FDA Approval of Medication With a Digital Monitoring System: Major Breakthrough or "Brave New World"?
There is a certain irony in the fact that the revolution of sensor-tracked drugs has begun with a drug for conditions that commonly involve paranoia and poor insight.
The answer to whether there's a way to track whether and when a patient took their medication is no longer simply, "There's an app for that," but now "There's a drug for that." At least, there is for patients taking aripiprazole, a drug primarily used to treat schizophrenia, bipolar disorder, and adjunctively, major depressive disorder.
The next question researchers, regulators, and physicians must now ask is, "Are there ethics for that?" And that's exactly what they're doing.
The US Food and Drug Administration's (FDA's) approval of Abilify (aripiprazole) MyCite in November 2017 has prompted a host of questions about how a pharmaceutical's benefits and, especially, risks might extend beyond biological effects into affecting physician-patient relationships, caregiver and family interactions, and legal and insurance concerns.1
Abilify MyCite adds a digital sensor to the medication aripiprazole. The sensor, an ingestible event marker, is activated by contact with stomach acids and transmits a signal to a skin patch the patient wears. The patch transmits the signal via Bluetooth to an app in the patient's cell phone that records when the medication was taken and allows patient input of mood, activity, and rest quality. The patient can elect to share the data on when they took the drug with their physician and up to 4 other people, although they can also block any of these individuals at any time.
As several have pointed out, there's a certain irony in the fact that the revolution of sensor-tracked drugs has begun with a drug for conditions that commonly involve paranoia and poor insight.2
"By focusing on psychotic disorders, particularly schizophrenia, a disorder where we know there are substantial problems with patients' adherence regimens, the message appears to be, if you have a patient who isn't taking their medication the way you prescribe, this will ensure they will do so," Paul Applebaum, MD, director of law, ethics and psychiatry at Columbia University, New York City, told Psychiatry Advisor. "But patients don't take medications for all kinds of reasons," such as disliking adverse effects, disliking therapeutic effects (such as reduced mania in bipolar patients), and refusal to accept one's diagnosis or need for treatment.
"Those are major problems which are not likely to be solved with this medication because those patients, whether because of side effects or therapeutic effects or lack of insight, are simply not likely to accept it," Dr Applebaum said. Although it could work for some people prescribed to take aripiprazole, it's likely a small, distinct subgroup, he said.
No Data Regarding Medication Adherence
Abilify McCite was approved based only on whether patients "could use the product as intended, in addition to the safety evaluation of adding the device to the drug," wrote FDA physicians in a commentary.1 The FDA neither received nor reviewed any evidence on whether the drug affects adherence, even though discussions of adherence have dominated articles about the drug.1,2,3
"[F]or a [digital health feedback system] to improve adherence, patients with a propensity toward nonadherence would have to use it," wrote Lisa Rosenbaum, MD, a cardiologist at Brigham and Women's Hospital in Boston, Massachusetts, and a national correspondent for the New England Journal of Medicine.2 "Furthermore, their lapses would probably need to reflect pragmatic rather than psychological obstacles, particularly for diseases for which medication taking isn't associated with relief of symptoms."
Yet "forgetting is not the primary driver of nonadherence," Dr Rosenbaum noted.
That's why Dr Applebaum believes the drug was introduced too early, "without sufficient data to allow an informed judgment regarding its use."
"Although it's presumed that the MyCite mechanism will improve adherence to treatment regimens, there actually are no data to support that assumption," Dr Applebaum told Psychiatry Advisor. "Not only don't we know what kinds of adverse impact there might be, particularly on people with psychotic disorders, from taking a medication that can transmit your behavior to your physician, but we also don't know what the positive effects of its use are."
Among his concerns are how prescribing the drug might affect trust in the patient-doctor relationship, and potential downstream consequences if taking the drug compounds a patient's paranoia and leads to reduced contact with the mental health system. Although 1 trial investigated whether taking a digital sensor tablet with regular medication worsened patients' psychosis (it didn't), the study involved only 28 patients.4
The FDA primarily focused on findings about Abilify MyCite's use in human factor studies. These findings yielded helpful information about the risk for medication error or overdose related to some patients' misinterpretation of instructions, and were then incorporated into revisions to product labeling.5
Can It Be Hacked?
Despite the patient's control over who can access the data, privacy concerns have dominated much of the discussion about Abilify MyCite. Data collected by the app are subject to compliance with the Health Insurance Portability and Accountability Act (HIPAA), and the Bluetooth signal is encrypted during transmission from the patch to the telephone.
