In late October, the Food and Drug Administration made the front page of the Times by announcing that it would recommend moving drugs like Vicodin, which combine hydrocodone with over-the-counter painkillers, to the restrictive Schedule II class of drugs. That would make it harder for people to access them: if all goes according to plan, patients could no longer receive automatic refills, nor could doctors phone in prescriptions.
It was seen as a landmark decision. Hydrocodone, when combined with ingredients like acetaminophen or aspirin, is the most commonly prescribed painkiller in the United States, with about a hundred and thirty-one million prescriptions dispensed in 2011, but it is also an opioid analgesic, a type of drug that is highly addictive and can be dangerous. From 1999 to 2010, the number of deaths involving opioid analgesics more than quadrupled, to nearly seventeen thousand, according to the Centers for Disease Control and Prevention.
Opioid treatment can help treat some kinds of pain—for instance, short-term pain from an operation or from cancer. But researchers have been raising questions about whether opioid analgesics work all that well to manage the pain from chronic conditions, like osteoarthritis, in the long term. Some evidence has suggested that long-term use of opioids may even increase sensitivity to pain rather than reducing it.
The same day the Times article ran, there came another announcement from the F.D.A.: it had approved, for Schedule II, a new opioid analgesic called Zohydro ER, despite a recommendation against the drug’s approval by an F.D.A. advisory committee. The medication, an extended-release painkiller developed by a California-based company called Zogenix, is made of pure hydrocodone and uses a higher dosage scale than hydrocodone-combination drugs like Vicodin. Unlike those drugs, Zohydro ER does not include acetaminophen or aspirin, which can cause liver damage if abused over a long period. But Zohydro ER will come in capsules—a form particularly prone to abuse—and is every bit as potent and addictive as other opioids. And there is no version of Zohydro ER meant to keep people from crushing or chewing the drug, though Zogenix is working with Altus Formulation, of Montreal, to craft an abuse-deterrent version.
Zogenix proposed that Zohydro ER be approved to manage “moderate-to-severe chronic pain in cases in which a continuous, around-the-clock opioid is needed,” for twelve hours a day and months at a time—in other words, to deal with persistent and long-term pain, such as back pain, that shorter-acting opioids don’t cover as well. But given the concerns about abuse of painkillers and evidence of the complications that can result over the course of long-term treatments, how did Zohydro make it through the approval process?
Zogenix began extensive clinical trials in March of 2010, on patients with back pain. The outcomes of the twelve-week-long efficacy trials, submitted with Zogenix’s new drug application in May of 2012, showed that Zohydro ER had reduced patients’ discomfort more than a placebo. The side effects weren’t any worse than other drugs in the same class.
In its application, Zogenix mentioned the F.D.A.’s earlier findings of “safety and efficacy” for Vicoprofen, which is, practically speaking, about as strong as Vicodin. Zogenix complied with the agency’s other requirements, too, providing hundreds of pages describing the outcomes of clinical trials and pharmacological analysis and submitting details about its proposed labelling for the product.
In December of 2012, the F.D.A. assembled a paid advisory committee of opioid experts in Silver Spring, Maryland, to consider the pros and cons of allowing Zohydro ER to enter the market.
At the meeting, Zogenix argued that because acetaminophen becomes toxic to the liver at higher doses, drugs like Vicodin were not safe for patients who needed long-term treatment. The company also made the case that Zohydro ER would be better controlled than its unruly predecessors, thanks to new F.D.A. requirements. Drug manufacturers now have to educate health-care providers about how to appropriately use high-risk medications. They also must carefully monitor the drug for signs of trending abuse or misuse.
Interspersed with Zogenix’s explanations were expert panelists’ discussions of Zohydro ER’s shortcomings. Several scientists observed that the F.D.A. requires similar drugs to be formulated so that they cannot be readily crushed or chewed, and they balked at Zohydro ER’s lack of an abuse-deterrent version. One drug expert wondered whether Oxycontin’s bad reputation had made it hard for physicians to prescribe the drug, opening the door for an alternative, like Zohydro, to replace it not only in patients’ medicine cabinets but also on the streets. Another panelist questioned whether the new F.D.A.-mandated program could meaningfully curb the potential for abuse and overdose.
