FDA Defends Decision to Approve Digital Aripiprazole

In a perspective piece published recently in the Journal of Clinical Psychiatry, members of the Psychiatry Products division at the U.S. FDA’s Center for Drug Evaluation and Research respond to critiques of its approval of digital aripiprazole late last year. The authors — one of whom is the division’s director, Mitchell V. Mathis — state that discussion surrounding the drug’s approval has been “obscured by sensationalism.”

“We hope that this piece facilitates a more rational and measured dialogue surrounding the product’s actual capabilities, FDA’s decision to approve the product, and any ethical concerns raised by the product,” the authors write.

In November 2017, the U.S. FDA approved digital aripiprazole (brand name Abilify MyCite). The drug’s maker, Otsuka Pharmaceutical, and its digital technology collaborator, Proteus Digital Health, first filed a new drug application (NDA) for digital aripiprazole with the FDA in September 2015. This NDA was rejected in April 2016, at which time the FDA requested further information, including data on the drug’s functioning under real-life conditions, and additional human factors studies. Proteus/Otsuka resubmitted their NDA to the FDA, along with the requested information, on May  7.

Digital aripiprazole’s clearance is notable in that it represents the first approval of a drug with a “digital ingestion tracking system” in the U.S. Equally remarkable is the fact that such technology was first approved for use in an antipsychotic drug. As Dr. Paul Applebaum, Director of Law, Ethics and Psychiatry at Columbia University told the New York Times, “You would think that, whether in psychiatry or general medicine, drugs for almost any other condition would be a better place to start [with digital technology] than a drug for schizophrenia.” It is also worth noting that Otsuka’s U.S. patent for aripiprazole expired in April 2015, not long before the company submitted its first NDA for the digital version of the drug.

Public reactions following the drug’s approval ranged from highly critical to admiring. The article’s authors hone in on the critical responses, however — including a perspective piece in the New England Journal of Medicine (NEJM) titled “Swallowing a Spy” — which they characterize as sensational.

“Recent publications expressed a wide range of concerns regarding the product, such as its potential to infringe on patient privacy and autonomy, create an adversarial dynamic between clinician and patient, be used in medicolegal situations, or affect insurance coverage,” the authors write.

The authors make a case for the FDA’s approval of digital aripiprazole by emphasizing the fact that their review of the drug and its related components (its internal sensor, the skin patch with which the sensor communicates, a mobile app, and web portal) was based on the results of human factors studies that examined whether patients “could use the product as intended,” as well as a safety assessment of adding a digital sensor to the drug. They state that the FDA focused on the extent to which the digital version might “interfere with prescribed… use,” as well as on identifying and reducing error in order to enhance “simplicity” of use.

Interestingly, one of the authors’ arguments in support of the drug’s approval is that “no data were collected during the product’s development suggesting that the product impacts adherence or influences patient behavior.” It is curious that a drug depicted as a boon to patient adherence was approved without review of its effects on adherence (or patient outcomes).

The authors also maintain that the FDA and Otsuka share the public’s concerns about “the potential ethical issues of monitoring drug ingestion,” and that in fact, the FDA worked closely with Otsuka to deal with some of these issues. They state, for example, that the requirement that patients “actively choose whether to share their information with clinicians and caregivers” was added based on recommendations from a team of bioethicists with whom Otsuka consulted regarding patient privacy issues.

Lastly, the authors assert that some of the public’s fears are based on “inaccurate assumptions” about the drug — for example, they state that the drug sensor’s Bluetooth signal is encrypted and cannot be intercepted, and that the patch does not contain a GPS transmitter and thus cannot act as a “spy,” as the NEJM piece’s title implies.

As they end the article, the authors write:

“The FDA shares the concerns raised by the public regarding potential product use in medicolegal situations and potential use by insurance companies in decisions to pay for care. Although it is outside the FDA’s regulatory and enforcement mandate, a national discussion could help determine if more efforts are needed to protect patient data from digital medicines and applications.”

In their closing sentence following this call for discussion, the authors take aim at their critics one last time, writing, “Our hope is that the necessary discussion rests on rational facts rather than emotional reactions to this new technology.”

 

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Lee, D. J., Farchione, T. R., Mathis, M. V., Muniz, J., & Muoio, B. M. (2018). US Food and Drug Administration’s Approval of Aripiprazole Tablets With Sensor: Our Perspective. The Journal of clinical psychiatry, (3). (Link)