FDA should take a more active role in updating drug labels — when there’s strong evidence

A system built for pharma will never realize the full potential of generics, but FDA can help fix this, argue Woodcock, Duke’s Boyer and Williams

Every year, promising new uses for generic drugs emerge from academia, non-profits, and patient groups — yet most never reach patients. Not because of scientific barriers, but because the U.S. drug development system was built for commercial sponsors.

Without a regulatory path that non-traditional developers can navigate independently, even well-supported new uses of generics rarely make it onto the label, limiting coverage, awareness and access.

As Washington looks to lower drug costs and FDA revisits its rare disease strategy, drug repurposing — the process of researching new uses for established drugs — stands out as an underused but potentially highly effective tool to accomplish these goals.

There are steps FDA could take to create a rational, evidence-based process for repurposing — without compromising its standards. Such a system would help avoid controversies like those around the recent recommendation to use leucovorin to treat cerebral folate deficiency.

Repurposing works, but the system limits its impact

Out of more than 18,000 known diseases, only a minority have approved treatments and developing new therapies is long and expensive. For patients battling conditions with no options, generic drug repurposing offers an alternative. Such was the case for people living with autoimmune lymphoproliferative syndrome (ALPS), a rare disorder of the immune system that causes debilitating symptoms. Once left with no clear treatment option, patients now have hope thanks to a repurposed generic drug called sirolimus.

Generic drug repurposing promises to unlock the full potential of the drugs already in our pharmacies. Especially for patients with rare and ultra-rare diseases, where there’s little to no incentive for traditional drug developers to invest, repurposing may be a quicker and cheaper alternative to de novo development.

Repurposing older drugs is not a new concept. Aspirin — an over-the-counter pain medication — is commonly used for cardiovascular disease because of its blood-thinning properties. And thalidomide — once notorious for its harms in pregnancy — has been successfully repurposed to treat multiple myeloma and complications of leprosy.

Despite the success stories, drug repurposing has not been systematically explored. Realizing the full potential of generics requires both scientific models and financial incentives to identify potential repurposing targets, generate evidence, and address regulatory barriers. Additionally, assuring patient access requires obtaining payer coverage and raising prescriber awareness.

For-profit pharmaceutical companies have the resources, expertise, regulatory experience, and infrastructure to explore new uses and ensure they reach patients; however, the low commercial value in new uses of generic drugs offers them little incentive. This leaves most repurposing work in the hands of “non-traditional developers” such as patient organizations, non-profits, and academics. And while these groups can conduct rigorous studies, they usually lack the same access to capital and the expertise needed to advance these opportunities.

The core issue is that the U.S. healthcare system is based on a commercial, for-profit system. The regulatory process for drug development is primarily structured on two-way communication between industry sponsors and the FDA. This leaves minimal opportunity for non-traditional developers to contribute to the drug development process beyond research.

As a result, most repurposing opportunities never reach the market and scale. And while off-label use is common in the U.S. and may appear to be a solution, it comes with its own limitations in terms of access, awareness, and insurance coverage. Busy prescribers may not be aware of research results, and insurers rarely cover drug uses that are not FDA approved.

How can FDA support repurposing efforts

If we want to fully harness generics, we should rethink how our drug development ecosystem can better support non-traditional developers. FDA can play a central role by adapting its processes to serve these groups, without lowering evidentiary standards.

In a recently published white paper, the Duke-Margolis Institute for Health Policy presented a range of recommendations informed by experts. While incremental efforts may have modest impact, fully leveraging generics will require more substantive actions. Here we highlight three recommendations that we believe can make the greatest impact:

1.   Education and guidance. FDA could create dedicated programs to help non-traditional developers navigate the current regulatory system and requirements. This may include educational materials, workshops, and advisory services to support non-traditional developers in designing trials and packaging data that meet regulatory standards. However, without a direct regulatory pathway, non-traditional developers would still need to partner with manufacturers to pursue label expansion.

2. Creating alternative regulatory pathways. FDA could establish new regulatory pathways designed for non-traditional developers while maintaining its standards. One option is a “labeling only” pathway that would allow non-traditional developers to reference the existence of the chemistry, manufacturing, controls (CMC) data and product samples that FDA already has for a generic product — reducing reliance on industry partners. However, the non-traditional developer would then be responsible for the potential liability that would come with the new uses of the product, which may be challenging for some organizations.

Another option is to use the Citizens’ Petition process, whereby an individual, group, or organization can ask FDA to take a specific action. While not equivalent to a full label expansion, FDA could issue a public notice following review of the evidence. Robust evidence of the drug’s efficacy and safety for the new use would be required, using established regulatory standards. A pilot program could demonstrate feasibility of this approach and generate a few “success stories” to build momentum and highlight the value of generic repurposing to regulators. This could open opportunities to establish a new, staffed and resourced “Repurposing Evidence Pathway” to review submissions on new uses of generics from non-traditional developers.

3. A coordinated government initiative. The impact of these FDA-led efforts could be maximized if they were to fall under the umbrella of a larger scale, government-led initiative that coordinated efforts across multiple government agencies such as NIH, BARDA, CMS, and more. Operating centrally within HHS, this could focus on opportunities that would benefit public health and unaddressed patient needs. For example, FDA and NIH could collaborate to establish research protocols and support trial designs for repurposing studies that could be used for FDA approval. NIH could fund and run these trials, with approval ultimately leading to CMS reimbursement.

A call for FDA to innovate how it protects and promotes public health

The recently released MAHA Commission report recognizes the potential value of repurposed drugs and FDA’s crucial role in enabling the full benefit of generic drugs. However, it’s important that repurposed drugs are backed by strong evidence to ensure patient benefit and public trust.

By adopting more innovative approaches to the approval of new uses of drugs already known to be safe, FDA can ensure drug labels are updated to “promote public health” — a critical component of the agency’s mandate. This would require resources, a willingness to test innovative approaches, and a culture shift that moves beyond a system that is focused on traditional drug sponsors.

In this moment, as the U.S. government endeavors to be more efficient while also delivering faster, cheaper treatments for patients, generic drug repurposing presents a unique opportunity to achieve these aims.

In her nearly 40 years at FDA, Janet Woodcock was most recently principal deputy commissioner of food and drugs, previously serving as acting FDA commissioner and director of Center for Drug Evaluation and Research (CDER). Beth Boyer, a policy research associate, and Mia Williams, a policy analyst, are on the Biomedical Innovation team at the Duke-Margolis Institute for Health Policy.

Signed commentaries do not necessarily reflect the views of BioCentury.