In 2017, the US Food and Drug Administration (FDA) broke ground by approving the first drug with an embedded biosensor to track its use. Proteus Health’s Abilify MyCite had an ingestible sensor that could track if a patient consumed the drug.

Proteus’s profile grew considerably; it was soon valued at $1.5 billion. The enthusiasm for digital approaches involving sensors, apps, and wearables that could transmit information across systems, commonly grouped under the term Internet of Things, also spread.

Yet, despite the landmark FDA approval, digital pills have not exploded in pharma. Privacy and logistical concerns, especially while studying such applications for vulnerable populations, have lingered.

Not even three years later, Proteus filed for bankruptcy.

There’s no dearth of interest, however, in applying digital solutions to healthcare. “Controlling the parameters of our health with an app has become comfortable, and many people welcome this type of progress,” says Marina Morla Gonzalez, an assistant lecturer in the public law department at Universidad de León in Spain. Glucose monitoring through implantable sensors, and portable electrocardiograms have also become increasingly common in real life.

Still, the field is in its infancy when it comes to unequivocally establishing a financial and clinical benefit with digital pills. But researchers hope that this may soon change.

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Privacy concerns present but variable

When you’re dealing with vulnerable populations, it is important to make sure patients are aware of what the sensors in digital pills intend to do; that there is no penalty if they forget a medication, and that they are intended to be helpful and not a hindrance, says Susanne Haga, PhD, associate research professor at the Sanford School of Public Policy, Duke University.

“You don’t want to use this to stigmatize patients or to ‘catch them lying.’ You want to use it to show what is working well, or tell ‘if you’re struggling in this situation, I want to identify the trigger,’” says Dr. Jose Castillo-Mancilla, associate professor, School of Medicine, University of Colorado, Anschutz.

Despite the fanfare associated with Abilify MyCite, it did not prove to be an attractive proposition. The digital pill, now marketed by Otsuka Pharmaceuticals, is forecasted to make $27 million in sales in 2022, as per GlobalData.

GlobalData is the parent company of Pharmaceutical Technology.

Abilify MyCite may not have been the best case study for how future applications of these ingestible biosensors may be viewed or taken up by patients and providers, says Haga. Abilify MyCite was FDA-approved to treat schizophrenia, and manic and mixed episodes associated with bipolar I disorder, and as an add-on treatment for depression. “One of the strongest mistrusts that existed towards [Abilify MyCite] was how are you going to treat a patient with a medicine that has a sensor to track and control them, when one of their main pathologies is paranoia,” says Gonzalez.

When it comes to working with vulnerable populations, it is important to have an open dialogue that allows participants to learn more about the technology and have the research team available to them for any questions, Castillo-Mancilla says.

Dr Peter Chai, an ingestible biosensors expert, has been involved in several studies to improve and measure drug adherence, including trials that have enrolled men who have sex with men with substance abuse disorders, and individuals with stigmatized or marginalized identities. His early research involved fieldwork on how people would integrate such interventions into their daily life. “It takes some groundwork to develop those messages. Once that is done, you can be honest with people who want to use the device or participate in the study, ” says Chai, who is also an assistant professor of emergency medicine at Brigham and Women’s Hospital.

But traditional consent forms and data privacy policies are written in a very complex vocabulary that is very hard to understand even for a lawyer, says Gonzalez. A patient probably does not know what they’re signing, but still does it in order to access whatever treatment they need, she adds.

When it comes to privacy-related concerns, the possible risk of third parties using that data in a way that affects the patient, for example while looking for a job, is a factor that contributes to loss of trust in this type of technology, says Gonzalez. Haga, whose background deals in genetics, says that such privacy concerns are still present in that field, but she did not view the information being transmitted through digital sensors any differently than other health data that we may or may not knowingly make available.

“A lot of those [scenarios] are opinions and kind of philosophical debates. When you go and talk to people who actually use the system, you find that that’s not the case,” says Chai.

In Chai’s experience, participants found such a digital approach improves their connection to the medical system. “It potentially helps individuals lend some kind of concrete evidence to discussions with their healthcare provider. So, it’s not essentially a ‘he said, she said’ about adherence, but this is more like what happened….’I’m trying to be better or I’m doing well or I’m not doing well.’” In the trial led by Castillo-Mancilla, when a patient takes a pill, that creates a signal that is stored in a phone. This is then acknowledged with a ‘Thank you.’ Something as simple as that positive feedback has been well-received, he says.

The fundamental thing is that the patient agrees to be treated with this type of therapy, says Gonzalez, adding that they would opt for such technologies if they think it empowers them to have better control of their health.

“Just because the population is vulnerable or difficult, doesn’t mean that you shouldn’t do anything for them. It’s the right thing to do, and it’s hard but I think hard things tend to be correct,” says Chai.

