To Boost Patient Participation, Clinical Trials Come Home

Last October, AOBiome Therapeutics, a life sciences company based in Cambridge, Massachusetts, announced the results of a 12-week clinical trial of an experimental acne drug. In the randomized double-blind and placebo-controlled trial, a topical spray containing a beneficial bacteria was shown to be safe and effective in reducing the severity and number of acne lesions, the company said.

The drug must successfully go through another round of testing — what’s called a Phase III trial — before AOBiome can apply to the Food and Drug Administration for marketing approval.

It all sounds like the standard drug development process, but it’s not.

Volunteers for the completed trial were recruited through social media and internet advertisements, and more than 8,000 people were screened online to see if they were eligible. The resulting 372 participants received the drug or a placebo in the mail and used company-issued iPhones to take selfies of their acne, a phone app to send the photos to physician-investigators for evaluation, and video conferencing to communicate with study staff.

That’s markedly different from a typical drug trial, in which patients are often required to visit a research site a dozen or more times for evaluation, said Dawn Anderson, a managing director in Deloitte Consulting LLP’s life sciences practice, who advises biopharma and research companies on drug development. They might have to take time off from work, drive hours to the site, and then wait for their appointment. Participation can be “quite a burden of time and effort,” Anderson said. And it can remain off-limits to patients who live too far away.

In the case of AOBiome’s acne drug trial, there were no in-person screening interviews, and no doctor visits. The trial was entirely what people in the trade call “virtual.”

“Because we bring trials to patients in their homes, we remove barriers, whether geography or time and inconvenience, that are preventing them from participating,” said Dr. Belinda Tan, co-founder and chief medical officer of Los Angeles-based Science 37, which uses proprietary software, along with wireless devices, to conduct virtual clinical trials with drug companies — including the one with AOBiome.

It’s a trend that many experts suggest is sorely needed. Fewer than 5 percent of Americans participate in clinical trials, and they often don’t stay. The average dropout rate is 30 percent. Nearly a fifth of trials are prematurely shut down due to participation shortfalls, according to a 2015 analysis, and many end up taking twice or even three times as long to complete as planned, experts say.

Whether virtual clinical trials are the way forward is a matter of some debate, and industry analysts say a host of challenges remain before virtual trials — which currently represent a tiny fraction of the more than 100,000 registered clinical research studies in the United States — become the norm. These include overcoming a conservative corporate culture, ensuring that the technology is easy for patients to use, managing and analyzing the enormous amount of data that round-the-clock sensors generate, and proving the data’s reliability and validity to regulators.

Still, according to analysts like Ken Getz, a research associate professor at Tufts University School of Medicine and founder of the Center for Information & Study on Clinical Research Participation (CISCRP) in Boston, a non-profit that educates the public about clinical research participation, easing the way for volunteers to enroll in clinical trials is critical to future drug development. Recent CISCRP research has suggested that the top five reasons for leaving a trial “are all associated with the inconvenience of having to go to a physical location to participate in the trial,” Getz said.

“What’s at jeopardy is the ability to bring new treatments into the marketplace efficiently, yet in an affordable way,” Getz added, “— and quickly.”

The response from many large biopharmaceutical companies, and even some midsize and smaller biotech firms, has been to test the feasibility of virtual clinical trials and the myriad digital technologies — smartwatches, mobile apps, and wearable biosensors — that make virtual trials possible.

So far, virtual participation has been tried in a mix of observational studies of the technologies alone, and mostly early-stage drug trials — often alongside traditional brick-and-mortar strategies. The pharmaceutical giant Pfizer was the pioneer. In 2011, its drug to treat overactive bladder was already on the market, based on the results of traditional trials. But the company wanted to compare those results to a virtual trial to determine whether site-less trials were feasible for future drug research.

In a study called REMOTE, either the active drug or a placebo was shipped to participants’ homes, where they entered data about their bladder function in an e-diary on a company-supplied mobile phone. Many participants dropped out, however, and only 18 individuals were randomly assigned to treatment — far fewer than Pfizer’s 283-person goal. The initial online registration process turned out to be too complicated and the e-diaries were not user-friendly, investigators said in a 2014 journal article.

Nevertheless, REMOTE was considered groundbreaking and inspired other scientists to explore the possibilities of virtual clinical trials. Merck, one of the world’s largest pharmaceutical companies, has completed two small pilot trials since the REMOTE trial results were published. In the first two-week trial, 14 healthy volunteers were given Januvia, a diabetes medication, and instructed to periodically draw blood at home through finger sticks, dry it in a stabilizing matrix, and ship it to investigators. The company then surveyed participants about their reaction to doing these things at home. “It was roughly neutral compared to coming into the clinic and getting your blood drawn,” said Matthew Moyer, director of clinical supply technology at Merck. “We don’t want to read neutral; we want to be better than the current state.” Responding to that, the 14 healthy volunteers in the second pilot were given a small device that sits on the forearm and draws a tiny amount of blood using micro needles. Moyer said the volunteers found it much less painful and easier to use than finger sticks — and they also preferred it to going to a clinic.

The French pharmaceutical company Sanofi has also tested the feasibility of digital technology in clinical trials. It extended a traditional Phase I trial of an experimental drug, in which healthy volunteers periodically visited a research site to have their weight, mobility, blood pressure, and blood glucose levels measured, into volunteers’ homes. Collaborating with Waltham, Massachusetts-based PAREXEL International, a biopharmaceutical service company, Sanofi instructed the volunteers to use various sensors and wireless devices to take their own measurements.

