FDA v. Opana ER: Opioids, Public Health, and the Regulation of Second-Order Effects

Earlier this month, the FDA announced that it is asking Endo Pharmaceuticals to remove the opioid Opana ER from the market.  Opana ER is an extended-release pain reliever often abused by those who take it.  While opioid abuse is nothing new, and many opioids leave those who take them addicted to narcotics or heroin, Opana ER is particularly dangerous because of how people misuse it.  The pill was designed to prevent would-be abusers from crushing and snorting it —  a popular means of ingesting prescription opioids.  Without the ability to crush and snort the drug, however, abusers turned to dissolving the pills and injecting them intravenously, leading to outbreaks of Hepatitis C, HIV, and other blood-borne diseases.  In Indiana’s Scott County, for instance, the prevalence of HIV has skyrocketed since the introduction of Opana ER to the local population, with 190 new cases since 2015.

While this foray into public health is somewhat surprising — given the anti-regulatory stance of the current administration and its billionaire backers — it is precisely the type of initiative the FDA should be taking.  Public health is a central part of the FDA’s mission statement, which notes that the agency “is responsible for protecting the public health by ensuring the safety, efficacy, and security of human and veterinary drugs, biological products, and medical devices.”  Traditionally, though, the FDA’s efforts to ensure safety and efficacy have been limited to the narrow context of individual patients taking medications as directed under physician supervision.  As the FDA noted in its Opana ER press release, this is the first time it has requested that an opioid be taken off the market as a result of its susceptibility to abuse and the associated public health consequences.

The FDA requires robust pre-clinical and clinical testing for both safety and efficacy before allowing medications on the market.  However, these requirements are far from comprehensive.  Not only are FDA approval requirements largely incapable of identifying rare or delayed risks,[1] they also focus predominantly on first-order effects — considering only the clinical impact on individual patients taking the drug as directed in a controlled setting. On one hand, this makes sense.  A drug’s safety and efficacy should be evaluated under standard conditions that assume people take it as directed.  It would be odd to judge a medication on the basis of non-compliant usage, and its unclear clinical studies could identify many negative second-order effects — it’s unlikely that participants in a tightly controlled clinical trial are going to start crushing and snorting their medication.  On the other hand, sending a drug into the real world — where people misuse and abuse prescription medications on a regular basis — armed only with the knowledge of its effects in sterilized conditions seems insufficient.

Thus, while the FDA’s clinical and pre-clinical testing doesn’t lend itself to identifying negative effects that arise beyond the doctor’s office, it’s encouraging to see the agency consider such a broad range of factors — including potential for and consequences of abuse — in its post-approval monitoring.  At the end of the day, nothing in medicine exists in a vacuum.  Economic conditions when one graduates from school can impact long-term health status; the availability of food to a pregnant mother can influence a child’s likelihood of heart disease as an adult.  Medical research over the past few decades has repeatedly shown that the connections between medical or social interventions and health status are messier and more complicated than we could have possibly imagined.  Considering the safety and efficacy of a drug without considering the various contexts in which it could be used or abused ignores this reality.  For many, Opana ER is a new lease on life, freeing them from debilitating, chronic pain.  For others, however, it wreaks havoc and destruction, leaving them trapped in a cycle of addiction and at risk for serious diseases.  If the FDA were to focus exclusively on the sterile conditions in which patients are likely to have successful experiences with a medication, ignoring the fact that nearly 50% of patients don’t take medications as directed by physicians, it would be neglecting its public health mission.

While the Opana ER request is a first for the FDA, it appears as though the agency is fully embracing this broader public health role.  “We are facing an opioid epidemic – a public health crisis, and we must take all necessary steps to reduce the scope of opioid misuse and abuse,” FDA Commissioner Scott Gottlieb noted in the agency’s press release. “We will continue to take regulatory steps when we see situations where an opioid product’s risks outweigh its benefits, not only for its intended patient population but also in regard to its potential for misuse and abuse.”  The real world is messy, and whether a drug has satisfied the regulatory benchmarks under sterile, laboratory conditions only tells part of the story.  The FDA should be applauded for stepping up and enforcing this more holistic view of patient safety. Hopefully, the agency will continue to pursue aggressive regulation when the negative second-order effects of a medication outweigh the clinical benefits.  For those caught up in the opioid epidemic, it could make the difference between life and death.

[1] FDA approval only requires that new drugs be tested on about 1000 people for a limited time.  This means that any risks impacting less than 0.1% of users or side effects that only manifest after four or five years will likely not be caught by FDA clinical trials as they are currently conducted.  To put those numbers in perspective, a side effect impacting 0.1% of prescription statins users would affect roughly 32,000 people.

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