Shire PLC’s drug Vyvanse became the first drug approved for sale in the U.S. to treat some of the estimated 2.8 million adults who have a binge-eating disorder.

Patients regularly eat more food than they need, often when they aren’t hungry and until they feel uncomfortably full, the FDA said. The condition can lead to weight gain, obesity and related health problems.

An estimated 2.8 million adults in the U.S. are binge eaters, two times more than those who have the eating disorders anorexia and bulimia combined, according to Shire.

In two pivotal studies, binge eating episodes declined to an average of one day a week among patients taking Vyvanse capsules for 12 weeks, down from an average of five days a week, Phil Vickers, Shire’s head of research and development, said in an interview.



'The approval of Vyvanse provides physicians and patients with an effective option to help curb episodes of binge eating,' Mitchell Mathis, director of the FDA’s division of psychiatry drug products, said in a statement.

For Shire, the approval could eventually add 'several hundred million' dollars in sales, and help the company reach its goal of $10 billion in yearly sales by 2020, said Flemming Ornskov, the company’s chief executive. Vyvanse is the company’s top-selling drug, notching $1.1 billion of the company’s $4.3 billion in total sales during the first nine months of last year.

One challenge: increasing the numbers of patients diagnosed as binge eaters. Shire estimates that just 3% of Americans with the disease have been diagnosed under the mental-disorder criteria, Dr. Ornskov said.

'Binge eating can cause serious health problems and difficulties with work, home and social life,' Mitchell Mathis, director of the Division of Psychiatry Products in the FDA’s Center for Drug Evaluation and Research, said in a statement.



The FDA gave Vyvanse priority review, a designation for drugs with promise to 'provide a significant improvement over available therapies,' the agency said.

Vyvanse is an amphetamine which, like other amphetamines, carries the potential for abuse and addiction. They also have been associated with increase blood press sure and heart rate, sudden death, stroke, heart attack, insomnia and psychiatric side effects such as hallucinations and mania.

The discovery of amphetamine energized the weight loss industry. Introduced as the Benzedrine inhaler in 1932 by venerable Philadelphia firm Smith, Kline, and French, the American Medical Association (AMA) soon recognized Benzedrine as a treatment of narcolepsy, postencephaletic Parkinsonism, and certain depressive psychopathic conditions. Several clinical studies first published in the late 1930s demonstrated amphetamine’s anorectic effect. The Clark & Clark Company of Camden, NJ, established in 1941, was one of the earliest manufacturers of diet pills combining amphetamine sulfate and thyroid along with phenobarbital, aloin, and atropine sulfate to counteract untoward effects.

adverse events, including deaths, began to be reported to the FDA as early as the 1940s. In the early 1950s, additional adverse reactions including deaths prompted a detailed investigation by the agency.

Efforts had been in place at least since the 1965 Drug Abuse Control Amendments to increase accountability of the use of amphetamine in medical practice. Diversion of the drug for recreational use and the concomitant public health concerns had been recognized as a serious problem by the 1950s, but prescribing amphetamine— whether alone, as part of the rainbow regime, or for indications other than weight loss—continued to rise in the 1960s. Under the Comprehensive Drug Abuse Prevention and Control Act of 1970, which established different schedules for certain drugs based on their medical value vis-á-vis their abuse potential, amphetamine was relegated to Schedule II. This status mandated even greater hurdles for the prescribing and dispensing of the drug as well as production ceilings. In the 1970s, FDA also reconsidered obesity as a safe and effective use of amphetamine and its congeners, ruling that amphetamines were effective but only safe for short-term use, which essentially 'marginalized the anorectics and contributed to the eventual decline in their use.'

'I’m concerned that the FDA’s approval of Vyvanse for binge eating disorder is going to worsen our problems with stimulant abuse,' Carlat says.



'Vyvanse is a derivative of Dexedrine. We’ve seen epidemics of Dexedrine abuse in the past when it was used to help people diet. I predict that the FDA has just opened the gates to another similar epidemic – after all, binge eating disorder is a subjective diagnosis that could be potentially expanded to cover many millions of people.'

