In a first, FDA tackles treatments for stimulant use disorder

A new draft guidance from the FDA gives developers a roadmap to advance the development of novel therapies to address stimulant use disorders. The draft document attempts to address a wide range of substances, populations, and use scenarios, some of which are unique to these particular disorders.

Quick background: Stimulant use disorder

• The FDA defines stimulant use disorder as a “substance use disorder (SUD) involving any of the class of drugs that include cocaine, methamphetamine and prescription stimulants.” Prescription stimulants are used to treat attention deficit/hyperactivity disorder (ADHD), binge-eating disorder, and narcolepsy. Stimulant use disorder is acknowledged in the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) with severity levels ranging from mild to severe.
• While stimulant use disorder is increasing, there are currently no FDA-approved medications. According to the Substance Abuse and Mental Health Services Administration (SAMHSA), “between 2008 and 2015, amphetamine-related hospitalizations more than tripled, increasing from 55,447 instances to 206,180. SAMSHA published an “evidence-based resource guide” on substance use disorder treatment in June 2020. The document outlined potential interventions such as motivational interviewing, contingency management, community reinforcement approach and cognitive behavioral therapy.
• The prevalence of stimulant use disorder has now risen to the point that the Centers for Disease Control and Prevention (CDC) recognizes it as a significant player in the fourth wave of the opioid crisis. The CDC marks the first wave as beginning with increased prescription of opioids in the 1990s. The second wave aligned with an increase in deaths involving heroin, which was followed by a third wave of increased mortality associated with synthetic opioids like illicitly manufactured fentanyl. During the COVID-19 pandemic, the number of opioid-involved deaths climbed sharply, with mortality rates increasing by 38% between 2019 and 2020. Now, data trends show that a fourth wave of polysubstance use, driven by stimulants like methamphetamine and cocaine, is again increasing mortality rates.
• In the absence of approved products, many providers today turn to off-label use of products approved to treat other substance use disorders. However, there is little evidence to demonstrate these products are actually successful in combating stimulant use disorder.

Regulatory context

• FDA held a workshop in December 2019 to discuss development of substance use disorder therapies. The goals of the workshop were to examine trends in stimulant abuse, discuss drug development for treatments, and gather stakeholder knowledge to develop new ideas for advancing development in this area.
• This was followed by a patient-focused drug development (PFDD) meeting in October 2020 on substance use disorder. The PFDD initiative, established in 2012 through the Food and Drug Administration Safety and Innovation Act (FDASIA), allows the FDA to receive patient perspectives through structured meetings which ask, among other things, how a patient feels about their condition, their tolerance for risk and what they would like to see in an ideal treatment. These meetings were originally only held by the FDA, but are now held by outside groups as well in accordance with FDA guidance. As AgencyIQ discussed at the time, the substance use disorder meeting focused on stigma, social determinants of health, and the impact of the Covid-19 pandemic.
• One year later, the FDA partnered with the Reagan-Udall Foundation and the National Institute on Drug Abuse to hold a workshop on creating a “practical research agenda” for substance use disorder. The meeting discussed the challenges associated with running trials for substance use disorder medications, from medication nonadherence to trial enrollment. Panelists emphasized concerns about abstinence endpoints, which present methodological challenges and may not reflect the patient’s goals. They also discussed some potential solutions, including utilization of adaptive trial designs and remote medication adherence monitoring technology.
• Most recently, the FDA issued a new contract notice funding work at the intersection of the opioid crisis and stimulant use. According to the new notice, the FDA will award a contract to incumbent American College of Medical Toxicology (ACMT) to provide “detailed real-time information on the fourth wave of the overdose crisis and the impact of stimulant co-consumption.” The agency has previously worked with ACMT, which should mean that the new contract, entitled “Near Real-Time Surveillance of Stimulants in the Overdose Crisis – Drug Overdose Toxico-Surveillance (DOTS) Expansion” will result in a productive collaboration.

What’s new?

