The next rare disease roadblock: American innovation moving ex-U.S.
As regulatory hurdles push early-stage trials out of the U.S., three things FDA can do to bring them back
U.S. biotech is at a critical juncture. An acceleration in genetic medicines promises more hope than ever to people living with rare diseases, but the U.S.’s biotech sector is losing competitiveness to other countries that provide regulatory environments much more conducive to early phase clinical science — especially for rare diseases.
Among the approximately 7,000 rare diseases that collectively affect more than 30 million Americans, the vast majority have genetic underpinnings that could be amenable to genetic medicines. Patients suffering from many of these rare diseases — from severe conditions such as Angelman and Dravet syndromes to nearly always fatal diseases such as amyotrophic lateral sclerosis (ALS), Duchenne muscular dystrophy (DMD) and frontotemporal dementia (FTD) — are desperate for effective therapies.
An ongoing revolution in biomedical science offers unprecedented opportunity to develop rationally designed meaningful treatments for many of these patient populations. Twin advances in genetic science and genetic medicine technologies are simultaneously unraveling the causes of rare diseases and offering tools to treat them. Moreover, these tools, which include RNA therapeutics, gene therapies and gene editing, can be tested in patient-derived stem cell models that promise a higher probability of successful translation to the clinic.
“Companies working on rare disease therapy development often encounter a regulatory framework within the U.S. FDA that is misaligned with the severity of the disease.”
As a biotech and healthcare sector, we have the responsibility to bring safe and effective therapies to these patients as rapidly and safely as we can. But this requires a cost-effective development path that does not create unnecessary barriers for investors, in a field where small populations already make the economics of drug development precarious.
Unfortunately, at this moment companies working on rare disease therapy development often encounter a regulatory framework within the U.S. FDA that is misaligned with the severity of the disease and the interests of American patients. We applaud FDA on the recent establishment of the Rare Disease Innovation Hub, and the many positive initiatives and developments on biomarkers, endpoints, surrogate endpoints and accelerated approvals. However, a critical bottleneck is holding back early-stage development, hampering the positive impact of these efforts and pushing companies ex-U.S.
An apparent lack of appropriate risk/benefit assessment and urgency within FDA, coupled with limited opportunities for early, meaningful dialogue with the agency, are driving companies to conduct clinical development, particularly early-stage trials, in other countries such as Canada, the U.K., Europe, Australia and New Zealand.
For example, FDA’s Pharmacology and Toxicology Division often requires very large safety margins throughout the clinical development paths of genetic medicines rather than the typical safety margins applied primarily to the starting dose. This has led to long delays in the clearance of INDs and many partial clinical holds, especially but not exclusively for promising RNA therapies.
This threatens to (i) prevent American patients from accessing potentially lifesaving therapies, (ii) increase drug development timelines, (iii) increase development costs at a time when drug prices are challenged, and (iv) cause American companies to invest abroad rather than in the U.S.
Because this is a rare disease-wide issue, QurAlis, together with more than a dozen other pioneering biotech companies including Stoke Therapeutics, Avidity Biosciences, Ultragenyx Pharmaceutical, Azafaros, ProJenX, Neurosense Therapeutics and Quiver Bioscience, formed a consortium to seek a dialogue with FDA, with the aim of working with the agency to identify and implement improvements. The companies in the consortium are all experiencing similar challenges. These are real pain points being experienced in real time, not just by our consortium members but throughout the community of companies developing therapies for rare diseases.
All of us want American patients to have access to American innovation. The consortium has therefore urgently requested the following from FDA, and in particular its newly formed Rare Disease Innovation Hub.
First – Advance regulatory science in early phase development
We request early phase risk/benefit assessments be calibrated to disease severity as well as available therapies, and that a dedicated workstream for specific guidance development and FDA reviewer training be created for preclinical and pre-IND development phases. We propose that dedicated and experienced reviewers from the Rare Disease Innovation Hub work closely with industry and academia on new regulatory science techniques for preclinical toxicology and early phase risk/benefit assessments.
Second – Ensure transparency and constructive communications with sponsors
Although mechanisms exist for engagement with FDA review divisions, such as INTERACT (Initial Targeted Engagement for Regulatory Advice on CBER/CDER ProducTs) and pre-IND meetings, upon receipt of FDA written responses companies have no ability to discuss scientific disagreements on preclinical and early phase development plans. In the absence of informed discussion, the lack of due process causes further delays. We request Hub consultation is obtained prior to FDA’s written feedback and request participation and actionable guidance from Hub leadership in a timely manner as part of these critical interactions.
Third – Expand START program to early phase development
FDA’s Support for Clinical Trials Advancing Rare Disease Therapeutics (START) program opens up new and efficient channels of communication for sponsors with the agency, but its scope is currently limited. We request that the Hub expand this program to further accelerate drug development so that sponsors have the ability to address program-specific early phase development issues, such as alignment and agreement on enabling toxicology plans to support clinical development.
We support and depend on FDA’s mission to ensure the safety, efficacy, and security of drugs and biologics and we share FDA’s commitment to achieving these goals. However, we are at an inflection point. It is crucial that FDA, through the Rare Disease Hub, urgently implements solutions for the above-mentioned issues so American patients will benefit from American innovation and U.S. biotech maintains global leadership.
Members of the consortium have had an ongoing dialogue with the hub, Critical Path Institute, the Reagan-Udall Foundation, and AMP ALS since mid-2024. We invite all companies working in rare diseases to join us. People with rare diseases can’t wait; they deserve solutions now and American patients deserve early access to American Innovation.
Kasper Roet is founder and CEO of QurAlis Corp.
Signed commentaries to not necessarily reflect the views of BioCentury.