By John Lavitt 12/19/13

The FDA defied its own experts to approve a new prescription narcotic in a form almost certain to cause addiction and death from overdoses. The Fix investigates

photo: Shutterstock

(page 2)


Key FDA staffers and scientists (the FDA has a large science research staff that handles analysis of new drugs) have been instructed not to talk directly with the press – a fairly standard practice. Calls from The Fix to specific staffers were referred to the FDA press office. After prodding by The Fix, that office responded to a series of our queries although it did not permit direct interviews with staff members.

First, the office made a point that the FDA “encourages” tamper proofing but doesn’t require it because the science is imperfect and differs with each pain-killing formula. Its practice has been to use FDA authority to withdraw drugs after there is sufficient reason to do so and based on a cost-benefit evaluation.

As example, FDA spokesperson Morgan Liscinsky noted in an email that accumulated evidence led the FDA to require that the original formulation of OxyContin be withdrawn from sale by generic manufacturers “for safety or effectiveness reasons." She added: "Reformulated OxyContin can be expected to make abuse via injection difficult and to reduce abuse by snorting compared to original OxyContin.”

In other words, once there was a more abuse-resistant Oxy available, the FDA decided it could ban the original formula. No matter how many deaths from or addiction to and abuse of Oxy occurred earlier, the FDA was loathe to ban it earlier because of its widespread use as an effective painkiller.

By stark contrast, the FDA also investigated another time release painkiller, Opana ER. It got a pass. As Liscinsky emailed: “In May 2013, the FDA concluded that while reformulated Opana ER and original Opana ER have the same therapeutic benefits, there is insufficient evidence that original Opana ER poses an increased potential for abuse compared to reformulated Opana ER.”

Ergo: lacking sufficient proof of damage done by Opana ER, the FDA left the original on the market.

And why did Zohydro also get a pass? What is the meaning of the statement that the FDA "could not not approve it?”

According to Liscinksy, “Zohydro met the same safety and effectiveness standard” with the same “risk-benefit profile” as other hydrocodone painkillers already on the market, none of which have developed effective abuse resistant formulas.

Translated, Z is not worse than anything else out there and, Liscinsky added, the FDA concluded its benefits for patients in pain outweighed the risks of additional addictions and abuse. Accordingly, the statement “could not not approve it” meant there were no compelling scientific, medical or legal reasons by which the FDA could allow similar drugs on the market and ban Zohydro, especially since Z will add a unique element to the pharmacy: long term relief from a hydrocodone with no liver-damaging acetaminophen in it.

The Fix pointed out to Liscinsky that, working with the same data sets, the advisory panel concluded that, owing to Zohydro's potency and “single entity” qualities, more deaths and drug abuse would occur as clever addicts made a beeline for Zohydro. Even in closely monitored clinical trials, people became addicted to the drug and found ways to obtain it illegally; some patients even died from overdose. Moreover, the advisory panel, which included treatment experts, concluded that all the new monitoring regulations “will at best be modestly effective in addressing the public health issues of opioid abuse.”

How could the full FDA come to a different conclusion than the panel and the CSS staff as to increased abuse and deaths?

Liscinsky replied that the full FDA, under no legal obligation to accept the panel's recommendation, had concluded it is a false premise that Z will increase the size of the overall pain market rather than simply substitute for other painkillers. It is also incorrect, she wrote, that doctors will rush to prescribe it in place of non-extended release painkillers, creating thereby a vast wave of new addicts. “Therefore, when factoring the risk for deaths due to opioids, there was no expectation that the approval of Zohydro would result in an [overall] increase,” she wrote. 

On the plus side, she added:

“Prescribers now have a hydrocodone option for patients who require an extended-release opioid, which is important for several reasons. First, individual patients can respond differently to different opioids. A given patient may experience better or worse pain management and/or more or less tolerable adverse effects from one opioid compared to another.

“Second, the benefits of opioids can wane as the patient becomes opioid-tolerant. A common strategy is to rotate the patient from one opioid to another in an attempt to address one or more of these issues. Zohydro ER provides an additional available opioid to which prescribers can switch patients if medically appropriate.

“Also, prescribers will now have the option of moving a patient who is responding well to an immediate-release hydrocodone combination product but who would benefit from treatment with an extended-release…hydrocodone product [i.e., Zohydro ER], obviating the need to switch the patient to a drug product with a different active ingredient.

“Next, because Zohydro ER is a single-entity product, prescribers may [prescribe] Zohydro ER for individual patients without the limitations or toxicity concerns associated with the non-opioid active ingredient (e.g., acetaminophen) present in all other approved hydrocodone products.”