• This week, FDA published its first-ever guidance on the development of products to treat stimulant use disorder. The guidance document opens with the FDA noting the draft is meant to “serve as a focus for continued discussions among Center for Drug Evaluation and Research staff (particularly the Division of Anesthesiology, Addiction Medicine, and Pain Medicine, or the division), pharmaceutical sponsors, the academic community, and the public.” This opener sets the context for a guidance document that addresses drug development in the new space of treatment for stimulant use disorder which, as yet, has no approved medications.
• The guidance document’s scope explicitly excludes treatment for intoxication or poisoning from various stimulants as well as treatment of withdrawal from stimulants. The FDA states that the guidance pertains to the development of products “to support indications for treatment of moderate to severe cocaine use disorder, treatment of moderate to severe methamphetamine use disorder, or treatment of moderate to severe prescription stimulant use disorder.” While FDA acknowledges that mild stimulant use disorders exist and that sponsors may be interested in developing products to treat them, the guidance cautions that these programs have presented significant challenges in the past. For this reason, these products should be discussed with the Agency on a case-by-case basis and are not addressed in this draft.
• So, what does FDA recommend as the intended use of products developed to treat stimulant use disorders? First off, FDA acknowledges that substance use disorders are complex and it may be challenging to assess the clinical benefit of treatments using their impact on the way patients feel or function. For this reason, surrogate or intermediate clinical endpoints, such as the detection of stimulant metabolites via urine analysis to evaluate abstinence or relapse in drug use, may be more practical. However, FDA states that even though negative urine toxicology findings have been used frequently in the past to measure response to substance use disorder treatment, this is not the only endpoint that sponsors should consider.
• For example, the endpoint of “changes in pattern of stimulant use” is also an option. This endpoint has been used to evaluate treatments for other substance use disorders because it offers more meaningful insight on whether a product disrupts the cycle of current drug use, when measures like frequency or dosage might be outside the control of patients. This is especially true when assessing nonprescription stimulant use. The guidance elaborates on this point: “Endpoints on frequency of drug use per day or amount of drug used per occasion are of uncertain significance when the stimulant used is illicit, and therefore of unknown and inherently variable potency.”
• However, to assess a change in the pattern of stimulant use, sponsors must first establish the underlying pattern of stimulant use for each patient prior to treatment. While it is expected that each individual may have a slightly different baseline pattern of drug use, selecting appropriate inclusion and exclusion criteria during trial enrollment can help to homogenize trial participants to some degree. For example, a trial that measures the “number of days [of stimulant use] per period of time” should include “a minimum frequency of use as an entry criterion, such that the target pattern represents improvement.” Sponsors should also consider empirical evidence on drug use patterns before choosing a pattern to focus on, since some participants may not use stimulants everyday and instead, infrequently binge their use cocaine use every several weeks).” As long as a target pattern is established, the change in pattern can be detected and analyzed.
• For this example, an appropriate endpoint could be the proportion of subjects achieving a reduction in use days per period of time, with a prespecified target pattern of use that defines the relevant within-subject response. However, sponsors should note that “evaluation of the difference between treatment groups in the mean number of days free of use is not recommended.” One exception where a sponsor may not need to establish an underlying pattern of drug use is when the product is being evaluated to enable prolonged abstinence from drug use, because the benefit of this pattern can be assumed. The guidance does note that sponsors using this endpoint would need to incorporate “allowances for a certain number of missing visits,” and that it may also be appropriate to “focus on the last several months of the treatment period, recognizing that treatment response may not occur right away.” For patients diagnosed with moderate to severe stimulant use disorder at baseline, the proportion of patients achieving early remission —defined as “meeting none of the criteria for stimulant use disorder for between 3 and 12 months” — could also be an appropriate endpoint.
• Although diagnostic criteria should be used to enroll trial participants and the definition of “early remission” is directly from the DSM-5, the FDA recommends against using “number of diagnostic criteria present” as an endpoint. The guidance expands on this point at length, “Although this may seem to be an appropriate way to detect changes in the severity of stimulant use disorder, this approach has several concerns. The DSM-5 is intended as a diagnostic instrument, not a method of monitoring response to treatment. The presence or absence of many criteria is determined based on an interviewer’s judgment of whether the problem occurs often, frequently, persistently, or recurrently. The frequency or intensity of symptoms may increase or decrease without the number of criteria changing; one symptom may resolve while another appears; or, potentially, several symptoms may resolve but a more concerning one may arise, yielding a misleading appearance of improvement.”
• FDA is open to other types of clinical outcome assessments. Given the multifaceted impact of substance use disorders on patients’ lives, the guidance explains that improvements in the ability of patients to “resume work, school, or other productive activity or [have] fewer encounters with the criminal justice system” could also demonstrate treatment benefit. Sponsors interested in assessing these outcomes should suitably develop a “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.” Likewise, another area FDA is interested in as a potential target for treatment is “stimulant craving,” though the guidance notes that this outcome has not been consistently defined nor understood to date. Even so, the Agency encourages the development of precise characterizations of “craving” and measurements that would demonstrate modifications in craving, which could then be potentially used as primary endpoints, or as secondary endpoints for drugs that are effective in treating stimulant use disorder.
• There are also a few interesting points the guidance document makes about the patients who should be included in trials to evaluate products for the treatment of stimulant use disorders. To start, the guidance does acknowledge that the various stimulants, including cocaine, methamphetamines, and prescription stimulants, differ in chemical composition, mechanisms of action, and route of administration. Furthermore, it states that the patient population with simulant use disorders is heterogenous. For example, patients might have different motivations for stimulant use, such as work performance enhancement, club drug use, escape, sensation seeking, or sexual performance enhancement. For this reason, patients who meet the criteria for stimulant use disorder more broadly should be assessed in smaller subgroups based on the specific product(s) used and with consideration for other differences in clinical presentation, such as those currently using stimulants, or those who are abstinent but looking to prevent relapse. These factors are critical for properly characterizing treatment response. Sponsors should also very carefully consider the potential that products could “prolong or potentiate stimulant effects such that subjects reduce use of the stimulant without reducing the subjective and rewarding effects, or reducing health harms of the stimulant use.”
• Finally, the guidance states that sponsors should only enroll subjects whose primary substance use problem is their stimulant use disorder. According to FDA, “Some individuals who use stimulants report using them to manage other problems, not because of a particular urge or desire to use stimulants. For example, some patients with opioid use disorder report using methamphetamines to manage the effects of opioids (either to treat withdrawal or to prevent overdose). These individuals may meet diagnostic criteria for a stimulant use disorder but would be unlikely to respond to a drug that addressed only that problem, and thus FDA does not recommend that such subjects be included in trials of drug treatments for stimulant use disorder.”

