There have been efforts in recent years to improve patient adherence to oncology medications; now, oncologists may soon have 1 more tool in the form of digital pills.
Kirollos Hanna, PharmD, BCPS, BCOP
There have been many efforts in recent years to improve patient adherence to oncology medications. Sticking to a regime that causes adverse events is not easy, and sometimes simple forgetfulness is to blame, but intervention by providers has been shown to work.1 Now, oncologists may soon have 1 more tool in the form of digital pills that transmit from inside the stomach to portable devices whenever patients take their medication. The technology, which has been deployed in limited extent across other areas of medicine, including cardiovascular and metabolic conditions, is being tested with oral oncology medication and could potentially make a dent in the problem of patient nonadherence. Some believe outcommes may be improved and more reliable clinical trials data may result from use of digital pill technology.
In 2012, Proteus Digital Health of California became the first company to receive FDA clearance for marketing an ingestible sensor. In 2017, the company got FDA appoval to combine this sensor with medication in a single pill: the Abilify MyCite system. Since September 2018, Proteus has pioneered a digital pill chemotherapy program in Minnesota, where the pills are being used to promote adherence and improve treatment guidance. Estimates by health authorities put overall adherence in developed countries at just 50% among patients with chronic diseases.2,3
“If digital pills get more people to take medicine as prescribed, these will be a major breakthrough, not only for conditions such as hypertension or diabetes, but for cancer care as well,” said Kirollos Hanna, PharmD, BCPS, BCOP, an assistant professor of pharmacy at Mayo Clinic College of Medicine and Science.
The Proteus ingestible pills come in various forms and are activated by the digestive process, which causes them to transmit to external receivers worn by patients. The receivers then relay that information to software loaded onto the patients’ smart phones or tablets (Figure).
If these signals indicate that patients are taking the right amount of medication at the right time, the software logs the data, along with some extra information on patient heart rate and activity levels that can help providers gauge how well patients are responding to treatment. The software tracks the number of pills patients are taking and when, so that patients and their providers can be alerted if patients don’t follow dosage or the medication schedule.
The potential for disclosing patient behavior to others in something approaching real time has raised concerns about patient privacy, but it also leads many to hope that “digital pills” will save lives and money. Small trials performed to date provide a basis for optimism, but the real test of the technology should come in the next few years when increasing usage provides enough real-world data to evaluate the effects of these pills on behavior.
Hanna notes that recent years have seen a major shift in cancer care, from administering entire treatment regimens in the office to delivering at least some component of care via medications that patients take at home. As a result, patient adherence has become a greater concern in oncology.
“Often, patients with cancer are elderly, so their memories can fail them at the best of times, and both their tumors and ‘chemo brain’ tend to increase the problem,” said Hanna, who is also a clinical pharmacist at Mayo and at the University of Minnesota Medical Center, where he is participating in a small trial of digital pills among patients with cancer. “There aren’t reliable adherence figures, but I’d guess that 40% to 50% of oral chemotherapy users have some adherence issues. If smart pills can reduce that by even a quarter, it would greatly improve outcomes.”The digital pill revolution extends to the use of wireless devices for colonoscopies which enable providers to inspect previously unreachable zones and conduct less-invasive procedures. Digital pills are just 1 product in the rapidly growing area of digital medicine. The bestknown segment of that market consists of wearable devices designed to monitor health or treat disease, such as Fitbits. Last year, the FDA approved the electrocardiogram software on the Series 4 Apple Watch,4 as well as its software for detecting an irregular heart rhythm.5 Wearables that treat disease range from insulin pumps for diabetes to electrotherapy for people with glioblastoma.
Another major component of digital medicine consists of software that is designed to replace medication as a treatment for a particular condition. A British company called Big Health offers an online insomnia therapy called Sleepio, which employs visualization exercises instead of pills.6 Sleepio therapy is covered by the United Kingdom’s National Health Service. The FDA, meanwhile, has approved several diabetes-management software packages7 and at least 1 program designed to treat people with drug and alcohol addictions.8
A third major component of digital medicine uses artificial intelligence (AI) to provide medical information and advice via chatbots, which converse with patients in a way designed to simulate human discourse. Such systems already are widely available to patients via smartphone apps that can tell users what their symptoms might indicate. They can also give doctors quick information on how well drugs interact with one another, among other topics.9
Looking forward, the hope is that providers will be able to integrate chatbots into their practices to automate many patient interactions that currently require staff time. Patients will access providers’ offices through an AI app that not only has comprehensive general medical knowledge but also access to each patient’s records. This will enable providers to schedule appointments, address billing concerns, manage symptoms, and determine whether patients need an appointment, a trip to the emergency department, or simple advice over the phone.
Although modest in size, digital pills have great potential to reduce costs of wasted medicine and therapy regimens that aren’t completed. Recent estimates put the direct and indirect costs associated with US patients who do not take their pills correctly from $100 billion to $337 billion annually.10,11 Those costs include hospitalizations and a substantial increase in morbidity. According to one report, about $1 of every $9 spent on healthcare in 2013 was wasted because patients didn’t take their medicines as directed.11
Investigators estimate that 10% of all hospital visits nationwide and deaths would decline dramatically if all medications were taken as directed. Failure to take medication as prescribed is thought to result in about 125,000 deaths a year.12
“Medications don’t work properly when patients don’t take them properly, so lots of those patients wind up in the hospital when they might have enjoyed reasonably good health,” said Joseph C. Kvedar, MD, vice president of connected health at Partners HealthCare.
Kvedar noted that forgetfulness is not the only reason for nonadherence. Adverse events, a desire to save money, an aversion to taking pills, and many other factors also play a role. However, Kvedar believes, digital pills could still improve adherence significantly.
