After Many Years, The FDA Announces Loosened Standards For Addiction Medication Approval

(Health Affairs)

Only a month after being sworn in, US Secretary of Health and Human Services Alex M. Azar II has announced, in a major breach with longstanding tradition, that the Food and Drug Administration (FDA) will loosen its approval requirements for medications to treat individuals with substance use disorders. In the context of the opioid overdose epidemic, his announcement builds on the FDA’s recent momentum to contain the crisis through improving access to evidence-based treatment under the impressive leadership of director Scott Gottlieb, MD. Changes in federal regulation are often needed to effectively respond to an epidemic of this scale, such as the AIDS epidemic during the 1980s and 1990s. However, Secretary Azar’s announcement is not free of peril.

Approval Requirements

Although official guidance will not be released until later this month, the crux of the announcement suggests that the FDA will now approve medications that show “substantial reductions” in drug use but no longer require trials to demonstrate improvements in rates of complete abstinence. While many researchers and the lead National Institutes of Health agency overseeing addiction research, the National Institute on Drug Abuse, have advocated for this position for quite some time, it risks opening the flood gates of medication development for medications that improve more readily modifiable subjective symptoms such as craving that are (counter intuitively) not necessarily associated with reduced drug use or improved clinical outcomes.

Paradoxically, this shift in drug approval may benefit patients with other substance use disorders (such as cocaine, methamphetamine, or cannabis use disorders) much more than those with opioid use disorder. We already have three FDA-approved medications with a robust evidence base for treating opioid use disorder and reducing overdose risk: methadone, buprenorphine, and injectable naltrexone (together referred to as medication assisted treatment or MAT). For patients who successfully initiate methadone or buprenorphine in particular, all-cause mortality has been repeatedly shown to drop by 50–90 percent during treatment adherence. New long-acting formulations, such as a six-month depot and a monthly injectable buprenorphine, hold promise to further improve outcomes. However, our treatment systems have too often proven incapable of scaling up access to these lifesaving medications. As a result, very few patients addicted to heroin or pain pills manage to access evidence-based treatment in a given care episode.

While the Diagnostic and Statistical Manual has long grouped all substance use disorders together under the same diagnostic criteria (irrespective of drug type), there are often differences between the behavioral manifestations of someone addicted to heroin compared to someone addicted to crack cocaine. In part, these behavioral manifestations reflect the differing underlying pathophysiology and resultant symptoms (of both intoxication and withdrawal) and consequences of the excessive use of a specific class of drugs (that is, heroin versus cocaine). As a result, the role of pharmacotherapy and related treatment response can differ depending on the patient’s drug of choice. Although all substance use disorders share common features (that is, ongoing compulsive use of a substance despite worsening consequences), it is often no more accurate to refer to all patients with “addiction” as being the same than it is to refer to all patients with “cancer” as being the same.

The FDA’s recent announcement will potentially allow it greater latitude in recognizing the differences between treatment advances specific to distinct substance use disorders. For instance, many candidate medications, such as topiramate and gabapentin for alcohol use disorder, naltrexone and mixed amphetamines for cocaine use disorder, and mirtazapine and quetiapine for cannabis use disorder have been associated with significant clinical improvement for some patients while falling short of significant improvements in requisite abstinence-based endpoints. As a result, their clinical use for these disorders is off-label. The downstream impact is that they are less likely to be included in medical training materials, fewer clinicians are comfortable with their use, and insurance companies can more easily refuse coverage for these off-label uses. These are all very real-world consequences that can impede effective patient care.

Determining Standards For Research, Diagnosis, And Clinical Practice

What is abstinence anyway? To a layperson, it may sound obvious, but just as with defining a pre-diabetic cut off for blood sugar or a hypertension-qualifying blood pressure, patterns of drug use are empirically evaluated by experts who must ultimately rely on professional judgment and expert consensus to determine standards for research, diagnosis, and clinical practice. Should abstinence be measured continuously from the first day of treatment or at an endpoint such as one month or six months following treatment inception? If someone is drug-free for many months but has a one-night binge, how should that be categorized? What counts as a binge? Given that addiction, like many other chronic diseases, often requires long-term treatment, there are competing implications for how to characterize someone’s drug use over time and in clinical versus research settings.

Most commonly, for instance, tobacco cessation researchers have reported continuous abstinence or point prevalence of use (that is, abstinence as confirmed at a pre-specified discrete date or time interval) as endpoints. The major benefits of continuous abstinence are that it is more stable, better approximates likelihood of lifelong abstinence and health benefits, and is more closely tied to the treatment intervention than point prevalence. The major benefits of point prevalence are that it has less recall bias (that is, when measured via self-report), has less variability due to missing data, and can detect delayed quitting. Given that drug testing (whether for tobacco or other substances) can often only detect use within the preceding few days, point prevalence is more readily validated biochemically than is continuous abstinence. However, depending on the substance, drug testing can approximate continuous abstinence (for example, when performed monthly) quite accurately as sustaining drug use only during intervals between tests is highly uncommon among those with severe substance use disorders.

All of these considerations beget a broader question: Why shouldn’t the FDA treat substance use disorders any differently than other chronic disorders? We often have treatments for symptoms but that do not directly target the underlying disease (consider cough syrup for someone with a case of bronchitis). Many medications currently approved today—for diabetes, hypertension, heart disease, renal disease, and so forth—are not curative and do not necessarily help patients achieve symptom remission (either completely or continuously) to receive approval to go to market. Patients with diabetes may fail to achieve an HbA1c under 8.5 but still benefit from treatment and slow end organ damage through partial glycemic control. It is common for patients managed for hypertension to present clinically with elevated blood pressures, sometimes due to medication nonadherence, but they are not kicked out like a methadone patient with an opioid-positive urine toxicology. There is a refreshing aspect to the health secretary’s announcement that suggests some of the old shackles of stigma and prejudice constraining our institutions are being pried loose.

As Secretary Azar stated, it is “a misconception that patients must achieve total abstinence in order for MAT to be considered effective.” There has long been a double standard in addiction medicine. While we tolerate imperfect outcomes throughout most of medicine, addiction treatment has often required perfection from patients who are otherwise reprimanded for their lack of will or poor choices in life. If the use of an addiction medication, such as buprenorphine, doesn’t eradicate drug use completely, it is too often vilified in the media along with the patients who take it, the doctors who prescribe it, and the pharmaceutical companies that make it. We need our institutions to join families and caregivers in standing up for these patients and defend their interests. Perhaps, ultimately, the FDA is signaling that individuals with addiction are now allowed to be imperfect, too.