One year after the FDA declined to approve Proteus Digital Health and Otsuka's new sensor-embedded formulation of Otsuka's antipsychotic drug Abilify, the companies are giving it another shot, resubmitting the application with additional information. As before, the application is a New Drug Application (NDA) -- both the Proteus system itself and Abilify are already FDA cleared and approved, respectively.

"I don’t think we would have made a submission if we didn’t feel confident that it was a high-quality submission and had a high chance of approval," Proteus CEO Andrew Thompson told MobiHealthNews. "I think we felt that the first time around, so there’s always room to be surprised. This is, of course, a brand-new category of therapy and potentially a precedent-setting approval, so I think we have to be reasonably appropriate about expectations. This would be the first time in history that a medicine would be approved that’s designed and manufactured to communicate with a cellphone when it’s swallowed."

Proteus Digital Health's signature product is the Proteus Discover platform, which involves a sensor embedded into a tablet which transmits to a patch worn by the user and from there into the cloud. This allows patients to have, in an app on their smartphone, an accurate record of their medication behavior as well as some other physiological data the pill sensor can pick up, and also – with the patient's permission – transmit this information to their care team. For patients with bipolar disorder or schizophrenia who might be taking Abilify, the technology could ensure that patient's caregivers know when they stop taking their medication in time to intervene before the nonadherence leads to an episode. 

Proteus is already in the market with the Discover platform, as, for example, at Children's Health in Dallas, Texas. But currently the sensor and the pill have to be co-encapsulated by a compounding pharmacy associated with the hospital. Approval for the combined drug would allow a combination pill and sensor to be prescribed and sold like any other drug.

"It points to a much broader possibility of distribution and much easier logistics," Thompson said. "But I think it's important to note that we have been very successful [even with co-encapsulation], in the sense that we have commercial customers, large health systems in the United States, making use of digital medicine. We had hundreds of patients in commercial settings on drug, not Abilify, but other drugs last year and the results are extremely positive, so that’s a very good thing."

Otsuka and Proteus started working together in 2012 and first submitted the first attempt at this application in September 2015. Just over a year ago, in April 2016, the FDA declined to approve the drug, citing concerns about human factor testing. Human factors investigations screen for risks related to human error and are meant to confirm a product can be used safely and effectively. The FDA issued a Complete Response Letter, which is not an outright rejection of an application but more of a request for additional information.

"In simple terms, FDA had some questions that related to software and what we’ve been able to do is to understand those questions and address them in ways that we think will comprehensively address the agency’s concerns about the software," Thompson said. "...The real review here and the substance of the review is around the integrated dose form, which is the combination of the drug and the device. What we found encouraging was that most of the questions [about the initital application] weren’t about the core of the approval but about things that were perhaps, from our perspective, a little less critical but related to software, which is OK."

Proteus and Otsuka expect to hear back from the FDA by Q4 of this year. Assuming the approval goes through, Otsuka could begin selling the drug shortly thereafter. Subsequent approvals of embedded drug-device pharmaceuticals, at least those from Proteus, will be able to benefit from the precedent set here.

"It’s obviously very important, we think, to the future of medicine that innovation that can be enabled by silicon and software gets to be added to the toolkit that includes chemistry and biology," Thompson said. "We think it’s a very important turn for the industry and obviously we’ve been working on this for some time. We believe we’ve done the work that’s required and we’re hopeful that others will see that and this will be a big step forward."