Pharma's Fraught Quest for Addiction Medication Pay Dirt

Examining the medical, moral, and monetary decisions that Alkermes made to bring its drug Vivitrol to market—including a controversial trial in Russia. Are the critics right to cry foul?
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(PHOTO: PATRICIA HOFMEESTER/SHUTTERSTOCK)

(PHOTO: PATRICIA HOFMEESTER/SHUTTERSTOCK)

Editor's Note: The post originally appeared on The Fix, a Pacific Standard partner site.

In part one of this investigation, The Fix evaluated Vivitrol's effectiveness.

Drugs are commercial products, and drug companies make a profit or die. In the late ‘90s, a Boston biotech called Alkermes picked naltrexone, an anti-craving addiction drug, as its first potential product. Alkermes’ specialty was making extended-release, longer-acting versions of existing drugs. Naltrexone was in dire need of this makeover: Alcoholics and opiate addicts were having a hell of a time taking the daily pill consistently, further compromising its modest effectiveness.

Using its space-age technology, Alkermes turned the one-a-day pill into a once-a-month injection. The resulting naltrexone shot comes packaged in tiny spheres made of polylactide-co-glycolide (PLG), a polymer often used in medicine. As the sphere decays, the naltrexone seeps into the blood at a steady rate, delivering a consistent dose for 30 days.

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That’s pretty cool technology. But even cooler, for Alkermes, was the potential payoff. There are more than 20 million alcoholics and one million drug addicts in the U.S., according to estimates by the National Institutes of Health (NIH). Recovery rates are dire. Most addicts never access a treatment program, and those who do often relapse repeatedly. The costs in health and health care terms alone are staggering. At the time Alkermes overhauled naltrexone, the opiate painkiller market was exploding, with dark predictions of a corresponding spike in abuse, addiction, overdoses, and deaths. (The reality has since exceeded those fears.)

And it was virgin forest: Naltrexone was one of only a handful of addiction medications, all mediocre.

As anticipated, Alkermes’ first drug—bearing the peppy new name Vivitrol—got FDA approval for use against alcohol dependence in 2006 and against opiate dependence in 2010. Its price tag is memorable: $1,100 for one shot. After spending hundreds of millions of dollars on the development of Vivitrol, the company wanted payback.

But Vivitrol is not selling very well. Last year, sales barely topped $40 million. A mere 1,100 U.S. doctors in 400 facilities, according to Alkermes, currently prescribe the injectable. About half of all prescriptions are written by just 130 physicians.

"There aren't many doctors using it, and I don’t understand why not," says one of those 130 doctors, Robert Woolhandler, a Pittsburgh addiction specialist who has given some 3,000 Vivitrol shots. "Why aren't more rehab clinics using it? After all, when you take away the cravings, you can start tackling the disease."

One reason patients are staying away is, of course, that $1,100 price tag. Marc Fishman, MD, medical director at Maryland Treatment Centers and a professor of psychiatry at Johns Hopkins University School of Medicine, agrees. “Right now there’s very poor penetration of insurance coverage, but that’s improving,” he says. “Most of my patients are middle-class or underserved, and if there’s no insurance coverage for Vivitrol, then it’s not an option.”

While the past two decades have seen a growing tolerance of antidepressants and other medications for psychiatric diagnoses, drugs prescribed specifically for substance dependence remain contentious cases.

Large private insurers, such as Aetna and Blue Cross Blue Shield, offer partial coverage, and $500 a month seems to be the industry average. This leaves you with a $600 copay. Alkermes offers a Vivitrol Value Program that covers up to $500 a month for copays and deductibles for eligible patients, according to Jennifer Viera, Alkermes’ PR rep.

Some top doctors vouch for Vivitrol’s ability to promote better compliance. “My patients say that every time they hold [a naltrexone] tablet in their hand, they get a craving—they know if they don’t take it that day, they can get high,” says Herbert Kleber, MD, director of the division on substance abuse at Columbia University’s medical school. “You don’t totally remove that feeling with Vivitrol, but at least you’re pushing it down the road for a month.”

Yet the pocketbook issue dictates that many doctors prescribe generic naltrexone instead of Vivitrol. Alkermes could improve Vivitrol’s biggest selling point—better compliance than oral naltrexone—by doing a head-to-head trial comparing the two drugs. Proof of superiority could tip the balance.

