05/27/15

Pseudoscience with Vyvanase?

© Pavel Parmenov | Abstraction. Pseudoscience 123RF.com

© Pavel Parmenov | Abstraction. Pseudoscience 123RF.com

There was an intriguing study done by Cosgrove et al. in 2014 that looked at the existence of financial conflicts of interest (FCOI) among individuals on the work groups of the DSM-5 approving new diagnoses. They found that among the 13 registered clinical trials testing drugs for a new DSM-5 disorder, 61% of the DSM Task Force members and 27% of the Work Group members had FCOI with the trial drug manufacturers. Principal investigators (PI) of these clinical trails were found to have ties other than funding to the drug manufacturer. Three PIs (23%) had financial ties to the drug manufacturer AND were DSM panel members with decision-making authority over the DSM revision process.

These findings suggest that increased transparency (e.g., registration on ClinicalTrials.gov) and mandatory disclosure policies (e.g., the American Psychiatric Association’s disclosure policy for DSM-5 panel members) alone may not be robust enough strategies to prevent the appearance of bias in both the DSM revision process as well as clinical decisions about appropriate interventions for DSM disorders.

One of these new diagnoses was Binge Eating Disorder (BED). In another article, “A Drug in Search of a Disorder,” I looked at how Vyvanase was fast tracked as a “treatment” by the FDA and immediately promoted in a marketing campaign by Shire, its manufacturer. One of the two clinical trials used for the approval of Vyvanase was just published in a JAMA Psychiatry article by McElroy et al. in March of 2015. It bears a closer examination because of the concerns raised by several experts on eating disorders regarding the approval of an amphetamine to treat BED.

Roy Posey, MD of Health Care Renewal reported that the McElroy et al. study randomized participants into one of four groups: individuals receiving the drug at doses of 30, 50, or 70 mg daily, and placebo. The participants were then followed for 11 weeks. The main outcome variable was the number of weekly binge eating days.  At the beginning of the study, participants were binge eating an average of 4.5 days per week. “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.” The difference between the placebo group and the maximum strength was .8 binge-eating days a week.  So, “it seems that the drug had only a small effect on binge eating compared to placebo.”

The study did not permit its participants to get any additional treatment besides the drug or placebo, again reinforcing the finding that the drug was not much better than the placebo. In addition, neither the study’s abstract nor the clinical trial data mentioned if the placebo was inert or not. If it was inert, which I’d guess it was, as most clinical trials still use inert placebos, then the nominal findings are even more concerting. The study’s participants could have guessed whether they were in a treatment group or the placebo group by the presence or lack of a drug effect. This would have broken the double-blind methodology and called the reported results into question as a result.

Posey pointed out that the reported reduction with placebo had several suggestions to be considered. First, merely calling attention to binge eating (by placing yourself in a trial) could lead to a marked decrease in binge eating. Second, people in binge eating trials may tend to report improvement regardless of which intervention they received. Third, binge eating may not be a stable phenomenon; its frequency and intensity could vary over time. Fourth, making a reliable diagnosis of binge eating could be difficult. Doctor Posey noted several additional problems with the study, which you can read in his article linked above. He also gave a short, helpful history of the problems with attempting to use amphetamines to treat obesity, “which can be, of course, a consequence of eating too much.”

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.

Both Posey and Katie Thomas, writing for The New York Times, reported that Shire received a warning letter for improperly promoting Adderall, another of its ADHD stimulants besides Vyvanase. The warning letter indicated that a video and webpage overstated the efficacy of Adderall XR and omitted information about the risks associated with Adderall XR.  “The webpage and video raise significant public health and safety concerns through their overstatement of efficacy and omission of important safety information.” Shire has sold its commercial rights to the Adderall name.

They also reported that Shire was ordered by the Department of Justice to pay $56.5 million to resolve civil allegations that it violated the False Claims Act as a result of marketing and promoting several of its drugs, including Adderall and Vyvanase. The false claims about Adderal XR included that it was clinically superior to other ADHD drugs; that it would “prevent poor academic performance, loss of employment, criminal behavior, traffic accidents and sexually transmitted disease.” The settlement also resolved claims that Shire sales reps “allegedly” made false and misleading statements about the efficacy and abusability of Vyvanase, concerns noted in the warning letter from the FDA.

