While research on narcolepsy advanced, other communities had discovered the drug too. GHB was taken up by some body builders for its reported ability to stimulate the release of growth hormone.22 Nightclub dancers found that “GHB induces a pleasant state of relaxation and tranquility and enhances one’s libido.”23

  A recreational dose of GHB is not far from a dose that quickly knocks someone out, and the dose-response curve bends upward, meaning that twice the dose can have three or more times the effect. That’s dangerous when a recreational user is not aware of precisely how much is being taken or is consuming alcohol as well. Consequences of overdose can include nausea, vomiting, incontinence, muscle spasms, coma, and even death.

  In 1990, public health officials in several states had become concerned by reports of GHB poisoning, often in combination with other drugs.24 That year, the FDA issued an advisory warning that GHB was unsafe and illegal outside of its use in narcolepsy research. Until that point, the substance was available in stores that sell vitamins and dietary supplements. In 1993, the rock star Billy Idol collapsed in convulsions outside a Los Angeles nightclub, reportedly because of GHB use.25

  The drug acquired a list of colorful street nicknames, such as Grievous Bodily Harm or Georgia Home Boy; outside the United States, Fantasy or Liquid Ecstasy. GHB was also relatively easy to make at home, because its chemical relatives GBL (gamma-butyrolactone) and 1,4-butanediol were used as industrial solvents.

  GHB attracted more attention when it was linked to incidents of drug-facilitated sexual assault and became known as a “date rape drug.” In 1997, a member of Congress from Texas introduced a bill that would have the Drug Enforcement Administration designate GHB as a Schedule I drug—the same as LSD and heroin. This would have stopped all research. A complicated dance took place, with Orphan Medical executives meeting with prosecutors, police, and advocates for victims of sexual assault. The company argued for tight controls on GHB in order to forestall an outright ban.

  In testimony before Congress in 1998, leaders of the sleep research community including William Dement joined together with Orphan Medical and the National Organization for Rare Disorders. They all pleaded with lawmakers, saying: don’t ban this drug, let research on narcolepsy play out.26 Mali Einen, a participant in one of Orphan’s studies and later a narcolepsy research coordinator at Stanford, said that GHB had significant effects in reducing her cataplexy: “I feel like I have gotten a chance to have a life. One where I don’t need to be afraid that I will fall and hurt myself or simply make someone else uncomfortable or afraid.”

  A compromise bill, signed into law in 2000, designated GHB as Schedule I but the prescription drug product would be Schedule III, allowing clinical research on narcolepsy to continue.

  CLOSED DISTRIBUTION

  When the FDA was evaluating GHB for narcolepsy, a large part of the safety data—in terms of total years of exposure—was from Martin Scharf’s open-label study, dating back to 1983. However, Scharf was penalized by FDA inspectors because he did not keep records that were detailed enough for the FDA’s standards.27 “I took an enormous beating from the FDA, being reprimanded for violating procedures which didn’t even exist at the time I was working on it,” Scharf commented later. “It was a very bitter experience.”28

  When the FDA’s advisory committee met to consider Orphan’s application for GHB in 2001, several people with narcolepsy spoke about how much it had changed their lives. But alarm over the drug’s non-narcolepsy uses meant that much of the discussion was about how to safely manage its distribution.

  An emergency medicine researcher in Minnesota, Deborah Zvosec, described her studies on people who had become dependent on GHB. She called GHB “perhaps the most addictive drug ever abused” and warned that Xyrem might be attractive to people wanting to avoid the risks of illicitly produced GHB.29

  In response to concerns about inappropriate use and diversion, Orphan Medical designed a closed distribution system for Xyrem, bypassing consumer pharmacies. There would be one manufacturing plant and one central pharmacy for the entire country. This is what people with narcolepsy who take the drug deal with today. Only a month’s supply is delivered at a time, and the patient has to sign for deliveries; redelivery attempts are limited to minimize the amount of time the drug sits around in a warehouse or delivery truck.