No comparison trial is in the works, however. Why? “This question might seem meaningful on its surface. However, clinically, the comparison does not realistically apply,” Alkermes said in an email to The Fix. Their reasoning appears to lie in a technicality: Naltrexone was approved for blocking opiates' effects “but not actually for the treatment of opioid dependence.” Both drugs are, of course, prescribed for the treatment of a disease in people, not as a science experiment in brain receptors.

But Alkermes may have another reason to beg off a comparison. In 2008, at the request of the FDA, the company ran a safety trial that pitted Vivitrol against naltrexone. It’s safe to say that the results did not deliver the headlines that Alkermes had hoped for.

The study, which lasted 48 weeks, included 315 patients who were addicted to alcohol, 69 to opiates, and 52 to a mix; one group got a shot of Vivitrol every four weeks and the other got a daily naltrexone pill. At the end of the study, half of the patients in both groups had dropped out, although the naltrexone group stuck it out for 36 weeks—eight weeks longer than the Vivitrol-takers. In addition, 40 percent of the alcohol-dependent patients completed the study, compared to 30 percent of the people addicted to opiates or to both.

These results underwhelmed some leading addiction specialists with doubts about Vivitrol’s “better compliance” claim. “It was no easier to keep the opioid addicts taking the injection agent over time than the oral drug," Kyle Kampman, MD, medical director of the Charles O’Brien Center for Treatment of Addictions at the University of Pennsylvania, reported when the study was first presented 2008.

Another critic, Meera Vaswani, MD, of the All-India Institute of Medical Sciences in New Delhi, said, "I question whether there is a need for [Vivitrol], in the absence of a clear efficacy advantage." If anything, she viewed the injection aspect less as less of a selling point than, well, a sticking point: “Anything that's invasive is not appreciated." Before she would prescribe Vivitrol, Vaswani said, it would have to earn an "extra point.”

In an interview with The Fix, David Gastfriend, MD, vice president for scientific communications at Alkermes, dismissed these criticisms, arguing that compliance could not be fairly judged in a test of safety. “In a safety study, you're trying to get as many adverse effects as possible," he says. "Therefore, it doesn't reflect the real world.”

In the study it conducted to win approval for Vivitrol for opioid dependence, Alkermes managed to raise the hackles of addiction activists. The company chose to locate the trial in Russia—a curious decision, since the U.S. has no shortage of junkies and pill heads. But given the mounting research showing that naltrexone my be no better than methadone, Suboxone, or placebo, Alkermes may have seen it as a wise move.

Russia has long had one of the world’s highest rates of heroin addiction. Many of these needle users have HIV. Russians under 30 are often called the Lost Generation: 10 percent use heroin, five percent have HIV. Russia also has some of the world’s most punitive public health approaches to addiction and HIV: Methadone is illegal, while syringe swaps and AIDS education are almost non-existent. These conditions are, however, ideal for a drug company testing an anti-opiate drug, since the only competition is placebo. Indeed, the results of the Vivitrol trial showed that of the 250 patients enrolled, the half on Vivitrol averaged 90 percent abstinence compared to the placebo’s 35 percent. (Only half of the Vivitrol-takers completed the trial.)

A problem in translation was, however, immediately apparent to experts: How do these results apply to the U.S., where conditions for people with opiate addiction are relatively humane and methadone is widely available? In the U.S., if you are so motivated to kick heroin that you enroll in a trial, you can always switch from Vivitrol or placebo to methadone, even if it means dropping out of the study. "There are concerns about the generalizability of the Russian trial to the U.S. population for a variety of reasons, including the fact that methadone and Suboxone are not available in Russia,” says James Garbutt, MD, medical director of the Alcohol and Substance Abuse Program at UNC-Chapel Hill.

The FDA sidestepped the issue when it approved Vivitrol for opioid dependence based on this single trial. It declared that the "absence" of methadone in the Russia trial "is analogous to patients who are specifically motivated to use antagonist therapy [Vivitrol] in the U.S." This qualification, however, was missing from the label.

Moderation advocates argue that controlled drinking is more likely to help a drunk eventually achieve sobriety than the hard-and-fast abstinence method.

