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Just Access to Digital Medicine: Do Fraud and Abuse Laws Block the Way? Jack SchwartzIn the psychiatrist’s officePatient A has schizophrenia, for which the psychiatrist has prescribed an oral antipsychotic. The patient reports little symptomatic relief. The psychiatrist, unsure whether the patient has followed the prescribed regimen, wants to try a new version of the medication, one with an embedded digital sensor that confirms ingestion. The psychiatrist asks, “Do you have a smartphone?” “Sure,” the patient replies, pulling out an iPhone 8, “why do you ask?” “Let me tell you about a new way of keeping track of your meds,” the psychiatrist begins.Patient B presents the same situation, except for the answer to the smartphone question: “No, they’re too damned expensive, I can’t afford that.” This answer ends the discussion of the digital alternative before it begins. Digital tracking of medication ingestion depends on the patient’s use of a smartphone.Digital medicine enters the marketOn November 13, 2017, the Food and Drug Administration approved the first digital medicine (“DM”). Called Abilify MyCite and marketed by Otsuka Pharmaceutical, this is a drug/device combination in a tablet. The drug component is Abilify (aripiprazole), an atypical antipsychotic approved in 2002 for the treatment of schizophrenia and two other serious mental illnesses. The medical device, made by Proteus Digital Health and FDA-cleared in 2012, consists of a grain-of-salt-sized sensor and a patch worn below the rib cage that transmits data via Bluetooth connection to the patient’s smartphone. The sensor, which disintegrates in gastric juice, confirms that the drug has been ingested. As described by the FDA, “The system works by sending a message from the pill’s sensor to a wearable patch. The patch transmits the information to a mobile application so that patients can track the ingestion of the medication on their smart phone. Patients can also permit their caregivers and physician to access the information through a web-based portal” (FDA 2017).When Otsuka and Proteus announced the FDA’s approval, they quoted a leading psychiatrist, Dr. John Kane, on the anticipated value of this DM: “For the first time in my years of experience as a psychiatrist, there is an innovative way to provide individuals with serious mental illness, and selected members of their families and care teams, with information on objective medication taking patterns to help inform the patient’s illness management and personalized treatment plan. This information allows the opportunity for an open dialogue with the patient” (Otsuka 2017).Abilify MyCite is not a long-term therapy. The typical period of use, in Otsuka’s estimation, is a few months. The idea is that reliable evidence of ingestion patterns gained during this time will help the psychiatrist and patient together determine future therapy, be it continuing to take conventional (non-DM) oral aripiprazole, with a plan for improved adherence and perhaps an adjusted dose; switching to a different oral medication; or switching to a long-acting injectable antipsychotic.This story of clinical benefit is a prediction, lacking direct evidence. The FDA’s marketing approval allows claims about reliable ingestion marking but not improved medication adherence. The approval has been criticized as based on inadequate evidence of benefit (Cosgrove et al. 2019). Indeed, citing lack of evidence, some payers reject coverage of Abilify MyCite. Cigna, for instance, pointing to “insufficient evidence to demonstrate that [ingestible] sensors have a discernable impact on patient compliance,” characterized medications with such sensors as “experimental, investigational and unproven” (Cigna 2019). In response, Otsuka has launched a prospective, open-label clinical trial, with outcome measures related to psychiatric hospitalizations and adherence.Likewise, there is not yet evidence of the cost savings, primarily from fewer hospitalizations, that would justify Abilify MyCite’s much higher price (LaMattina 2019). Data about this may emerge from use. At least one major insurer will cover Abilify MyCite only if, among many other prerequisites, the prescriber attests that “that Abilify MyCite is medically necessary for the patient to maintain compliance, avoid life-threatening worsening of symptoms, and reduce healthcare resources utilized due to lack of adherence” (United Healthcare 2019). With experience, United Healthcare and other insurers will learn whether these cost savings materialize.Abilify MyCite is a DM harbingerWhen the FDA approved Abilify MyCite, it spread a welcome mat for DM manufacturers: “The FDA supports the development and use of new technology in prescription drugs and is committed to working with companies to understand how technology might benefit patients and prescribers’” (FDA 2017, quoting Mitchell Mathis, M.D., director of the Division of Psychiatry Products in the FDA’s