The advent of precision medicine, marked by the need to recruit relatively rare cohorts of patients into studies, has ignited interest in new, more efficient models of clinical development ranging from “just-in-time” rapid enrollment to trials requiring no sites at all, according to Gaurav Singal, chief data officer at molecular insights company Foundation Medicine. The traditional site initiation process takes weeks or months, time many patients—particularly those with cancer—don’t have to avail themselves of the trial option.
From a drug development standpoint, the old model of opening a trial at a handful of sites also doesn’t work for needle-in-a-haystack scenarios where less than 1% of the population is even eligible to join a study based on the molecular driver of their particular cancer, says Singal. Enrollment goals can be impossible to meet if sponsors are relying on a few academic sites that may or may not be anywhere near a single potential participant.
Perhaps more importantly, clinical trials are now listed as a treatment option in the Clinical Practice Guidelines in Oncology of the National Comprehensive Cancer Network, he continues. A clinical study may be the best or only option for some cancer patients.
As the leading tumor sample sequencing entity in the U.S., Foundation Medicine finds itself in the unique position of bridging the gap between enrolling oncology trials and patients with the specific molecular subtype to meet the key eligibility requirement, Singal says. “One out of every two oncologists in the country has ordered a Foundation Medicine test. We’ve sequenced as many if not more [patient samples] than all academic medical centers in the country put together.”
All told, more than 350,000 patient genomic profiles are in the company’s knowledgebase. Effectively thousands of patients are being pre-screened for trials every week by virtue of getting tested by Foundation Medicine, he says. “But for a myriad of reasons… unless patients have local access to a clinical study, they’re not going to be able to take advantage of that treatment option.”
In partnership with site-oriented companies such as Pharmatech and Optimal Research, Foundation Medicine works to ensure that trials are an option for identified patients no matter where they reside or seek care, says Singal. That means a large, nationwide network of sites is ready to open as needed on a moment’s notice with all the non-protocol-specific terms negotiated and documents collected.
Back in 2012 Pharmatech published data showing that, based on enrollment statistics, the just-in-time methodology was comparable if not better than the traditional approach of prioritizing site selection once there’s an approved protocol (DOI: 10.1177/0092861512443436). But given the dwindling eligibility pool for any one trial, the need to be more patient-focused has grown acute, Singal says.
A Win For Everyone
Foundation Medicine teamed up with Ignyta (a trial sponsor) and Pharmatech to present a poster at ASCO in 2017 demonstrating the utility of its trial education and access program for matching patients to studies targeting rare genomic findings. Of 107 treatment-eligible patients, 33% expressed interest in trial participation and a just-in-time trial site took just seven days from patient identification to initiation of therapy.
Patients sequenced by Foundation Medicine are automatically matched to clinical trials based on a specific biomarker they harbor, and that list is included in reports sent back to the ordering physician. “The interaction is still between patients and their doctor,” Singal says. “We’re arming doctors with information so they can make the best choice for their patients.”
Through partnerships with biopharma companies on trials seeking enrollees with exceptionally rare genomic mutations, Foundation Medicine proactively phones or emails providers with qualified candidates to ensure they’re aware of the opportunity, Singal notes. On a pro bono basis, the company has played a big role in bumping up enrollment in the NCI-MATCH Trial by identifying patients and engaging their physician.
“This is one of the few cases I can think of in medicine where everyone in the entire healthcare ecosystem wins,” Singal adds. “Patients get access to treatment they might not otherwise, drug developers get a more expedient path to approval… and payers get [enrollees] on medicines in a clinical study, not prescribed off-label.”
Point of Agreement
The decentralized trial model is complementary to just-in-time solutions but not nearly as well defined. The phrase is used in conjunction with everything from online patient diaries and eConsent programs to data-generating wearable technology and completely siteless trials enabled by Science 37—as well as ongoing interest at the U.S. Food and Drug Administration (FDA) to expand use of real-world evidence in medical product development.
