Zohydro: The Fix Is In

A reluctant bet against public health

Published on December 19, 2013by June H. Kim

By going long on the California-based pharmaceutical company Zogenix, I am, unfortunately, betting against public health. Full disclosure: I’ve purchased shares in the company.

I placed this bet on the heels of a recent, and exceedingly bizarre decision, by the FDA to approve of the company’s newest product, Zohydro ER (extended-release), the first hydrocodone-only prescription painkiller to hit the market. Despite an 11-2 vote against approval by a committee of the FDA’s own advisors, the world’s largest market for hydrocodone will soon have a new prescription to add to one already sizeable problem.

Believe me, I would be ecstatic if public health ends up victorious, if the risk evaluation and mitigation strategies (REMS) proposed by the FDA are effective deterrents against abuse, and if I don’t make a dime.

So why would I bet against my field?  Have I lost my lust for public health?

No. In truth, I have lost faith is some of the guardians of public health. I will explain why, but first I need to provide some context. Back in 1995, the FDA approved an extended-release (ER) formulation of an oxycodone-containing opioid called OxyContin, under the pretense that it would be less prone to abuse than immediate-release formulations.

Boy, were they wrong!

The more resourceful soon found that simply crushing OxyContin into a fine powder allowed for instant access. Abusers could then snort the powder or cook it up and inject it. It would take more than a decade of unprecedented abuse and one $600 million lawsuit before a change was deemed necessary.




In 2010, OxyContin ER was silently reformulated with the abuse deterrent properties shown above, which make crushing the pill into powder nearly impossible. Ostensibly, this new formulation was not as popular as the old version. Using data from the National Poison Data System, one study (underwritten by Purdue Pharma) showed that abuse exposures to OxyContin decreased 36% in the two years after reformulation compared to the year prior, while exposures to other opioids, including street heroin, increased.

The FDA has acknowledged the effectiveness of these abuse deterrent properties in their approval of a new label for OxyContin, and has even said the development of new painkillers with similar formulations is a “public health priority for the FDA.”

So, why haven’t they ensured Zohydro comes with these same protections? Why block generic versions of OxyContin ER (without the abuse deterrent properties) one day and switch course and approve Zohydro the next?

Confused yet? So am I.

There’s more. In the rush to get Zohydro on the market, only one efficacy study was deemed necessary. Further, the study used an enriched enrollment design, which includes what amounts to a wash-out period. In this design, all 510 study participants are given Zohydro over a six week period. Those who did not respond to or did not tolerate the medication (e.g., due to adverse effects) were excluded.

Only 59% of enrolled subjects made it to randomization, where they were randomly selected to either continue the treatment or receive a placebo while being tapered off the drug. Inherent in this design is the study question, “among people already responding well to Zohydro, will continuing to receive treatment be more effective for pain relief than discontinuing treatment?”

Beyond the valid concern that adverse effects due to treatment are often underestimated in these designs, there is the even greater problem of the limited generalizability of the findings. Excluding patients that did not react well to Zohydro does not give us an understanding of the drug’s effects in a representative population. Yet, these results were used to make a case for the effectiveness of Zohydro for all pain patients, not just among those who are already responsive.

Further, in the FDA’s summary review of the approval, Bob Rappaport (Director, Division of Anesthesia, Analgesia, and Addiction Products) states that severely restricting access to opioid formulations is “not acceptable in the absence of equivalently effective analgesic products” (page 32).

When making comparisons of treatment effectiveness against a placebo, how could you find any equivalent alternatives?

For the FDA, public health is apparently taking a backseat to industry in this battle. The game appears to be fixed, and I am just hedging my bets.

Disclosure: As stated above, the author has holdings (along with mixed feelings) in Zogenix. The position stated by the author is his own, and does not reflect those of the2x2project.org, the Mailman School of Public Health, or Columbia University. A copy of the FDA’s Summary Review of the Zohydro ruling can be found here.

Edited by Joshua Brooks