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ZOHYDROGATE: AND HERE COME THE ADDICTS

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

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By John Lavitt

12/19/13

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On October 26 the savvy investor’s website SeekingAlpha.com published the following remarkable comment about a new and highly addictive painkiller called Zohydro ER, which only the previous day had been approved for sale by the U.S. Food and Drug Administration despite consistent warnings - including from the FDA’s official advisory panel - that Z is potentially more addictive and dangerous than its sister opiate drug, the original and deadly OxyContin.

Said Seeking Alpha: “Many bullish investors believe that [Zohydro] will be a huge commercial success. Ironically, their arguments hinged on the thesis that ‘many drug addicts would be willing to pay through the nose for Zohydro.’"

And as certain as heroin will get you high, addicts are expected by drug treatment experts to flock to Zohydro with their bucks…and those newly addicted to Zohydro ER will regularly join their ranks as Zohydro replaces the now tamper-resistant OxyContin in black market desirability - a market which helped Oxy become one of the top-selling prescription painkillers, with worldwide sales of $3.6 billion in 2010 before it was reformulated in a manner that made it abuse deterrent (and now for 2013 at an estimated $2.5 billion). 

You don’t have to be the best journalist in the world to quickly discover that the FDA’s approval was a premium rare act in four ways.

First – and making major headlines – was that in green-lighting Zohydro, the FDA brass swept aside protestations of its own advisory panel of addiction experts and doctors that the drug should be kept off the market until it includes an abuse deterrent in its formulation. The vote was 11-2 for banning Z with one abstention.

The FDA position is that they actually could not not approve it. Nor could they require Zohydro to include an abuse deterrent.

Secondly, the FDA decision was extraordinary because anyone with even a vestige of street smarts, much less the smart asses among Wall St. investors, knows exactly what will happen when Zohydro ER is released next year in a capsule form that can easily be chewed by addicts, or crushed for purposes of snorting or injecting it.

According to one pained father’s statement submitted at an FDA hearing, "If you approve this pill, you surely will be signing a death sentence for thousands of people, especially young kids." This was Avi Israel speaking, a father whose 20-year-old son committed suicide after becoming addicted to a doctor-prescribed hydrocodone painkiller.

Third, along with overriding the panel’s recommendation, the FDA also ignored a damning report from its Controlled Substance Staff unit, the mission of which is to manage drug abuse risks. Its finding: “It is expected that Zohydro ER (if approved and marketed) will be associated with higher levels of abuse than the hydrocodone combination products. These expected higher levels of abuse are based on what has been observed for oxycodone products.”

Translated, the two major forms of opioids on the market are oxycodone based and hydrocodone based. Each of these comes with or without the liver-damaging chemical acetaminophen common in Tylenol and other over-the-counter drugs. The FDA has made it clear it favors minimizing or eliminating acetaminophen whenever possible and allowing “single entity” products without it such as Z on to the market.

Here, though, is the CSS staff telling the brass that addicts seek out the single-entity products far more than they do those combined with acetaminophen.  As evidence the staff cited the damages caused by single-entity OxyContin as compared to Oxy with acetaminophen. The pure version resulted in 85 emergency room visits per 1 million tablets dispensed, the staff reported, as compared to 24 visits for the combination Oxy. Projecting forward, the staff predicted that single-entity Zohydro will create far more emergency room visits than combo hydrocodone products currently on the market (14 visits per million tablets).

This staff analysis was also insufficiently persuasive in the final “cost-benefits” analysis the FDA undertook that led to Z’s approval.

Fourth, the decision was announced without the FDA issuing a thorough and compelling factually-based response to the specific areas of disagreement with the panel. (It did, however, seek to call some attention to its most detailed case for Zohydro and explain its larger vision in a response to the critical citizens group the Center for Lawful Access and Abuse Deterrence. Released on October 25 along with the announcement of Zohydro's approval, the FDA open letter to the organization didn't get the attention a response to its own panel might have.) 

Mostly, the FDA more public case has been that Z is valuable as a time-release painkiller because it does not contain acetaminophen and that its timed-release benefits are needed in the field for many individuals suffering great pain who require “a continuous, around-the-clock opioid therapy for an extended period of time.”

The FDA subsequently also argued that abuse resistant technology is imperfect and must be created uniquely for each drug. It added that no effective ones had ever been created for any hydrocodone based product such as Zohydro. Moreover, the FDA said, it had installed new regulations on doctors and pharmaceutical companies that were themselves abuse deterrents. Overall, it argued that “the benefits of Zohydro ER outweigh its risks, including its risks of addiction, abuse, and misuse, despite its lack of abuse-deterrent properties.”