“Even if forgetfulness isn’t the only problem, it’s still a significant problem, and if we can eliminate it with inexpensive and reliable technology, this would go a long way toward reducing costs and improving outcomes. What’s more,” he said, “there is some reason to hope that these pills can reduce other sources of nonadherence.” For example, patients who need urging to take their medication could rely on others to monitor and remind them.
Concerns have been raised that some patients may eventually be forced to use digital pills. One example provided was a potential provision that medicine be taken as a condition for release from in-patient psychiatric care.13,14Proteus completed initial development of its system in 2008 and then went to the FDA to determine what was necessary to demonstrate safety and efficacy. The FDA established a testing protocol after deciding that the digital pills were low-risk devices—the copper, magnesium, and silicon inside them is less than the amounts that naturally occur in everyday diets, and the electric signal is less than that generated by a single heartbeat.
Results from multiple clinical trials, some on healthy volunteers and some in patients who were taking medication for various conditions, found no adverse events related to the system and collectively reported that the system posted a positive collection accuracy of 99.1% (321 detected/324 ingested under direct observation; 95% CI, 97.3%-99.7%).15
The results of small trials of Proteus Discover also suggested the system can improve outcomes. Pharmacists on the Isle of Wight in England used the system on 39 patients with uncontrolled hypertension to help determine who needed adjustments in medication to control their conditions or improve prescription adherence. The system enabled investigators to determine whether nonadherence to medication or failure to respond to medication was the reason for lack of blood pressure moderation in the patient population. Based on these results, the system was deemed to have utility.16
In theory, the Proteus capsules can work with any pill, although the company’s existing panel of supported medications numbers just 31. Providers simply need to program the relevant information about each patient’s regimen into the system and co-encapsulate the sensors with the regular pills. Ultimately, Proteus plans to sell its system to any providers who believe their patients could benefit, but access is currently limited to 10 healthcare systems that have collectively given over 180,000 pills to hundreds of patients.
“We are working with our current partners to perfect how the system is delivered and to structure a value-based contracting model that works for everyone. We are also working with the makers of electronic health records to integrate the data our system provides onto their platforms, which hasn’t always been easy, and on ways to automate the co-encapsulation process so that pharmacists don’t have to co-encapsulate each pill by hand,” said Scooter Plowman, MD, MBA, MHSA, the company’s senior director of US markets and franchise strategy.
Proteus is also working with pharmaceutical companies to combine its technology with medications at the factory stage. The FDA approved the first such combination, a smart pill for schizophrenia called Abilify (aripiprazole) MyCite, in 2017.17
According to clinicaltrials.gov, the company is now testing its product for a variety of conditions. The Proteus program under way at the University of Minnesota for patients with colorectal cancer currently includes only a handful of patients with stage III/IV cancer who had been struggling to take capecitabine (Xeloda) properly. This investigation will expand to an open-registry study at practices ranging from urban academic medical centers to community practices in rural areas.18
“We see oral chemotherapy as a place where digital medicines could be a huge help to patients,” Plowman said. “It is a complicated sort of medicine to take. Patients often need to take 6 to 8 pills a day for a couple weeks, then take time off, then resume treatment often at a different dose. It’s hard to keep track.”Although Proteus Discovery is the only digital pill system to win approval so far, many other companies produce products or software designed to help patients take medications as directed. This reflects both corporate interest in the space—any company that finds an affordable way to significantly boost adherence may have a successful product—and the FDA’s desire to spur innovation and competition with a thorough-but-efficient approval process.
For a long time, the agency has declined to exercise any oversight of products that display health data collected elsewhere or that promote general wellness, which is why wearable health information—generating products like Fitbits don’t require rigorous review. As the risks associated with a product rise, the level of oversight increases, according to the FDA’s Digital Health Program. The FDA’s Digital Health Innovation Action Plan outlines the agency’s proposed criteria for deciding the level of oversight that will apply to new health technology.19
There are at least 9 companies that make smart caps for pill bottles, which note when patients open a bottle and when they replace the cap. More than a dozen companies also manufacture smart pill organizers, which light up individual pockets that contain the medicine patients are supposed to take and text them reminders when patients forget to do so. There is also at least 1 company, etectRx, that is developing a smart pill to compete with Proteus’ version.20
The etectRx pill works like the Proteus pill, except that the receiver device is different. Unlike the adhesive units from Proteus, which must be discarded and replaced regularly. The company’s receiver is a more permanent device that patients wear around the neck, like a pendant. They can remove it when it needs recharging or there is no need to take medication.
Like Proteus, etectRx also plans to work with pharmaceutical manufacturers to explore the sale of prepackaged combinations with specific medications and to investigate encapsulation possibilities for various medications in the pharmacy. The company, which has tested its capsules in trials for adherence to opioid prescriptions and substance abuse therapies, submitted its 510(K) application for marketing to the FDA at the end of last year and is anticipating clearance in 2019.
“We haven’t announced what we intend to charge. There are many potential pricing models that include outcomes-based pricing, adherence service models, and license fees for the technology. We will work with our initial partners to define these,” said Harry Travis, MBA, BS Pharm, etectRx president and chief executive officer.
“It’s hard to speculate just how much this technology will be able to improve adherence, but we know that there is room for improvement in adherence in practically every therapy category,” Travis said. “We don’t even really know the size of the problem because we can never really know what people are doing at home. What this technology will enable us to do is see if adherence in people who use it is better than expected and whether the interventions it allows when patients don’t take medicines correctly lead to improved adherence over time. I don’t think that smart pills will be the answer for all patients, but there is definitely strong interest in this technology from all of the major parties in the healthcare equation: patients, providers, pharmaceutical companies, and payers.”