The researchers are currently writing up the results for a paper, but Lionel Bascles, Sanofi’s global head of clinical sciences and operations, shared some results. “The compliance is slightly lower as soon as the volunteers reach home — still high but lower,” Bascles conceded. “Second, the compliance is lower when it’s more invasive…So at home, the volunteers did not feel like complying too much with blood glucose, but blood pressure, weight, or mobility was easy for them to measure.”

Todd Krueger, AOBiome’s president and CEO, said the virtual nature of his company’s trial yielded significant benefits. Online recruitment was relatively fast, dropout rates were lower than expected, and compliance was better than expected. “Once you develop a relationship with somebody online, it’s not particularly difficult to send them emails to remind them to take the product,” said Krueger.

Krueger also said the trial was cheaper to administer than a traditional trial because he didn’t have to train and manage investigators at multiple research sites. In addition, paying research sites for patient visits is expensive, costing anywhere from $3,000 to $7,000 per visit, said Deloitte’s Anderson. “Now multiply that by 12 to 24 visits for every single patient in the trial, multiply that by hundreds or thousands of patients, and you’re talking about a tremendous component of your budget, anywhere from 60 percent or more,” she said.

Companies also want to get more and better data through virtual trials. In 2016, for example, the British pharmaceutical company GlaxoSmithKline sponsored a feasibility study of an iPhone app for use by rheumatoid arthritis patients. Patients answered questions about joint stiffness and pain, and the app recorded data that the smartphone’s accelerometer sensors captured as patients did wrist motion exercises.

“The study found that raw accelerometer data could be converted into a score that was much more precise than motion-scoring exercises conducted in a physician’s office,” a Deloitte report noted.

Companies also see virtual trials as a way to add new yardsticks — what scientists call endpoints — for evaluating the efficacy of experimental drugs. “There are life sciences companies who are not taking away their focus on traditional endpoints, on things like survival in cancer, but they are adding endpoints that are objective, quantitative measures of quality of life,” said Glen de Vries, president and co-founder of Medidata Solutions, a U.S. company whose cloud-based software platform is used by scientists, physicians, statisticians, and others involved in clinical trials, including the GlaxoSmithKline trial. Participants can use smartwatches, sensor-laden patches, and other digital devices at home, de Vries said, to measure things like sleep quality and movement.

Moyer said Merck plans to continue to conduct pilot studies, and Bascles said Sanofi also has more studies in the works. The Swiss pharmaceutical company Novartis has three trials underway with Science 37, including one testing an experimental drug for the treatment of cluster headaches and another testing an experimental drug for NASH syndrome, a non-alcoholic fatty liver disease. In each trial, Science 37 is recruiting patients online who will then participate remotely, while other patients will be recruited and followed in the traditional brick-and-mortar method.

“Cluster headache is another great example of why this [remote] technology can be so powerful,” said Jake LaPorte, global head of digital development at Novartis. 

“Oftentimes, these folks are incapacitated,” he continued, “depending on how bad the headache is. So it’s very hard for them to get to a site so they can be observed by a physician.”

Of course, there will always be trials that could never become entirely virtual, including those that require X-rays, MRIs, or biopsies, for example. And some diseases and disorders lend themselves more readily to the virtual approach than others because patients are already using digital tools at home, said Tan of Science 37. “We selected our initial therapeutic areas where telemedicine is more common as a practice and where you can reach out to people and capture outcome measures virtually — diabetes, dermatology, and psychiatry,” she said.

Eventually, however, digital tools could be used to reduce patient visits to research sites even for cancer drugs, Tan said, as long as a medication’s side effects are not severe.

For all the experimentation, a number of obstacles remain before completely or even partly virtual trials become the norm. The biopharmaceutical industry is far behind other industries, such as banking and retail, that have embraced digital technologies. Moyer of Merck co-leads the patient technology initiative at TransCelerate Biopharma, a consortium of 19 of the world’s largest biopharmaceutical companies that works to streamline and improve clinical trials. The initiative recently surveyed member companies and others to find out why the industry has been slow to incorporate digital technologies into clinical trials.

“The one thing that came up again and again was the risk from a pharmaceutical company perspective of feeling like you’re a first-mover in an area,” said Moyer. “So perhaps you’re trying something out that is cutting edge but there is a high degree of risk and a relatively high degree of investment in testing that technology out. If it doesn’t work or if it’s not accepted from a regulatory perspective, the burden is on you as a single company to bear that cost.”

TransCelerate is trying to overcome this reluctance by, among other things, building a database for members to share their experiences with using digital technology in trials.

Another challenge is making sure that the sensors and digital tools used in a trial are generating accurate data — that a heart monitor is correctly measuring the number of heart beats, for example — and that the data is not corrupted or its security breached. And of course, researchers must also convince the FDA, which approves the design of clinical trials before they can begin, that digital data is a valid way to measure the safety and efficacy of a drug. “The FDA is very comfortable in engaging right now in study-by-study discussions, and we’ve been happy with their response,” said LaPorte of Novartis. But the industry really needs some general guidelines from the agency about how to run virtual trials, he adds.

Theresa Eisenman, a spokesperson for the FDA, confirmed in an email message that the agency is interested in virtual trials. “The FDA is open to innovative trial designs that create efficiencies, serve the needs of patients while protecting their interests and safety, and create data that will be fit for use for regulatory decisions,” said Eisenman.

Eisenman declined to comment on any industry guidance the FDA may be considering beyond what is already publicly available, but given all of the variables and patients’ differing comfort levels with technology, several experts believe that hybrid trials that include both a virtual component and in-person visits will have the greatest chance for success.

“What the data shows us is that patients value, more than anything else, the relationship that they establish with the study coordinator and with the investigator,” said Getz of Tufts University School of Medicine. “It’s very, very hard to create that kind of rapport remotely.”

Barbara Mantel is a New York-based reporter who writes about health care and other social issues.