A controversy flared in the medical press, fanned by advocates and public health officials who viewed the Russian trial as unethical. They charged that in using a placebo—and withholding the “standard of care” (methadone)—Alkermes violated national and international guidelines protecting human subjects in medical experiments. “In light of past reports of overdose deaths of opioid-dependent patients offered placebo, and the overwhelming evidence that methadone and Suboxone are safe and effective, the trial should have tested naltrexone against one or both of these medications,” wrote the Soros Foundation’s Daniel Wolfe in The Lancet in 2011.

Alkermes’ David Gastfriend defends his company’s decision to conduct the trial in Russia. He even says that rather than favoring Vivitrol, the conditions in Russia raised the bar for success. "Russia turned out to be an excellent place for drug research," he says. The patients in the study had very severe addictions—some had spent 10 years taking heroin by IV—so Alkermes wagered that if Vivitrol could make it there, it could make it anywhere—even if making it meant besting no treatment.

Gastfriend also disputes the assertion that the results do no translate. "There's a tremendous public health need in Russia, and the quality of care is superb," he says. Since addiction treatment in the U.S. is similar, the study was a way "to model the real world." Few advocates would agree with the latter assertion.

Alkermes would no doubt like to do well by doing right. Ethics and economics aside, in marketing Vivitrol it has advanced treatment for people with addictions. It could do more. It could lower the price, for one, and run better tests of effectiveness. Instead Alkermes is crunching numbers intended to show that Vivitrol, at $1,100 a month, is cost-effective—for insurers if not individuals. In a 2011 paper in the American Journal of Managed Care, Alkermes noted that inpatient admissions for people on Vivitrol were significantly lower than for those on competing drugs. In addition, it stated that the overall health care costs for Vivitrol patients were lower than those of patients on methadone: $8,582 and $16,752, respectively.

But there is one challenge that is almost beyond Alkermes’ control: the traditional resistance in the recovery community to all addiction medication. While the past two decades have seen a growing tolerance of antidepressants and other medications for psychiatric diagnoses, drugs prescribed specifically for substance dependence remain contentious cases. Even naltrexone, which inhibits intoxication, is widely seen as counter to total abstinence.

Even more deeply entrenched is the belief in abstinence as the exclusive goal of recovery. Controlled drinking, moderation management, and harm reduction have been greeted with suspicion. Ironically, Vivitrol’s strongest suit appears to be helping people decrease—rather than stop outright—heavy drinking and drugging. While it often has potent anti-craving effects for the newly sober, its anti-euphoric effects for people who either relapse or are active drinkers may be more impressive. But the FDA approved it solely for abstinence, so Alkermes cannot promote it for the goal of controlled drinking. (Doctors do in fact often prescribe naltrexone to active drinkers who are motivated to cut back on booze.)

Moderation advocates such as Andrew Tatarsky, a New York clinical psychologist who heads Moderation Management, argue that controlled drinking is more likely to help a drunk eventually achieve sobriety than the hard-and-fast abstinence method. “The debate is whether to let people hit rock bottom before offering treatment,” says Tatarsky, “or get to them earlier to begin a process of positive change.”

It is a debate that Alkermes has avoided. “You will not see us making claims anywhere near [a controlled-drinking outcome],” Alkermes CEO Richard Pops told Boston Magazine.

When you do the math, the addiction medication market looks to a fledgling drug maker like the ideal breeding ground for a cash cow. But what that market really represents is many millions of people with a life-threatening disease—and both the disease and the people are poorly understood and even more poorly treated. As a result, over the years, addiction has attracted a community of advocates, doctors, researchers, other professionals, and, above all, survivors who are, by necessity, skeptical of the quick fix or easy sell.

Any company that aims to make a profit off an addiction drug has to be willing to get in the ring and mix it up with these people. New drugs are desperately needed, but that demand comes with moral and medical challenges that only a drug maker with a long-term commitment can supply.

Raphael Rosen did much of the research, reporting, and fact checking for this investigation. Rosen is a Brooklyn-based science communications professional, social media strategist, and independent museum consultant. He has written for the Wall Street Journal, The Fix, the World Science Festival, Discover magazine, and others.

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