The rise of digital therapies has prompted a slew of studies aimed at proving – or disproving – the effectiveness of the new class of therapies. But as researchers design trials to evaluate digital therapies, they face a new question: What kind of control can digital therapies meaningfully compare to?
Serge Marchand, Ph.D., chief scientific officer of digital therapy company Lucine, said that question isn’t always easy to answer.
“It’s not a pill and you can’t treat it like a pill,” he said. “You have to treat it like any other type of treatment.” That’s not to say that digital therapies deserve any less scientific scrutiny, he cautioned. Rather, it means that researchers must find innovative approaches to achieve scientific rigor.
Lucine is developing a therapy for chronic pelvic pain associated with endometriosis. Marchand said pain from endometriosis represents a significant unmet need, given that about 1 in 10 women — and possibly more — suffer from the disease.
Distraction as an analgesic
“It’s like terrible menstrual pain, but almost all the time and in different places,” he said.
There are therapies available for this, but not all therapies work for all patients, and some therapies have significant drawbacks. For example, women planning to become pregnant cannot receive hormone therapy. Worse still, some women go without treatment because of mistaken assumptions that the pain is “normal” or that the patient exaggerates its severity.
Lucine’s digital therapy, which she calls Endocare, is an immersive three-dimensional (3-D) experience that combines auditory and visual therapy procedures designed to help reduce pain during a 20-minute session. For example, users can experience an immersive environment reproducing a calming scene such as a beach with palm trees. According to Marchand, research has shown that this type of visual and sound experience can be pain-relieving.
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 a situation, you’ll stop and touch your feet and say, ‘Oh my God, this is bleeding and this is really painful,'” he said. Then he describes a second scenario, in which just after cutting off their feet, the person sees a bear watching them from a short distance. In the latter scenario, the pain from the cut would seem to disappear as the person focuses entirely on the bear’s escape, he said. “Then you won’t have any pain,” he said, “even if it’s real pain.”
He said the same concept is at work at Endocare, where therapy is designed to lessen the patient’s perception of pain.
The perfect placebo is impossible
However, proving that it works requires judging it against some kind of control. In a study recently published in the Journal of Internet Medical Research, Marchand and colleagues used a two-dimensional (2-D) version of Endocare software as a control. Instead of the typical immersive 3D virtual reality experience, people in the control group received a tablet with the same software, without the immersive factor.
The study showed that people using the full 3D version reported a greater decrease in the average intensity of their pain compared to the control group, with an average perceived pain relief of 28% compared to 15% in the group witness. The Endocare group achieved superior pain relief at 15, 30, and 45 minutes after treatment, and the authors found that some patients experienced pain relief for four hours after their 20-minute session. Marchand said the effect could last even longer; four hours was their data limit for the study.
“What we think is that we’re probably triggering some part of the patient’s endogenous (pain-relieving) system, and when that’s triggered, it’s like releasing a drug,” he said.
Marchand said the 2D 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 study control was successful in providing an apparent benefit to patients, which, in turn, suggests that the full immersive experience offers a significant advantage over this baseline.
“It’s extremely important, when you’re doing a project like this, that your control does something,” he said. “Because if your control does nothing, you compare [your therapeutic] to nothing.
Yet Marchand said that control in the JMIR the study could be improved. In a new, yet unpublished study, he and his colleagues used a different version of a control. This time, the tablet computer was replaced with a headset, but inside the headset users still saw a two-dimensional version of the software. Essentially, it was as if users had the tablet strapped to their head, but without the overall 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 path for products like Endocare, as he said regulators in the United States and Europe are beginning to better understand how to assess digital therapies, acknowledging that control arms for trials of digital therapies will have to be different. than those of traditional small molecule drugs.
At the same time, Marchand said the digital therapy industry must be prepared to conduct scientifically rigorous trials. He recalls that when he was offered the Scientific Director position at Lucine, he only accepted after gaining assurances that they understood the need for a rigorous development and evaluation process.
“When they told me that you would like to help us with the scientific part?” I said, “Yeah, but we’re going to do hard science, and it’s going to take a little longer, and it’s going to be expensive.”