Bob Rappaport, the director of the F.D.A’s Division of Anesthesia, Analgesia, and Addiction Products, observed at the meeting that it was reasonable to anticipate that a single-entity hydrocodone product “will contribute to the already critical public-health problem of prescription opioid abuse and misuse.” But he also chastised the expert panel for some of their more pointedly critical remarks about Zohydro ER, observing that they were “punishing this company and this drug because of the sins of the previous developers and their products” and that “from a regulatory standpoint, that’s not something we can do.” He explained that as long as the drug met F.D.A. requirements, it ought to pass muster; Zohydro ER could not be scapegoated simply by virtue of being an opioid. “We are obligated at the agency to operate within the regulatory framework,” he said, “and that includes providing a level playing field for industry. We don’t have a choice by that. It’s the law.”
Indeed, a company that wants to market a new drug must test it and submit evidence to the F.D.A. that the product is as safe and effective as another drug in the same class that has already been approved. Also, the drug’s health benefits are supposed to outweigh known risks. And the company must show that there is no new “signal” that the drug presents a health risk above and beyond the general problems endemic to its entire drug class—in the case of Zohydro ER, the Schedule II class of opioid analgesic drugs. In other words, to be approved, a drug does not have to be better than drugs that have been approved in the past. It just can’t be worse.
If the drug fails to meet these qualifications, the F.D.A. can take regulatory actions—for instance, requiring more tests or better labelling—or it can simply decide not to approve the application. But what if the new drug has a problem that is known to exist throughout the entire drug class—for instance, the high propensity for abuse, misuse, and addiction that are common to all opioids? In that case, the F.D.A. cannot simply refuse to approve the new drug.
The reasoning behind this is sound enough: refusing to approve Zohydro ER because it is a dangerous opioid would require revisiting the approvals of all other opioids on the market. That would be expensive and time-consuming for the F.D.A. and pharmaceutical companies. It would also likely be unproductive, because previous efforts to limit access to these drugs have met with resistance from groups—some funded by the pharmaceutical industry—that point out, reasonably, that adults with chronic pain deserve to have their suffering mitigated as much as possible.
And yet, isn’t there something problematic about a system in which a new drug can be pinpointed as prone to abuse—but can pass muster because other drugs, equally hazardous, were approved?
Andrew Kolodny, a physician who has fought for stronger restrictions on pain-pill prescriptions, attended the December meeting as a member of the public and spoke up during a period reserved for comments. “One has to wonder how many more pain patients have to be harmed, how many more people have to become addicted, how many more lives will have to be lost,” he said, “before the F.D.A. finally begins to exercise its authority and responsibility to prohibit drug companies from marketing opioids as if they have been proven safe and effective for long-term use.”
The advisory committee voted 11–2, with one abstention, to recommend that the agency refuse to approve Zohydro ER’s new drug application, because of concerns about the risk of misuse and abuse and the resulting potential impact on public health.
The F.D.A., in its approval of Zohydro ER, said “that the benefits of this product outweigh the risks” and that hydrocodone has “abuse liability similar to other drugs [in] its class.” Zohydro ER will enter the market in 2014, manufactured by an Ireland-based company called Alkermes. Zogenix will handle sales and marketing, as well as the F.D.A.-mandated tracking of escalating abuse or misuse.
Morgan Liscinsky, an F.D.A. spokeswoman, said that advisory meetings for new drug approvals happen often and that the F.D.A. is not obligated to follow advisory committees’ recommendations.
But the F.D.A. often does follow the recommendations. As Ian Parker wrote in the current issue of the magazine, Merck is revising its application for approval of a new insomnia drug at the F.D.A.’s request, after a committee recommended that the drug not be approved at some of the higher dosage levels that Merck had sought in an earlier application.
Kolodny had left the December meeting feeling that there wasn’t much chance that Zohydro ER would make it to market following the committee’s strong vote against it. When he heard the news of its approval almost ten months later, while driving through Delaware, he felt deflated.
The previous day, he had celebrated the F.D.A.’s decision to tighten restrictions for hydrocodone-combination products with a dinner and a cocktail at P. F. Chang’s. “Realizing that the benefits of up-scheduling combos were likely to outweigh the downsides of Zohydro ER’s approval made me feel a little better,” he said, “but it wasn’t a pleasant ride home.”
Jillian Keenan provided additional reporting for this piece.
Illustration by Jon Han.
Cathryn Jakobson Ramin
from Currency http://www.newyorker.com/online/blogs/currency/2013/12/zohydro-why-did-the-fda-approve-a-new-pain-drug.html
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