By Deborah Borfitz 

May 12, 2021 | Pragmatic clinical trials (PCTs) require a more nuanced playbook than traditional explanatory studies when it comes to informed consent and respect for individuals, according to Stephanie Morain, Ph.D., MPH, assistant professor in the Center for Medical Ethics and Health Policy at Baylor College of Medicine. New models for engagement, transparency, and accountability will also be needed to accommodate the scale and heterogeneity of PCTs. 

The established regulatory framework was designed for decision-making about the risks and benefits of enrolling in placebo-controlled studies where participants are closely monitored for adherence to an allocated treatment regimen with relatively few confounding factors. But PCTs are intended to evaluate the effectiveness of interventions under messy, real-world conditions and may involve an enormous number of individuals who may or may not be aware of their participation, says Morain. 

They also produce broadly generalizable results that can be used to improve clinical care, she adds. The motivations and rationales for conducting PCTs align well with “learning health systems” endeavoring to generate better evidence to drive medical decision-making based on the real-world needs of patients and healthcare providers. 

The learning health system is a model proposed by the National Academy of Medicine for offering the best care at a lower cost, where patient‐engaged research is the default rather than the exception, Morain says. It is an “aspirational vision” that large health systems, notably Intermountain Healthcare and Geisinger, have been actively working to achieve.

The goal with PCTs is to efficiently generate research that is more reflective of the underlying patient population, she explains. Traditional clinical trials, in contrast, often exclude individuals with comorbidities like heart disease and hypertension that can limit the relevance of their findings for real-world clinical care.

Currently, PCTs are being conducted by health systems that stand to benefit from enhancing patient outcomes and optimizing resource use. They can be done much more rapidly than traditional clinical trials, says Morain, and at a fraction of the per-patient cost because of lower administrative overhead. 

PCTs are often “large, randomized, incredibly rigorous trials,” says Morain, and arguably provide more relevant data than standard clinical studies. The challenge is in implementing change within healthcare systems. PCTs may need to demonstrate relatively large effect sizes to get stakeholders to adopt new clinical care practices—particularly if what they are already doing is working reasonably well. 

Funding for PCTs has come largely through the Patient-Centered Outcomes Research Institute (PCORI) and the NIH Collaboratory, says Morain, who sits on the Collaboratory’s Ethics and Regulatory Core. The Collaboratory sponsors the broader infrastructure supporting the use of PCTs at scale, which also includes core working groups focused on biostatistics and study design, electronic health records, health care systems interactions, and patient-centered outcomes.

Big And Fast

As a rule, PCTs either compare therapies already approved by the Food and Drug Administration or different health system practices to see which ones work best for patients, says Morain. One example is the Active Bathing to Eliminate Infection (ABATE) trial, supported by the NIH Collaboratory, the results of which published two years ago in The Lancet (DOI: 10.1016/S0140-6736(18)32593-5).

The ABATE trial tested different antiseptic bathing techniques and decontamination strategies for preventing healthcare-acquired infections outside of the intensive care unit, says Morain. It was conducted at 53 HCA hospitals over a 21-month period and engaged 330,000 patients. A nasal infection-control technique and patient bathing with chlorhexidine were found to reduce bloodstream infections by 31% and, importantly, lowered infection with antibiotic-resistant bacteria by 40%.

The University of Washington collaborated with Kaiser Permanente, Northern California Kaiser Permanente Washington Health Research Institute, Mayo Clinic Health System, Henry Ford Health System, and Oregon Health and Science University on the Lumbar Imaging with Reporting of Epidemiology (LIRE) trial, whose results published in JAMA Network Open last fall (DOI: 10.1001/jamanetworkopen.2020.15713). This PCT demonstrated that inserting epidemiologic benchmarks into lumbar spine imaging reports read by primary care physicians reduced subsequent opioid prescriptions, Morain says. 

The LIRE trial involved over a quarter million patients randomized at the clinic level to either have or not have the provisional information available to their doctor when discussing appropriate next steps, she says. Participants had imaging of their backs done over a three-year period, and data analysis took just under a year.

Pragmatic trials have also been conducted to compare different drugs within a class or the best time to take a medication—both of which have “huge implications for population health” as well as the cost and efficiency of healthcare delivery, says Morain. Drug companies have no obvious incentive to do such trials, she adds. “They are generally not looking to demonstrate their drug is better than someone else’s on the market, just that it meets a certain threshold for approval and to be covered by insurance.” 

