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.”