Center for Drug Evaluation and Research). Reflecting confidence in the FDA’s receptivity and the future market for DM, Otsuka invested $88 million in Proteus to expand its portfolio of mental health drugs with Proteus’ sensor (Dearment 2018).In addition to Abilify MyCite, DM versions of a wide range of previously approved drugs have been developed. For example, a digital cancer therapeutic (capecitabine, for colorectal cancer) has already been given to a handful of patients at Fairview Health Services in Minnesota and “is just one of about 40 approved medications that Proteus has packaged with?a sensor in a capsule. The company has tried the technology with drugs for diabetes, hepatitis C, and tuberculosis, among others” (Robbins 2019). Proteus evidently is confident that its DM products will demonstrate meaningful clinical benefit, for it is willing to assume the risk of value-based contracting, which links its profits to improved outcomes and cost savings (Proteus Digital Health 2018).In addition to the core function of marking ingestion, DM systems record other data. The patch in the Abilify MyCite system, for instance, transmits step count, heart rate, body position (upright or lying down), and body surface temperature. The app also allows the patient to enter information about mood and quality of rest. As DM technology advances, more information potentially relevant to patient care will be captured.Hence, the advent of DM means that many drugs will be offered in two versions: the garden-variety version, for which uncertainty about ingestion might cloud the question of patient adherence to the prescribed regimen; and the digital version, for which highly reliable evidence of ingestion and related physiological data are generated and available to the patient, clinicians, and (with patient authorization) family or friends. This paper assumes that, for many drugs with a DM version, physicians will consider that version clinically preferable for a subset of patients.This subset likely includes many low-income patients. Poor people are at increased risk of mental illness (Sareen et al. 2011), diabetes (Beckles 2016), and other diseases. Moreover, low income and financial strain (difficulty in paying monthly bills) are associated with greater risk of medication nonadherence (Osborn 2018; Rolnick 2013).DM and the digital divide The introduction of DM into clinical practice requires, as the National Academies put in a recent summary document about the ethics of innovative biotech, a “commitment to advancing patients’ interests,” which in turn obliges “careful consideration of justice and fairness issues related to access” (National Academies 2019, p.7). Justice considerations suggest that if DM is deemed beneficial for a patient, access ought not to be foreclosed because the patient cannot afford the prerequisite for DM: a smartphone that works with the app (Klugman et al. 2018b, p. 45).Sophisticated DM systems will be developed using the capability of the most recent mobile operating systems, which in turn means that many old smartphones won’t suffice (nor, of course, will flip phones of any vintage). Also, for technical reasons, some DM apps will be developed first for Apple devices, as was true of Abilify MyCite. Then, a patient would need an expensive iPhone running the app-compatible iOS version.Poor people are less likely to own a phone and have a data plan that will support DM use. “Roughly three-in-ten adults with household incomes below $30,000 a year (29%) don’t own a smartphone” (Anderson and Kumar 2019). Even among smartphone owners, there’s a digital divide. According to one survey, the average annual salary of iPhone users is 44% higher than that of Android users (Williams 2018). If DM is available only to those who own a costly smartphone, some low-income patients will be excluded from the presumed clinical utility.A straightforward response to this problem would be for a DM manufacturer to give, or loan, a compatible smartphone to patients who can’t afford one (and pay for the necessary data plan). Providing a smartphone with standard features would not only allow access to DM but also improve the lives (maybe as much as the medication itself) of people who now get by with a flip phone or have no mobile phone.If the people who lack a compatible smartphone have health insurance, however, it is most likely through Medicaid or Medicare. Consequently, giving or loaning an off-the-shelf smartphone to these DM patients would run headlong into federal laws that seek to protect these programs against mercenary skewing of health care decisions – decisions like whether to use the expensive DM version of a drug rather than a cheap generic.Otsuka decided to set up a loaner program for poverty-level patients who lack a smartphone compatible with the Abilify MyCite system. It could proceed, however, only with assurance that the company would not be ensnared by federal fraud and abuse laws. To that end, Otsuka sought an