  ATTEMPT TO GO WIDER

  For the first few years, Xyrem was unprofitable. But Orphan Medical executives seemed to have a strategy in mind for Xyrem similar to Cephalon’s for modafinil/Provigil: obtain FDA approval with narcolepsy, then move on to other conditions that are more prevalent. “Xyrem is critical to Orphan Medical’s future,” the company’s CEO said in 2000. “It will not only transform us into a profitable company, it will make us a recognizable emerging drug company.”

  Orphan’s 2005 acquirer, Jazz, had fibromyalgia as a priority. Scharf had already begun research on GHB for fibromyalgia, which was estimated to affect millions of Americans.30 Like other chronic illnesses, fibromyalgia has had a societal “legitimacy deficit” because it predominantly affects women and has subjective symptoms: fatigue and muscle or joint pain.

  Unrefreshing sleep is a feature of fibromyalgia, and in the sleep lab, some people with fibromyalgia displayed “alpha intrusion”: alpha EEG waves from wakefulness appearing during non-REM sleep. Scharf pushed for more studies on fibromyalgia, proposing alpha intrusion as a more objective measure of the disorder’s severity. His study showed that treatment with GHB could reduce both measures of pain and fatigue.

  When Jazz Pharmaceuticals bought Orphan in 2005, Orphan had already begun a clinical trial of Xyrem in fibromyalgia.31 Since it represented many more potential customers than narcolepsy, the condition was mentioned in Jazz’s annual reports as a market opportunity. Around this time, a few sleep specialists who worked with Jazz suggested that the company conduct studies with Xyrem on IH. Two, who were not willing to be identified, told me that this initial effort didn’t go far, because FDA officials then regarded IH as too poorly defined, and company executives were focused on the larger prize of fibromyalgia.

  During this period, Jazz was under financial strain. In 2007, after a public stock offering, the company had accumulated a deficit of more than $300 million since its founding.32 In 2008 and 2009, the company missed more than one interest payment on its bonds, and its annual reports warned of the possible need to scale back research or declare bankruptcy.33

  In 2010, the FDA rejected Jazz’s bid to have GHB approved for fibromyalgia.34 Although people with fibromyalgia testified to its benefits, efficacy was not the primary problem. Some of the FDA advisory committee thought scaling up Jazz’s distribution and risk management system for Xyrem would be dangerous. They said it would result in too many opportunities for diversion and abuse, and GHB might be mixed harmfully with other medications such as benzodiazepines and opiates. At the advisory meeting, the Baylor College of Medicine psychiatrist Thomas Kosten was forceful in voicing his concerns about GHB.35 “It’s going to have to be very tight and otherwise you’re going to have the street flooded with this [version] that is supplied by the manufacturer,” said Kosten, who had studied GHB in people with opioid dependence.36 “Right now it’s viewed as a drug for a very unusual condition [narcolepsy] that doesn’t get prescribed very much. That does not describe what fibromyalgia is.”

  GHB’s inconvenience and cost, along with the existence of other options for people with fibromyalgia, made it a long shot anyway. But the FDA’s negative decision showed the limits of what mainstream medicine would allow—at least in the United States. Xyrem was acceptable for people with narcolepsy but not for those with something more common and less well defined.

  OFF-LABEL PROSECUTION

  At the time when Orphan was applying to the FDA for approval of Xyrem, FDA officials asked the company to consider having doctors agree to prescribe the drug for patients with narcolepsy with cataplexy only.37 The FDA’s medical reviewer agreed, writing: “It is also to be expected that if Xyrem is approved without any restrictions on off-label use it is likely that it will be prescribed not just for the daytime sleepiness of narcolepsy (for which there is inadequate evidence for efficacy at present), but for daytime sleepiness of other causes and even for daytime fatigue.”

  The FDA’s advisory committee voted in favor of restricting Xyrem prescriptions to “on-label use.” However, implementing this restriction would have gone against policies on interfering with physicians’ judgment and was something that the FDA counsel didn’t feel the agency could legally do. Making the restriction explicit might have avoided trouble later. Orphan and Jazz became enmeshed in an “off-label promotion” case that eventually had far-reaching legal implications.

