Bioethics Forum Essay

Genetic Therapies for Rare Diseases: Developing Ethical Regulatory Policies

Last year, researchers saved an infant named KJ from a life-threatening rare metabolic disorder using a customized gene editing therapy. This was the first time that an individualized gene therapy was used to treat a human patient, and it has stirred hope. The next frontier is scalability.

There are over 10,000 rare diseases, 80% of which have a genetic cause, making them particularly amenable to yet-to-be-developed gene-based therapies. In recent years, dozens of precision genetic medicines have been approved, many for the treatment of rare diseases. Still, approximately 95% of rare diseases lack an approved drug. How can we transition from dozens of approvals to hundreds or even thousands, so that more rare disease patients and families have effective treatments? 

To boost innovation in gene-based therapies, it is important to address not only scientific, manufacturing, and commercial challenges, but also ethical and regulatory issues. Bioethicists have an obligation to advocate for regulatory policies that support the development of safe and effective genetic therapies for rare diseases and enable timely access to them.

The Food and Drug Administration has created regulatory programs to stimulate the development of treatments for patients with high unmet medical needs. These initiatives aim to balance the tradeoffs between giving patients greater access to new treatments and protecting them from harms when safety and efficacy are uncertain. However, rare disease patient advocates and some biopharmaceutical leaders have argued that regulatory hurdles are too high.

In response, federal health officials recently released a draft guidance to speed the development of individualized therapies for treating a rare disease. There is a 60-day public comment period, beginning on February 23. The proposed “plausible mechanism” pathway would base approval of therapies on one well-controlled human study – which may include only a small number of patients – supported by confirmatory evidence from laboratory or patient data. To streamline processes, the guidance also indicates that therapies targeting different mutations associated with a disease could be evaluated together.

Patient advocates and many professionals support the plausible mechanism pathway because of its potential to improve access to treatments for patients with rare disease. Others raise concerns about weakening evidentiary standards for treatments of rare diseases, as well as more broadly. Just days before releasing the plausible mechanism draft guidance, the FDA announced that a single pivotal trial, rather than the longstanding requirement for two trials, would be the “default option” for proving safety and effectiveness for approval of all types of drugs.

Patients with rare diseases – like all patients – deserve safe and effective treatments. How should regulators balance access to such treatments with protection against harms?

One approach that the FDA uses is to require post-marketing studies of some approved drugs to confirm safety and efficacy. However, companies do not always complete these requirements in a timely manner, and enforcement has been lax. In some cases, post-approval studies have failed to confirm efficacy, and yet the drugs remain on the market.

To strike the right ethical balance between access and protection, we believe that the U.S. should not only consider different regulatory pathways, but also different levels of regulatory approval. We support a differentiated approval system in which regulators confer different tiers of approval based on different levels of evidence.

This type of approach, which has some precedent in the European Union and the U.K., might enable patients to benefit from earlier access to innovative therapies, while also clarifying that all approvals do not meet the same evidentiary standards. Increased transparency would help patients and their families – and doctors – make informed decisions about whether to use the therapies. Importantly, improved communication about pharmaceutical products could also foster trust in regulatory authorities.

A differentiated approval system would also provide a greater incentive for companies to conduct confirmatory, post-marketing studies in a timely manner. Companies would be financially motivated to gather additional trial and/or real-world evidence to support moving up to a higher tier of approval, particularly if it justifies increased pricing or reimbursement. Evolving knowledge could increase, maintain, or weaken approval levels, or potentially even lead to product withdrawal.

For gene-based therapies for rare diseases (and other therapies, as well), a differentiated approval system might facilitate access, transparency, and trust, while ensuring that products are safe and effective – an ethical regulatory policy we should be seeking.

Carolyn Riley Chapman, PhD, MS, is an independent consultant. She is a faculty affiliate of NYU Langone Health Section of Medical Ethics and a member of its Pediatric Gene Therapy & Medical Ethics working group. Until recently, she led the Cell and Gene Therapies project at the Multi-Regional Clinical Trials Center of Brigham and Women’s Hospital and Harvard. LinkedIn Carolyn Riley Chapman

Nirvan Bhatia is a research associate in the Department of Anesthesiology and Critical Care Medicine at Johns Hopkins Medicine. LinkedIn Nirvan Bhatia

The opinions expressed in this piece are those of the authors and do not represent the positions of the MRCT Center, Brigham and Women’s Hospital, Harvard Medical School, NYU Langone Health, PGTME, or Johns Hopkins Medicine.