Tag: Otsuka

07/7/20

Rebranding Problems With Abilify

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Abilify had a profitable and expansive run for Otsuka Pharmaceuticals since it was approved by the FDA for the treatment of schizophrenia in 2002. The FDA then expanded its treatment use to include bipolar disorder in 2005, irritability associated with autistic disorder in 2009 and Tourette’s disorder in 2014. It was also approved by the FDA as an add-on with antidepressants for treatment-resistant depression in 2007. Abilify is used off-label to treat insomnia, delusional disorders and anxiety. In 2013 this enlarged treatment market brought in $7.8 billion in global sales for Otsuka. FiercePharma noted the end of Abilify’s patent exclusivity in April of 2015 left a big revenue hole for Otsuka and Bristol-Myers Squibb, who marketed and promoted it in the U.S. But instead of quietly surrendering to the generic market, Abilify (aripiprazole) was rebranded into three new drug applications with the FDA: Abilify Maintena, Abilify MyCite and Aristada.

Abilify Maintena was approved as an extended-release once-monthly depot shot of aripiprazole for the treatment of schizophrenia in March of 2013. Otsuka said it was a new treatment option to address the need for relapse prevention in patients with schizophrenia. It was the first dopamine D2 partial agonist approved as a once-monthly injection. In July of 2017 its approved use was extended to include maintenance monotherapy treatment of Bipolar I Disorder in adults.

Abilify MyCite has an ingestible sensor embedded in aripiprazole tablets that records that the medication was taken. Approved by the FDA in November of 2017, it is the first drug in the U.S. with a digital tracking system. This was a second try for Otsuka, as the FDA initially failed to approve Abilify MyCite in April of 2016, saying it needs more information about the product’s use, and further human factor investigations. “The goal of human factors testing is to evaluate use-related risks and confirm that users can use the device safely and effectively.”

The pill’s sensor sends a message to a wearable patch that in turn transmits the information to a mobile application that allows the patient to track the ingestion of the medication on their smart phone. Patients can give their caregivers and doctors permission to access the information through a web-based portal. Mitchell Mathis, the director of the Division of Psychiatry Products in the FDA’s Center for Drug Evaluation and Research, said: “Being able to track ingestion of medications prescribed for mental illness may be useful to some patients.” Actually, the digital tracking capability of Abilify MyCite is a selling point for psychiatrists concerned with patient adherence. Getting people who are prescribed antipsychotics to stay on their drugs can be a challenge. See “Doublespeak With Abilify MyCite” for more information on this.

Aristada (aripiprazole lauroxil) was approved by the FDA as an extended release injectable form of aripiprazole to treat adults with schizophrenia on October 5, 2015. It is a prodrug, meaning it is a biologically inactive compound that is metabolized into a pharmacologically active drug within the body. Unlike Abilify MyCite and Abilify Maintena, its parent company is Alkermes, not Otsuka. Similar to the price of another Alkermes drug, Vivitrol, Aristada costs about $1,500 per month.

According to ProPublica, Alkermes has successfully marketed Vivitrol to the criminal-justice system, emphasizing its use in drug courts. The Atlantic wrote how the relationship between drug companies and the criminal-justice system has expanded in “Marketing Psychiatric Drugs to Jailers and Judges,” as drug companies realized the potential market behind bars. Free samples are distributed to detention facilities; jail and prison doctors attend free luncheons to learn about medications. Payments are made to doctors and criminal-justice employees, such as sheriffs and drug-court judges, to promote certain medications.

Alkermes and other drug companies have marketed not only to jailers but to judges as well. Earlier this year, at a conference for drug- and mental-health-court professionals in Maryland, Alkermes sponsored a closed-door promotional session about using long-acting shots in a court setting. Featured at the session was Richard Jackson, a former psychiatrist at the Women’s Huron Valley Correctional Facility in Ypsilanti, Michigan, and Ernie Glenn, a magistrate in Bexar County, Texas, who had helped defendants in his court get access to long-acting antipsychotic shots. While Glenn had received no payments from Alkermes, the company had paid Jackson more than $250,000 between 2015 and 2018 for speeches, travel and lodging, and meals, according to the Centers for Medicare and Medicaid Services’s open payments database. (Jackson also received $252,608 in payments from Otsuka from 2015 to 2018, and said he has continued receiving payments from drug companies in 2019; it wasn’t immediately clear whether Alkermes was one of them.) The conference program, as in the conference in Nashville, directed people to learn about Aristada at Alkermes’s exhibit booth.