  In 2006, federal prosecutors indicted a Maryland psychiatrist, Peter Gleason, for starring in Orphan and Jazz’s promotional efforts. According to his indictment, he advocated Xyrem for a wide array of neurological and psychiatric disorders beyond narcolepsy. He gave hundreds of promotional talks to doctors around the country, for which Orphan paid him more than $100,000 in 2005. Gleason was recorded telling other doctors that “table salt was more dangerous” and that Xyrem was safe for children. In a press release, an FBI official compared his conduct to that of “a carnival snake-oil salesman.” Martin Scharf, who had championed GHB for years, told the New York Times: “He is a very smart man, and I believe he is extremely well intentioned.… But this is not candy. It’s not a cure-all.”

  It was the first time the federal government had prosecuted a physician for off-label promotion, rather than pharmaceutical companies. Gleason told the press that he was charged because he did not help the government build a case against Jazz. After pleading guilty to a misdemeanor, Gleason ran into trouble with multiple state medical boards and committed suicide in 2011, which relatives blamed on overzealous prosecution.38

  Jazz settled its off-label promotion cases, civil and criminal, for $20 million. The company entered into corporate probation: a five-year agreement providing for monitoring of its marketing practices. Prosecutors also obtained convictions of two Jazz employees who worked with Gleason. One former sales representative, Alfred Caronia, successfully appealed his conviction on free speech grounds, with possible implications for how off-label drug promotion can be regulated.39 If researchers can publish papers on off-label uses of a drug, why can’t a pharmaceutical company tell doctors or even consumers about that research?

  PRICE INCREASES

  Xyrem was Jazz’s main source of revenue. After the company was unable to expand the size of Xyrem’s customer base beyond narcolepsy, it increased the price. According to data published by Bloomberg, no drug maker made a larger price increase for the period between 2007 and 2013 than Jazz did with Xyrem.40 By 2019, Xyrem sales in the United States were $1.6 billion, with fewer than 15,000 active patients. On average, that’s more than $100,000 per person in a year (figure 15.2). This parallels a similar increase in the cost of disease-modifying therapies for multiple sclerosis.41 The six-figure yearly cost of Xyrem was considerably higher than that of other commonly prescribed wake-promoting medications, but it was more typical for drugs for other rare or orphan indications.42

  FIGURE 15.2. Estimates for the wholesale price of Xyrem, obtained by dividing total U.S. sales by active patients that year.

  Source: Data obtained from Jazz Pharmaceuticals annual reports.

  To be clear, not everyone paid full price. Often an insurance company paid most of the cost, and Xyrem’s price made it a fat target for prior-authorization screens. Some health insurers’ policies stated that Xyrem should only be considered after a narcolepsy patient has already tried conventional stimulants or was unable to tolerate them.43 Insurance coverage for off-label Xyrem was difficult to obtain, although it was possible.44 Jazz has established support programs for patients who are uninsured or lack insurance coverage. The company was investigated for allegedly influencing an industry-funded charity, Caring Voice Coalition, which appeared to prioritize Xyrem patients over less expensive cases.45 In 2019, Jazz agreed to pay $57 million in a settlement of the investigation with the Justice Department.

  Unable to patent GHB itself, Jazz had patented Xyrem’s risk management system, which it contended was an essential part of distributing its product.46 It used that patent to fend off challenges from generic manufacturers. When Xyrem’s patent exclusivity was set to expire at the end of 2022, FDA-approved generic versions and an extended-release formulation were waiting as competition—an explanation for the company’s drive to develop the new low-sodium version.