advisory opinion from the Office of Inspector General, Department of Health and Human Services (“OIG”), that its proposed loaner program was lawful.Is access to a smartphone unlawful “remuneration”?One statute, on beneficiary inducements, imposes civil monetary penalties on any person who offers or transfers “remuneration” to a Medicare or Medicaid beneficiary that the benefactor knows or should know is likely to influence the beneficiary’s selection of a particular item or service provider. Remuneration includes providing items or services free or for a cost less than fair market value. Another provision, the Anti-Kickback Statute (“AKS”), prohibits any person from knowingly and willfully paying, or offering to pay, remuneration to induce use of items or services covered by federal health care programs.Trying to avoid these pitfalls, Otsuka’s approach was to make the loaner phone have as little value as possible beyond what is needed for the Abilify MyCite system. Specifically, the phone would have the Abilify MyCite app and domestic calling functionality, so that patients could reach a call center for help in using the system. Otsuka would also provide a voice and data plan to allow these uses. But all the other features that characterize a smartphone would be disabled – no other apps, no music, no camera, no games, no internet browser. Because Abilify MyCite is seen as a temporary intervention, the maximum loan period would be six months. Once the course of Abilify MyCite treatment ended, the patient would be asked to return the phone; those who didn’t would discover that the phone had been bricked. Finally, Otsuka said that the loaner program would be made known to prescribers but wouldn’t be advertised.In an advisory opinion focusing on the beneficiary inducements prohibition, the OIG approved Otsuka’s proposed loaner program (Office of Inspector General 2019). Although the ability to make telephone calls had value and therefore was “remuneration” to the patients, the program met the criteria for an exception under which remuneration is permissible if it promotes access to care without posing undue risk to the federal programs. The OIG concluded that, for those who couldn’t otherwise access the Abilify MyCite system, the loaner phone would enable them to do so and thereby obtain potentially improved care. Moreover, because the loaner phone “would be a smartphone in name only,” given its limited functionality, and the program would not be advertised, the risk is negligible that psychiatrists’ decisions whether to prescribe Abilify MyCite would be skewed by patient pressure.Concerning the AKS, the same reasoning led the OIG to conclude that, although there was remuneration in the form of domestic calling capability, this was of such minimal value as to fall below the threshold for enforcement. The OIG was at pains to observe that, “if the smartphone had additional functionality (e.g., access to an internet browser or a camera or the ability to add other apps) such that it could relieve a patient from the burden of purchasing a smartphone or paying for a smartphone contract, then our conclusion likely would be different.”So, the OIG opinion opens the door a crack for manufacturers to help poor people gain access to DM. Although the opinion includes the usual caveat that it “may not be relied on by any persons other than” Otsuka, health lawyers view it as a guidepost. For example, one law firm observed that DM initiatives “may present new and unexplored fraud and abuse questions,” and companies “considering these initiatives should consider carefully the factors identified in Advisory Opinion No. 19-02 and any future guidance” (Hogan Lovells 2019). Another wrote that, “This advisory opinion offers a potential path forward for manufacturers of digital medicines as they develop programs to help needy patients access the appropriate technology needed to benefit from cutting-edge products and therapies …” (Pepper Hamilton 2019).A path forward for access to DM?Otsuka’s OIG-blessed strategy, to provide a short-term loaner phone smart enough for the app but otherwise as dumb as can be, works for Abilify MyCite. One can foresee DM systems, however, that would be used for much longer than a few months or that integrate other smartphone capabilities into the system, like fitness app or smartwatch data or camera-based image transmission. For all the law firms’ enthusiasm, it is difficult to discern a “potential path forward” for these more advanced systems. The ominous “our conclusion likely would be different” language reflects the OIG’s qualms about giving useful technology to patients, no matter how poor they are. For there to be genuine access to DM for poor people, a less grudging approach is called for.One possibility would be for the OIG to apply an evidence-based sliding scale: the stronger the evidence of clinical benefit, the more tolerant of technology for poor people the OIG should be. In the case of Abilify MyCite, there