Archives for : @GovPenceIN

Why Opana MUST be removed from the market: “Enriched Enrollment”

Opana approved despite history of abuse,

limited effectiveness in trials

By John Fauber and Kristina Fiore of the Journal Sentinel

Updated May 9, 2015

In 2006, in the midst of a growing national opioid epidemic, the U.S. Food and Drug Administration approved the new narcotic painkiller Opana.

It was a familiar drug.

Known generically as oxymorphone, the drug is 10 times as potent as morphine when injected. Under the name Numorphan, it had been abused in the 1960s and ’70s until it was removed from the market.

And now there is a familiar problem.

After initially approving Opana as both an immediate-release and extended-release product, the FDA in December 2011 approved a formulation designed to prevent abuse by making the drug tough to crush or dissolve.

But users have been able to foil the anti-injection mechanism and have continued to shoot up Opana.

In addition to overdose risk, the abuse of Opana by injection has been associated with a blood-clotting disorder and permanent organ damage — a problem that didn’t occur with the earlier version.

And it has been tied to a recent outbreak of HIV in rural Indiana as well as a surge in hepatitis C infections in Kentucky, Tennessee, West Virginia and Virginia.

When the FDA approved Opana, manufactured by Endo Pharmaceuticals, the drug 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, 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 the street name “blues” — was used primarily by white males. The report focused on 309 Philadelphia-area Numorphan addicts who were interviewed in 1970, with many saying they preferred the drug over heroin. The drug was taken off the market in 1979.

Asked about the basis for approving Opana, FDA spokesman Eric Pahon said opioids 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 wrote in an email. “We must balance this effort, however, with ensuring prescribers and patients maintain access to these medications and a variety of treatment options are available.”

The extended release version of Opana alone 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 spokeswoman 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.”

Drug’s reappearance

A Milwaukee Journal Sentinel/MedPage Today examination found oxymorphone’s reappearance 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 Pharmaceuticals 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.

That investigation examined 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.

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.

Sens. Joe Manchin (D-W.Va.) and 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.”

Pahon, the FDA spokesman, said it is misleading to describe the sessions as 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.

‘Enriched enrollment’

Those meetings did help lead to a new approach to winning approval of drugs known as “enriched enrollment.”

The approach, which is faster and less expensive for drug-makers, allows 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 win FDA approval. 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 first 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.

So Endo conducted new clinical trials using enriched enrollment.

In those trials, only the patients who initially responded to the drug were entered into the trial, where they were given either Opana or a placebo. The idea was that the drug’s effects can be clearly demonstrated in comparison to a placebo, because it is already known to work for these patients.

Pahon of the FDA said companies use a variety of strategies to select those in the general population in which the effect of a drug can be more shown. He would not say whether the FDA encouraged Endo to use the enriched enrollment approach for Opana.

When the drug was approved in 2006, the FDA’s own medical review acknowledged that, given the enriched study design, “one could argue that the results may not be generalizable to the wider chronic pain population.”

Opana is not the only opioid approved using enriched enrollment. In 2013, drug-maker 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 that drug despite its own advisory committee voting 11-2 against it.

“The FDA should be in the business of requiring high-quality evidence and not shortcut evidence,” said Lewis Nelson, a medical toxicologist at NYU Langone Medical Center. “Unfortunately, they’re under pressure to make pharmaceuticals available to the general public.”

John Fauber is a reporter with the Journal Sentinel. Kristina Fiore is a reporter with MedPage Today. This story was reported as a joint project of the Journal Sentinel and MedPage Today, which provides a clinical perspective for physicians on breaking medical news at

Read past investigations

For past investigations into prescription painkillers, and related examinations of medical conflicts of interest, go to

More Coverage

Graphic: New drug, familiar concerns

Stats 2009-2013