Scholars argue that FDA should use larger health data sets in its approval process for high-risk drugs.
Tens of thousands of Americans have died from prescription opioid abuse since 2016, and millions more have exhibited misuse and dependence symptoms during the same period.
Recently, several health law scholars have argued that the U.S. Food and Drug Administration (FDA) is partly responsible for the nationwide opioid epidemic. They claim that FDA’s current regulatory oversight process for high-risk drugs like opioids fails to take into account sufficient information about their safety and efficacy.
FDA’s current regulatory approval process narrowly focuses on clinical trial data to evaluate the health impact of drugs, overlooking broader public health effects such as those created by opioid addiction, according to a recent paper by Patricia J. Zettler, Margaret Foster Riley, and Aaron S. Kesselheim. The federal agency should instead turn more consistently and frequently to broader sources of data—such as studies on population health impacts of high-risk drugs—when it decides whether to approve drugs or withdraw them from the market, argue Zettler and her coauthors.
Drug manufacturers typically resort to tightly controlled clinical trials to prove—through the use of “substantial evidence”—that their products have benefits that outweigh risks, which is a requirement under current FDA regulations, say Zettler and her coauthors.
But the particular sample of individuals included in a clinical trial often does not represent the population that ends up using the drug, assert Zettler and her coauthors. Indeed, researchers have an incentive to keep human variability to a minimum when selecting a sample of patients for a clinical trial. For this reason, they will study the effect of a drug on one population subset—people with lower back pain, for example—and disregard others, even if studying multiple subsets would paint a better picture of how patients react to the tested drug.
Assuming FDA approves a particular high-risk drug through its benefit-cost analysis of clinical trial data, FDA will continue to monitor the approved drugs through several mechanisms, including its Adverse Event Reporting System.
But the agency does not require manufacturers to report adverse incidents related to FDA-regulated drugs and medical devices when they encounter product flaws, write Zettler and her coauthors. The agency’s Adverse Event Reporting System is completely voluntary, which explains why a mere estimated 10 percent of adverse events actually appear on the database.
According to Zettler and her coauthors, the Federal Food, Drug, and Cosmetic Act (FDCA)—which grants FDA its broad authority to regulate high-risk drugs—allows the agency to demand a wider array of health data in its regulatory approval process. Systematic reform of data protocols and regulatory review of new drugs is possible without any legislative changes, they argue.
The kind of data that Zettler and her authors believe are needed can come from studies that investigate a wide range of potential drug-related problems, such as “off-label drug use”—that is, how and when people use a drug for purposes that FDA has not approved. For example, research has found that patients who misuse pain-reducing drugs containing acetaminophen are at risk of acute liver failure. Several years ago, these findings prompted FDA to remove all high-dose acetaminophen pain drugs from the market by 2014.
Moreover, under current FDA regulations, when a manufacturer submits a New Drug Application to the agency, the application must include all “studies or information related to abuse of the drug.” FDA has used this broad regulatory language—albeit very rarely and unpredictably—to withdraw from the market drugs associated with misuse and abuse, note Zettler and her coauthors.
In a rare instance of such a withdrawal decision, FDA recently requested the removal of Opana ER—a painkilling opioid manufactured and marketed by Endo Pharmaceuticals—from the pharmaceutical market.
The agency issued its request on the basis of research data that revealed an association between injection abuse of Opana ER and an outbreak of HIV and hepatitis C, signaling its ability to make withdrawal decisions on the basis of infectious disease data. Unfortunately, according to Zettler and her coauthors, FDA has not sufficiently applied this ability in the context of the opioid epidemic.
Another evidence-based tool that FDA can use is its power to require a Risk Evaluation and Mitigation Strategy under the FDCA to ensure that the drug’s benefits outweigh its risks. FDA can do so at any time between a manufacturer’s submission for approval of a drug to when consumers can purchase the drug on the market. If FDA decides to require a Risk Evaluation and Mitigation Strategy, it can consider “any known or potential adverse events that may be related to the drug,” such as those reported in epidemiological studies.
But despite FDA’s ability to use larger health data sets to assess the safety and efficacy of high-risk, it has failed to do so in a consistent and systematic way. Correcting this failure will allow Americans to access safer and less addictive drugs, argue Zettler and her coauthors.
Zettler and her coauthors’ paper appears in the Food and Drug Law Journal.