Recurrent episodes of binge eating. An episode of binge eating is characterized by both of the following: eating, in a discrete period of time (for example, within any 2-hour period), an amount of food that is definitely larger than most people would eat in a similar period of time under similar circumstances a sense of lack of control over eating during the episode (for example, a feeling that one cannot stop eating or control what or how much one is eating)

The binge-eating episodes are associated with three (or more) of the following: eating much more rapidly than normal eating until feeling uncomfortably full eating large amounts of food when not feeling physically hungry eating alone because of feeling embarrassed by how much one is eating feeling disgusted with oneself, depressed, or very guilty afterwards

Marked distress regarding binge eating is present.

The binge eating occurs, on average, at least once a week for three months.

The binge eating is not associated with the recurrent use of inappropriate compensatory behavior (for example, purging) and does not occur exclusively during the course Anorexia Nervosa, Bulimia Nervosa, or Avoidant/Restrictive Food Intake Disorder.

Excessive eating 12 times in 3 months is no longer just a manifestation of gluttony and the easy availability of really great tasting food. DSM-5 has instead turned it into a psychiatric illness called Binge Eating Disorder.

The retired tennis player Monica Seles spent this month making the rounds of television talk shows, appearing on everything from 'Good Morning America' to 'The Dr. Oz Show' to share her personal struggle with binge eating.



'It took a while until I felt comfortable talking about it,' she said in a People magazine interview, explaining that she secretly devoured food for years while she was a professional athlete. 'That’s one of the reasons I decided to do this campaign: to raise awareness that binge eating is a real medical condition.'



But that is not the only reason. Ms. Seles is a paid spokeswoman for Shire, which late last month won approval to market its top-selling drug, Vyvanse, to treat binge-eating disorder,...

And patient advocacy groups — freshly infused with donations from Shire — began driving social media traffic to a company website that provides advice on how to raise the issue of binge eating with a doctor.

Shire appeared to be following a familiar drug industry playbook by promoting awareness of a disorder, in this case binge eating, before more directly marketing its treatment. A company website, BingeEatingDisorder.com, makes no mention of Vyvanse but provides detailed information about how to talk about the disorder with a doctor, including a printable symptom checklist and sample opening lines to start the conversation. The site also tells patients 'don’t give up' if a doctor initially resists.



Some experts in prescription-drug abuse said the content was troubling because it appeared to coach patients about how to receive a diagnosis for a relatively uncommon condition, or shop for a new doctor if they were not successful.

In 2011, the F.D.A. cited Shire, which is based in Dublin, for misleading advertising, and last fall the company paid $56.5 million to settle federal charges that it improperly promoted Vyvanse, Adderall and other drugs. Among the allegations, which Shire denied, was that the company played down Vyvanse’s addiction potential and said it would prevent car accidents, divorce, arrests and unemployment.

With the approval of Vyvanse for binge eating, 'now we have another reason for the public to learn about the glories of amphetamine — it’s very worrisome,' said Dr. Lawrence H. Diller, a behavioral pediatrician in Walnut Creek, Calif., who has written about A.D.H.D. drugs. 'My hat’s off to Shire. They’ve done it again.'

Several drug safety and addiction experts said the approval was of particular concern because of amphetamines’ troubled history as a treatment for weight loss. Vyvanse is converted by the body into an amphetamine when it is swallowed.

became addicted. After public outcry and tighter government controls, companies stopped selling amphetamines as obesity treatments and their use is now tightly restricted. In 2012, rom the 1940s through the 1970s F , the drugs were commonly prescribed to overweight people who then. After public outcry and tighter government controls, companies stopped selling amphetamines as obesity treatments and their use is now tightly restricted. In 2012, the F.D.A. approved Qsymia , a drug combination that treats obesity and contains the amphetamine phentermine, although unlike Vyvanse, it is classified by the federal government as having a low potential for abuse.

The F.D.A. expressly forbade Shire from promoting Vyvanse as an obesity drug, but some drug safety experts said they worried its weight-loss attributes could be attractive to people who habitually overeat. The company says about 80 percent of people with the disorder are overweight or obese. Weight loss and appetite suppression are a common side effect of amphetamines.

