In the 2012 science-fiction film Prometheus, viewers encounter a futuristic medical device, the Pauling MedPod 720i – a capsule large enough to accommodate a human and capable of diagnostics, administering anaesthetic and conducting surgery. While it may seem a far-off vision of medical care, the MedPod’s ability to offer a medical device and drugs in tandem makes it, according to FDA guidelines, a combination product: a concept familiar to patients, healthcare professionals and the pharma industry today.

Defined by FDA as “a product composed of any combination of a drug and a device; a biological product and a device; a drug and a biological product; or a drug, device and a biological product,” combination products, first developed in the 1970s, include items such as an asthma inhaler, a condom containing spermicide, or a prefilled insulin syringe.

“In the past, injectable products tended to be administered by healthcare professionals, but that’s changed,” Paul Jansen, formerly associate vice-president of medical device development at Sanofi, now a board member and senior adviser at Haselmeir, previously told World Pharmaceutical Frontiers. “We now need to make sure patients can easily understand how to administer drugs. Patient populations cover a very wide spectrum so you have to make products that are very simple to use and very safe. This is the trend we have been seeing over the past few years and I think it is going to continue to accelerate.”

Beyond insulin syringes and other products that allow patients to safely administer their own treatment, combination products have transformed healthcare. Drug-eluding stents, used in the treatment of coronary artery disease, prevent excess scar tissue developing to maintain blood flow and represent a considerable improvement on the previous bare metal stents. Medtronic’s INFUSE Bone Graft comprises an absorbable collagen sponge soaked with a protein that stimulates bone growth, a combination product which accelerates healing. Now combination products have reached a new frontier, as the growing development and application of digital health solutions offers the opportunity to unite this new technology with drugs or biologics. This is a development that may lead to a future even more advanced than the medical solutions envisaged in Ridley Scott’s space epic.

“People are looking at these combination products, which now have devices wrapped around them and they are asking how they can gather data from them and connect them to their ecosystem,” Jansen said in the same interview. “They want to be able to gather technical information that is needed to help with patient reimbursement, compliance, and helping physicians with recovery and treatment of their patients.”

Peace of mind

The buzz around digital combination products has grown significantly since the 2017 FDA approval of Abilify MyCite, a medication that combines treatment for schizophrenia and other mental health disorders with a sensor designed to provide information on adherence.

The result of collaboration between Otsuka Pharmaceutical and Proteus Digital Health, the treatment drug – aripiprazole – is administered as an ingestible pill containing a tiny sensor coated in digestible metals. This then transmits information to a sensor patch worn on the skin after its activation is triggered by contact with gastric fluid. This information is transferred to a mobile app, giving healthcare providers information on when the medication is being taken and allowing more accurate assessment and treatment of the patient.

“Until now, pharmacologic therapy for serious mental illness has been missing a systematic approach to objectively track and signal that a patient has taken their drug,” commented John Kane, MD, SVP, Behavioral Health Services, Northwell Health and chair, psychiatry, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, upon the release.

“Being able to track ingestion of medications prescribed for mental illness may be useful for some patients,” Mitchell Mathis, director of the Division of Psychiatry Products in FDA’s Center for Drug Evaluation and Research, agrees. “FDA supports the use of technology in prescription drugs and is committed to working to understand how technology might benefit patients.” Proteus Digital Health, the developer of the sensor, is pushing the applications of ‘digital medicine’ further, announcing a pipeline of 31 medicines under development in April 2018. These are aimed at the treatment of cardiovascular and metabolic conditions, infectious diseases and cancer as well as mental health.

“Our extensive clinical trial and commercial experience with digital medicines with thousands of patients has been overwhelmingly positive,” says Proteus Digital Health’s CEO, Andrew Thompson, explaining that the use of digital medicines had raised adherence to around 90%, as opposed to around 50% when using traditional drugs. “Wider use of digital medicines will help many patients and will help save a lot of money.”

As well as tracking adherence in patients, it is obvious that this kind of digital technology has much to offer clinical trials, as responses to drugs can be more accurately monitored when exact data exists on the time at which the drug was taken; this information could also be paired with sensor data that records aspects of a trial subject’s state, such as heart rate.

Working towards a common goal

Other developers are also exploring the potential in adding sensors to medical devices. Digital therapeutics company Propeller Health manufactures sensors that attach to asthma inhalers, measuring the use of the medication. As well as tracking adherence, the sensor collects data on air quality and other conditions, feeding into an app that allows the patient, and their healthcare provider, to more accurately assess their condition and triggers.

This technology also raises the real possibility of a revolution in diabetes care: a sensor that can link detection of blood glucose levels with the automatic delivery of insulin, essentially creating an artificial pancreas. Medical device developments are certainly approaching this point, as the components of a closed loop ‘artificial pancreas’ exist separately. Continuous glucose monitoring with the use of a sensor is already available, as is technology such as the Omnipod. This digital combined product is made up of an insulin pump worn on the body, which connects wirelessly to a handheld device and administers insulin according to instructions programmed into the device. While digital combination products promise numerous breakthroughs in medical care, their development is not without challenges for pharmaceutical and medical device companies. As is true for all combined products, regulatory processes can be complex.

“In the past when you submitted a vial and a syringe, you only had to go to one part of the group in the regulatory agency to get approval,” Jansen says. “Now, when you have a drug-device combination, you have to establish which of the two bodies is the lead reviewer, and then that agency will have to work with, and get comments and input from, the other agency. The net effect is that everything is much more complex. There are more people involved with different skills, all of whom are required to make an accurate review of the key aspects of the product – safety and efficacy.”

FDA is certainly aware of this. In 2016, the agency created the Combination Products Policy Council, described in an FDA Voice blog as a “senior-level, agency-wide forum for discussing, resolving, and implementing product and policy issues”.

Another significant issue regarding the development of digital combined products is common to digital health at large: patient privacy. A 2017 research paper published in the Journal of Pharmacy Technology raised concerns regarding the security of the information gathered by Abilify MyCite, noting that the transmission of the data via Bluetooth could allow misuse.

In addition, the digital products currently available, such as Abilify MyCite and Propeller’s inhaler sensors – used with traditionally developed inhalers, such as those produced by GSK – reflect the result of cooperation between drug development or pharma companies with more specifically medtech organisations. Collaboration requires effort in aligning vision, work plans and contracts in order to get the best out of a partnership.

Nevertheless, it appears that this approach – aligning with others in order to create a product that excels in all of its combined parts – is the route to success in the development of digital combined products.