Sandra Steingard, MD, also critiqued the McElroy et al. study in: “Stimulants and Food.” She commented how historically, physicians knew amphetamines were dangerous drugs and that their effects in dampening appetite tended to wear off over time. She warned that we should not lose sight that this study was not only sponsored by a drug company, but used the assistance of professional writers in its composition. She commented on the unreliability of it being a multi-center study with no site having more than 10 subjects. She also gave a long citation of the conflict of interest disclosures from the article. Dr. McElroy was noted to be a consultant to or member of the scientific boards of nine pharmaceutical companies (including Shire); and had received grant support from twelve pharmaceutical companies (including Shire).

She voiced concern that in the real clinical world, that Vyvanase will be used much longer than the time of the 11-week study; perhaps indefinitely. Pointing out the existing diversion problem with stimulants, she also said: “We already have a diversion problem with stimulants; widening their approved indications will only exacerbate that problem.” Steingard then pointed out how amphetamines has been long used to create animal models for psychosis and was stupefied that her colleagues seemed to downplay this risk in humans. “I see at least one student a year who developed psychosis after using stimulants; sometimes after convincing a doctor (often at their college health service) that they have ADHD.”

04/22/15

A Drug in Search of a Disorder

© Sergey Nivens | 123RF.com

© Sergey Nivens | 123RF.com

When the DSM-5 was published in May of 2013, binge eating came out of the closet of Appendix B, the section for potential “disorders” needing further study. “Binge Eating Disorder” became a psychiatric diagnosis (Code: 307.51) in its own right. Before that time, binge eating had received a backhanded diagnosis under the rubric of “eating disorder not otherwise specified.”  Without official standing as a coded eating disorder, binge eating suffered from diagnostic insecurity and poor self-esteem. It didn’t have an official diagnostic category like anorexia and bulimia or an FDA-approved medication to treat it. But now, less than two years since it became an official psychiatric disorder, that is no longer the case.

The American Psychiatric Association (APA) defined binge eating disorder as: “recurring episodes of eating significantly more food in a short period of time than most people would eat under similar circumstances.” Some episodes would include marked feelings of a loss of control. A binge eater might eat too quickly, even when not hungry. They may feel guilty, embarrassed or disgusted. They may binge eat alone to hide the behavior. “This behavior is associated with marked distress and occurs, on average, at least once per week over three months.” There is a more complete description of the diagnostic symptoms here in “Promoting Amphetamines for Over-Eating.”

On January 30, 2015, the FDA announced that the ADHD drug Vyvanse (lisdexamfetamine dimesylate) was approved to treat binge-eating disorder in adults. It is the first such drug approved to treat this condition. “Vyvanse was reviewed under the FDA’s priority review program.” Expedited reviews can be done to treat a serious condition, especially if it’s seen to provide “a significant improvement” over available therapies. But, “Vyvanse is not approved for, or recommended for, weight loss. Its efficacy for weight loss has not been studied.”

Common side effects from Vyvanse include: dry mouth, insomnia, increased heart rate, jittery feelings, constipation, and anxiety. More serious, but less common side effects include: “psychiatric problems and heart complications, including sudden death in people who have heart problems or heart defects, and stroke and heart attack in adults.”  Vyvanse might also cause “psychotic or manic symptoms, such as hallucinations, delusional thinking, or mania, even in individuals without a prior history of psychotic illness.” Oh, and it’s a Schedule II controlled substance with a high potential for abuse. In fact, OxyContin, fentanyl and cocaine are also Schedule II controlled substances. The DEA said these drugs are considered dangerous, “with use potentially leading to severe psychological and physical dependence.”

The FDA Adverse Events Summary for Vyvanse reported the following adverse events out of 14,311 consumers to its FDA Medwatch reports between 2004 and 2012: off-label use; insomnia; DECREASED APPETITE; aggression; headache; anxiety; nausea; DECREASED WEIGHT; irritability; fatigue; SUICIDAL  IDEATION; depression; agitation; overdose; feeling abnormal; abnormal behavior.