is no evidence yet, just plausible expert opinion, so only a tiny sliver of technological “remuneration” is acceptable. But the OIG might be called upon to apply the fraud and abuse laws when the clinical care benefits of the next DM, or the one after that, are established by good-quality evidence. If access to an evidence-backed DM requires a smartphone with more capability than one app and a telephone, under this approach its loan or gift would be permissible. That is, the OIG should accept some residual (though probably still small) risk of skewed prescribing rather than effectively bar poor people from a pathway to better care.ReferencesAnderson M and Kumar M (2019). Digital divide persists even as lower-income Americans make gains in tech adoption. Pew Research Center, May 7, 2019. Accessed at GL and Chou CF (2016). Disparities in the prevalence of diagnosed diabetes — United States, 1999–2002 and 2011–2014. Morbidity and Mortality Weekly Report (MMWR), 65(45): 1265-1269.Cigna (2019). Pharmacy benefit coverage criteria, Abilify MyCite, May 1, 2019. Accessed at . Climo CJ (2015). A laboratory of regulation: the untapped potential of the HHS advisory opinion power. Vanderbilt Law Review, 68(6): 1761-1794.Cosgrove L, Cristea IA, Shaughnessy AF, Mintzes B, and Naudet F (2019). Digital aripiprazole or digital evergreening? A systematic review of the evidence and its dissemination in the scientific literature and in the media. BMJ Evidence-Based Medicine,?doi:?10.1136/bmjebm-2019-111204.Dearment A (2018). Otsuka, Proteus expand agreement around digital medicines. MedCityNews, October 12, 2018. Accessed at Z (2018). Survey reveals why people ditch Android for the iPhone, and vice versa. BGR, August 24, 2018. Accessed at and Drug Administration (2017). FDA approves pill with sensor that digitally tracks if patients have ingested their medication. Accessed at S, Minssen T, Yu H, and Cohen IG (2019). Ethical and legal issues of ingestible electronic sensors. Nature Electronics, 2(8): 329-334.Hogan Lovells (2019). HHS OIG: Smartphone loaner to needy patients may not violate Anti-Kickback Statute. Accessed at CM, Dunn LB, Schwartz J, and Cohen IG (2018a). Response to open peer commentaries on “The ethics of smart pills and self-acting devices: Autonomy, truth-telling, and trust at the dawn of digital medicine.” American Journal of Bioethics, 18(10): W4-W7.Klugman CM, Dunn LB, Schwartz J, and Cohen IG (2018b). The ethics of smart pills and self-acting devices: Autonomy, truth-telling, and trust at the dawn of digital medicine. American Journal of Bioethics, 18(9): 38-47.LaMattina J (2019). Smart pill schizophrenia drug unlikely to move payers. Forbes, July 22, 2019. Accessed at Academies of Sciences, Engineering, and Medicine (2019). Framework for addressing ethical dimensions of emerging and innovative biomedical technologies: a synthesis of relevant National Academies reports. Accessed at of Inspector General (2019). OIG Advisory Opinion No. 19-02. Accessed at Minds (2019). OIG approves Otsuka plan to loan smartphones to people taking its digital medicine antipsychotic, Abilify MyCite. Accessed at CY, Kripalani S, Goggins KM, and Wallston KA (2017). Financial strain is associated with medication nonadherence and worse self-rated health among cardiovascular patients. Journal of Health Care for the Poor and Underserved, 28(1): 499-513.Otsuka (2017). Otsuka and Proteus? announce the first U.S. FDA approval of a digital medicine system: ABILIFY MYCITE? (aripiprazole tablets with sensor). Accessed at Hamilton LLP (2019). OIG advisory opinion has key takeaways for programs designed to assist needy patients. Accessed at Digital Health (2018). Digital medicines value-based contract focused on improving patient outcomes established between Desert Oasis Healthcare and Proteus Digital Health?. Accessed at R (2019). A “digital pill” for cancer patients is rolled out for the first time, in hopes of improving outcomes. STAT, January 17, 2019. Accessed at R (2018). At $1,650 per month, the first digital pill will soon roll out to certain Medicaid patients with mental illness. STAT, August 30, 2018. Accessed at SJ, Pawloski KA, Hedblom BD, Asche SE, and Bruzek RJ (2013). Patient characteristics associated with medication adherence. Clinical Medicine & Research, 11(2): 54-65.Sareen J, Afifi TO, McMillan KA, and Asmundson GJG (2011). Relationship between household income and mental disorders: Findings from a population-based longitudinal study. Archives of General Psychiatry, 68(4): 419-427.Steinhubel SR and Topol EJ (2018). Digital medicine, on its way to being just plain medicine. npj Digital Medicine?1: article?number?20175. Accessed at Healthcare (2019). Clinical pharmacy programs coverage criteria, Abilify MyCite, July 1, 2019. Accessed at R 2018. Survey: iPhone owners spend more, have higher incomes than Android users. Mobile Marketer, October 31, 2018. Accessed at . ................
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