FDA standards for addiction medicine studies are discouraging the development of medications

A shift away from abstinence-only and other binary metrics is overdue.

CASPR, our organization, is currently working on a broad and collaborative policy project to drive innovation in the development of addiction medicine. Our core belief is that addiction is not solvable without breakthrough medicines. We hope to publish this work in the next few weeks along with our partner organizations on the project.

Today, I want to share one of the recommendations that we make in the paper, based on conversations with a number of researchers in the field and several recent publications.

Proposal: Modernize FDA Standards of Efficacy for Substance Use Disorder Trials

A significant barrier to pharmaceutical innovation in substance use disorders is outdated and unpredictable efficacy standards often set by the FDA for clinical trials. Efficacy expectations for substance use disorder indications have been rooted in abstinence-only and other binary measures that the scientific and medical community has moved past when evaluating substance use disorder harms.

This article in the American Journal of Drug and Alcohol Abuse demonstrates that binary outcome measures like “number of heavy drinking days” can underestimate the efficacy of treatments. And this recent report from NIAAA on alcohol trial endpoints recommends a shift away from abstinence-based endpoints and towards more meaningful consumption-based endpoints. The FDA should adopt this approach not only for alcohol, but more broadly for all substance use disorders.

For example, in the recent Phase 2b CB1 agonist for cannabis user disorder from AELIS, the FDA required a standard of efficacy of an 80% reduction in use. The trial failed for unrelated reasons, but many researchers in the field have expressed frustration that this requirement, a reduction far beyond what will improve a patient’s health, sends a negative signal to other companies interested in advancing effective addiction treatments.

In a recent article in the American Journal of Psychiatry, Dr. Wilson Compton and Dr. Nora Volkow (Director of NIDA) examine the evidence that use-reduction for cannabis and other substances is clinically meaningful and important as an endpoint. They emphasize that the FDA’s outdated outcomes reduce industry activity to develop new medications:

“While achieving continuous abstinence has been documented to be clinically beneficial, such an outcome is difficult to achieve or sustain and is made particularly challenging as the brain circuits involved with self-regulation and stress reactivity have been compromised by drug use. Moreover, the weakening of social and economic support systems that many people with substance use disorders face imposes further barriers to abstinence. Such a difficult-to-achieve outcome has deterred the development of new agents to treat substance use disorders.“

There are some signs that the FDA has begun a process of modernizing their approach. This recent paper from the NIH and the FDA on smoking cessation therapies provides updated guidance that moves in the right direction.

More broadly, the FDA should work to adopt endpoints and standards of efficacy that align with standards in other disease areas. This shift would be best achieved through new guidance or statements issued by the FDA, which would offer positive assurance to pharmaceutical companies that they have achievable paths to approval. Predictability throughout the medication development life cycle is absolutely essential for companies considering investment.

To encourage the FDA’s evolution in this direction, Congress should include statements in upcoming appropriations and authorizations that state:

1. The FDA should adopt non-binary use-reduction standards of efficacy for addiction treatments that are aligned with standards for other common disorders and the FDA shall, within 12 months, report on the standards employed for substance use disorder relative to other prevalent chronic conditions and report steps to eliminate disparities in evidentiary standards and issue new guidance on the subject.

2. The FDA should publish clear guidance on endpoint targets across substance use disorders to support decision-making for pharmaceutical companies considering work in this field.