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On June 8, 2017, the FDA did something it had never done before. It formally requested that a pharmaceutical company voluntary remove its opioid pain medication from the market. The company was Endo Pharmaceuticals and the opioid was Opana ER. “Should the company choose not to remove the product, the agency intends to take steps to formally require its removal by withdrawing approval.” Way to go FDA.

The FDA decision was based on a review of post marketing data, which showed a drastic shift in the route of Opana ER abuse after the drug was reformulated in 2012. This review demonstrated that instead of crushing and snorting Opanas, individuals abusing the drug were now dissolving and injecting it. The FDA’s decision follows a March 2017 FDA advisory committee meeting where a group of independent experts voted 18-8 that “the benefits of reformulated Opana ER no longer outweigh its risks.” The newly appointed FDA Commissioner, Scott Gottlieb said:

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. . . . 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 NPR program, All Things Considered, interviewed Janet Woodcock, the director of the FDA’s Center for Drug Evaluation and Research about the decision on June 9^th. She said the decision was made due to the risks of abusing the product. An outbreak of HIV and hepatitis C, as well as cases of a serious blood disorder (thrombotic microangiopathy), were associated with individuals injecting the reformulated Opana ER. The request to remove Opana ER from the market is not an outright ban. When asked what the response from Endo Pharmaceutials has been, Dr. Woodcock said the company is evaluating the request.

Well, FDA does not have the authority for drugs to immediately remove them from the market. Generally we ask companies to voluntarily pull their drug off the market. If they are not willing to do that, we will issue a notice of a hearing, and we have to go through a judicial type of process.

Another NPR report on April 1, of 2016 said that the reformulation in 2012 effectively stopped people from snorting Opana, which had been the preferred method of abuse. “But the change also led a significant number of people to abuse the drug by injection.” Endo said the company’s decision to reformulate Opana was “a well-intentioned attempt to prevent abuse.” But there seems to have been an additional motivation for the action. According to NPR, “interviews with experts, court filings, documents from the FDA, as well as Endo’s own statements, suggest the company’s decision to reformulate Opana was also motivated in large part by financial interests.”

Soon after its release in 2006, there were reports of abuse and overdose deaths with Opana from around the country. But the painkiller was a major moneymaker for the company. It accounted for 14% of Endo’s total revenue; $384 million in net sales in 2011. In late 2011 the FDA approved Endo’s reformulated version of Opana and Endo began replacing the old version of Opana in pharmacies. That August, Endo filed a petition with the FDA (available in the NPR article), arguing that it removed the crushable version of Opana because it was a safety hazard. It also asked that the FDA refuse or withdraw the approval of generic versions of Opana because they were not crush-resistant.

In 2012 Endo filed a lawsuit to compel the FDA to speed up its review of their petition, predicting a spike of misuse and abuse if generic, crush-resistant versions of Opana went to market. It also estimated that if a generic version went to market, “annualized net sales will decrease by an amount up to $135 million.”

This was nothing new. In 2010 Purdue Pharmaceuticals reformulated OxyContin to make it crush resistant. And the FDA determined the reformulated version was much safer and that the benefits of the original no longer outweighed the risks. The agency blocked generic versions of OxyContin, which made Purdue billions. Dr. Anna Lembke, an assistant professor of psychiatry at Stanford University Medical Center said: “We see this again and again in the pharmaceutical industry. . . . They come up with some new fancy formulation of basically the same old drug … and then that way they have a new drug that they can charge a lot of money for.”

But on May 10, 2013, the FDA decided Endo’s tamper-resistant formula didn’t actually prevent drug abuse better than earlier versions of Opana without the abuse-deterrent feature. That day the price of Endo shares dropped more than 5 percent. The FDA said the reformulated version could be compromised when it was subjected to “cutting, grinding and chewing.” It could be “readily prepared for injection.” The agency also warned the preliminary data suggested the possibility “that a higher percentage of reformulated Opana ER abuse is via injection than was the case with the original formulation.”