'There’s so many reasons to be concerned about this,' said Dr. Andrew Kolodny, the chief medical officer of Phoenix House, a drug treatment organization.

He questioned why the F.D.A. approved the new use of Vyvanse so swiftly and said that given amphetamines’ troubled past, more caution was necessary. 'We had a horrible experience with amphetamines in this country, so the fact that this would just get rushed through without even bringing it before an advisory committee is especially concerning,' he said.

Every day seems to bring the latest breathlessly touted innovation in modern health care. The endless hawking of new health care wonders is beginning to inspire some skepticism, but maybe not enough.For example, at the end of January, 2015, reports of the first ever drug therapy for binge eating disorder appeared. For example, see Jonathan Rockoff writing in the Wall Street Journal Rather ominously, the article described this disorder thus,Furthermore, it appears to be common,However, now there is a pharmaceutical solution!Because the disease is common, that may mean a lot of money for ShireThe only hitch is that all those long suffering victims of binge eating disorder have to be found, and presented with this wonderful new alternative:Brief coverage of the initial approval of Vyvanse appeared in the NY Times Bloomberg also weighed in, adding to the urgency by underlining how seriously the FDA had handled this:Among the major media covering the rollout, only Reuters noted a potential fly in the ointment in this article So Vyvanse is actually lisdexamfetamine, and having been a child when the slogan "speed kills" referred to methamphetamine, not driving automobiles fast, I thought it might be worth looking into the evidence that this somewhat new amphetamine, a relative of that infamous "speed," was now deemed a wondrous treatment for eating too much.In particular, a recent article in JAMA Psychiatry reported results of one of the two trials Shire did of Vyvanse for binge eating disorder.(1) The study by McElroy et al randomized patients with binge eating disorder to one of four groups, to receive the drug at dosages of 30, 50, or 70 mg/ day or placebo. The investigators followed patients for 11 weeks. The main outcome variable was the number of binge eating days per week reported by the patients.Patients in all groups were binge eating during approximately 4.5 days/ week at the beginning of the study. At 11 weeks, the average number of binge eating days/ week declined in all groups, dropping 3.3 days/ week for the placebo group, 3.5 for the 30 mg group, 4.1 for the 50 mg group, and 4.1 for the 70 mg group. Thus, by this measure, the difference between patients given placebo versus patients given maximum dosage of the drug was an average decrease of 0.8 binge eating days a week. That does not seem like a very big effect size, or in other words, it seems that the drug had only a small effect on binge eating compared to placebo.That impression was reinforced by looking at some other study outcomes. The average numbers of binge eating episodes per week at 11 weeks were 1.1 for placebo, 1.2 for the 30 mg group, 0.5 for the 50 mg group, and 0.5 for the 70 mg group. Again, patients given the maximum dose of the drug had only a slightly smaller number of binge eating episodes than those given placebo, reinforcing the impression that the drug is not very effective.A graph of binge eating days/ week measured over time makes things clearer. It showed that all groups, including patients given placebo, markedly reduced their reported binge eating over the 11 week period. Since the study did not allow any patients to get any other treatment for binge eating other than placebo or the study drug, this again suggests that the drug was not much better than placebo. Further, the apparent reduction in binge eating by patients given placebo suggests a number of possibilities:- Just paying more attention to patients by putting them in a trial could lead to marked decreases in binge eating, or- People in binge eating trials could tend to report they are improving, whatever treatment they get, or- Binge eating may not be a stable phenomenon, and its intensity could vary over time, or- It may be difficult to make a reliable diagnosis of binge eating disorder.In summary, at best, the trial showed that Vyvanse only caused small reductions in binge eating, and that binge eating may decrease spontaneously, or at least when patients are given more attention or scrutiny. Thus, even putting the best face on the evidence from a trial done by the maker of Vyvanse does not greatly support the benefits of this drug.In addition, according to evidence-based medicine advocates, the benefits of a treatment must be balanced with its potential harms. In this study, about 5% of patients given any dosage of Vyvanse had to discontinue its use because of adverse effects. 