Experts countered to the FDA that the number of deaths and degree of social devastation from acetaminophen pales before the assault on human life by addictive painkillers. They also questioned the FDA’s favoring the convenience of time-release medicine as opposed to seeking to minimize the number of addict overdoses and deaths, and were skeptical of the untested effectiveness of the new regulations meant to minimize addict access to addictive painkillers. Some critics also argue that current medications can do the job and Z is not needed. Cost-conscious experts noted that Zohydro ER would drive up insurance costs if ever widely prescribed. (See The Fix earlier report on the cons and pros of Z for more details,)

SOME BACKGROUND:

According to the Institute of Medicine of The National Academies, 100 million Americans suffer from chronic pain. Opioids – and in particular oxycodone products like Oxycontin – are a predominant choice as painkillers for moderate to severe pain despite the fact they don’t cure the pain and usually lead to worse medical problems, including high rates of very hard-to-beat opioid addiction. In 2011, hydrocodone-based meds alone accounted for 137 million prescriptions in in an overall hugely lucrative opioid market: $7.83 billion in 2012 (29% of the overall painkiller market).

In the latest statistics available, 12 million people (one in every 20 in the U.S. age 12 and older) in 2010 used prescription painkillers non-medically. This staggering number produced 16,651 opioid overdose deaths that year (more than 45 a day) - more OD deaths than from heroin and cocaine combined and up from 4,030 in 1999.

There were also 885,348 emergency hospitalizations from overdoses in 2011 vs. 289,498 in 2004.

The total cost in health care from painkiller abuse: $72.5 billion.

The costs of the average worker’s compensation claim in 2011: $13,000. The cost of a claim related to long term painkillers such as Oxy: $39,000.

Shortly after you have finished reading this article, at least one more person will have died from an overdose. Once Zohydro ER is made available to the general public by the FDA, such disgusting numbers are predicted by drug experts to continue to rise.

AND THEN THERE WAS THE PUSHBACK….

Shortly after the FDA announcement, a bipartisan group of eight House Representatives, mindful of the long trail of lives wrecked and overdose deaths wrought by OxyContin addiction, sent a letter to the Obama administration vehemently protesting the approval of Zohydro ER.

“On many levels we simply cannot afford to move yet another highly addictive opioid into the mainstream and potentially onto Main Street,” wrote the group’s leader, Congressman Stephen Lynch (D) of Massachusetts. Calling the decision “a giant step backward,” Lynch cited a study that claimed the total overall cost of substance abuse in the U.S., including lost productivity and health and crime-related costs, exceeds $600 billion annually.

Two weeks ago four Senators sent a similar letter demanding an explanation for the FDA’s action.

This Congressional response was only the spearhead of a far wider and more furious reaction within the drug treatment and enforcement communities. Not surprisingly, accusations of the FDA caving in to Big Pharma and its big bucks lobbying and campaign donations erupted from a number of quarters after the FDA decision, amid a widespread sense of astonishment.

Typical of the anger was the statement of Lyle Fried, CEO at The Shores Treatment & Recovery in West Palm Beach, Fl.: “The only plausible answer I have heard [for the FDA overturning its advisory panel] is that "Big Pharma" has powerful lobbyists, and money has won out over true concern for the people of our nation.”

Typical of the astonishment was Dr.Julie Zito’s reaction. Dr. Zito is a voting member of the FDA advisory panel that rejected approval of Zohydro and a professor of pharmacy and psychiatry at the University of Maryland School of Pharmacy.

“After our vote against,” she told The Fix, ”after such a negative recommendation, I was very surprised when Zohydro was approved. I think it is unusual for the FDA to go against its own advisory panel when there is a landslide vote.

“When I asked why this happened, the answer I received seemed strange to me. The FDA position is that they actually could not not approve it. Nor could they require Zohydro to include an abuse deterrent. Their answer was hard to understand in light of recent history supporting abuse deterrent formulations. I surmised that the FDA wants more information on how effective abuse deterrent formations are.”

We have here then a major news story in itself. Look deeper into Zohydrogate and what emerges is a novelistic landscape that pits FDA staff scientists and researchers against outside professionals, with each seeking to define the “cost benefit” of pain relieved against deaths and addictions caused – all within the context of a highly aggressive pharmaceutical industry pitted against the communities and professionals most affected by drug addiction. It’s a Balzacian tale that includes the raw fact of profiteering from both ends of the legal drug cycle by Big Pharma company Alkermes – i.e. “sell them addictive stuff which makes them dependent, and then treat them with other stuff you sell them.”

And most importantly, we encounter a reality that can potentially knife into and destroy the life of anyone who goes to a hospital or doctor seeking pain relief.