The FDA said Endo could not refer to Opana ER as “abuse deterrent.” Writing for FiercePharma, Emily Wasserman quoted Douglas Throckmorton, a deputy director for the FDA’s Center for Drug Evaluation and Research, as saying: “We think the public health would not be served if a company can market itself as ‘abuse deterrent,’ if the scientific evidence did not support that claim.” The problems with Opana seemed to put the FDA on alert that abuse-deterrent technology may not be all that effective. An FDA spokesperson, Sarah Peddicord said: “The FDA is very concerned about potential unintended consequences of abuse-deterrent opioids (and purportedly abuse-deterrent opioids) and it is something we are actively looking at.”

FDA is requiring all sponsors of opioids with approved abuse-deterrent labeling to conduct long-term epidemiological studies to assess their effectiveness in reducing abuse in the real world. . . . Abuse-deterrent does not mean abuse-proof.

So while the June 8^th request by the FDA may be unprecedented, it seems to have been coming for a few years. Then a week after the FDA request, Scott Gottlieb ordered a review of all opioid pain relievers with abuse-deterrent formulas to see if they actually help prevent abuse and addiction. In a statement released on June 13^th, Gottlieb said there would be a public meeting to discuss whether they have the right information to determine if the abuse-deterrent products “are having their intended impact on limiting abuse and helping to curb the epidemic.”

The FDA, he said, recognizes there is a gap in their understanding of whether these products have a real-world, meaningful effect on opioid misuse and abuse. At the July 10-11 meeting, the FDA will engage external thought leaders to discuss how to better “evaluate the impact of these products in the real world.” There is a link in the statement to an issues paper that outlines some of the existing regulatory and public health challenges they face.

Opioid formulations with properties designed to deter abuse are not abuse-proof or addiction-proof. These drugs can still be abused, particularly orally, and their use can still lead to new addiction. Nonetheless, these new formulations may hold promise as one part of a broad effort to reduce the rates of misuse and abuse. One thing is clear: we need better scientific information to understand how to optimize our assessment of abuse deterrent formulations; and I look forward to a productive discussion on how to best tackle this challenge.

Sidney Wolfe, the founder of and senior advisor to Public Citizen’s Health Research Group supported the FDA request for Endo to remove Opana ER from the market. He also said the FDA had enough information before its approval in late 2011 to “reject the drug as possibly more dangerous than its older … version.” He was a member of the FDA’s Drug Safety and Risk Management Advisory Committee at the time, but for some reason, the approval decision was not presented to the Committee. Had the Committee advised rejecting the drug, and the FDA followed the Committee’s advice in 2011, the adverse effects leading the current request could have been avoided.

In addition to FDA’s serious mistake in approving the OPR version, Endo’s defiant response yesterday that they would not necessarily take this more dangerous form of the drug off the market is reckless. In proportion to how many people will use and, in many cases abuse the drug, causing deaths, hospitalizations and other preventable between yesterday’s FDA decision and the ultimate, but certain forced removal of the drug, Endo will be exposed to many product liability lawsuits from those damaged or their surviving families.

Endo suffered some significant financial withdrawal symptoms after the FDA request. The company’s shares were down more than 12% afterwards, according to Fortune. A financial analyst for RBS Capital Markets referred to Opana ER as a “declining asset” with sales expected to fall to $97 million in 2019 from an estimated $134 million in 2017. But Endo seems to have counted the potential future cost if it challenged the FDA recommendation and fought to keep Opana ER on the market. On July 6, 2017, Endo International announced it would voluntarily withdraw Opana ER from the market.

Ed Silverman reported for STAT News that Endo executives “blinked” by saying they were reconsidering their initial statement that they would review the FDA request and evaluate “the full range of potential options.” Silverman noted Opana ER hadn’t been a huge seller for Endo. And it seems the FDA request would impact sales even further. It only generated around $159 million in revenue in 2016. Through the first quarter of 2017, sales were $35.7 million, down from almost $44.7 million in the first quarter of 2016. Given the adverse impact on public health, and the potential for future product liability lawsuits, Endo did the right thing in deciding to go “cold turkey” with Opana.