populations. By definition, a rare disease affects fewer than 200,000 people in the U.S., and patients are likely geographically dispersed. Only a few of these patients may be eligible to join the study, and many people decline to participate due to the severity of their condition or distance from research centers. As a result, preparing conventional clinical documentation to support a new drug application is often impossible.

We’ve experienced these challenges and regulatory changes firsthand at TMC, a full-service global clinical research organization specializing in rare, orphan and oncology diseases. Today, to enable our clients to benefit from the latest regulatory changes, our team is focused on creating and implementing innovative trial designs that enable an accelerated path to market. This requires careful consideration of specific diseases and treatments. While the FDA can provide a new framework, there is no one-size-fits-all solution in the world of rare disease research. Ultimately, it is up to biotechnologies to push the boundaries in trial design.

Evolution of the regulation on rare diseases

The FDA recognizes that rare diseases are highly heterogeneous, with varying incidences, rates of progression, clinical manifestations, and degrees of heterogeneity. So while all research must adhere to strict quality and pharmacovigilance protocols, many industry leaders are advocating for greater flexibility in adhering to regulatory standards.

For example, Peter Marks, director of the FDA’s Center for Biologics Evaluation and Research, recently advocated for nonrandomized, single-arm trials when testing gene therapies for rare diseases based on adaptive biomarkers and surrogate endpoints to support approvals. US regulators agree that this approach may be beneficial in specific cases. While the FDA has launched an “accelerated approval” mechanism since 1992 to green light drugs for life-threatening diseases based on surrogate endpoints, the agency is now taking more active steps to meet the needs of rare diseases.

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 Rare Disease Therapeutics Development Assistance (START) Pilot Program, which allows a limited number of sponsors to communicate more frequently with FDA staff and provides a mechanism to address clinical development issues.

The goal of these initiatives is simple: to shorten the development timeline and make rare disease research more accessible to both researchers and patients. However, there is no universal solution that would enable effective treatment of patients.

Regulators may deem single-arm trials inappropriate for very heterogeneous patient populations or sample sizes that are too small, and drugs for rare diseases must still have substantial evidence of their effectiveness and safety to gain FDA approval. As a result, to effectively leverage new regulatory flexibility to bring therapies to market, biopharmaceutical companies must consider the specific parameters of each disease and drug study as they work to align trial design with regulatory standards.

Taking advantage of new regulatory opportunities

At TMC, we encourage biotechnologists to use innovative approaches to research design. In particular, we have seen promising results in combining trial phases to accelerate marketing approvals. For example, we are working with a biotechnology company developing a rare disease product that is currently in Phase I/IIa. Through early interactions with the FDA, the company expanded the existing study to include Phase IIb requirements, rather than conducting a separate Phase IIb study.

If the current study yields positive results, investigators will be able to immediately engage in future stages of development, including planning a Phase III trial. The company calculated that this could save an impressive 15–18 months on the overall development schedule.

FDA also encourages sponsors to evaluate the identification and use of biomarkers. Scientists must collect enough information to support each biomarker and validate test methods to determine quality, but greater flexibility in the field is progress. Identification of a biomarker or surrogate biomarker, if possible, will strengthen trial data, which is essential to maximize the use of the limited number of patients with rare diseases.

Moreover, many biopharmaceuticals are conducting more patient-centric studies to address issues involving small groups of participants. We believe that site selection is crucial, as is the involvement of key opinion leaders and patient associations from the outset. By decentralizing research and targeting people affected by a target disease, biotechnologies can create patient-friendly trials that generate meaningful endpoints and bring drugs to market quickly.

Use flexibility and avoid pitfalls

While global authorities are offering new financial and regulatory incentives to accelerate the development of drugs for rare diseases, this flexibility has its limits. Modifying original protocols to meet regulatory standards may be acceptable on a case-by-case basis, but some practices are non-negotiable.

For example, biotechnologists do not necessarily have to conduct natural history studies on every drug they develop for rare diseases, but they will still need to demonstrate that they are familiar with existing natural history studies and have demonstrated in-depth knowledge of the natural history of the condition.

From understanding disease development, innovations can be made to clinical trials using non-standard methods and controls such as real-world data, historical control groups, Bayesian analysis, “nz-1” clinical trials, and mainstream protocols – but only if the FDA approves these unconventional approaches .

The Agency continues to expect that, where possible, normal clinical and non-clinical testing will be carried out, so obtaining early approval is crucial to speeding up product approval to the market. With this in mind, sponsors must work closely with regulators, skilled protocol designers and statisticians to find the right course of action.

Fortunately, as FDA regulators continue to advocate for flexibility in rare disease therapy research, we expect sponsors will encounter fewer obstacles in this area. By collaborating with patient groups, regulators and medical experts, even small biotechs can overcome the problems associated with conventional trial design, ultimately helping them deliver rare disease therapies to the people who need them most.

Carol Woodward is Chief Operating Officer and Catherine Moncad is Vice President of Regulatory Services at TMC Pharma Services Ltd, a clinical research organization that supports biotechnology and pharmaceutical companies in developing innovative, often life-saving, treatments for orphan, rare and oncology diseases.