Because of concerns about liver failure from acetaminophen, the FDA appointed an Acetaminophen Hepatotoxicity Working Group, which made its report to the FDA on Feb. 26, 2008. Regarding hydrocodone-acetaminophen combination products, the report states: "Patients develop tolerance to narcotics and need to increase the dose of prescription combination products. If they do this on their own, they may not realize that they are increasing the dose of acetaminophen to toxic levels."
It appears that following this report, the FDA let pharmaceutical companies know that it was interested in a formulation of hydrocodone without acetaminophen. Within the next few years, four pharmaceutical companies were actively involved in development of acetaminophen-free, extended-release formulations of hydrocodone.
The first such product was Zohydro ER. An AP article on Dec. 29, 2011 says that when Zogenix chief executive, Roger Hawley, was asked whether Zohydro would be abuse-deterrent, he "said the FDA was not pressuring Zogenix to put an abuse deterrent in Zohydro. '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.'" Mr. Hawley said the FDA priority was a "safer hydrocodone," that is one without acetaminophen.
That the FDA was concerned to have a product which was hydrocodone free of acetaminophen is also demonstrated by the black box warning on hydrocodone-acetaminophen products. The black box warning is about acetaminophen, not opioids: "Warning: Acetaminophen has been associated with cases of acute liver failure, at times resulting in liver transplant and death. Most of the cases of liver injury are associated with doses of acetaminophen that exceed 4000 mg per day and often involve more than one acetaminophen-containing product."
It may be that the FDA saw extended-release acetaminophen-free opioids as safer than available hydrocodone-acetaminophen products, but such a belief is bizarre. The only difference between Zohydro and OxyContin is that the relevant opioid is hydrocodone rather than oxycodone.
The fact is that a black box warning is hardly necessary for acetaminophen, while it is really necessary for prescription opioids. The best CDC numbers for number of accidental deaths due to acetaminophen (in all products) was 458 annually between 1990 and 1998, and 157 annually between 2001 and 2010.
And during the years 2001-2010, in which there were 1,567 accidental acetaminophen overdose deaths, there were more than 100,000 prescription opioid overdose deaths. Indeed, the FDA’s Controlled Substance Staff found nothing to make them think that Zohydro would be safer than the currently available hydrocodone products.
Despite all this, the FDA was eager to get an extended-release acetaminophen-free hydrocodone on the market. Zogenix (the manufacturer of Zohydro) held an End-of-Phase 2 meeting with FDA on May 5, 2008, where agreement was reached on that Zohydro could follow a shortened path to approval.
On Dec. 7, 2012, a meeting of the FDA’s Anesthetic and Analgesic Drug Products Advisory Committee was held to determine the advisability of approving Zohydro. Members of the Committee were primarily MDs and PhDs from prestigious academic medical institutions; two were “patient representatives.”
After hours of testimony and questions, the Committee voted 11-2 against Zohydro approval.
Perhaps the most compelling argument against approval was made by committee member Dr. James G. Ramsay, Director of Critical Care Services at Emory University Hospital, “I would just say that the way that I put this together is that there's potentially a large amount of drug in these pills, up to 50 milligrams, with no additional deterrent for somebody who wants to try to extract the drug. It's the best-known and widely abused of the oral opioids. So it's likely to be the choice of illegal use. It's got the most drug, and it's going to be relatively easy to extract. I would say that this will be the choice drug for diversion and extracting hydrocodone. So that's what makes it different.”
The FDA took an unusually long time to make its decision regarding Zohydro. Because of the long delay Zogenix was forced to lay off employees.
Why the delay? It appears the FDA was caught between its desire to approve Zohydro ER and the strongly negative view of the advisory committee regarding Zohydro ER approval. Knowing that its decision to approve Zohydro under these circumstances would bring on negative publicity, the FDA attempted to bury its decision to approve Zohydro ER by announcing the approval on Oct. 25, 2013, the day after the FDA decided to upschedule of hydrocodone-acetaminophen products to Schedule II. To a significant degree, this strategy worked. On Oct. 27, the New York Times lead Business Day article was titled "FDA shift on painkillers was years in the making." The article was almost entirely about the upscheduling of hydrocodone-acetaminophen products; Zohydro ER approval was buried in paragraphs 10-12 of a 38 paragraph article.
The FDA's reasoning in approving Zohydro ER was stated by by Dr. Bob Rappaport, Director of the FDA's Division of Anesthesia, Analgesia, and Addiction Products in his “Summary Review” accompanying the letter of approval of Zohydro ER, “…I find that the overall risk-benefit balance for patients who will be properly, thoughtfully and carefully prescribed Zohydro ER for the management of pain severe enough to require daily, around-the-clock, long-term opioid treatment and for which alternative treatment options are inadequate, falls firmly on the side of approval of this application.”
How could Dr. Rappaport be so sure that the risk-benefit balance favored approval of Zohydro ER when an FDA Advisory Committee made up largely of scientists voted 11 to 2 against approval? There was certainly no basis for his statement.
The decision to approve Zohydro ultimately met with widespread opposition, mostly from states that were dealing with the prescription opioid and heroin epidemic and recognized the danger of throwing gasoline on a burning fire.
A few examples:
On Dec. 11, 2013, 28 state attorneys general from across the country asked the Commissioner of the FDA to reconsider its decision to approve Zohydro ER.
On March 27, 2014, Massachusetts Governor Deval Patrick last month ordered a ban on the Zohydro ER. The bad was overturned in Federal Court.
On 3 April, Peter Shumlin, the Governor of Vermont, issued an emergency order requiring prescribers of Zohydro to conduct a thorough medical evaluation and risk assessment before prescribing Zohydro.
On Aug. 28, 2014, 5 New England governors wrote to HHS Secretary Sylvia Burwell, requesting that she “overturn the FDA’s erroneous decision to approve Zohydro Extended Release (ER).”
But the FDA chose to stand firm with its decision while those taking FDA approved opioid drugs continued to die at increasing rates.
However, the FDA had "learned its lesson": advisory committees may vote against FDA desires, and the best way to deal with this is to avoid having advisory committee votes. After this debacle, the FDA systematically avoided Advisory Committee meetings on potentially controversial decisions regarding prescription opioid approvals.
It literally took an Act of Congress for the FDA to bring the issue of upscheduling hydrocodone-acetaminophen to Schedule II before an advisory committee.
No advisory committee meeting was held regarding Targiniq ER, approved July 23, 2014. Targiniq ER, which the FDA labeled abuse-deterrent, is a combination of oxycodone and naloxone, which cannot be abused intravenously but cannot be easily chewed and swallowed, resulting in release of a large dose of immediate-release oxycodone which has exactly the same problems that the original oxycodone had.
No advisory committee meeting was held prior to the approval of OxyContin for pediatric use on August 13, 2015. This highly controversial decision was made in the absence of knowledge as to the long-term consequences of opioid use in the child and adolescent population.
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