FDA offers first guidance on stimulant use disorder drug development

The US Food and Drug Administration (FDA) has published a draft guidance that for the first time offers recommendations for drug development and clinical trial design for therapeutics for stimulant use disorder, including use of cocaine, methamphetamine, and prescription stimulants.

“Currently there is no FDA-approved medication for stimulant use disorder,” Marta Sokolowska, deputy center director for substance use and behavioral health at FDA’s Center for Drug Evaluation and Research (CDRH), said in a statement. “When finalized, we hope that the guidance will support the development of novel therapies that are critically needed to address treatment gaps.”

The draft guidance, published on 5 October, is one piece of the FDA’s Overdose Prevention Framework, according to the agency, which encompasses appropriate prescribing and the development of evidence-based treatments for stimulant use disorder.

Early development

The guidance applies to the development of therapeutics for moderate-to-severe cocaine use disorder, moderate-to-severe methamphetamine use disorder, or moderate-to-severe prescription stimulant use disorder. However, it does not apply to treatment of intoxication or poisoning with stimulants or to the treatment of withdrawal from stimulants.

FDA recommends that sponsors investigate the potential for interactions between the investigational drug and any relevant stimulants early in the drug development phase.

“Because stimulants have the potential for single-dose lethality, sponsors should establish that the investigational drug does not potentiate the toxicity of the stimulant (e.g., with adverse effects such as tachycardia, hypertension, and central nervous system (CNS) activation),” FDA stated. “It should be expected that the subject with stimulant use disorder may be exposed to both the investigational drug and the stimulant concurrently”

The agency says that after completing any necessary drug-stimulant interaction nonclinical studies, sponsors should also conduct the initial investigation drug-stimulant interaction human trials among participants who are experienced with stimulant use through the route of administration of interest and who are not seeking treatment for their stimulant use disorder. It also added that study participants should be otherwise medically healthy.

Furthermore, FDA offered advice on study population selection. For instance, the agency suggested that sponsors evaluate individuals who use cocaine, methamphetamine, and prescription stimulants separately. It also added that evidence from initial clinical data that suggests that therapeutic response is similar for different stimulants could be useful for broader patient populations in later-stage trials.
FDA recommends that sponsors design randomized, double-blind, and placebo-controlled efficacy trials that include a standardized behavioral treatment for all study subjects and that the behavioral treatment is described in the protocol.

Assessing stimulant use and benefit

FDA says the guidance provides its current thinking on the use of a combination of self-reports and biological testing to measure drug use. If self-reports are used, sponsors can propose daily reports, a staff-assisted timeline follow back reconstruction during visits, or other self-reporting tools. Since self-reporting may be inaccurate due to recall bias or issues of social desirability, FDA noted that it “may not provide persuasive data by itself.”

While biological testing is an important way to monitor response to treatment, FDA noted that it does not have evidence to support any recommendations on the frequency of biological testing, including urine toxicology.

“Sponsors should consider expected effects and any impact of the investigational drug on the biological detection window, striking a balance between minimizing subject burden and providing some degree of biological confirmation of self-report,” the agency added.

FDA also signaled that it is open to endpoints other than abstinence to assess improvement in stimulant use disorder, including periods of nonuse.

“We have previously advised that a sustained period of negative urine toxicology findings, indicating abstinence, could be a valid surrogate for clinical benefit,” the agency said. “However, FDA does not, and has not, advised that the only appropriate endpoint based on urine toxicology results is the number of subjects achieving complete abstinence.

“FDA is open to other endpoints that reflect meaningful improvement in stimulant use disorder, noting that measuring other changes in pattern of stimulant use and establishing their clinical benefit may be more complex,” the agency added.

When looking at changes in patterns of stimulant use, sponsors could evaluate the proportion of subjects who achieve a target pattern of use days per time period, with a prespecified target pattern of use that defines a “relevant within-subject response.” The agency does not recommend evaluating the difference between treatment groups using the mean number of days free of use.

One suitable primary endpoint for trials, outlined in the guidance, is the proportion of subjects who meet criteria for early remission from stimulant use disorder at the conclusion of the trial. Early remission is defined as meeting none of the DSM-5 (Diagnostic and Statistical Manual of Mental Disorders, 5^th edition) criteria for stimulant use disorder between 3 and 12 months.

FDA also said that input from patients, family members and clinicians could be used to identify the “most concerning symptoms or experiences” associated with stimulant use disorder, which could then be used to develop a clinical outcome assessment.

“A suitably developed, fit-for-purpose measure that assesses relevant aspects of a subject’s health status, functioning, and/or symptoms may be appropriate as a primary endpoint for a clinical trial and may be the most suitable approach for some investigational drugs,” the agency wrote.

FDA acknowledged that the evidence around stimulant use disorder treatment is in flux, requiring flexibility. The agency said that as such evidence evolves, it may update its guidance recommendations and any recommendations it gives to sponsors during milestone meetings.

Stakeholders can comment on the guidance on regulations.gov under docket no. FDA-2023-D-1848 until 4 December.

Draft guidance on stimulants

FDA offers first guidance on stimulant use disorder drug development

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