In a policy speech delivered early last year on incorporating real-world evidence into regulatory decision-making, FDA Commissioner Scott Gottlieb, M.D., noted that decentralized trials could help biomedical research become more agile and efficient. He also indicated that the agency has a formal working group tasked with developing guidance on its approach.
One point everyone can agree on is that the burden is too high for people to participate in a clinical trial when they want to, says Brian Alexander, chief medical officer for Foundation Medicine. And that has generated interest in removing the arbitrary barriers between clinical research and medical practice to expand access to novel therapies and start learning as much as possible from every patient’s journey.
Siteless Trials
One certain component of the broadening clinical trial ecosystem are siteless trials, as epitomized by Science 37 (winner of a 2016 Best Practices Award). The premise behind the model is that every patient deserves access to clinical trials as a treatment option—and that includes removing barriers that exist by having a site involved at all, says Singal.
“If we’re really going to take a patient-centric view of the world, patients should be able to decide [a trial] is something they want to do without being limited by what their site is able, or wants, to do,” Singal says. Science 37 removes that obstacle by shipping clinical research materials directly to patients and having them make virtual study visits through a telemedicine app.
The Science 37 model won’t work for every trial, including those that involve complex procedures and hospitalization, says Singal. But it might be perfectly suited to some oncology trials where a sponsor is trying to expand the indications of use for a drug that is already market-approved.
Metasite Model
The “metasite” model, as Science 37 terms its approach, describes a “functional site that is agnostic of geography,” says Chief Medical Officer Jonathan Cotliar. It can either be juxtaposed with traditional brick-and-mortar sites or replace the need for them entirely. “We have doctors and nurses who are [located] broadly throughout the U.S. and can bring trials to patients in their home no matter where they live.”
One key to success of the model is the company’s Network Oriented Research Assistant (NORA) technology platform, which patients access via an app on a smartphone—their own or one provided to participants for the duration of the study, as preferred by the study sponsor—to get direct access to the investigator and study coordinator, says Cotliar. NORA successfully cut its teeth five years ago in a phase III study for a rare autoimmune skin condition (PEMPHIX trial) in conjunction with the nonprofit LA BioMed (recently renamed the Lundquist Institute).
Since then, the consensus among big-pharma companies and regulatory authorities is that decentralized trials are “where the industry is going,” Cotliar says. “That’s not to say that any trial can be adapted to fit this model.”
Trial enrollment is hampered by traditional, site-based research where recruitment tends to be confined to patients of hospitals and clinics or people within a specific geographic radius of those sites, says Cotliar. Beyond those geographic boundaries, folks are less likely to be open-minded about participating, even in cases where they otherwise might be.
“If you look at the statistics, nearly nine out of 10 people who get an opportunity to participate in a research study in a site-based model say they’re interested,” he says. “We also know that about 70% of those people live two hours or more away from the nearest enrolling site.”
With the Science 37 model, the conversation doesn’t break down due simply to the inconvenience of getting to study visits, Cotliar continues. But since the company isn’t a care provider, it doesn’t have its own electronic medical records to mine or an incoming stream of patients to invite into a research project.
Instead, it conducts multi-channel, multi-pronged campaigns that typically include advertising on social media and the Google Search Network and partnerships with patient advocacy groups. Patients’ medical records are usually required to confirm that they meet the study’s eligibility criteria, which are easily obtained directly from patients via Apple Health Records or the patient portal offered by their local care providers, Cotliar says.
Speedier Enrollment
The trials Science 37 bring to patients have all the normal study team personnel as any traditional trial—including principal investigators, research nurses, study coordinators and project managers—plus NORA as the connecting point with patients and for end-to-end trial management, says Cotliar. When Science 37 isn’t the sole metasite for a trial, it will refer patients to the nearest brick-and-mortar site if that is how an individual prefers to participate or the company has reached its enrollment cap.
In the PEMPHIX trial, Science 37 quickly reached its full cap of 10 patients in nine months, he notes. The other 65 traditional sites, which had been activated 12 to 18 months earlier, enrolled no more than one patient. These days, the company typically handles at least one-quarter of a trial’s target enrollment, and in many cases is entrusted to deliver more than one-third of the overall goal to further decrease costs associated with initiating a slew of sites that ultimately don’t perform.
