The FDA has released a draft guide to offer their perspective and thoughts on the development of treatments for stimulant use disorder.
The US Food and Drug Administration (FDA) published a new draft guidance to assist in the development of treatments for stimulant use disorders: Stimulant Use Disorders: Developing Drugs for Treatment. This will be the first guide that contains the FDA’s recommendations on the development program and clinical trial design for drugs intended for the treatment of cocaine use disorder, methamphetamine use disorder, and prescription stimulant use disorder.1
Thomas R. Kosten, MD, the Jay H. Waggoner Endowed Chair and co-founder at the Institute for Clinical and Translational Research, offered his thoughts on the draft’s release:
“This is excellent news about having guidelines for development of these stimulant use disorder medications. Lack of such guidelines have left potential manufacturers with no clear standards for approval of new treatment agents or for approval of expanded indications for repurposing existing agents such as bupropion for methamphetamine (MA) use disorder. Bupropion has of course shown efficacy for MA use disorder, as published in the NEJM.2
Overall, the current list of FDA non-approved medications for stimulant use disorders has been appalling, including such potential blocking agents such as a cocaine vaccine that was halted in development at phase 3 testing. This vaccine development was halted because its efficacy could only be shown among cocaine use disorder patients who attained a minimal level of antibodies needed for the threshold level needed to block cocaine. That threshold antibody level was established in previous studies, independent of the pivotal outpatient clinical trials, and two-thirds of the vaccinated subjects attained this threshold antibody level in the phase 2 studies and this pivotal multisite study. Those patients who attained this threshold antibody level (good responders) had successful outcomes based on 3 separate outcome measures (treatment retention, 2 weeks of sustained abstinence, and significant reductions in cocaine use after vaccination compared with before vaccination) compared with either the placebo patients or that third of patients who did not attain this threshold level (poor responders).
The efficacy analysis acceptable to the FDA for consideration of this vaccine was only an intention to treat comparison, completely ignoring the independent biological measure of level for the antibody response. For an infectious disease outcome such as resistance to COVID-19 infection or response to a new antibiotic, a 66% response rate would be considered outstanding success. This particular success would strongly consider if the excluded patients from the pivotal studies were based on a poor antibody response in the vaccinated patients for a COVID-19 vaccine. Similarly, if individual patient differences in metabolism of an antibiotic led a third of patients to be unable to attain therapeutic antibiotic levels.Whatever the medicine or preventative intervention is, the agent must be able to attain established therapeutic blood levels of the antibody for vaccines or of the drug itself for pharmacotherapies. Why has this same standard for attaining therapeutic levels not been applied to medications or immunotherapies for substance use disorders, particularly stimulant use disorders?
From a different perspective, the outcome measures themselves of complete abstinence rather than a simple reduction in use of the abused drug are unrealistic. Even FDA alcohol approvals can be given for a medication that reduces binge use of alcohol, but does not lead to sustained abstinence. Clarifying this rigid outcome of abstinence for stimulants is unrealistic, in view of the widespread prescribing of these stimulants to both children and now adults with attention-deficit/hyperactivity disorder (ADHD). We have many years of safety data in millions of children, adolescents, and now adults who are prescribed these ADHD agents within therapeutic doses without significant adverse events.”
If you would like to offer comments on the draft guidance, they must be submitted within 60 days to ensure consideration.
Dr Kosten is the Jay H. Waggoner Endowed Chair and co-founder at the Institute for Clinical and Translational Research. He is also a professor of psychiatry, neuroscience, pharmacology, and immunology at Baylor College of Medicine in Houston, Texas.
1. FDA takes steps to advance the development of novel therapies for stimulant use disorders. US Food and Drug Administration. October 4, 2023. Accessed October 9, 2023. https://www.fda.gov/news-events/press-announcements/fda-takes-steps-advance-development-novel-therapies-stimulant-use-disorders
2. Trivedi MH, Walker R, Ling W, et al. Bupropion and naltrexone in methamphetamine use disorder. N Engl J Med. 2021;384(2):140-153.