The New York Times reported that the marketing strategy for Vyanse sheds light on how pharmaceutical companies seek to “influence the treatment and diagnosis of a medical condition” in order to make billions of dollars in sales. Shire, the pharmaceutical company dispensing Vyvanse, seems to have followed a familiar drug industry method of promoting awareness of a disorder before more directly marketing its treatment.

Soon after Shire won FDA approval of its drug to treat Binge Eating Disorder, Monica Seles began to make the rounds of television talk shows such as “Good Morning America” and “The Dr. Oz Show” to relate her personal struggle with binge eating. She was also interviewed by People Magazine. Seles said that one of the reasons she decided to do this campaign was “to raise awareness that binge eating is a real medical condition.” Seles is a paid spokesperson for Shire. She declined to say what she’s getting paid by Shire.

Shire CEO Flemming Ornskov said that about five years ago researchers noticed the similarities between ADHD and binge eating, so they decided to study Vyvanse for the condition. As early as 2011, Shire’s CEO said that the company hoped to generate “multiple billions of dollars” from expanding Vyvnase use into new areas of illness, like schizophrenia, depression and binge-eating. International Business Times reported that in 2014 Vyvanse made $1.5 billion for Shire in sales for 2014. The company hoped to grow its revenue from the $4.91 billion it made in 2013 to $10 billion by 2020 And Vyvanse is a significant part of that projection. Shire’s current patents for Vyvanse don’t expire until 2023. The approval of Vyvanase for BED means that Shire will gain an additional three years of exclusivity with the drug.

In her article for The New York Times, Katie Thomas quoted Dr. Timothy Walsh of Columbia University, as saying: “Once a pharmaceutical company gets permission to advertise for it, it can often become quite widely prescribed, and even tend to be overprescribed, and that’s a worry.”

There were 3 clinical trails in process for additional potential drug treatments for BED:  Cymbalta (Eli Lily), Lamictal (GlaxoSmithKline), and Nuvigil. Cosgrove et al. reported that the DSM-5 work group that approved binge eating as a diagnosis included three individuals with financial ties to Eli Lily, three people with relationships to GlaxoSmithKline and one person with a relationship to Shire.

Several articles have noted a variety of concerns with the FDA approval of Vyanse to “treat” Binge Eating Disorder. International Business Times quoted Sandy Walsh of the FDA office of media affairs as saying they had no direct evidence of how Vyvanse worked in BED: “The exact mechanism of action of the drug in reducing the symptoms of BED is … unknown.”  Melissa Gerson, the clinical director of an outpatient treatment center specializing in eating disorders, said she would not recommend a drug alone to treat BED. “I can’t imagine how you would see any long-term improvements in the symptoms.”

A Shire website, BingeEatingDisorder.com noted how someone could talk to their doctor about BED. They provided a Doctor Discussion Guide, saying on its link, “Not sure how to start the conversation with your health care provider?” A tip at the bottom of the homepage suggested that the individual could “Print, e-mail, or take a screen shot of this page, and bring it to discuss with your health care provider.”  The New York Times reported that some experts were concerned that the content appeared to coach patients on how receive a diagnosis or shop for a new doctor if they weren’t successful.

Some drug safety experts questioned why the FDA fast tracked approval of Vyanase—even foregoing a review by an advisory committee. For decades, amphetamines like Vyanase, have been known to be a widely abused class of drugs when prescribed for obesity. The marketing end run done by Shire to avoid this pitfall was to promote Vyanase for binge eating and acknowledge that about 80% of the people with BED are overweight or obese WHILE COMPLETELY IGNORING the history of amphetamine abuse with weight loss. Don’t forget that weight loss and appetite suppression are already known to be common side effects when taking Vyanase and other amphetamines. And the FDA didn’t see this move or call them on it?

A spokesperson for the FDA said that Vyanase was granted priority approval because there was no other drug treatment available for BED. “And it did not ask an advisory committee to review the issue because Vyanase is already sold as an ADHD drug and its safety profile is well known.” REALLY?  Dr. Daniel Carlatt said:

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