THE FDA CREATES A MYSTERY

Zito’s comments generate a host of questions: The FDA has absolute authority by law to regulate pharmaceuticals, and legal responsibility for making them safe for the public. Abuse deterrents that prevent drugs from being crushed, smoked or injected are now a part of the marketplace, a la the current versions of Oxy, and have had significant positive effect since being introduced.

What could the FDA possibly mean that it “could not not” approve Zohydro or delay approval until a tamper-proof form was developed? Why did anyone from the FDA suggest to Dr. Zito that the FDA lacked authority to compel Z to go tamper-proof when it had already “encouraged” (its word) similar opioid makers to do so? Was it pressured by higher-up government officials to take a “must approve” stand? Was it afraid of lawsuits? What were the plausible scientific and medical reasons it needed to rush yet another opioid painkiller into a marketplace full of them already?

For its part, the FDA initially defended its decision with exactly one press statement. In the statement the FDA pro-formally cited its commitment to “reduce opioid misuse and abuse” and then laid the decision at the foot of its concern over what it considers the need for an opioid such as Z that does not contain the liver-damaging acetaminophen.

“We consider the development of opioid analgesics with abuse deterrent properties to be a public health priority…but the science is still in its early stages and abuse deterrent formulations are not available for most extended-release/long-acting opioids. Accordingly, the FDA does not believe it is feasible at this time to require that all new solid oral dosage form opioids have abuse deterrent properties.”

This statement has satisfied few and angered many of the knowledgeable experts who, like the Wall St. investors, fully expect Zohydro to ignite another wave of vicious, hard-to-heal addictions among people simply seeking pain relief—and another black market in “highs” that lead to far more deaths and damage than from acetaminophen.

Adding to the outrage and suspicions - and mystery - about the FDA process, is the fact that almost two years before the FDA rejected its advisory board and approved Z, it had already signaled to the U.S. developer and marketer of Zohydro, a company called Zogenix, that it was not going to push for an abuse deterrent. Zogenix CEO Roger Hawley revealed this in an interview reported by the AP (Dec. 26, 2011) in which he stated that the company was getting no pressure from the FDA to convert to a safe form.

He elaborated, “We would certainly consider later launching an abuse-deterrent form, but right now we believe the priority of safer hydrocodone—that is, without acetaminophen—is a key priority for the FDA."

So, even back when it had plenty of opportunity to “encourage” Zogenix to seek to be ready for market in a much safer way, and at a moment in history when it had been encouraging tamper-proof technology on other opioids, the FDA was giving Zogenix a free pass from the outset.

The time gap raises questions of whether FDA’s top brass was already behind Zohydro even before the advisory panel finished its work. Was approval in the cards no matter what the results of the advisory panel vote turned out to be, including the panel’s seemingly obvious, if not predictable, recommendation to delay sale of Z until protections were in place?

This, of course, would have made the entire panel process a farce.

Bolstering this possibility are some raw numbers that were put before the FDA during the approval process.

While liver toxicity from acetaminophen is indeed a problem, fewer than 250 Americans die annually from it due to the acetaminophen-opioid combination – and an unknown number of these people may have been addicted abusers. Meanwhile, more than 16,000 died in 2011 of prescription opioid overdoses, with the numbers climbing.

Apart from the acetaminophen issue, the FDA statement also doesn’t jibe with the actual statistics that have been collected about OxyContin since it was required to go tamper-resistant.

According to RADARS System (The Researched Abuse, Diversion and Addiction-Related Surveillance System) that was designed to measure rates of prescription drug abuse, misuse and diversion throughout the United States, OxyContin prices on the black market fell dramatically once the new tamper-resistant version was introduced. With the new version no longer an attractive option for drug dealers, abusers and addicts, negative abuse statistics about the injecting, snorting and smoking of the prescription painkiller have fallen.

Given that it is an extended release formula, addiction experts argued to the FDA that Zohydro ER may well lead to an even greater number of overdoses than has Oxy because there are so many more addicts seeking a replacement opioid since Oxy was made abuse deterrent. Moreover, there will be brand new addicts whose opiate dependence will result from being prescribed Zohydro.

The reason for this prediction lies in what happened with the original extended release version of Oxy. Thousands of people abusing the drug were unaware of the time-release formula and so kept taking more, chasing the magical pain-relieving high like Dorothy running through the poppy fields to reach the dream of the Emerald City - only to end up in a ton of massive overdoses and deaths when the narcotics in the formulations activated and hit all at once.

More savvy addicts can also fairly easily remove the particles mixed in with the opiated pain killer that create the time-release effect, and thereby get an instant high.

As one former Oxy addict told the New York Times about the addictive power of opioids: “Honestly, I prayed to God to let me die. That's how bad it is.”

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