Clinical Researcher—November 2021 (Volume 35, Issue 8)

OPINION

Mary Costello

Everyone’s familiar with paradoxes that seem contradictory, but still true—for example, “less is more”—and oxymorons that combine contradictory words but are contextually logical, such as “jumbo shrimp.” However, there’s one phrase dominating recent clinical headlines that makes little sense no matter its label—“siteless trials”—an oxymoron disguised as a paradox. How can decentralized clinical trials (DCTs) be compared to trials that bypass sites completely?

It’s too big of a leap, a contradiction of terms, a wolf in DCT’s clothing.

Sites are the center of clinical research, even in a decentralized trial, and are crucial for success and health outcomes. This is especially true for companies seeking to expand access to clinical research opportunities to underserved communities where trust remains a barrier.

“Given our medical establishment’s history of mistreatment, there’s a deep distrust and negative perception of clinical research by many black Americans and other minority groups,” said Melissa Opraseuth, COO of par 80, which provides care coordination services and technology to more than 11 million patients and recently launched a network to improve health equity and access to research among health center patients.

Opraseuth, who is a member of Medable’s new Site Network Council, continued, “Local sites are a lynchpin to overcoming some of these sensitive barriers because they foster a more intimate and ongoing personal connection with patients. Principal investigators don’t just do blood draws; they do community outreach and educate patients. There’s familiarity.”

How Did We Get Here?

Clinical trial designs today span a wide continuum, ranging from 100% site-based trials, where all interactions with study participants occur at the site, to 100% decentralized trials, where all interactions are remote and leverage wearable technologies supplemented by occasional visits by trial nurses to the participants’ homes. The latter are often referred to as “siteless,” but the vast majority are hybrid. This is true even as decentralization, accelerated by the COVID-19 pandemic, jumped to a 77% CAGR between the second halves of 2019 and 2020, according to data from more than 1,000 trials.{1}

Even so, “siteless” trials are not optimal. The site, together with trial coordinators, should remain a key part of the trial ecosystem, whether the trial leverages a single site or a network of coordinated sites, local pharmacies, community clinics, and home health aids supported by wearable devices and platform solutions. Technology simply cannot replace people.

Recent industry experience offers a relevant analogy. Between 2005 and 2015, many pharmaceutical companies rapidly adopted salesforce automation tools for their sales representatives while cutting sales jobs at the same time. From its height at 101,000 sales reps in 2005, the number of reps in the U.S. market dipped to 76,000 by 2010 and hit its lowest level of just 66,000 in 2012.{2} Accenture research showed that one in four pharmaceutical sales rep interactions was replaced by digital alternatives, but it did not achieve the intended effect of improved profitability.{3} The strategy backfired and sales dipped. Now, there are more than 100,000 pharma sales reps in the U.S., according to various estimates, and overall revenues have been setting records year over year.{4} The ship has righted itself.

Today, we are on the doorstep of a similar technology revolution, largely accelerated by COVID-19 when clinical researchers had no choice but to leverage innovative digital technologies to continue their work. Now, the excitement around technology’s potential is soaring again. The innovative technologies enabling remote or decentralized trials have the potential to dramatically reduce the burden for patient participation in research and for sites hosting studies.

Recent data back this claim, with at least half of the respondents to a recent Signant Health survey described in Clinical Researcher anticipating “strong” use of eConsent (63%), eSource (56%), remote monitoring (55%), and wearables (50%) post pandemic.{5} Further, a recent Oracle survey found 76% of respondents have recently accelerated their adoption of decentralized clinical trial methods.{6} Decentralized trials are here to stay just as a new generation of sites are, too.

Caution: Watch What You Say

Industrywide, there is confusion over terms like “virtual,” “remote,” and “siteless” when applied to trials. A review of current literature on DCTs will demonstrate phrases like “decentralized” and “hybrid” blur the distinction between trials with or without patient site visits. The DCT concept traces back to a 2018 Clinical Trials Transformation Initiative white paper that specifies that “DCTs can be conducted as 100% decentralized or as a hybrid study in which the DCT offers the additional flexibility of incorporating both in-person visits and virtual visits into the study as appropriate.”{7} Although the intent was to standardize terminologies, this definition proposes that “decentralized” and “hybrid” are synonymous.

The COVID-19 pandemic has changed industry perspectives on the meaning of “siteless” or fully virtual trials versus hybrid DCTs. A July 2020 Society for Clinical Research Sites (SCRS) survey found that a mere 3% of clinicians “had participated in a completely virtual trial, where all visits are conducted remotely.”{8} However, a December 2020 SCRS white paper (downloadable by visitors who supply demographic information at https://myscrs.org/learning-campus/white-papers/), based on a May-to-July survey, found that use of “the fully virtual approach” had risen to 15.46%. More recent data from Avoca found that 22% of respondents conducted “siteless” trials pre-pandemic; 17% had done so during the pandemic “but not because of it”; and 12% had done so “because of COVID-19.”{9}

The clinical trial lexicon will continue to evolve, but “siteless” should not receive a dictionary reference.

The Future is NOT All or Nothing

For the near future, most research sponsors will leverage the hybrid approach and adopt some elements of decentralization in trial design. For example, a trial protocol may require initial in-person site visits prior to patient enrollment and then leverage remote tools to maintain communication and data collection.