The director of the ACLU’s National Prison Project, David Fathi, expressed concern that the marketing has been aimed at judges and prison officials instead of the incarcerated people themselves. A ProPublica analysis found that doctors who accepted money from pharmaceutical companies were more likely to prescribe those companies’ medications. Incarcerated patients may not feel they have a real ability to choose. In cases where patients choose to take a psychiatric drug, it may be a choice made under duress. “If you know you can be forcibly medicated, can you really make a free and noncoercive choice about medication?”

The makers of drugs like Abilify Maintena and Aristada are banking on long-acting injections as the future of schizophrenia treatment. A 2015 study found that patients who were given injections of long-acting risperidone were more likely to comply with treatment and led to better long-term outcomes. The lead author of the study, Kenneth Subotnik, said, “We know that not taking antipsychotic medication is the single greatest modifiable risk factor for psychotic symptoms returning.” Yet as Max Blau noted in The Atlantic, there is a possibility the side effects will last longer than with the pill form. The most common side effect with Aristada is akathisia (a feeling of inner restlessness and inability to stay still). Other side effects include: Neuroleptic Malignant Syndrome, Tardive Dyskinesia, Diabetes, weight gain and seizures.

In 2016 the FDA published a Safety Communication about impulse-control problems associated with aripiprazole (Abilify, Abilify Maintena and Aristada). They warned of reports of compulsive, uncontrollable urges to gamble, binge eat, shop, and have sex with the use of aripiprazole. The impulse-control problems were rare, but may result in harm to the patient or others. “These uncontrollable urges were reported to have stopped when the medicine was discontinued or the dose was reduced.”

Although pathological gambling is listed as a reported side effect in the current aripiprazole drug labels, this description does not entirely reflect the nature of the impulse-control risk that we identified. In addition, we have become aware of other compulsive behaviors associated with aripiprazole, such as compulsive eating, shopping, and sexual actions. These compulsive behaviors can affect anyone who is taking the medicine. As a result, we are adding new warnings about all of these compulsive behaviors to the drug labels and the patient Medication Guides for all aripiprazole products.

A search of the FDA Adverse Event Reporting System (FAERS) database and the medical literature identified 184 case reports with an association between arpiprazole use and impulse-control problems. Pathological gambling was the most common with 164 cases, “but other compulsive behaviors including compulsive eating, spending or shopping, and sexual behaviors were also reported.” None of the patients had a history of pathological gambling, compulsive sexual behavior, binge eating or compulsive shopping before starting arpiprazole treatment. None of the patients had concurrent substance abuse disorder or symptoms of mania at the time of developing the impulse-control problems.

Despite the problems with Abilify, Otsuka and Alkermes have repackaged it with digital tracking technology and a slow-release, depot injection and then promoted these products as improving treatment adherence, reducing the risk of overdose and improving relapse prevention and reducing rehospitalization rates.

Pharmaceutical companies seem to disregard the problems with antipsychotics like Abilify while they pursue their potential profits. Bristol-Myers Squibb paid $515 million to settle charges it illegally marketed Abilify for children and the elderly. See “Broken Promises with Ability” for more information on this issue. Persistence in addressing problems with nonadherence seems to ignore the larger issue of adverse side effects antipsychotics. See “Abilify in Denial,” “Pick Your Poison: Diabetes and Psych Meds,” “Downward Spiral of Antipsychotics,” “Pros and Cons of Antipsychotics” and “Biomedical Big Brother” for more on concerns with adherence and adverse side effects with Abilify and other antipsychotics. The rebranding Abilify as Abilify Maintena, Abilify MyCite and Aristada does not appear to address the concerns with aripiprazole and other antipsychotics.

