Digital Therapeutics Research Needs to Up its Game to Pass Scientific Muster

Serge Marchand, Ph.D., of Lucine told his employer that doing scientifically rigorous trials of digital therapeutics was “going to take a little longer, and it's going to be costly.”

The rise of digital therapeutics has sparked a host of studies seeking to prove — or disprove —the efficacy of the new class of therapies. But as investigators design trials to evaluate digital therapeutics, they face a novel question: What type of control can digital therapeutics be meaningfully compared to?

Serge Marchand, Ph.D., the chief scientific officer at the digital therapeutics firm Lucine, said answering that question is not always easy.

“It’s not a pill and you cannot treat it like a pill,” he said. “You have to treat it like another type of treatment.” That’s not to say digital therapeutics deserve any less scientific scrutiny, he cautioned. Rather, it means investigators must find innovative approaches to achieve scientific rigor.

Lucine is developing a therapy for chronic pelvic pain associated with endometriosis. Marchand said endometriosis pain represents a significant unmet need, given that an estimated 1 in 10 women — and perhaps more — experience the condition.

Distraction as an analgesic

“It's like terrible menstrual pain, but almost all the time and at different places,” he said.

There are therapies available for it, but not all of the therapies work for all patients, and some therapies have significant drawbacks. For instance, women who plan to get pregnant cannot be given hormone therapy. Worse yet, some women go without treatment due to misguided assumptions that the pain is “normal” or that the patient is exaggerating its severity.

Lucine’s digital therapeutic, which it is calling Endocare, is a three-dimensional (3-D) immersive experience that combines auditory and visual therapeutic procedures designed to help reduce pain over the course of a 20-minute session. For example, users can experience an immersive environment replicating a soothing scene such as a beach with palm trees. According to Marchand, research has shown that this type of sight-and-sound experience can be analgesic.

To illustrate the pain-relieving potential of mental distraction, he suggests a scenario in which a person steps on a sharp rock, cutting their foot. “In one situation you will stop and touch your feet and say, ‘Oh my God, this is bleeding and it's really painful,’” he said. Then he describes a second scenario, in which right after cutting their feet, the person sees a bear eying them a short distance away. In the latter scenario, the pain from the cut would seem to disappear as the person’s focus shifts entirely to fleeing the bear, he said. “Then you will have zero pain,” he said, “even though it's a real pain.”

He said the same concept is at work in Endocare, where the therapeutic is designed to alleviate the patient’s perception of the pain.

Perfect placebo is impossible

However, proving that it works requires judging it against some sort of control. In a recently published study in the Journal of Medical Internet Research, Marchand and colleagues used a two-dimensional (2-D) version of the Endocare software as their control. Instead of the typical, immersive, 3-D virtual reality experience, people in the control group received a tablet computer with the same software, sans the immersive factor.

The study showed that people using the full 3-D version reported a greater decrease in their average pain severity compared to the control group, with a mean perceived pain relief of 28% compared to 15% in the control group. The Endocare group had superior pain relief at 15, 30, and 45 minutes after treatment, and the authors found some patients experienced pain alleviation for as long as four hours after their 20-minute session. Marchand said the effect may last even longer; four hours was their data cutoff for the study.

“What we think is that we are probably triggering some of (the patient’s) endogenous (pain relieving) system, and when that is triggered, it's like releasing a drug,” he said.

Marchand said the 2-D experience used in the study is not a perfect control; he said it’s virtually impossible to have a “placebo” version of an immersive digital experience. However, he said the control in the study succeeded in providing some apparent benefit to patients, which, in turn, suggests that the full immersive experience provides a meaningful advantage over that baseline.

“It's extremely important when you do a project like that, that your control do something,” he said. “Because if your control does nothing, you're comparing [your therapeutic] to nothing.”

Still, Marchand said the control in the JMIR study could be improved upon. In a new, as-yet-unpublished study, he and colleagues used a different version of a control. This time, the tablet computer was replaced by a headset, but inside the headset users still saw a two-dimensional version of the software. In essence, it was as if users had the tablet attached to their heads, but without the all-encompassing, immersive features of the 3-D version. The new study also differed from the original in that patients used the intervention at home.

Marchand said he is optimistic about the regulatory pathway for products like Endocare, because he said regulators in both the United States and Europe are beginning to better understand how to evaluate digital therapeutics, recognizing that control arms for trials of digital therapies will need to be different than those for traditional small-molecule drugs.

At the same time, Marchand said the digital therapeutics industry has to be prepared to conduct trials that are scientifically rigorous. He recalled when he was offered the job of chief scientific officer at Lucine, he accepted only after getting assurances that they understood the need for a rigorous development and evaluation process.

“When they told me would you like to help us for the science part? I said, “Yes, but we're going to do hard science, and it's going to take a little longer, and it's going to be costly.’”