Waiting for Zohydro

I cannot remember a time when the imminent release of a new medication caused as much widespread terror and suspicion as has Zohydro. Given the experience of the Oxycontin addiction epidemic, it’s not hard to understand why.

First, some facts about the drug. It’s hydrocodone, a common painkiller. But it differs from other hydrocodone based medications in important ways. First, whereas Vicodin (which also contains hydrocodone) is prescribed in pills ranging from 5 to 10 milligrams, Zohydro will be an order of magnitude higher: 10 milligrams will be the lowest available dose, 50 mg the highest. Second, while most hydrocodone products are combined with acetametaphin or ibuprofen, which discourages overuse, Zohydro is pure hydrocodone. Third, after pledging that opioids without misuse-resistant features would not be approved, the FDA reversed itself with Zohydro, which includes no such protections whatsoever.

The FDA’s expert review committee took note of these concerns and voted 11-2 not to approve Zohydro. The drug was approved anyway. Subsequently a majority of the nation’s attorneys general and a coalition of health groups have both written to the FDA asking for Zohydro’s approval to be withdrawn.

Investigative journalists at the Milwaukee Journal Sentinel and Medpage Today recently discovered that the makers of Zohydro had a series of private meetings with FDA officials for which they allegedly paid handsomely. Several U.S. Senators are now calling for an investigation.

Whether the meetings involving the FDA and the company were improper is not something I claim to know (How could I when I wasn’t there?). FDA officials say the meetings were not unethical and that is entirely possible. However, everyone involved agrees that one of the topics of the meeting was enriched trial enrollment, and I do know what that is and what it means for medicines.

In enriched designs, patients who seem likely to have a bad outcome are excluded from the research. The ostensible goal is to find out which patients will benefit the most from a treatment. This would make sense if, post-approval, the use of the medication were restricted to patients like those in the enriched sample. But that’s not the case. If for example a study that leads to drug approval did not enroll anyone thought likely to misuse it, patients like those excluded from the study will legally be prescribed it anyway in everyday front line clinical practice. Estimates of adverse event rates in an enriched trial will thus tend to be much lower than what will be evident when the drug is in wide use in the health care system. Zohydro’s effectiveness data came from an enriched trial, and that’s another reason that its launch is causing such anxiety.

Everyone who is fearful of course could be wrong about Zohydro. Perhaps it will be carefully prescribed, provide relief to long-suffering pain patients and not result in a spate of overdose deaths. My own fingers are crossed, but like everyone else I’ll be watching the data closely for signs of the second coming of the Oxycontin addiction epidemic.