10/1/19

Doublespeak with Abilify MyCite

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Abilify MyCite was approved by the FDA in November of 2017, but it isn’t being used much. At least one expert said that was because the antipsychotic pill contains a tracking chip the size of a grain of sand that confirms whether or not an individual actually takes the medication. A psychiatrist from Columbia University said people with psychotic disorders often struggle with some degree of paranoia, believing that outside forces are trying to monitor and control them. “The idea that we’re giving this group of patients a pill that, in fact, transmits info about them from inside their body to the people that are involved in their treatment almost seems like a confirmation of the worst paranoias of the worst patients.”

The Daily Mail reported medication nonadherence is a particular problem for doctors treating schizophrenic patients. Otsuka Pharmaceuticals replied that people who are afraid of their medicine, are not likely to be given Abilify MyCite. The medication is supposedly designed for people who ask for it as a way of improving their mental health. A spokesperson for Otsuka said, “It’s really about patients who want to improve their treatment goals. If they have any concerns, it’s probably not the right solution for them.”

Really? A medication that tracks when you have taken your medication is for motivated clients who want to improve their treatment goals, meaning to be more compliant with taking Abilify MyCite? What about patients who seek to minimize or eliminate the adverse side effects from the medication, including weight gain, agitation, unusual urges, akathisia (a feeling of inner restlessness), and more, including thoughts about suicide?

An individual who participated in the clinical trial for Abilify MyCite and who was compliant with his medication hasn’t had paranoid thoughts in a long time. He said that if he had an opportunity to take ‘digital Abilify,’ “I wouldn’t take it.” See, “Biomedical ‘Big Brother’” for more on the adverse side effects of Abilify and other antipsychotics.

The metallic tracking chip contains copper, magnesium and silicon sends a signal to a patch worn on the patient’s arm. It is activated when it becomes immersed in stomach juices, completes a circuit and generates a small electric charge. “The patch then synchronises with a mobile app on the patient’s smartphone or tablet, and sends data to their doctor over the internet to show whether the pill has been taken.” Ingestion is recorded between 30 and 120 minutes after the patient swallows the drug.

The BMJ Evidence-Based Medicine journal published research by Lisa Cosgrove and others that analyzed evidence submitted to the FDA for approval of digital arpiprazole (Abilify MyCite). This was the first such drug-device combination to receive FDA approval, and it “sets a precedent for how technology-enhanced products will be evaluated before marketing.” The authors also said it was important to examine how the clinical trial evidence supporting this approval was represented in news stories and reports. Recent research had documented the presence of ‘spin’ (distorted interpretation of trial evidence) when the results of clinical trials are reported in journals and news reports. This spin gives the impression of there being a greater benefit to the drug than is warranted by the data in both media reports and the scientific literature.

Their review of the clinical trial data submitted to the FDA for the approval of Abilify MyCite revealed the data were limited to trials that “simple assessed whether patients could use the product as intended.” There was no evidence of superiority or non-inferiority compared with non-digital versions of arpiprazole, other antipsychotics or placebo. In the FDA’s clinical review letter, one simulated trial (where the participants did not ingest the drug, but simply placed it in a container to simulate ingestion) provided no additional data about adherence or regarding transmission times. “Considering these limitations, the most accurate statement regarding Abilify Mycite’s capabilities is that ‘Abilify MyCite successfully tracks ingestion of aripiprazole with embedded sensor.’” The lack of even a single comparative trial was said to mean “there is no way to know whether digital aripiprazole improves treatment adherence, quality of life, psychiatric symptoms or remission.”

Patients with serious psychiatric illnesses often suffer from paranoia. An ingestible drug with a sensor brings surveillance to a new level, and the potential negative effects on this patient population merit careful consideration. The potential harm of the surveillance aspect of this technology to the therapeutic alliance and to patients has not been adequately assessed. Thus, it is reasonable to ask if there was a financial rather than a scientific impetus for choosing aripiprazole as the first-ever digital drug.