Liscinsky was also challenged about the FDA’s tardiness in moving aggressively to go beyond “encouraging” drug companies to develop abuse resistant opioids. Only in January of this year, after many years of creating addiction among non-addicted pain relief seekers, did the FDA issue a “draft guidance” for drug companies on developing abuse-resistant formulas. Meanwhile, it was telling Dr. Zito that the FDA lacked authority to compel Zohydro ER to go tamper-proof.

Does it lack authority?

“The FDA is currently evaluating whether, and under what circumstances, it may require abuse deterrent formulations as a condition of approval,” Liscinsky wrote. “While FDA strongly supports a transition to abuse-deterrent opioids…the science of abuse deterrence is relatively new. Both the drug and formulation technologies involved and the clinical, epidemiological and statistical methods for evaluating those technologies are rapidly evolving.

“It is essential that every abuse-deterrent formulation be grounded in science and supported by evidence. Any claims regarding abuse-deterrent properties must be truthful and not misleading, and supported by sound science taking into consideration the totality of the data for the particular drug at issue. Absent sufficient science, there can be no claim of abuse deterrence. To do otherwise does not serve the public health."

Liscinsky was asked what would prompt Zogenix CEO Roger Hawley to report to investors two years ago that he was getting no pressure from the FDA to add abuse deterrents to Zohydro if in fact the FDA had an “encouraging” policy (even if not a mandating policy) regarding the development of abuse resistant formulas. Liscinsky’s response: “All of the companies have been equally encouraged to develop abuse deterrent formulations over the past decade.”

As The Fix went to press, we were awaiting a response from the FDA as to exactly which FDA personnel two years ago had encouraged Zogenix and in what manner to develop an abuse resistant model. 


The public face of Zohydro is Zogenix. In 2010, Zogenix purchased the right to develop and market Zohydro in the United States from the Irish biotech company Elan using Elan’s proprietary “delayed release” technology. Under the agreement, Elan would be the exclusive manufacturer of Z.

In 2011, everything changed when the Ireland-based global biopharmaceutical giant Alkermes bought the division of Elan that produces Zohydro, thereby also inheriting the existing agreement with Zogenix and the right to manufacture Zohydro.

Disturbing to many in the drug treatment community, the major factor in the company’s takeover of Z, according to online investor reports, is that Alkermes produces Vivitrol, the most highly effective opioid blocker on the market designed to treat addiction to prescription painkillers (at an average cost of $15,000 per addict per year). Do the math: the more Zohdyro ER becomes a major painkiller in the marketplace and spawns addictions, the more high-profit margin Vivitrol will sell. It is a very sweet closed loop in the cynical and opportunistic world of Big Pharma.

Also troublesome is that Alkermes happens to be one of the more aggressive marketers in the business and is unlikely to stand idle as Zogenix launches Z with all its addictive properties into the American marketplace.

All this was backdrop to the dramatic meeting of the FDA advisory committee on Zohydro ER in December, 2012 to consider the pros and cons of approving Z for the U.S. market.

At the meeting, Zogenix representatives argued that in light of new FDA opioid drug monitoring requirements for doctors and pharma companies, Z would be better controlled than had been earlier painkillers. (Drug manufacturers now must educate healthcare providers on how to prescribe and administer high-risk medications, and pharmaceutical companies making prescription painkillers are required to track signs of trending abuse or misuse.)

Several addiction experts and scientists countered that given that the FDA had pressured Purdue Pharma to change the formulation of OxyContin to include an abuse deterrent even though Oxy is also covered by the new monitoring rules, doing the same with Zogenix and Z would be a wise precaution. Would that not be a perfect example of learning from past mistakes rather than relying on new and unproven monitoring regulations? As one expert put it in a communication to the FDA before the meeting:

“If all extended-release opiate products were required to incorporate tamper-resistant technology, we believe that we would start seeing a beneficial societal impact of less abuse of opioid products, fewer prescription drug overdoses, and fewer deaths,” said Steve Pasierb, CEO of The Partnership at Drugfree.org. “As a public policy matter, we should all be encouraging companies to ‘retrofit’ their current products so that they are more difficult to abuse. And we certainly should not be approving any new opiates without these protections.”

At one point during the proceedings came the odd testimony of Bob Rappaport, director of the FDA’s Division of Anesthesia, Analgesia, and Addiction Products. Although a supporter of Zohydro approval, Rappaport conceded that a single-entity hydrocodone product like Z “will contribute to the already critical public-health problem of prescription opioid abuse and misuse” when it goes on the market (a statement in obvious conflict with the current FDA public position).