  In Europe, Xyrem was distributed by UCB, a Belgian company focused on neurological disorders. It cost several times less than it did in the United States, but it was still relatively expensive.47 Until 2016, in parts of the United Kingdom, filling prescriptions for children with narcolepsy required a special request from a physician and a claim that a patient’s need was “exceptional.”48

  Separate from its use for narcolepsy, GHB became available in the 1990s as a treatment for alcohol withdrawal in Italy, because of interest from addiction specialists there. Known as Alcover and formulated as a syrup, it has been prescribed to about twenty thousand people per year in Italy and Austria—more than the number of people who take Xyrem in the United States.49 For alcohol withdrawal, the drug is given several times per day, in smaller doses than when used as a sleep aid for narcolepsy.50

  In 2014, the French firm D&A Pharma applied for marketing approval across the European Union for Alcover. It ran into the same type of benefit-risk calculation that limited modafinil’s approval. Regulators in several countries raised concerns about safety and misuse. D&A submitted studies on Alcover, some claiming its superiority to alternatives for managing alcohol withdrawal. Despite D&A offering to limit treatment to inpatient use, the application was denied in 2017.51

  JAZZ’S INFLUENCE

  Xyrem’s high prices suggest consideration of Jazz’s influence in the narcolepsy and hypersomnia communities. It was difficult to separate the company’s role as a stakeholder from its status as a for-profit entity. Several prominent sleep neurologists were paid consultants for Jazz.52 The company also employed people trusted by the narcolepsy community, such as the former Stanford research coordinator Mali Einen. Jazz has supported programs and events held by patient advocacy groups such as Narcolepsy Network, Wake Up Narcolepsy, and the Hypersomnia Foundation.53

  From Jazz’s point of view, expanding from narcolepsy to idiopathic hypersomnia was natural, given that the cohort of sleep neurologists who prescribed Xyrem for narcolepsy (about 1,300 nationwide) was already familiar with its peculiarities.54 In response to questions, a Jazz spokesperson sent a statement, which said in part: “Since Jazz’s inception, we have focused on identifying and developing the therapies people with serious sleep disorders need.… As one of the first and only companies to invest in and continuously commit to sleep medicine, we are uniquely positioned to influence the future of sleep disorder treatment, and we take this responsibility seriously.”

  Others may take a more critical look at Jazz’s activities—which are typical for a pharmaceutical company—with the argument that commercial promotion distorts priorities. However, for the hypersomnia community, one goal of banding together was to get industry players interested—“to treat this like it’s a real disease.” Companies like Jazz have the muscle to get something through the FDA, so that drugs don’t languish in limbo, like flumazenil had.

  For other neurological disorders, patient advocacy groups such as the National Multiple Sclerosis Society have brought forward constituents’ concerns about insurance coverage and out-of-pocket costs.55 Narcolepsy advocacy groups have not done so to the same degree—possibly because of Jazz’s dominance of the field. For multiple sclerosis, more companies are involved, and advocacy groups are less dependent on one single company or product.

  Jazz’s interests do sometimes coincide with the goals of narcolepsy patient advocates. For example, the company has sponsored awareness campaigns, and its “More Than Tired” advertising has contributed to greater public awareness of narcolepsy. In addition, Jazz has sponsored the only published studies of the cost of medical services for narcolepsy patients in the United States. In a 2018 paper, the authors’ published conclusion was that timely diagnosis and treatment reduces other health care costs. Their data show that average pharmacy costs for people newly diagnosed with narcolepsy were around $6,000 per year and that claims for stimulant medications tended to decline after the first year.56

  SAFETY ISSUES

  People with narcolepsy sometimes report reluctance by physicians to prescribe Xyrem because of its reputation as a “date rape drug.” However, it is unfair to confuse Xyrem’s use for a legitimate medical purpose with crimes that have been committed with the aid of illicit GHB. Jazz’s initial review of Xyrem’s safety record did reveal some examples of abuse or dependence and two confirmed reports of sexual assault.57 But a 2010 review concluded that other drugs were more likely to be connected to sexual assaults, and GHB’s reputation was “counterproductive and misleading.”58

  More concerning for patients are the hazards Xyrem poses to the people who are supposed to benefit from it. The drug’s safety has been a topic of debate in medical journals, some of it propelled by the Minnesota emergency medicine researcher Deborah Zvosec. For sleep specialists, the valued place Xyrem holds in the management of narcolepsy became clear when its safety was questioned.