3/196 patients initially randomized to Vyvanse had serious adverse effects, and one patient died, apparently of an amphetamine overdose. Oddly, the article declared that the one death, due to methamphetamine overdose, was thought by a study investigator not to be related to treatment with another amphetamine, lisdexamfetamine. That makes little sense, given that in a randomized controlled trial, the presumption is that differences in groups given different treatments were caused by these treatments.In addition, patients given Vyvanse (lisdexamfetamine) had higher rates of various symptoms that are commonly associated with amphetamines, including insomnia, nausea, constipation or diarrhea, anxiety, feeling jittery, palpitations, and sleep disorder.This suggests that the relatively small apparent benefits of the drug must be weighed against rates of adverse events that are not negligible, especially given the short amounts of time patients were followed. So this study did not show that the benefits of Vyvanse clearly outweigh its harms.Finally, there were many problems with this trial that further cloud its validity, or applicability to patients (generalizability):- Patients were diagnosed using DSM-4 criteria, rather than the new DSM-5 criteria- Patients with any other psychiatric illness were excluded, limiting the applicability of its results.- Patients with an ostensibly chronic disease were only followed for 11 weeks, so the effects of this drug given for the treatment duration that might be needed to treat a chronic problem are unknown- The loss to follow-up rate, about 5% for treated patients decreases precision of the results given the relatively small effect size- The study was done at a large number of sites, initially 32, given the size of the patient population (starting at 260), and one site was dropped because of an "investigation," raising questions about the quality of the study implementation and data collectionSo, in my humble opinion, even this Shire sponsored study, which was responsible for half the evidence used to support the approval of Vyvanse for binge eating disorder, provided only weak and questionable evidence that the benefits of the drug outweigh its harms in the short term, and no evidence about long-term use of the drug.However, no media coverage so far has addressed the weakness of the clinical evidence supporting the use of Vyvanse. I have yet to see any other attempts at a rigorous, skeptical review of the clinical trial evidence supporting Vyvanse in this application. Instead, the media reporting so far seems to have accepted the word of the manufacturer's executives, who obviously have an interest in promoting the drug. (See the WSJ article above which just repeats assertions by a Shire executive.This lack of skepticism was particularly baffling given the nature of the drug that was being promoted, and its long and unfortunate history. As I noted, the amphetamines have proved to be dangerous drugs when abused, and they are abused frequently.The beginnings of widespread amphetamine abuse grew out of previous efforts to promote these drugs for obesity (which can be, of course, a consequence of eating too much). As documented by Cohen and colleagues(2),These rainbow pills were used with great enthusiasm, however,By the 1960s, the problem was acute,That is, until they were resurrected as a treatment for attention deficit disorder in children, and then their use was extended to adult patients with so-called adult ADHD, and now to patients with binge eating disorder.Given this history, the rapid approval of Vyvanse by the FDA, without the benefit of an expert panel, especially given that it was for a supposedly common disorder of adults, is very curious, and worrisome. As Dr Daniel Carlat said (quoted on the WBUR CommonHealth blog ),Why So Much Enthusiasm about Treating Such a Doubtful Diagnosis?As Dr Carlat noted above, it is not so obvious that binge eating disorder should be considered to be a disease. Starting with first principles, its definition is very vague and subjective. According to the Alliance for Eating Disorders , the DSM-5 criteria for it are:"An amount of food that is definitely larger than most people would eat in a similar period of time under similar circumstances?" In this case, how are "larger," "most people," and "similar circumstances" defined, and by whom? If I go out to eat with friends, and am the only one who has desert, or soup, for that matter, does that qualify? Similarly subjective are "a sense of lack of control," and "eating more rapidly than normal."In fact, the DSM-5 which ordained the new binge eating disorder diagnosis has been roundly criticized for embodying "diagnostic hyperinflation," turning aspects of the human condition, symptoms, and behavioral variants into disease. Dr Allen Frances, who has been one of its prime critics, described "binge eating disorder" thus Perhaps the enthusiasm to make binge eating disorder a disease had to do more with the financial relationships among the authors of DSM-5 and pharmaceutical companies that wanted to market drugs for the problem. An article by Cosgrove