Rappaport then startled the audience when he later claimed not to understand why the experts testifying before the advisory panel were “. . . punishing this company and this drug because of the sins of the previous developers and their products.”

The FDA told The Fix that “Dr. Rappaport’s statement was intended to provide some balance to some of the advisory committee members who referred back to what happened with OxyContin instead of considering the changes in risk management and mitigation that have been undertaken over the past two decades and the fact that the original improprieties and misleading labeling associated with OxyContin promotion in the late 90s and early 2000s were acknowledged and punished and changed, respectively.”

Predictably, a number of outsiders took the remarks as an important FDA official displaying an odd defense of a company which, to them, was about to repeat the mistakes of the past if no abuse deterrents were applied. Why such cozy protection of Zogenix? became a buzz in treatment circles. 

Put more bluntly, as some critics have, was the FDA brass willing to protect Zohydro as a useful drug by protecting Zogenix? Or was it protecting Zogenix?

Last May Zogenix CEO Roger Hawley told investors and analysts that the company had experienced unusual delays in getting approval for Z, compounded by the negative advisory panel vote. By then, the company had spent millions on its Zohydro efforts in anticipation of reaping what some Wall St. analysts predicted would be hundreds of millions in sales in a relatively short period.

In June, Zogenix announced the layoff of 55 employees—or 37 percent of its workforce—in an effort to conserve cash through the summer. Zogenix later reported a $10.9 million net loss for the third quarter of 2013, down from a $19.3 million net loss for the third quarter of 2012. As of Sept. 30, 2013, the company had an accumulated deficit of $374.6 million.

Did Zogenix’s $100,000 a year lobbyists somehow persuade the FDA leaders such as Rappaport to factor in the company’s financial status in their decision? According to the FDA, there are no such considerations and the only exchanges with Zogenix have been on development and clinical testing issues. Moreover, exchanges with Alkermes representatives have been “on matters limited to addressing routine manufacturing and controls issues concerning Zohydro ER.”

While it may take a whistleblower to determine whether any improper influence or consideration took place in the FDA’s decision, the decision unmistakably altered a bad cash situation for Zogenix. Just two weeks after the FDA October 25 approval announcement, with its stock prices rising, the company announced a $56 million stock offering to meet cash needs.

As a gigantic footnote, well over two years after the FDA could have prodded Zogenix to do so and only ten days after winning approval for the Zohdyro ER, the company entered into an agreement with Altus Formulation Inc., a private Montreal-based drug company, to develop abuse deterrent formulations of Zohydro ER using Altus's proprietary drug delivery platform.

Development of such new drug formulations will take anywhere from 1 to 3 years to be finished and approved. Within the drug treatment community, the obvious question remains: why didn’t the FDA push for this process to start earlier?

Now, with Oxy so diminished in the black market, the Seeking Alpha wiseguys and FDA critics are predicting that, despite the FDA's rosy outlook and its discounting of the research of its own CSS staff and the conclusions of its advisory panel on the amount of damage Zohydro may cause, Z is indeed poised to take over a decent percentage of both the legal and black market – the latter until such time as an abuse deterrent formula replaces the existing one.

When so much money is involved, is it fair to speculate on whether the FDA top echelon was influenced at all in its Z decision by issues that go well beyond public safety? It depends who you ask.

One question is certainly fair: Why did the FDA wait so long to issue guidelines on developing abuse deterrents when the abuse issue was so stark and the drug companies were dragging their heels on spending the money needed to research alternatives?

Jack Maroney is the president of the board of Massachusetts Corporation for Sober Housing. His take:

“Zohydro is just another chapter in a long history of Big Pharma creating high potency narcotics without the prudence or inclination to address the high cost of collateral damage that results from these drugs. We, here in the treatment community in Massachusetts, know that the moment people are placed before profits will be the moment when meaningful change will actually occur.”

In short, Zohydrogate is simply one element of BigPharmagate.

John Lavitt is the Content Director for Open Interactive and a patient advocate at Hepatitis Connect.

Please read our comment policy. - The Fix

Growing up in Manhattan as a stutterer, John Lavitt discovered that writing was the best way to express himself when the words would not come. After graduating with honors from Brown University, he lived on the Greek island of Patmos, studying with his mentor, the late American poet Robert Lax. As a writer, John’s published work includes three articles in Chicken Soup For The Soul volumes and poems in multiple poetry journals and compilations. Active in recovery, John has been the Treatment Professional News Editor for The Fix. Since 2015, he has published over 500 articles on the addiction and recovery news website. Today, he lives in Los Angeles with his beautiful wife, trying his best to be happy and creative. Find John on Facebook, Twitter, and LinkedIn.