Before it went off patent in 2015, Abilify made over $7.5 billion. It was the best-selling drug in the US for 2014 with an average cost of $800 for a month’s supply. After the patent expired, sales of arpiprazole dropped to $600 million in 2015, which was when Otsuka and Proteus first submitted an application for market approval for digital arpiprazole. The cost for a month’s supply of the Abilify MyCite is $1,650. In comparison, the generic oral version of arpiprazole costs less than $20 per month. In order to avoid this dramatic loss in revenue, pharmaceutical companies have developed several different schemes.

Drug manufacturers have developed a number of strategies to extend market monopoly after a blockbuster drug (defined as over US $1 billion in yearly revenue) goes off-patent. These are known as ‘evergreening’ strategies, with highly questionable benefit to patients. Evergreening involves the patenting of a slight modification (eg, subtle changes to the medicine’s structure) of an existing drug as a new invention. For the manufacturer, the result is that their product is considered as a new chemical entity that qualifies for market exclusivity (ie, no generic version is available). The possibilities afforded by sensor-based technology make room for a new dimension of practice, an evergreening 2.0. That is, ‘digital evergreening’ may develop as a means whereby manufacturers can gain market exclusivity for a generically available medicine (such as aripiprazole) by combining it with a monitoring technology.

Cosgrove et al added to the growing body of literature documenting the extent and effects of spin in the scientific literature and in media reports by noting the affiliation of authors with the parent pharmaceutical company, Otsuka. Researchers searched the Web of Science to identify all publications in English citing the clinical trials for arpiprazole. Then they reviewed the database NexisUni for all news stories and press releases about the approval of Ability MyCite from January 1, 2015 to January 23, 2018. The researchers defined spin as ‘a specific way of reporting, intentional or not, to highlight that the beneficial effect of the experimental treatment [digital arpiprazole] in terms of efficacy or safety is greater than that shown by the results.’ They identified 70 articles and two press releases which met their inclusion criteria for their study.

Of these, 57% (40/70) did not acknowledge the lack of efficacy data from RCTs [randomly controlled trials], 93% (65/70) did not report on the scarcity of safety data, and no story reported on the absence of a non-digital comparator in clinical trials. Three-fourths (52/70) conveyed an impression of benefit without mentioning the lack of research to support that impression. Most of the news stories (77%, 54/70) cited an expert, and of those 39% (21/54) cited experts who had financial ties to either Otsuka or Proteus.

Not only were some authors of the published studies Otsuka employees, there was evidence of ghost writing in the dissemination of the trial data: “’Editorial assistance was provided by the medical communications company C4 MedSolutions LLC (Yardley, PA, USA), a CHC Group company’, with Otsuka funding.” Both of the positive clinical trial studies were published in the journal Neuropsychiatric Disease and Treatment, whose editor is described as an ‘independent pharma consultant [who] advises and consults worldwide to several pharmaceutical and venture capital organizations’.

Our case study reveals that the approval of this digital drug for marketing in the USA was granted on very limited data. Both the scientific literature and the popular news reports conveyed an unsupported impression of benefit. As a result, the general public and healthcare professionals may be making medical decisions based on industry-friendly, but not necessarily scientifically accurate, information about the efficacy and safety of this new product. Also, if patients are incentivised to take the digital version (eg, by being offered lower copayments or by being offered outpatient treatment—rather than forced inpatient treatment), the line between incentivising and coercion will be blurred. We recommend that other regulatory bodies (eg, the European Medicines Agency) take note of the findings in the current study as well as the medicolegal issues that emerge with the use of digital drugs.

The authors suggested the general public and healthcare professionals may be making medical decisions based on industry-friendly, but scientifically inaccurate, information about the safety and efficacy of Abilify MyCite.

Please do not let the allure of a new pharmaceutical technology seduce you. This doublespeak about how digital arpiprazole will improve your treatment goals, is simple marketing rhetoric. Also do the math, one month of Abilify My Cite is $1,650 and a generic pill will cost you less than $20 per month. The savings leaves you enough to hire a skilled mental health coach and have an even better chance of improving your treatment goals.

