Yet Another Drug Company Fined for Off-Label Marketing of Psych Medication

Since I started this blog way back in March of 2010, I have posted several times about big Pharma companies being fined for the off-label marketing of various psychiatric medications. Well, the hits just keep on coming.

The Consumerist was one of several news sources to recently report that: 

"New York Attorney General Eric Schneiderman announced the settlement Thursday resolving allegations that Bristol-Myers Squibb improperly marketed and promoted the drug Abilify.

Abilify — the brand name for the prescription drug aripiprazole – is a second-generation antipsychotic prescription drug, commonly, commonly referred to as “atypical antipsychotics,” that were originally used to treat schizophrenia.

According to the states’ complaint, which was also filed today, BMS engaged in off-label marketing, which is the promotion of drugs for uses that are not FDA-approved.

For example, the complaint claims that BMS improperly promoted Ability for pediatric use and for use in elderly patients with symptoms consistent with dementia and Alzheimer’s disease.

This, despite the fact that in 2006, Abilify received a “black box” warning stating that elderly patients with dementia-related psychosis who are treated with antipsychotic drugs have an increased risk of death.

Additionally, the complaint alleges that BMS violated state consumer protection laws by misrepresenting and minimizing the risks of the drug including metabolic and weight gain side effects and by misrepresenting the findings of scientific studies.

Under the proposed agreement, BMS is prohibited from promoting Ability from off-label uses; making false or misleading claims about the drug; compensating health care providers for attended promotional activities; using grant funds to promote Ability; and providing samples of the medication to health care providers who do not intend to use it for labeled purposes."

Bristol-Myers Squibb settled the claims with 43 states for a total of 19.5 million dollars. That sounds like a lot of money, but for big drug companies, it is actually a paltry sum. Fines like that are considered a cost of doing business

As readers know, I am rabidly against the use of antipsychotic medications in non-psychotic children, which is unfortunately becoming more and more common. However, I must admit I have negative feelings about that black box warning regarding the use of any (not just Abilify) antipsychotic medication in patients in nursing homes with advanced dementia due to Alzheimer's disease or other severe brain conditions. 

Things have gotten to the point where docs are afraid to prescribe these medications even in such patients who are actively psychotic with hallucinations and/or paranoid delusions, for which there are no other effective treatments.

Even in non-psychotic demented patients, antipsychotic meds are often the best agents for controlling assaultive behavior in this population. Unlike other sedatives, they do so while only minimally exacerbating memory and cognitive deficits in these people. Our society seems to want to pay nursing assistants only the minimum wage to take care of our impaired family members as they age. Long-term facilities are very expensive as it is. Not only that, but we under-staff them as well. While there may be psychosocial interventions which would reduce assaultive patients with dementia, we do not want to pay people to provide them.

Given those conditions, what is left? Medications, that's what. Do we really want to expose underpaid and overworked caretakers to dangerous aggressive behavior from patients who basically have no life anyway - just to prevent a tiny percentage of them from dying a little sooner due to the medications' cardiovascular side effects? Time to either pay up or shut up.

Direct to Consumer Drug Advertising: There's a Sucker Born Every Minute

Have you seen them? TV and print ads advocating the use of a new drug called Rexulti as something that can be used to augment an antidepressant when the antidepressant alone does not completely relieve all of your symptoms. These ads are only slightly different than ads you may have seen in the past for Abilify, which was also touted for the exact same indication.

As it turns out, both of these drugs are manufactured and distributed by the same companies: Otsuka Pharmacuetical Company and its marketing partner Bristol-Myers Squibb. And guess what? Abilify recently went generic (which means its original manufacturer has lost its patent protection and therefore its monopoly on the drug) under its chemical name, aripiprazole. 

Rexulti's chemical name seems oddly similar: brexpiprazole. Coincidence?

Well here are pictures of the chemical structures of the two compounds.

Remarkably similar, no? In fact, these drugs have effects on people that are nearly identical, have only slightly different side effects, and they both have the exact same indications. And of course they are not antidepressants at all as many of you have probably been led to believe, but antipsychotics: meant to treat delusions and hallucinations in schizophrenia, bipolar disorder (the real kind), and major depression with psychotic features.

(BTW, we've always known that any antipsychotic medication can augment an antidepressant in some patients. However, they have potentially very toxic side effects, and there are other, safer drugs which can also augment an antidepressant, such as lithium and a thyroid hormone named T3. I think benzodiazepine drugs such as clonazepam do as well, but drug companies are not about to do studies confirming that, because benzo's are so cheap and free of side effects).

There is one very big difference between Rexulti and Aripriprazole: the price. Generic Aripiprazole will be much, much cheaper. Why on earth would anyone ask for an expensive drug when a cheaper, nearly identical drug with the same effectiveness and nearly the same side effects is available?

Well of course they would not. Which is where the direct to consumer ads come in. The company wants to keep up its profits, so it pushes their new drug without any reference to their old one. And people are suckered into demanding it from their doctors. As someone once said, no one ever went broke underestimating the intelligence of the American people.

Now I can't prove that the company developed Rexulti in anticipation of losing its patient protection on Abilify, but the timing is a bit suspicious, wouldn't you say?

