US Pharm. 2019;44(7):22-24.
ABSTRACT: In November 2017, the FDA approved the Abilify MyCite system. This drug-device combination product consists of aripiprazole tablets with an ingestible event marker (IEM) sensor and a wearable sensor patch that detects the signal from the IEM sensor after ingestion, which in turn transmits data to a smartphone application. Patients can use a Web-based portal to allow monitoring by healthcare professionals and caregivers for the purpose of tracking drug ingestion and adherence. Although this new digital technology provides a means to potentially enhance adherence and yield better patient health outcomes, ethical issues may arise for both patients and providers.
Historically, poor adherence to prescribed medication regimens negatively affects health outcomes, resulting in disease progression, increased hospitalizations, and patient fatalities—all of which impact overall healthcare costs in the United States. According to the World Health Organization, 3.8 billion prescriptions are written each year, and 20% of these are never filled. Of those that are filled, up to 50% of patients receiving these medications for chronic conditions are nonadherent to their oral regimens, resulting in almost $300 billion a year in added healthcare costs. These negative effects are largely preventable, making the need to improve medication adherence a public-health priority.1-4
Behaviors affecting patient nonadherence are not simple or entirely clear. Patient-, healthcare provider-–, and healthcare system–related factors can all contribute equally to medication nonadherence. From a patient perspective, nonadherence issues include forgetting to take the medication, not filling or refilling prescriptions, actively discontinuing or modiifying a regimen, having little to no involvement in treatment decisions, and decline in mental or cognitive health. Healthcare-provider factors impacting nonadherence include polypharmacy, prescribing complex dosing regimens, and poor communication (both interprofessionally and with patients and caregivers). Healthcare-system barriers to medication adherence include patients’ lack of accessibility to certain providers, limited drug coverage, high prescription costs and copayments, and confusing medication instructions.3
The ability to monitor medication adherence is complex, yet crucial, to better address the associated challenges. Adherence can be monitored both directly and indirectly. Directly observed therapy and the monitoring of drug plasma concentrations and other therapeutic endpoints through bloodwork are examples of direct monitoring methods. Indirect methods consist of self-reporting by the patient, announced and unannounced counting of remaining medication, monitoring prescription refills, the use of electronic bottle caps, and visual and audio bottle prompts.
Despite these methods and tools, none are considered to be the gold standard for adherence assessment, as a majority of them only provide subjective data, relying ultimately on the patient as the historian. As a result, the development of an ingestible biosensor system offers an alternative solution for accurate and measurable medication adherence monitoring. This new technology is unique in that it has the potential to provide instantaneous feedback regarding medication adherence that can be promptly shared with healthcare providers in order to develop improved and more immediate communication and counseling with patients.5,6
Digital Medicine Technology
Digital medication combines an array of advanced technologies, including a biosensor, a wearable sensor patch, and some form of mobile online interface. A 1-mm intelligible sensor, coated with digestible dietary minerals of copper and magnesium, is embedded into an oral, solid dosage formulation of a medication such as a tablet or a capsule. After ingestion and contact with digestive fluid, the digital tablet dissolves and activates. Upon activation, a unique, time-stamped signal emits and is detected by the sensor patch worn by the patient. The patch is approximately 10 cm long, made of a waterproof foam surface, and typically applied to the torso. The patch is made to withstand most physical activities of moderate intensity; however, excessive sweating or contact with water will affect the adhesiveness of the patch.
Once the signal is received, data are transmitted and stored in a Bluetooth-enabled device, thereby providing direct evidence of medication ingestion and adherence. It also has the ability to record other behavioral and physiological metrics such as physical activity, heart rate, skin temperature, and sleep. Furthermore, data received by the mobile application also give the patient the option of uploading information to a cloud-based, encrypted, HIPAA-compliant personal health record. In doing so, the patient has the ability to share information with their healthcare provider in an effort to promote and enhance collaboration and communication, as well as the ability for the healthcare provider to respond to nonadherence and deliver interventions in a timely manner. After the medication dissolves and absorbs, the sensor continues into the bowel and is excreted in the stool.5-7
In November 2017, the FDA announced its approval for the first time of an existing drug that will utilize a digital ingestion tracking system: Abilify MyCite (aripiprazole tablets with sensor). The Abilify MyCite system, distributed and marketed by Otsuka America Pharmaceutical, Inc., is a drug-device combination product consisting of aripiprazole tablets embedded with an ingestible event marker (IEM) sensor; a MyCite wearable sensor patch that detects the signal from the IEM sensor after ingestion and transmits data to a smartphone application; a MyCite app (a smartphone application used to display information to the patient); and a Web-based portal for healthcare professionals and caregivers for the purpose of tracking drug ingestion and adherence.8,9
Abilify MyCite is indicated for the treatment of schizophrenia in adults, the acute treatment of manic and mixed episodes associated with bipolar I disorder in adults, and adjunctive treatment of major depressive disorder in adults.9 Patients suffering from major psychiatric disorders such as these often lack the necessary reasoning to adhere to their medications. Whether due to complete denial of their diagnosis or perhaps concerns about side effects, nonadherence to psychotropics result in significant poor health outcomes.9,10
Prior to initiating therapy, patient willingness and capability to use all components of the MyCite system should be assessed, including compatibility with their specific smartphone device. Abilify MyCite is manufactured in bottles of 30 tablets at 2-mg, 5-mg, 10-mg, 15-mg, 20-mg, and 30-mg strengths with seven patches in each system. Sensor patches should be replaced every week or sooner.