Hybrid protocols are highly beneficial for trials involving rare and ultra-rare diseases, which often require patients to receive specialized and invasive treatments at designated sites. Routine lab tests and follow-up appointments, however, can be handled in a decentralized manner at local healthcare facilities, community health clinics, pharmacies, or through telehealth to reduce the burden of participation for both patients and their caregivers. In this example, patients appreciate the comfort of a familiar face on a more regular basis but under circumstances that create less stress or take less time.

According to Opraseuth, “Technology is changing the traditional site-research model, but to make research better. It’s a balance. Sites will look very different in five or 10 years, but they will still be here. In fact, I hope we will have more clinical research site locations, even if they look differently than they do now, so they can be embedded in the communities where patients live, work, and play. It’s the best way to familiarize and educate patients so they will be more comfortable participating in research.”

Rather than a “siteless” trial, the better approach is to build fit-for-purpose clinical research with a next-generation site at its center. Some trials might be, in fact, wholly decentralized, but even those should incorporate a site whose role may be a different iteration of what a traditional site looks like today. The best-performing trials will continue to have human interactions between physicians and patients. They will not be without sites—rather, they will be enabled with the technologies needed to reduce burdens and improve efficiency. That is what well-designed technology should do—both for patients and for trial administrators.

Community Site Connection Drives Diverse Participation

Among other benefits, DCTs promise to improve the recruitment and retention of trial participants and increase diversity in trials, thereby improving the efficacy of approved therapeutics for all.

Given that only seven of 100 enrolled patients complete trials,{10} ensuring patient retention through all means is vital to trial execution and research efficiency. Frequent interactions with trial physicians, care coordinators, and staff are vital to these goals—and while technology can supplement in-person interactions to increase those touches, it cannot completely replace the human connection.

“Compassion and inclusivity combined with a community-based approach to patient recruitment is essential,” noted Opraseuth. “As more people within a community become comfortable with clinical research and have a positive experience, they are more likely to become evangelists. Others will listen to familiar faces, and patient recruitment will not be the barrier to research that it is now.”

The proof is in the people—31 cancer drugs have been approved since 2015, yet 24 of the trials for them included fewer than 5% African Americans, despite Blacks making up 13.4% of the U.S. population. Asians account for about 6% of the U.S. population but account for less than 2% of clinical trial participants; and Native Americans and Alaska Natives account for 2% of the U.S. population but were not represented at all in two-thirds of drug trials.{11}

People of all ethnicities are foundational to clinical research, and the physician/patient relationship is the building block for long-term participation in a trial. It also builds trust, something that is especially critical today as public confidence among minority communities has eroded dramatically since the start of the pandemic. Patients develop close relationships with their study coordinators, who spend time engaging on a very personal level and deliver tender care. Coordinators and site staff give hugs, call patients by their first names, and nurture the relationship. In fact, this is the number one determinant of a patient’s completion of a trial. A “siteless” experience takes this away.

DCT technology should assist site administrators in fostering a trusted patient relationship, while at the same time provide improvements in data quality, data collection, study startup speed, informed consent, regulatory compliance, and all the other goals of a well-run trial. In the aforementioned Avoca report from 2020,{9} respondents indicated the two most substantial benefits of DCT technologies are retention of study participants (with a mean score of 4.2 on a 1–5 scale) and diversity of study participants (3.9). Technology along with real-life patient engagement are the one-two punch to overcoming two of our greatest trial obstacles.

Besides the obvious obstacle to better patient recruitment and retention of travel to and from trial sites, patients can also suffer from limitations in handling modern technologies, ranging from lack of familiarity with smartphones to poor WiFi connections in their homes. In these cases, site-driven, hands-on guidance is paramount to the success of a DCT—and is another instance where the personal touch provided by the staff at a high-quality trial site is important.

The Role of Sites Will Evolve, Not Fade

While technology can make onboarding patients into trials easier thanks to eSource, eConsent, and remote monitoring tools, there’s a misconception that these technologies eliminate the need for sites. On the contrary, new DCT technologies open the door for growth and new expertise, including more tech support, but do not change the fact that there needs to be a centralized location for research and the back-end aspects of a well-executed trial.

The life sciences industry is having the wrong conversation. Rather than focusing on cutting sites out of research, we need to discuss how to better support sites. Technology companies and site managers should not be at odds with each other. Instead, they should be collaborators in providing the best patient experience and enabling successful trials.

References

Mary Costello (mary.costello@medable.com) is Head of the Site and Investigator Network for Medable. She has spent more than 30 years in the healthcare and clinical research fields, working in commercial leadership roles with such large organizations as Covance and Thermo Fisher and, more recently, supporting the growth and expansion of eClinical Solutions and Elligo Health Research. She also has served on several industry advisory groups and is a founder and board member of BioAustin.

Are “Siteless Trials” a Paradox or Oxymoron in Modern Clinical Research?

How Did We Get Here?

Caution: Watch What You Say

The Future is NOT All or Nothing

Community Site Connection Drives Diverse Participation

The Role of Sites Will Evolve, Not Fade

References

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