FDA Approval of First Digital Pill Based on 'Weak Evidence'

The 2017 US Food and Drug Administration (FDA) approval of a digital version of the second-generation antipsychotic aripiprazole (Abilify MyCite, Otsuka Pharmaceutical/Proteus Digital Health) that includes an ingestible digital tracker was based on "weak" evidence and conveyed an "unsupported" impression of benefit, new research suggests.

Lisa Cosgrove, PhD, lead investigator of the systematic evidence review, told Medscape Medical News the case of digital aripiprazole "illustrates the ways in which sensor-based technology can facilitate 'evergreening' – the patenting of older, off-patent drugs with a sensor as a new invention to regain, or maintain, market exclusivity."

The research was published online July 19 in BMJ Evidence-Based Medicine.

Setting a Precedent

In 2014, aripiprazole was the best-selling drug in the US. With an average cost of $800 US for a month's supply, the drug generated over $7.5 billion in sales the year before it went off patent in 2015, the authors note.

After the patent expired, sales of aripiprazole dropped to $600 million. It was then that the application for market approval of digital aripiprazole was first submitted to FDA.

It was proposed that the digital version of the drug, which costs almost $1700 per month, might improve medication adherence. In comparison, the cost of the generic oral version of the drug costs less than $20 per month.

"This first approval of a drug/device combination sets a precedent for how technology-enhanced products will be evaluated before marketing," said Cosgrove, clinical psychologist and professor at the University of Massachusetts Boston.

The investigators conducted a systematic review to examine the evidence supporting the FDA's approval of digital aripiprazole. They also looked at dissemination of the evidence in the scientific literature and looked for "evidence of spin" in press releases and related news reports.

They found the data submitted to the FDA were limited to trials that only assessed whether patients could use the product as intended.

In other words, said Cosgrove, there were no prospective, double-blind, randomized controlled trials comparing digital aripiprazole with non-digital formulations of the second-generation antipsychotic, or other active comparators or placebo.

None of the studies provided data on remission, quality of life, or any efficacy outcome, and showed no evidence of better adherence with digital aripiprazole compared with the non-digital version.

The researchers also identified 14 scientific papers that cited the trials as well as 70 news stories. They concluded that nearly 80% (11/14) of the scientific papers and three quarters (52/70) of the news stories were misleading with regard to potential benefit.

Cosgrove said there was also "clear evidence of ghost writing in the dissemination of the trial data in the scientific literature. This finding adds to the concern about high-tech medical companies operating in a climate of 'stealth-research,' where their products are sheltered from the scrutiny of other scientists."

FDA, Companies Respond

Medscape Medical News reached out to the FDA for comment on the analysis.

In an email, FDA press officer Sandy Walsh said, "In general, the FDA does not comment on specific studies or reports, but evaluates them as part of the body of evidence to further our understanding about a particular issue and assist in our mission to protect the public health."

Walsh noted the FDA’s decision and reasoning in approving the drug is detailed in a summary review document and separate clinical review document.

Walsh also pointed out that the "Limitations of Use" on the drug label for digital aripiprazole states: "The ability of Abilify MyCite to improve patient compliance or modify aripiprazole dosage has not been established."

In a statement sent to Medscape Medical News, Otsuka Pharmaceutical said the company never requested a claim for "improved adherence," when requesting FDA approval for aripiprazole tablets with digital sensor.

This technology is designed to track drug ingestion, which can provide "objective data with regard to patient medication-taking behaviors and other activities," the company said. "That data can enable clinicians to make more informed therapeutic decisions. Further, it can allow patients to take a more active role in their treatment plan and personal well-being," it added.

In a separate statement, Proteus Digital Health said the safety and performance of the Proteus ingestible event marker was "extensively evaluated in more than 115 clinical studies and approved by the FDA in 2012 through a de novo process.

"Proteus strongly believes in the ability of digital medicine to provide valuable insights into patient medication-taking behaviors and overcome health disparities in the most vulnerable patient populations, including those with mental health disorders, infectious diseases, cancer, and other conditions," the company said.

Adherence Studies Not Done

As reported by Medscape Medical News, the FDA approved digital aripiprazole in November 2017. Commenting at that time, Jeffrey Lieberman, MD, professor and chair of psychiatry at Columbia University and psychiatrist-in-chief at NewYork-Presbyterian Hospital, New York City, told Medscape Medical News he would "categorically say this innovation of marrying this technology to pharmacologic therapeutics is good and positive."

However, he noted, "there are a lot of questions in terms of what added value it will provide to patients and healthcare providers and whether it's worth whatever the incremental cost may be. That will depend on what the evidence ultimately shows in terms of improving adherence and reducing the consequences of treatment nonadherence. But we don't know how effective in that regard this will be because those studies have not been done."

The study had no specific funding. The authors have disclosed no relevant financial relationships.

BMJ Evid Based Med. Published online July 19, 2019. Full text

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