01/16/18

Biomedical ‘Big Brother’

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The FDA approved a new pharmaceutical product that combines technology and medication: Abilify MyCite, “the first drug in the U.S. with a digital tracking system.” The pill contains a sensor that tracks whether or not a patient has taken their medication. The pill’s sensor sends a message to a wearable patch, which then transmits the information to a mobile app, enabling the patient to track their ingestion of the medication on their smart phone. Patients can also “consent” for others to access the information through a web-based portal. As more than one person observed, the old hide-the-pill-under-your-tongue trick doesn’t work with the new technology.

Science Alert said the sensor, called an Ingestible Event Marker (IEM) is about the size of a grain of sand. It’s made of safe levels of copper, magnesium and silicon.  When the pill and IEM are swallowed, stomach acid activates the sensor, which sends an electrical signal to the patch. “The patch records the date and time the pill was ingested, and relays this information to a smartphone app.”

A New York Times article on the approval, “First Digital Pill Approved to Worries About Biomedical ‘Big Brother,’ noted where experts estimate nonadherence or noncompliance with medications costs about $100 billion per year. Much of that cost is said to be due to patients getting sicker and needing additional treatment or hospitalization. Dr. William Shrank said: “When patients don’t adhere to lifestyle or medications that are prescribed for them, there are really substantive consequences that are bad for the patient and very costly.”  Ameet Sarpatwari said while the pill has the potential to improve public health, “If used improperly, it could foster more mistrust instead of trust.”

The IEM could be used to monitor medication compliance with post-surgical patients or for individuals required to use a digital medication as a condition for release from psychiatric facilities. “Asked whether it might be used in circumstances like probation or involuntary hospitalization, Otsuka officials said that was not their intention or expectation, partly because Abilify MyCite only works if patients want to use the patch and app.”

Nevertheless, Abilify was said to be an unusual choice for the first sensor-embedded medication. As an antipsychotic or neuroleptic, Abilify is approved for treating schizophrenia, bipolar disorder and as an adjunct for major depression. Some of these individuals may have delusions or become paranoid about their doctor or what the doctor intends. How receptive will they be to using a system that monitors their behavior and then potentially signals their doctor?

Dr Paul Applebaum of Columbia University’s psychiatric department said: “You would think that, whether in psychiatry or general medicine, drugs for almost any other condition would be a better place to start than a drug for schizophrenia.” Dr. Jeffrey Lieberman said many psychiatrists will likely want to try Abilify MyCite, but it has not yet been shown to improve medication adherence. “There’s an irony in it being given to people with mental disorders that can include delusions. It’s like a biomedical Big Brother.”

Many patients aren’t compliant with neuroleptics because of the side effects. These side effects can include: weight gain, diabetes, pancreatitis, gynecomastia (abnormal breast tissue growth), hypotension, akathesia (a feeling of inner restlessness), cardiac arrhythmias, seizures, sexual dysfuntion, tardive dyskinesia, anticholinergic effects (constipation, dry mouth, blurred vision, urinary retention and at times cognitive impairment). For more on the adverse effects with Abilify and other antipsychotics, see (“Abilify in Denial,” “Broken Promises with Abilify,” “Antipsychotic Big Bang,” “Wolves in Sheep’s Clothing,” and “Downward Spiral of Antipsychotics”).

Otsuka, the pharmaceutical company with the patent rights to distribute Abilify MyCite, has not set a price for the drug yet. Although Abilify alone is now off patent, Otsuka will have a new patent time frame for Abilify MyCite. Here may be the reason that Otsuka invested so much capital into Proteus Digital Health, the California company that developed the IEM technology. Profits from Abilify will continue to be made by Otsuka with the newly patented formula.

The labeling information for Abilify MyCite notes the ability of the product to improve patient compliance hasn’t been demonstrated yet. Additionally, it should not be used to track drug ingestion in “real-time” as detection may be delayed or may not occur. Robert McQuade, an executive vice president for Otsuka, confirmed the company does not have current data to say it will improve adherence. But they will likely study that after sales begin.