and colleagues(3) noted that members of the DSM-5 work group that approved binge eating disorder as a disease included three people with financial relationships with Eli Lilly, maker of Cymbalta, three people with relationships with GlaxoSmithKline, maker of Lamictal, and one person with a relationship to Shire, maker of Vyvanse.Yet the discussion of Vyvanse in the big media outlets did not address these past questions about the validity of the binge eating diagnosis for which it is now being promoted.This week, however, at least some skepticism about other aspects of Vyvanse's promotion appeared in a major media outlet. Just a few weeks after that initial coverage, the NY Times published a somewhat more skeptical take on the promotion of Vyvanse. It noted that Shire was underwriting celebrity endorsements without disclosing its financial backing of them,Shire also was funding patient groups as part of its promotional efforts,Furthermore, Shire has been trying to raise awareness of the new binge eating disorder diagnosis in ways that obfuscate its promotional interests,Note Shire's use of undisclosed payments to celebrity spokespeople and patient advocacy groups and a disease awareness website whose connection to the company's drug was obscured suggests the operation of a stealth marketing campaign . Furthermore, the article noted that Shire has been accused of deceptive marketing in the past, and specifically for its marketing of Vyvanse and another stimulant.We posted about that settlement here The article also emphasized concerns about this new pushing of amphetamines,Also,However, the NY Times article still did not address the lack of good evidence that the drug provided a substantial benefit even in terms of just reducing binge eating, and questions raised whether binge eating disorder is a valid diagnosis.Once again we see the overenthusiastic promotion of the latest wonder drug, starting with uncritical media reports that parroted drug company executives. At least this time some skepticism appeared about how an apparent stealth marketing campaign was organized, and about how the drug's riskiness was soft-pedaled.However, so far there has been little skepticism about the efficacy of the drug. In fact, close reading of the report of one major trial showed that at best it has minimal efficacy, and even the evidence for that is weak and sketchy. Furthermore, major news media have been hesitant to cite the real questions that have been raised about the nature of the disease for which the drug was advocated.Most concerning is that this promotion was of an amphetamine, a type of drug with a very dark past, a type of "hard drug" responsible for major abuse problems, and known to cause particularly bad side effects, a type of drug whose illicit use has been previously sparked by over-enthusiastic marketing for dubious indications.So once again I get to say that physicians need to be much more skeptical about the new "innovations," often promoted as miracle cures, that seem to appear weekly. Attempts to educate physicians about clinical epidemiology, the principles of evidence based medicine , and just simply how to read a clinical research article with an appropriately skeptical and critical eye seem to have fallen by the wayside. Furthermore, the diminishing number of health care journalists with diminishing resources may not be able to sufficiently skeptical of the marketing and public relations hype surrounding new drugs and devices. Physicians and journalists need to have the courage to be more skeptical, and the public, who may trust journalists and physicians to cut through the bloviation, need to advocate for better training of physicians and journalists.Finally, health care professionals and the public at large have been told to trust government regulators to only approve medicines that are safe and effective. Yet the US Food and Drug Administration increasingly seems too cowed to challenge the pharmaceutical industry, and did not seem to exert much critical thinking before approving an amphetamine for over-eating. The public and health care professionals ought to be advocating intensely for regulators that are less captured by the industry they are supposed to oversee.As we have said until blue in the face, true health care reform would bring some skeptical thinking and regard for evidence and logic into the health policy discussion.For our closing musical inspiration, or warning, note the chorus in "Amphetamine Annie" by Canned Heat..."Speed Kills"1. McElroy SL, Hudson JI, Mitchell JE et al. Efficacy and safety of lisdesamfetamine for treatment of adults with moderate to severe binge eating disoder: a randomized clinical trial. JAMA Psychiatry 2015; Link here 2. Cohen PA, Goday A, Swann JP. The return of rainbow diet pills. Am J Pub Health 2012; 102: 1676-1686. Link here 3. Cosgrove L, Krimsky S, Wheeler EE et al. Tripartite conflicts of interest and high stakes patent extensions in the DSM-5. Psychother Psychosom 2014; 83: 106-113. Link here