Recent advances portend future interest

“When I did my first clinical trial, we were stuck with a device that required a cutaneous patch to capture a signal, and now we are working on off-body devices,” says Chai.

These days, he is leading trials involving a system developed by the digital health company etectRx (pronounced as e-tect-are-ex), which works with investigators who can use such real-time data. The company’s FDA-cleared ID-Cap system involves an ingestible capsule, plus a device worn around the neck with a lanyard. An app relays messages from the device to a secure cloud-based server. “We’re trying to find high-value applications, for patients at large, researchers, and us,” says etectRx CEO Eric Buffkin.

Digital pills offer the chance to monitor and potentially improve adherence to medications. High adherence is critical in HIV to get the viral load to undetectable levels and to protect people from getting AIDS, says Castillo-Mancilla. Hepatitis C treatments cost several thousand dollars, and digital pills can help us understand if a lack of a response is because the patient hasn’t taken their pills or it’s something else, he adds.

Castillo-Mancilla’s work deals with quantifying adherence by using a digital pill to establish the expected concentrations of adherence biomarkers. One of his projects, the QUANTI-TAF cohort study, is using a digital pill approach based on etectRx’s ID-Cap system to track adherence to Gilead Sciences’ tenofovir alafenamide (TAF) in persons living with HIV who are taking the drug as part of their antiretroviral regimen.

But the pharmacology to quantify adherence also depends on race, gender, weight, and other factors. Castillo-Mancilla’s group has established specific socio-demographic characteristics that impact the biomarker concentration beyond adherence, which can be used to establish reference values. Such information can then be used to inform the physician that if a particular patient’s data is not in a particular range, then that’s likely due to adherence issues, he explains.

Payers remain to be convinced

Ultimately, the commercialization of these products is what’s going to bring them into the hands of the people who need them the most, says Chai. However, as seen in the last few years, that is easier said than done.

Proteus is not the only company that has found the market challenging. Pear Therapeutics, a digital therapeutics company with three FDA-authorized products, recently announced an operations restructuring exercise. In an SEC filing made public on 25 July, Pear announced the company would lay off 9% of its full-time staff, among other things, and shift focus to prioritizing certain commercial efforts.

“The issue here is we haven’t created a compelling case from an economic, payer, and user space, all at the same time, in such a way that everybody can win,” says Buffkin. If the field were to show a pharma company that a digital pill can reduce costs because it can improve adherence, which then consequently prevents a negative outcome, then that’s a compelling enough reason for all the stakeholders in this field, says Castillo-Mancilla. Payers have to see the health and economic benefit to buy in.

There have been some recent steps in that direction. Buffkin points to the Centers for Medicare and Medicaid Services’ (CMS) Remote Therapeutic Monitoring program as a good example of the role payers can play in incorporating digital solutions into operations. In its 2022 Physician Fee Schedule, CMS included five codes that can be used to seek reimbursement for remote therapeutic monitoring and included therapy adherence, respiratory system status, and musculoskeletal system status as examples. This presents a straightforward therapy monitoring reimbursement system in those areas, says Buffkin.

While there haven’t been breakthrough digital pill approvals, the agency has made some strides in the broader digital therapeutics space, where prescription devices are used by patients with the help of a smartphone or tablet. The FDA has authorized three digital products by Pear—reSET and reSET-O are indicated to treat substance abuse disorder and opioid abuse disorder, while Somryst is meant for patients with chronic insomnia. Another company, Click Therapeutics, which raised $52 million in Series B funding last year, has the Click Neurobehavioral Intervention (CNI) platform that uses digital biomarkers and phenotypes, while harnessing data analytics and machine learning. The FDA has also cleared Akilii’s EndeavorRx, a prescription-only medical device for attention deficit hyperactivity disorder.

Still, one thing that has come up during the regulatory discussions, Gonzalez says, is that while we can track whether the patient has taken the medicine, it is not clear if the adherence will improve with digital pills. There hasn’t been strong evidence generated regarding improvements in adherence, but it may be that it just hasn’t been studied in a wide array of populations, says Haga. 

The way forward for digital pills

In the future, Chai says solutions involving base stations could eliminate the need for a wearable relay and capture a signal from afar. In addition to diseases like tuberculosis that have a high pill burden and where adherence is crucial, ingestible biosensors could also play a role in chronic diseases like heart failure and diabetes. Medication adherence can prevent the progression of some of these diseases. If sensors can capture the necessary information earlier on, then that could advance the paradigm around how these diseases are currently managed, he says.

In addition to ensuring safety and data transparency, it is important that patient access is not affected, says Haga. We don’t want to create another area of disparity based on whether or not an application a patient gets is linked to sensors, adds Haga.

“At the end of the day, the patient has to be of a mindset that this medicine is helping,” says Buffkin. Without that, let alone digital therapy, even a traditional one will not succeed, he says.