How patients themselves view Abilify MyCite is mixed. One person who takes Abilify for schizoaffective disorder participated in the clinical trial for Abilify MyCite. Compliant with his medication, he doesn’t think he needs digital monitoring. He hasn’t had paranoid thoughts for a long time. If he had a chance to take ‘digital Abilify,’ “I wouldn’t take it.” Another person who sometimes will stop taking his medication thought the idea behind Abilify MyCite was “overbearing.”

A third person reported his use of Abilify for 16 years to prevent recurrence of episodes of paranoia. He thought some people might use the new drug to avoid the injections of Abilify if they were noncompliant with their pills. But he said he would not use the digital Abilify. He didn’t want an electrical signal, strong enough for his doctor to read, coming out of his body. “But right now, it’s either you take your pills when you’re unsupervised, or you get a shot in the butt. Who wants to get shot in the butt?”

The above are the milder responses to the FDA’s news about Abilify MyCite. What follows are the thoughts of Michael Cornwall. He is a Jungian/Langian psychotherapist who specializes in providing psychotherapy for people in psychotic states (which he refers to as ‘extreme states’) without the use of medication. He has his own website and commented there how digital Abilify “can now automatically send signals to your doctor, family members and the courts, to show them when you comply and swallow the pill.”  Not one to pull punches, his article on Mad in America was titled: “The Orwellian New Digital Abilify Will Subjugate Vulnerable People across the US.”

He predicted there will be tragic personal injury coming from the use of Abilify MyCite to control people’s dosing compliance, “something that I believe would even make dystopian visionaries George Orwell and Aldous Huxley shudder.” Singling out California as an example, he said the state was ripe for an even more oppressive mental health “best practice” service model and standard of care for people in “extreme states” who are receiving forced in-home treatment. Like California, most states now have some version of in-home compulsory court-ordered medication treatment. Research has shown that 74% of people prescribed antipsychotic medications who are in extreme state stop taking their medications by 18 months. Pro-medication people find this unacceptable.

Tremendous pressure, I believe, will also be exerted by mental health care providers for people to voluntarily accept taking the new digital Abilify. I see that pressure being put on people seeking discharge from in-patient units, and pressure will be put on people in extreme states or with such histories, who will be involved anywhere on the spectrum of community mental health services and in jails and prisons too. In both mental health and penal systems, medication compliance, not providing humanistic care, is clearly the highest priority.

Yet there is reliable evidence suggesting long-term use of antipsychotics like Abilify is not necessary. Robert Whitaker wrote a paper, “The Case Against Antipsychotics” where he critiqued the research cited by psychiatry as evidence for long-term use of antipsychotics. Additionally, he presented a history that tells how antipsychotics, on the whole have actually worsened long-term outcomes. Whitaker described a long-term study by Harrow that followed an original group of patients for 20 years (and counting) after their initial hospitalization for schizophrenia.

Harrow discovered that patients not taking medication regularly recovered from their psychotic symptoms over time. Once this occurred, “they had very low relapse rates.” Concurrently, patients who remained on medication, regularly remained psychotic—even those who did recover relapsed often. “Harrow’s results provide a clear picture of how antipsychotics worsen psychotic symptoms over the long term.” Medicated patients did worse on every domain that was measured. They were more likely to be anxious; they had worse cognitive functioning; they were less likely to be working; and they had worse global outcomes. Also see “Worse Results With Psych Meds” for more on the Harrow study.

Returning to the thoughts of Michael Cornwall, he said treatment with Abilify MyCite was “a morally bankrupt approach that ensures a soul-numbing, hi-tech compliance-monitoring device be in the digestive tract of every DSM-labeled person in an extreme state, in order to keep them in line.” It places the controlling impulse of psychiatric care “within our very guts.” To the uninitiated, Cornwall’s rhetoric may sound extreme. But I suspect that for individuals wanting to cope with their “extreme state” without medication or struggling to live with the side effects from antipsychotics, it is spot on. Clearly as the technology behind the IEM improves, it will be used to “convince” individuals that using a digital antipsychotic like Abilify MyCite is in their best interests, particularly if they want to be discharged from a psychiatric facility, or to continue living outside of one. The first Biomedical Big Brother has arrived.