What’s next?

• Patients with substance use disorders are more likely to have additional underlying comorbidities and struggle with polysubstance use. In a 2018 study, researchers found that among adults with SUDs misuse, just 4.6% reported using cocaine, 0.4% reported using methamphetamines, and 0.3% reported the use of prescription stimulants. In contrast, 90.2% of patients who reported using cocaine had multiple SUDs. Similar patterns existed for patients who reported the use of methamphetamines and prescription stimulants, with 88.9% and 62.5%, respectively, presenting with multiple SUDs. Overall, less than 1% of study participants had a substance use disorder that was singularly related to stimulant use. This study highlights an important point that has been corroborated many times over: patients diagnosed with SUD seldom misuse just one substance. In light of these data, the FDA’s proposed limitation of the patient population to patients with a stimulant-only SUD means that participants will not be representative of the vast majority of adults with stimulant use disorder.
• Interestingly, the FDA has previously stated that pediatric patients must be included in studies that evaluate the effectiveness of investigational products to treat ADHD. Per the Agency’s 2019 guidance, “Because ADHD is a disorder that begins in childhood, a new drug application (NDA) for any drug intended to treat ADHD should include data from adequate and well-controlled studies in pediatric patients” and that the relevant pediatric age groups are “4 to 5 years of age, 6 to 12 years of age, and 13 to 17 years of age.”
• Yet, this guidance makes no mention of pediatric patients whatsoever. This omission is striking, seems odd given studies have shown that the age group with the highest prevalence and severity of substance use disorders are individuals ages 18 to 25 years, and that three out of four patients with substance use disorders began misusing substances before the age of 18.
• Furthermore, medication discontinuation or nonadherence is common in patients diagnosed with ADHD who are prescribed psychostimulants (with estimates ranging from 13.2% to 64%). Coupled with this statistic, diversion remains a significant concern given a common pattern in adolescents to initiate nonmedical misuse of prescription stimulants, rather than illicit simulants. However, researchers have also found that adolescents most likely to misuse stimulants are those who are already using other substances, indicating that stimulants represent another product compounding existing substance misuse, rather than a “gateway drug.”

Featuring prior research by Amanda Conti.

To contact the author of this item, please email Rachel Coe ( rcoe@agencyiq.com).
To contact the editor of this item, please email Kari Oakes ( mailto:koakes@agencyiq.com).

Key Documents

• Stimulant Use Disorders: Developing Drugs for Treatment Guidance for Industry
• Docket no. FDA-2023-D-1848
• Comments close December 4, 2023