With increasing frequency, Science 37 is conducting completely decentralized trials where it is wholly responsible for enrollment, says Cotliar. The first such trial, completed in October 2017, was for a treatment for mild to moderate acne for AOBiome. Science 37 enrolled 372 patients in seven months—twice the speed of the traditional, site-based model—and an impressive 41% of them were non-Caucasian.
To date, Science 37 has either completed or is actively enrolling in 27 decentralized trials, Cotliar says. Twenty-two of the 27 have been industry-sponsored and, of those, 16 have been interventional studies. Another five have been internal prototyping studies.
Decentralized trials have been conducted in a variety of therapeutic areas, including diabetes, major depressive disorder, fatty liver disease, cluster headache, atopic dermatitis, psoriasis, and Alzheimer’s disease. Currently, decentralized trials are underway for lupus, restless leg syndrome and migraine, says Cotliar, and Science 37 is soon to branch into oncology.
“We’re going to be doing our first precision medicine decentralized clinical trial in oncology later this year,” he reports. Cotliar says it should be a “real game-changer” in terms of improving trial participation among cancer patients and adding efficiencies to the recruitment process.
Doing The Math
Even a partial move to the decentralized model represents time and money savings for trial sponsors since they’d be activating and running fewer traditional sites, getting to their enrollment targets quicker and retaining a little over 90% of enrollees for the duration of the trial—more than 20 percentage points better than bricks-and-mortar sites—lessening the time traditional sites need to stay open, Cotliar says.
The shorter time-to-market gains is offset by higher spending on social media and other digital channels for recruitment purposes, continues Cotliar. But it’s “a tradeoff most companies are willing to make” once they compare overall spending relative to a traditional trial.
The math probably wouldn’t work as well for studies of a primary intervention for stroke, myocardial infarctions or a hematological malignancy in an acute care setting, says Cotliar. But even then, the company has an opportunity to work with site-based partners as patients transition from hospital to home and, if needed, facilitate their long-term follow-up.
“We have the ability with our services and platform to follow patients over the course of 15 years [for potential delayed adverse events],” as advised by the FDA for patients receiving gene therapy products, says Cotliar. Patients are unlikely to be in the same home in the same city or even seeing the same doctor for that long, but a platform like NORA can follow patients virtually no matter where they might go—all the while aggregating data and providing a seamless experience for patients.
For any type of trial requiring boots on the ground, including procedures such as lumbar puncture and tissue biopsies, Science 37 could likewise partner with site-based entities to follow patients virtually for the duration of the trial, he says.
Quantifying potential savings in using the metasite model can be tricky, Cotliar says, since the company is typically not privy to the projections and budgets of its competitors. However, a few sponsors have selectively shared this information after Science 37 won the work. For the AOBiome trial, the company bested the enrollment time estimates of bidding contract research organizations by about 30%.
Forward Leaps
Cotliar says Science 37 is fortunate to have had several direct and “very positive” interactions with the FDA regarding operational issues with the decentralized trial model, including eConsent, direct shipping of medicinal product to patients, using telemedicine to perform certain assessments and—most recently—operational considerations specific to decentralized oncology trials to safeguard patient safety and data integrity.
By the looks of it, the FDA will be learning from the experiences of Science 37 as it develops its policy-level guidance on the guardrails that need to be in place, he says. Reaching consensus on nomenclature, including the definition of a decentralized trial, may be a good starting point since the offerings of companies calling themselves virtual clinical service providers varies immensely in scope.
Science 37 plans to execute studies beyond the U.S. later this year, Coltair says. By 2020, he predicts, most of its work will be providing evidence for a drug marketing approval, and a significant proportion of patient visits will be performed in the home via telemedicine. Siteless trials will be well accepted, with several new players entering the field.
Having a head start and recognition as the trailblazer will serve Science 37 well, says Coltair. The company has already enabled its expansion beyond the U.S. with partnerships broadening the clinical trial services offered by its metasite model.