Administration is once daily by mouth without regard to meals. Starting dose for adult schizophrenia is 10 mg to 15 mg by mouth once daily; treatment for bipolar I disorder is 15 mg once daily as monotherapy or 10 mg to 15 mg once daily with adjunctive lithium or valproate treatment; and adjunctive treatment for major depressive disorder is 2 mg to 5 mg daily. Dosage adjustments of 5 mg every 1 to 2 weeks can be made based on clinical response. Maximum daily dose is 30 mg in schizophrenia and bipolar I disorder. Major depressive disorder dosages should not exceed 15 mg daily. Tablets cannot be divided, crushed, or chewed, so patients should swallow the tablets whole.9
Abilify MyCite is 87% orally bioavailable with peak plasma concentrations within 3 to 5 hours once the initial onset of action of 1 to 3 weeks sets in. The drug is 99% protein-bound, primarily to albumin, and mainly undergoes hepatic metabolism involving CYP2D6 and CYP3A4 isoenzymes. Dose adjustments are therefore required in patients who are known CYP2D6 poor metabolizers and in patients taking CYP3A4 or CYP2D6 inhibitors and strong CYP3A4 inducers. Half-life elimination is 75 hours (95 hours in poor metabolizers of CYP2D6). Excretion occurs 55% in the feces and 25% in the urine.9
Side effects are similar to that of other aripiprazole products. The most common side effects reported were nausea, vomiting, constipation, headache, dizziness, uncontrollable limb and body movements (akathisia), anxiety, insomnia, and restlessness. Skin irritation at the site of the application of the MyCite sensor patch is also a concern for some patients. Boxed Warnings for Abilify MyCite indicate that patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death and should not be prescribed this medication. It also warns of increased risk of suicidal thinking and behavior in children, adolescents, and young adults taking antidepressants. Patients should always be monitored for signs or worsening of suicidal thoughts and behaviors. A patient Medication Guide must therefore be dispensed with the drug to properly inform patients of the drug’s uses and risks.9,10
A digital medication combines drug delivery and technology to increase adherence and monitoring, as well as better disease-state management and overall patient health outcomes.8,11,12 A sensor embedded in the Abilify MyCite tablet records that the medication was ingested, sending a message from the tablet’s sensor to a wearable patch, which then transmits the information to a mobile application. The patient can track their adherence on a smartphone and also give permission to their caregivers and/or clinician to access the information through a Web-based portal.8 Although this may seem ideal for certain conditions and certain patients, ethical issues arise.
Ethical challenges for patients include the understanding for autonomy and informed consent, therapeutic misconceptions, external influences on decision-making, confidentiality and privacy, and device dependability. For example, comprehending user agreements of software and/or hardware and the provision of informed consent and access to personal information and health data for an undetermined period of time in order to access and use a digital medicine product can be issues for patients.11 Many patients may also have difficulty understanding the purpose of a digital medicine product—specifically, its use for monitoring and adherence purposes rather than therapeutic purposes. In the prescribing information for Abilify MyCite, the manufacturer indicates that studies have not been conducted to determine the product’s ability to improve patient adherence with the treatment regimen. The product labeling states that Abilify MyCite “should not be used to track drug ingestion in real-time or during an emergency because detection may be delayed or may not occur.”8
Clinicians also face a number of ethical challenges. These include changes in patient trust/relationships, patient/therapeutic expectations, and liability.11 For example, a change in the therapeutic monitoring of a medication is quite different for a digital medication that can be tracked by a clinician versus a medication that cannot be tracked. The relationship between the clinician and the patient may require a different level of trust, therefore, in order for the digital medication to be an option for a particular patient. In addition, patients may have different expectations of clinicians if they believe that clinicians will spend more time monitoring their therapeutic responses to therapy using a digital technology. Changes in patient expectations may also cause some patients to skip or deprioritize follow-up appointments since they may believe that the clinician has the information to contact them with any issues. This can potentially increase the clinician’s liability and change the relationship with the insurance companies.
Although digital medicine may not require clinicians to utilize patient data, it may become an expectation of both patients and insurance carriers. This would place greater liability on clinicians who may otherwise not be under any obligation to monitor patient adherence or progress more regularly. In addition, digital medicine may lead to greater clinician oversight and increased clinician workload due to implementation of additional evaluation/performance measures. Therefore, clinicians may ultimately reject the use of digital medicine-device products and the potential benefits to patients and society.1
Digital medicine technology is a promising field, particularly for certain patient populations. Increasing adherence and monitoring to improve patient outcomes is a goal for patients, clinicians, and insurance carriers. However, ethical challenges exist and must be considered as use of digital medicine-device products become available.
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7. Plowman RS, Peters-Strickland T, Savage GM. Digital medicines: clinical review on the safety of tablets with sensors. Expert Opin Drug Saf. 2018;17(9):849-852.
8. U.S. Food and Drug Administration. FDA approves pill with sensor that digitally tracks if patients have ingested their medication: new tool for patients taking Abilify. FDA News Release. November 13, 2017. www.fda.gov/newsevents/newsroom/pressannouncements/ucm584933.htm. Accessed June 18. 2019.
9. Abilify MyCite [package insert]. Princeton, NJ: Otsuka America Pharmaceutical, Inc; 2017.
10. Semahegn A, Torpey K, Manu A, et al. Psychotropic medication non-adherence and associated factors among adult patients with major psychiatric disorders: a protocol for a systematic review. Syst Rev. 2018;7(1):10.
11. Klugman CM, Dunn LB, Schwartz J, Cohen IG. The ethics of smart pills and self-acting devices: autonomy, truth-telling, and trust at the dawn of digital medicine. Am J Bioeth. 2018;18(9):38-47.
12. Dotolo D, Petros R, Berridge C. A hard pill to swallow: ethical problems of digital medication. Soc Work. 2018;63(4):370-372.
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