This has been a week of (almost) non-stop coverage of Abilify, which, in 2015, was the best-selling drug on earth.
In summary, Abilify (aripiprazole) is a “second-generation antipsychotic.” It’s both a dopamine partial agonist (activating postsynaptic dopamine receptors at low concentrations and blocking them at higher concentrations) as well as having serotonergic effects at 5ht-2a, 5ht-7, and 5ht-1a receptors (the last of which it also has the partial agonist effects. The most important part of this complex pharmacology? It makes psychiatrists—ne, psychopharmacologists!—feel like they have something novel to talk about, to discuss at conferences, and the like. It’s a whole week's worth of indications, mechanisms of action, and binding affinities. Does it work that well? “Eh.”
Prior articles in this thrilling series include:
Abilify III: Bipolar Depression
Akathisia (aka Abilify IV)
As well as honorable mentions as part of my articles about CATIE (Part 1 and Part 2), a large NIH-funded trial in which Abilify was compared to other medications for schizophrenia.
And now, in what may or may not be the final installment depending on how I feel, is the final article of this week on the topic. Abilify: Federal Enforcement.
Abilify was developed by Japanese Pharma Giant Otsuka and Bristol Meyers Squibb together. This drug, like most blockbuster antipsychotics, has attracted endless lawsuits. In part—it’s a multibillion-dollar product. OF COURSE, there are lawsuits.
The Federal Settlements
As a dilettante historian of the pharmaceuticals I both took (for my bipolar disorder) and was trained to prescribe as a psychiatrist, I have learned that when there is a best-selling drug, there is a federal case brought for illegal marketing. These cases are routinely settled by the DOJ for way, way less money than the drug made thanks to said illegal marketing. One might even hypothesize that this activity, as illegal as it may be, is a completely rational strategy on behalf of the companies involved.
aripiprazole is no different, at the federal level:
The DOJ got a 515 million dollar settlement in 2007 (for reference, in 2013, the drug made 1.5b in the first quarter of the year).
“The integrity of our health care system rests on physicians being able to make decisions based on the best interests of their patients,” said Keisler. “This settlement reflects the Justice Department’s strong commitment to holding drug companies accountable for devising and implementing fraudulent marketing and pricing schemes that undermine that decision-making process at the expense of federal health care programs for the poor and the elderly.”
This “broad array of allegations” were mostly about marketing Abilify for use in dementia and pediatric cases, when they didn’t have an FDA label to do so. The specific allegations are as follows:
“from approximately 2000 through mid-2003, BMS knowingly and willfully paid illegal remuneration to physicians and other healthcare providers to induce them to purchase BMS drugs”.
Some of these programs involved travel to luxurious resorts.
I WAS NOT INVITED, I will add. In fairness, I was only an Abilify patient at the time, not a physician, so that adds up).
“from 1994 through 2001, Apothecon [a BMS subsidiary] knowingly and willfully paid illegal remuneration such as stocking allowances, price protection payments, prebates, market share payments, and free goods in order to induce its retail pharmacy and wholesaler customers to purchase its products”
I CAN’T GET ENOUGH OF THE TERM “prebates”
“from 2002 through the end of 2005, BMS knowingly promoted the sale and use of Abilify, an atypical antipsychotic drug, for pediatric use and to treat dementia-related psychosis, both “off-label” uses.”
“both BMS and Apothecon set and maintained fraudulent and inflated prices for a wide assortment of oncology and generic drug products with the knowledge that federal healthcare programs established reimbursement rates based on those prices. By reporting false and fraudulent prices that were substantially higher than commonly and widely available prices in the marketplace, BMS and Apothecon created a “spread” between the reimbursement rates for federal health care providers and the actual prices for the drugs charged to its customers.”
This “spread pricing” activity is both legal and the actual business model of Pharmacy Benefit Managers, as I’ve detailed in this prior article.
The last part of the settlement had to do with Serzone pricing. SNORE!
The whistleblowers who brought those cases on behalf of the government walked away with $50m between them.
All over again, in 2008, the DOJ settled for another $4m with Otsuka, separately from BMS:
These allegations were also part of a Qi Tam enforcement1 (where citizen whistleblowers file on “behalf of the king” and thus get to keep some of the settlement):
from 2002 through the end of 2005, Otsuka knowingly promoted the sale and use of Abilify for pediatric use and to treat dementia-related psychosis. Otsuka is alleged to have participated in directing its sales force to call on child psychiatrists and other pediatric specialists, and urge those physicians and others providers to prescribe Abilify for pediatric patients. Otsuka sales representatives also participated in a specialized long-term care sales force that called almost exclusively on nursing homes, where dementia-related psychosis is far more prevalent than schizophrenia or bi-polar disorder. Because of the potential market benefit, the long term care sales force promoted Abilify off-label for the treatment of dementia-related psychosis.
Here, I feel compelled to briefly mention the CATIE-AD study, in which Alzheimer’s Dementia was treated with antipsychotic drugs, as a follow-up to CATIE in schizophrenia. Spoiler alert: these medicines were discontinued in, at most, 8.1 weeks. Abilify wasn’t included in that sample, but in meta-analysis data, it outperforms other agents2:
One of the reasons I love writing this newsletter is the fact that I am routinely surprised. In this case, the DOJ sued Otsuka, and won a settlement, for illegally marketing a drug…that worked in the indication.
As opposed to virtually all the other drugs in the class, which do not work in Alzheimer’s dementia:
Now, originally I was going to write just one article about litigation about Abilify…but like most things abilify, there is just SO MUCH that I will require another article to even get to state-level or private class action lawsuits about abilify. And those? I promise, they are much more exciting than these federal cases.
Abilify—a best seller, with regulatory action and litigation that barely made a dent in its balance sheet. A drug that was illegally marketed for things it did WELL? Can it get weirder? Well, I hope you will compulsively read the next article in this series, in a moment of ham-fisted foreshadowing.
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Please listen, on repeat, and add to playlists liberally.
United States ex rel. Richardson v. Bristol Myers Squibb, Civil Action No. 06-11821-NG (D. Mass.); United States ex rel. Piacentile v. Bristol-Myers Squibb Co., Civil Action No. 05-10196-MLW (D. Mass.); United States ex rel. Forden v. Bristol-Myers Squibb Co., Civil Action No. 04-11216 -RGS (D. Mass.); United States ex rel. Cokus v. Bristol Myers Squibb, Civil Action No. 01-11627-RGS (D. Mass.); United States ex rel. Barlow v. Bristol-Myers Squibb, Civil Action No. 04-11540-MLW (D. Mass.); United States ex rel. Ven-A-Care of the Florida Keys, et al. v. Apothecon, et al., Civil Action No. 00-10698-MEL (D. Mass.); and United States ex rel. Ven-A-Care of the Florida Keys, Inc. v. Bristol Myers Squibb Co., Civil Action No. 95-1354 (S.D. Fla.).
Schneider, L. S., Dagerman, K., & Insel, P. S. (2006). Efficacy and adverse effects of atypical antipsychotics for dementia: meta-analysis of randomized, placebo-controlled trials. The American Journal of Geriatric Psychiatry, 14(3), 191-210.