The FDA did, however, acknowledge that concerns about digital security with this product will always exist in light of how quickly technology changes.
"All networked computer systems are potentially vulnerable to cybersecurity threats, and medical devices are no exception," FDA spokesperson Jeremy Kahn, MA, told Psychiatry Advisor. Cybersecurity controls for the device's digital sensor were found to be adequate at the time the FDA reviewed and cleared it, but "cybersecurity risks are constantly evolving," Kahn said.
"The FDA has been working diligently to address medical device cybersecurity in all phases of a product's lifecycle, from initial design and development of the device to management of a device once it is on the market and being used by patients," Kahn said. "Medical device manufacturers and hospitals must be vigilant and monitor for emerging and changing threats so that potential vulnerabilities can be addressed in a timely manner. The primary goal of proactively addressing cybersecurity risks in medical devices is to keep patients safe."
FDA resources for manufacturers include their guidance for Content of Premarket Submissions for Management of Cybersecurity in Medical Devices Final Guidance and Postmarket Management of Cybersecurity in Medical Devices.
Concerns About Coercion and Informed Consent
Other ethical concerns about the drug have centered on the "potentially coercive" aspects of prescribing Abilify MyCite, as psychiatrist Peter Kramer, MD, told the New York Times.3 Excessive insurance incentives are 1 way prescribing the drug could become de facto coercive, but it's the drug's potential use in the criminal justice system that most concerns Dr Applebaum.
"I think there's a lot of room for the criminal justice system here to overreact to a level of granularity in information that they've never had before," Dr Applebaum told Psychiatry Advisor. Judges, probation officers, parole officers, and similar professions are ones in which people "are used to issuing orders and having people comply with their orders and punishing them when they don't," Dr Applebaum said.
Can a person who is required to take aripiprazole as a condition of their parole or probation be compelled to take Abilify MyCite? It's not clear. If they are taking it and miss a dose, what will the response be?
"It often frankly doesn't make much of a difference to their clinical stability if they miss a dose here or there," Dr Applebaum said, so the possibility of punishing them for a medication, and even incarcerating them, "is worrisome, particularly when that's being done on the basis of an assumption that unless they take every dose at the time it's prescribed to be taken, they're vitiating the effectiveness of their treatment."
Another concern expressed by some in the medical community is the extent to which patients fully understand the treatment before providing informed consent, particularly patients with low health literacy or cognitive abilities or those whose condition potentially interferes with their decision-making abilities. In response to these concerns, the FDA simply points to the product labeling that patients should read and understand, adding that the FDA does not regulate informed consent between physicians and patients.
The FDA similarly demurred from responding to what doctors should do if patients develop paranoia in association with the drug's use: "Physician response is variable and personal, and based upon each physician-patient relationship," Kahn told Psychiatry Advisor. "This is not regulated by FDA."
Rosenbaum suggests that the true value of a treatment like Abilify MyCite lies in offering "an opportunity to understand rather than just remind" when it comes to nonadherence.2
"It's often easier to tell people what to do than explore why they don't do it," she writes, noting the need for doctors to talk to patients and find out why they may not be taking medications as directed.
Although the drug's approval may indeed be an opportunity, it remains to be seen what kind of opportunity it will be and what the cost of finding out will be.
"The big headline is, 'We just don't know yet,' " Dr Applebaum said.
- Lee DJ, Farchione TR, Mathis MV, Muniz J, Muoio BM. US Food and Drug Administration's approval of aripiprazole tablets with sensor: our perspective [published online May 29, 2018]. J Clin Psychiatry. doi: 10.4088/JCP.18com12255
- Rosenbaum L. Swallowing a spy — the potential uses of digital adherence monitoring. N Engl J Med. 2018;378(2):101-103.
- Belluck P. First digital pill approved to worries about biomedical "Big Brother." New York Times. https://www.nytimes.com/2017/11/13/health/digital-pill-fda.html. Updated November 13 2017. Accessed July 18, 2018.
- Kane JM, Perlis RH, DiCarlo LA, Au-Yeung K, Duong J, Petrides G. First experience with a wireless system incorporating physiologic assessments and direct confirmation of digital tablet ingestions in ambulatory patients with schizophrenia or bipolar disorder. J Clin Psychiatry. 2013;74(6):e533-40.
- Peters-Strickland T, Hatch A, Adenwala A, Atkinson K, Bartfeld B. Human factors evaluation of a novel digital medicine system in psychiatry. Neuropsychiatr Dis Treat. 2018;14:553-565.