Breakthrough Therapies Act: Good idea, wrong solution

The Breakthrough Therapies Act, recently proposed by Senators Rand Paul (R-Ky.) and Cory Booker (D-N.J.) as a way to expand access for therapeutic purposes to potentially beneficial but highly regulated Schedule I substances like psilocybin and LSD, has the right underlying idea but provides a solution that is wrong.

The act would automatically reclassify to Schedule II any experimental medicine designated by the Drug Enforcement Agency as a Schedule I controlled substance — defined as a drug “with no currently accepted medical use and a high potential for abuse” — that receives a Breakthrough Therapy Designation from the Food and Drug Administration.

Schedule 1 substances include heroin, lysergic acid diethylamide (LSD), marijuana (cannabis), 3,4-methylenedioxymethamphetamine (MDMA, Ecstasy), psilocybin, and others.

Paul and Booker seek to give Americans greater therapeutic access to these often-abused drugs before being tested in clinical trials. According to their press release, the act would “facilitate a phased roll-out of these potentially lifesaving therapies via FDA-approved Expanded Access pilot programs.”

Despite the act’s good intentions, there are multiple flaws in their proposed legislation, each of which limits the potential to meaningfully help individuals in need.

The first is the sponsors’ misunderstanding of what is required to achieve FDA Breakthrough Therapy designation. The FDA says this designation “is a process designed to expedite the development and review of drugs that are intended to treat a serious condition and preliminary clinical evidence indicates that the drug may demonstrate substantial improvement over available therapy on a clinically significant endpoint(s)” (emphasis ours.) In other words, to receive Breakthrough Designation, an experimental medicine must already be in clinical development, as there is no other way to demonstrate the required “substantial improvement.”

If an experimental medicine is a Schedule I drug, such as psilocybin or LSD, it is subject to the dual oversight of both the FDA and the Drug Enforcement Administration (DEA). In the early stages of development, before a Breakthrough Designation can even be sought, a clinical trial sponsor must first work with the FDA to structure the proposed clinical study and then, after the FDA has signed off, must work with and receive further clearance from the DEA. This is where the most significant time and thus, access delay, can occur.

We know of multiple instances in which this secondary approval process has delayed the initiation of clinical trials and/or the ability to enroll patients at clinical sites for Schedule I drugs by months and in some cases, years. Here’s one example: GW Pharmaceuticals’ cannabidiol product, Epidiolex, was regulated by the DEA as a Schedule I drug throughout its development program; only after the FDA approved the product in 2018 was it reclassified by the DEA from Schedule I to Schedule V, thus allowing marketing to begin.

The second flaw in the proposed legislation is that allowing an experimental medicine to be used through the expanded access process, or via the utterly ill-conceived Right to Try process that both Senators tried to “clarify,” does not advance the potential approval process for psychoactive medicines or, in fact, for any experimental medicines. While a small number of individuals in need may — but not necessarily will — benefit by gaining access to an experimental medicine through expanded access, benefits to the greater population can be accomplished only via FDA approval after rigorously controlled clinical testing.

Simply put, expanded access is not clinical development. It does not advance the research or drug approval processes. It is, instead, a way to offer an early chance at a possible therapy. A Breakthrough Designation does not in any way guarantee ultimate success in clinical trials or availability as a prescription drug.

Does it make sense for two federal agencies to simultaneously be regulating the clinical development process for the same experimental medicine? We think not. Could the FDA itself take on the oversight work to review how a Schedule I experimental medicine is being utilized and access is being controlled in a clinical experiment, or must the DEA provide a second level of review as historically has been the norm when it comes to Schedule I psychoactive drugs? We think the former is possible.

We suggest that a more appropriate approach — designed to accomplish the what the Breakthrough Therapies Act seeks to do but in a way that reduces the burdensome two-step regulatory process — would be to allow the FDA to itself review the release parameters for any Schedule I drug to assure there is no abuse or misuse during the course of the clinical development process. This would not be dissimilar to the existing Risk Evaluation and Mitigation Strategies process the FDA has already established for medications with serious safety concerns to help ensure that the benefits of a new medication outweigh its risks.

It is right to have concerns about the complexity of clinical development, just as it is appropriate to have concerns that Schedule I drugs that hold the possibility of treating disease or improving health might be misused. But the best solution — and the only long-term solution — is to directly address and fix the regulatory complexity that increases the cost and delays the timeline for access to potentially beneficial therapies.

Arthur L. Caplan is professor of bioethics and the founding head of New York University Grossman School of Medicine’s Division of Medical Ethics. Kenneth I. Moch, the president of Euclidean Life Science Advisors, LLC, has been the co-founder or CEO of five companies developing therapies for life-threatening diseases. He is a board member of Zynerba Pharmaceuticals, which is developing a synthetic cannabidiol product for Fragile X and 22Q disorders.

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