On Thursday, the FDA said it wants the oxymorphone product Opana ER removed from the market, capping years of controversy over the opioid painkiller. MedPage Today and the Milwaukee Journal Sentinel in 2015 published an investigation of how the FDA came to approve Opana ER and what had gone wrong. Here we republish that investigation to provide context for the recent FDA action. In 2006, in the midst of a growing opioid epidemic, the FDA approved the new narcotic painkiller Opana. It was a familiar drug. Under the name Numorphan, it had been abused in the 1960s and 1970s until it was removed from the market. When injected, the drug is 10 times as potent as morphine. And now there is a familiar problem. Known generically as oxymorphone, the FDA approved the new version of the drug -- made by Endo Pharmaceuticals -- in 2006 as both an immediate-release and extended-release pill. Then in December 2011, the agency approved a new abuse-deterrent version -- but users have been able to foil the anti-injection mechanism and have been shooting up Opana. In addition to overdose risk, abuse of Opana by injection has been tied to a recent outbreak of HIV in rural Indiana as well as a surge in hepatitis C infections in several Appalachian states. It also has been associated with a blood-clotting disorder and permanent organ damage -- a problem that didn't occur with injection abuse of generics and the earlier version of the drug. When Opana was approved, it joined more than a dozen other narcotic painkillers on the market. "There certainly didn't seem to be a need for it," said James Roberts, MD, a professor of emergency medicine at Drexel University College of Medicine in Philadelphia. "There are plenty of narcotics around for pain relief." As Numorphan, the drug's popularity among addicts was due to its quick and sustained effect, according to the 1974 report "Drugs and Addict Lifestyle" by the National Institute on Drug Abuse. The report said the drug -- which carried a street name of "blues" -- was used primarily by white males and highlighted 309 Philadelphia area addicts who were interviewed about their Numorphan abuse in 1970. Many of the addicts said they preferred the drug over heroin. Originally approved in 1959, FDA records indicate the pill form of Numorphan was taken off the market in 1979 for what is described as "commercial reasons." Its intravenous and suppository formulations were allowed to remain on the market. In an email, FDA spokesman Eric Pahon said opioids, including Opana, are important medications for the treatment of pain, when used properly. "The FDA is concerned about the misuse and abuse of prescription opioids, which is a serious public health challenge, and is working in many ways to help prescribers and patients make the best possible choices about how to use these powerful drugs," he said. "We must balance this effort, however, with ensuring prescribers and patients maintain access to these medications and a variety of treatment options are available." Opana ER generated 756,000 prescriptions and sales of $385 million in 2013, according to data supplied by IMS Health, a drug market research firm. Since 2009, its annual sales have ranged from $246 million to $640 million. In an email, Endo spokesperson Heather Zoumas Lubeski said the drug "was approved by the FDA based upon its demonstration of safety and effectiveness in clinical trials and its successful submission of an application for approval." Meetings Impact Approval? A Milwaukee Journal Sentinel/MedPage Today examination found oxymorphone's re-appearance on the market followed a pattern identified in past investigations, including cozy relationships between regulators and drug company executives and the use of questionable clinical testing methods allowed by the FDA. Endo was a frequent participant at meetings of an organization funded by pain drug companies that brought together pharmaceutical executives and federal regulators during the 2000s, records show. The group, known as IMMPACT, was the subject of a 2013 Journal Sentinel/MedPage Today investigation. The story highlighted how federal health industry officials, members of academia, and executives of companies that make pain drugs held private meetings at expensive hotels at least once a year beginning in 2002, according to emails obtained through a public records request. Each year, a handful of drug companies paid up to $35,000 each to send a representative to the meetings where they could discuss clinical trial design with FDA officials. The arrangement was criticized as appearing to be pay-for-play connection between regulators and companies anxious to get products onto the multibillion-dollar-a-year pain market. In 2014, two U.S. senators wrote to the medical school dean at the University of Rochester demanding financial records related to the IMMPACT meetings. A researcher at the school was a co-founder of the group. Sen. Joe Manchin (D-W.Va.) and Sen. David Vitter (R-La.) wrote that they were "deeply troubled by allegations that the FDA gave manufacturers of prescription drugs the opportunity to pay thousands of dollars to the University of Rochester Medical Center for the privilege to attend private meetings with FDA officials." FDA spokesman Pahon said it is misleading to imply that the IMMPACT meetings were private meetings between FDA officials and members of industry. Though the meetings were invitation-only, he said, they were attended by a variety of government officials, academics, and pain advocates. "These were large scientific meetings at which the outside experts almost always outnumbered the attending companies," he said. "We are not aware of any separate, private meetings between FDA and pharmaceutical companies during or as a result of IMMPACT meetings." He said the meetings had no bearing on the approval of Opana and did not include the discussion of any particular product or the standards for FDA approval of pain products. Stacking the Deck? The IMMPACT meetings helped develop a new approach to winning approval of drugs known as enriched enrollment. The approach allows drugs companies to weed out people who don't respond well to a drug or who can't tolerate taking it before an actual clinical trial for the drug begins. Independent doctors say that approach makes it much more likely a drug will be found effective and possibly win FDA approval. It's also cheaper for drug companies to conduct such trials. Critics say the approach essentially stacks the deck in favor of the drug. More importantly, experts say, drugs tested that way are not likely to reflect what will happen when a medication gets on the market and is prescribed for large numbers of people. When Endo tried to get Opana approved in 2003, the FDA said the drug didn't appear effective enough in clinical trials. It also raised safety concerns after several postoperative pain patients overdosed on the drug and had to be revived with naloxone. So Endo conducted new clinical trials using enriched enrollment. In those trials, only the patients who initially responded to the drug were entered into a randomized, controlled trial, where they were given either Opana or a placebo. The idea is that the drug's effects can be clearly demonstrated in comparison with placebo because it is already known to work for all of the patients. The results of those trials helped get the drug approved by the FDA in 2006. But the FDA's own medical review of the drug acknowledged that, given the enriched study design, "one could argue that the results may not be generalizable to the wider chronic pain population." "The FDA should be in the business of requiring high-quality evidence and not short-cut evidence," said Lewis Nelson, MD, a medical toxicologist at NYU Langone Medical Center. "Unfortunately, they're under pressure to make pharmaceuticals available to the general public." Nelson said the enriched trials "find the people who are most likely to respond to a drug and not suffer from side effects." "I don't think enriched enrollment studies are truly valid," he added. FDA spokesman Pahon said companies use a variety of strategies to select those in the general population in which the effect of a drug can be more readily shown. He would not say whether the FDA encouraged Endo to use enriched enrollment for Opana. "You'll need to FOIA [apply under the Freedom of Information Act to see] those pre-approval meeting minutes," he said. Opana is not the only opioid approved using enriched enrollment. In 2013, drugmaker Zogenix used the strategy to win approval for Zohydro, a high-dose, hydrocodone-only drug that was originally approved without any abuse-deterrent mechanisms. The FDA approved the product despite its own advisory committee on pain drugs voting 11-2 against it. Source
