The approval of the digital antipsychotic may open the door for more pharmaceutical company profits without evidence of benefits to patients.

The US Food and Drug Administration (FDA) recently approved a digital sensor-enabled form of the antipsychotic aripiprazole (brand name Abilify MyCite). While this move has garnered positive attention in the press, a new review of evidence submitted to the FDA scrutinizes these claims and cautions against premature celebration.

The researchers, led by Lisa Cosgrove at the University of Massachusetts Boston, conducted this thorough review and found that the trial evidence does not show that this technology improves treatment adherence. They also point to lack of data on remission and quality of life, conflicts of interest, and an unsubstantiated positive spin in reporting in both scientific journals and the press.

“The present study raises concerns about digital evergreening and approving a ‘novel’ drug/device that may not be either as efficacious or as safe but will cost significantly more,” Cosgrove and her co-authors write.

Antipsychotics are often the first line of treatment for schizophrenia and other psychotic disorders in the United States. They are now increasingly used for other mental disorders, and their off-label use to control behavioral problems in children has been heavily criticized.

While it is an industry-wide belief that long-term and continuous use of antipsychotics is the right treatment for those with schizophrenia, such claims have been scrutinized, especially after it was revealed that they could cause the proliferation of dopamine receptor sites and potentially exacerbate psychotic symptoms. Further, alternative approaches from across the world, from the Western Lapland in Finland to the Maori in New Zealand, have claimed patient recovery without the need for heavy drug use.

In light of these findings, the FDA’s approval of Abilify MyCite, a second-generation antipsychotic developed by Proteus and Otsuka, requires more in-depth examination. Psychiatric drugs are a booming industry, and aripiprazole was the most sold drug in the USA in 2014.

Recently, the pharmaceutical industry has been designing technological solutions to improve “treatment adherence.” Treatment adherence refers to patients taking their drugs as prescribed. Digital aripiprazole, the antipsychotic medication reviewed in this study, includes an ingestible digital sensor, which sends real-time information about medicine compliance when the drug-device combination mixes with gastric acids. Abilify MyCite is the first such technology to receive FDA approval and thus sets an important precedent for others to come.

The researchers first conducted a thorough review of the evidence submitted for to the FDA for the new drug-device approval, and then analyzed the spin in its reporting in scientific journals and the press. Previous research has found that media reports are not good at assessing the quality of findings, and studies show that this problem of biased reporting of research findings has persisted.

The review highlights the problems of “evergreening” in the pharmaceutical industry, which is a process whereby older drugs are slightly modified and patented as a new and better invention. It further steers attention to the problem of bias and spin in reporting in scientific journals and the press, and alerts us to the pitfalls of empty narratives of progress. It also raises concerns about the ethical ramifications of such a device and its adverse effects on the trust that grounds the therapeutic alliance.

“Patients with serious psychiatric illnesses often suffer from paranoia. An ingestible drug with a sensor brings surveillance to a new level,” they write. “It is reasonable to ask if there was a financial rather than a scientific impetus for choosing aripiprazole as the first-ever digital drug.”

The researchers of this review wanted to analyze the quality of evidence upon which the FDA based their approval and further understand how the launch of this new drug/device combination was conveyed in scientific literature and the broader media. They formulated a standard protocol which was then registered with the prospective international register of systematic reviews (PROSPERO). They included randomized controlled trials (RCT) made available to the FDA as evidence of efficacy, and in their absence, non-comparative studies.

All disorders for which aripiprazole has regulatory approval, for example, schizophrenia and bipolar one were included. Non-randomized and non-comparative studies on the use of digital aripiprazole, and prospective, double-blind RCTs comparing the digital version with non-digital form, other active comparators, or placebos were included. Apart from searching through the PubMed/Medline, Cochrane, Embase, and other databases, the researchers also asked the FDA, Otsuka, and Proteus for any unpublished trials.

The Web of Science database was accessed to look for scientific reporting of trial findings, and NexisUni was utilized to search for press releases and news stories about AbilifyMyCite. The definition of ‘spin’ was operationalized using previous research and conceptualized as an intentional or unintentional way of reporting experimental studies, which highlights the benefits while downplaying the adverse effects and failures.

The researchers found “no prospective, double-blind RCTs comparing digital aripiprazole with non-digital formulation, other active comparators or placebo.” The three included studies were with non-comparative uncontrolled cohorts, and no data was provided on relapse and remission. One of them was unpublished.

It appears that the submitted evidence only assessed whether patients were able to use the drug/device combination as was intended and did not demonstrate that the drug-device combination improved adherence.

“The lack of a single comparative trial means that there is no way to know whether digital aripiprazole improves treatment adherence, quality of life, psychiatric symptoms, or remission.”

The FDA’s clinical review letter summed up the research on digital aripiprazole as follows:

‘The most accurate statement regarding Abilify MyCite is that Abilify MyCite successfully tracks ingestion of aripiprazole with an embedded sensor.” “There was no evidence of superiority or non-inferiority compared with non-digital versions of aripiprazole, other comparators or placebo, and scarce data on safety.”

When examining for spin in the scientific literature, the researchers found that 71% of the 14 papers that reported on the two studies failed to address the lack of efficacy in trials, 93% did not acknowledge the scarcity of data on safety or that no comparator studies were a part of the experiments. Further, 57% had at least one author who maintained financial ties with either Otsuka or Proteus, and, in 43% of these cases, the authors were actively employed by these companies.

Of the 70 media reports that met the criteria for inclusion, 57% failed to comment of the lack of efficacy data, 93% left out information about the lack of safety data, and three-fourths portrayed the drug to have benefits that were unsupported by the evidence. Most stories mentioned an expert, and 39% of those experts had financial ties with the drug or device company.

These figures led the researchers to conclude that the level of spin in these reports had to be industry controlled. They also make the point that spin in the scientific and media literature becomes a public health concern because it will guide prescribing practices of doctors and healthcare choices of patients and their families. The authors express concern that these practices might be leading people away from better treatments.

This review comes at a time when more organizations are recognizing the limitations of antipsychotic drugs more generally. The 2015 British Psychological Society’s report ‘Understanding psychosis and schizophrenia’ highlighted the inconsistencies in the evidence of efficacy and adverse side-effects of antipsychotics. A recent analysis of 16 RCTs showed that only one-third of the patients on antipsychotics showed improvement in the short term.

The authors of this review suggest that the approval of digital aripiprazole appears to be a first attempt at “digital evergreening,” increasing the profitability of drugs that are going off-patent by seeking approval for technologically modified versions of the drug.

This research raises additional questions about how a drug that costs USD 1700/month, as opposed to its older version that costs only USD 20/month, is supposed to increase adherence and compliance once it is on the market.

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Cosgrove, L., Cristea I.A., Shaughnessy, A.F., Mintez, B., & Naudet, F. (2019). Digital aripiprazole or digital evergreening? A systematic review of the evidence and its dissemination in the scientific literature and the media. BMJ: Evidence-Based Medicine. Published Online First: 18 July 2019. DOI: 10.1136/bmjebm-2019-111204 (Link)