Drug companies have lots of tricks to extend their patent protections aside from just coming up with new conditions for which a drug is indicated, coming up with an extended release version of the same drug, or newly combining the drug with a second drug. 

Some drugs are converted to other drugs in the body which are in fact the compounds that have the desired effects (active metabolites). So after the parent drug goes off patent, they release the active metabolite as a "new" drug. Think Effexor vs. Prestique.

Some drug compounds come in two different versions which have the same chemical formula but different geometry - the two molecules (enantiomers) are mirror images of one another. One of the two versions may be effective for a given symptom while the other may have little effect. So drug companies first issue a mix of both versions (racemic mixtures), and when that drug goes off patent, they release a drug which is  the pure, active enantomier. Voila, new more expensive drug, new patent, and the clock keeping track of how long the company retains exclusive ownership of the drug starts to tick anew. Think: Celexa vs. Lexapro, and Prilosec vs. Nexium.

So if you pay attention to those ads, you will be being taken as sucker.

Able Was I Ere I Saw Abilify

You've all seen them. Screaming, direct-to-consumer advertisements for Abilify for use as an adjunct to antidepressant drugs in treating depression. "Only a third of depression responds to an antidepressant alone! Ask your doctor about Abilify!"

Just before these ads started, I predicted that as most antidepressants were going off patent, so that they would be available as cheaper generics instead of just as expensive brand-name medications, we would start to hear about how ineffective or problematic they were. I was right. Newspaper stories and even journal articles on this subject have become more and more frequent. We hear that antidepressants can increase suicidal ideation (misleading, but I won't cover this in this post), how they are completely ineffective for mild to moderate depression, and even how they don't work at all in true Bipolar patients who are in the depressive phase of their illness (Complete B.S. Also not covered here; I describe the hanky panky employed by the authors of a major journal article that came to this conclusion in my upcoming book).

Meanwhile, use of potentially highly toxic "atypical" antipsychotics like Abilify has skyrocketed. Many patients think Abilify is an antidepressant.

Now another atypical, Seroquel (quetiapine) has received an FDA approval for use as an adjunct to antidepressants. Of note is that its manufacturer, AstraZeneca, also tried to get it approved as a treatment for depression all by itself. Even the FDA, which is often in bed with the pharmaceutical companies, rejected this effort.

So what about that one-third business touted in the Abilify ads? It is a totally misleading figure. Notice ads use the word "depression" and not "major depressive episodes." This is important distinction because there are several types of depression. The two most prominent are dysthymia and major depression.

Dysthymia is a chronic mild form of depression that is usually caused by CCS (crappy childhood syndrome) and/or is reactive to ongoing interpersonal difficulties. It has never responded particularly well to antidepressants, but responds better to psychotherapy.

Major Depression, however, is a true inherited brain disorder. While it is often triggered by external stress, it can also occur spontaneously and can occur in otherwise well-adjusted, relatively happy individuals. It is usually self-limited, meaning it often goes away by itself after 6 to 18 months - only to return some time later.

It is characterized by what we used to refer to as "vegetative symptoms," or "diencephallic" symptoms: difficulty staying asleep, loss of appetite with weight loss, poor energy, loss of pleasure from activities that were previously enjoyed by the individual, poor concentration, and loss of sex drive. It is often also characterized by a complete and all-encompassing sense of utter doom, futility, and loss of joy. The more severe form is called "melancholia" and may also be characterized by feeling the worst when one first wakes up in the morning.

While dysthymia may have some of these symptoms, in major depression the symptoms are pervasive and persistent. This means that they are present almost all day almost every day for two weeks straight at the very minimum. People do not "come out of it" when they are forced to go out and do things, while dysthymic depression tends to lessen considerably when the patient is otherwise occupied or distracted.

Clearly there is overlap in the symptoms of the two types of depression, but the distinction is important. If your sample of patients includes both types - as in the more generic use of the word "depression" in the Abilify adds - then the percentage of people in your sample responding to the drugs will be lower. Many so called "empirical" randomized clinical trials of drugs do a terrible job of distinguishing the two types of depression due to their use of symptom checklists, as discussed in a previous post.

Another issue is that patients who do have major depression and do not respond to one antidepressant often do respond to a second or even a third agent. The one third figure in the ad also applies to patients who have only been tried on one agent.

Last, one can have both dysthymia and major depression. This is called double depression. If the antidepressant is given to this type of patient, the vegetative symptoms often go away, but the patient is still left with his chronic mild depression due to his crummy life. It is totally misleading to say that these patients only had a partial response to antidepressants, but these folk are also included in Abilify's one third figure.

The last point I would like to make is that we have always known than antipsychotics can augment antidepressants in some patients who don't respond to the antidepressants alone - the old ones do this too. However, an antipsychotic augmentation strategy is the last one a good psychiatrist will employ. (I am not referring here to depressed patients who actually become psychotic - hear voices, have delusions, etc.- when they go into a major depressive episode. In these patients, an antipsychotic combined with an antidepressant is the first choice). Lithium and thyroid hormone can also augment anti-depressants, and are far safer. Even one of the managed care panels I am on sent out a newsletter trying to make that point with psychiatrists!