With the Time to Reduce Mortality in End-Stage Renal Disease (TiME) study a few years back, the focus was on the appropriate length of time for a dialysis session, she says. The University of Pennsylvania teamed up with Fresenius Medical Care North America and DaVita Clinical Research to conduct the TiME study to see how session length relates to survival, hospitalization, and quality of life for patients with kidney failure.

The trial enrolled more than 7,000 patients over more than five years but was terminated in 2019 because intervention uptake was insufficient to determine whether use of longer hemodialysis sessions improves outcomes, she says. The lesson learned here was that effective approaches for engaging clinical personnel and patients are required to evaluate interventions fully embedded in care delivery.

Respect-Promoting Practices 

It is often impractical, even unnecessary, to do prospective individual informed consent for a pragmatic trial because of its size and the fact that the risk profile of people receiving care inside and outside of the study may not be meaningfully different, says Morain. A PCT might, for example, randomize people newly diagnosed with diabetes or hypertensions to one of two standard-of-care treatments where there is no current evidence which one is better to enable better downstream decision-making. 

The infeasibility of obtaining informed consent from participants up front highlights the importance of employing other respect-promoting practices—specifically, engagement, transparency, and accountability, she says. Health systems might seek the buy-in for a PCT from the larger patient community, based on which types of trials they believe should be prioritized over others and the likely value of the research in improving clinical care. 

Patients can be similarly engaged in decisions about when informed consent should be waived and, if so, what new trial features they might embrace. For the ABATE trial, for example, flyers were put out in clinics where patients were being randomized so patients and their families knew the trial was underway, she says. 

The tradeoffs to be discussed will differ depending on whether the PCT is an “A vs. B trial” comparing two standard-of-care options or an “A vs. A+ trial” where the standard of care is being supplemented with an additional intervention thought to be helpful but with limited evidentiary support, she notes.     

For organizations that have committed to becoming a learning health system, it is crucial that they demonstrate accountability by not just doing the research but applying what is learned moving forward, Morain continues. Even if patients are being asked to take on “very minimal” risks or burdens as trial participants, such as filling out a few more questionnaires, it creates an additional obligation to use that socially valuable information for the betterment of clinical care if that is the justification for streamlining or eliminating informed consent 

That means having integrated processes, perhaps through an electronic heath record system, to bring the evidence to bear at the point of care. Whether that is instructing patients to take their blood pressure medication at night or in the morning, or the step-by-step instructions on the antiseptic bathing practices to follow to reduce infections, health systems need a mechanism in place to facilitate systemwide adoption. 

Unique Challenges

In the broader world of clinical trials, the return of study results to participants is one way to demonstrate respect and gratitude for their contributions, as well as increase trust and engagement in the research enterprise. That is problematic for PCTs, where participants may not even know they were enrolled in the study in the first place, says Morain. The sharing of individual or aggregate results would also need to happen differently if the study involved several hundred thousand rather than a few hundred participants.

A related challenge is that some PCTs “look more pragmatic than others,” she adds. “I might argue that there are different obligations to individuals based upon how much that trial in any way changed the clinical care they otherwise would have received.” 

The engagement of patients, as a demonstration of respect, plays to the patient-centric notion of “nothing about me without me… especially if we can’t ask people for their prospective permission,” Morain says. It extends to conversations with patients and their delegates about what matters to them, what trials should move forward, and how best to design studies for certain populations. 

“People generally prefer to be asked in advance for their participation [in a specific study] with traditional written informed consent,” she says. But when they understand the tradeoff of doing that may make the research hard to do at all, they are “generally willing to move toward a more streamlined model.” The question here is how to address the minority of individuals who “just say no” to that approach. 

A fully realized learning health system might adopt a policy whereby patients, in choosing to be treated there, are also agreeing to participate in certain low-risk trials with broad population health importance, Morain says. The policy might be brought up with any new patient entering the system or written as a “contract” of sorts spelling out the obligations of the organization (to use the best possible data at any given time) and patients (to participate as needed in PCTs with waived or streamlined consent). 

In deciding what consent and oversight practices are appropriate for a given PCT, Morain says, it is important to remember that what people will tolerate may be more important than what they prefer because what is being studied often has potentially high societal value and the burden of research participation is relatively low. “That calculus means that what we shouldn’t necessarily… optimize for every given individual.” 

The goal is instead to identify the “overlapping priorities and preferences and values by which we can realize benefits for as many people as possible,” Morain continues. But the majority cannot always rule on what is considered acceptable, she quickly adds, because that is how the interests of disadvantaged minority groups have historically been superseded. “It’s important when looking at what the general attitudes are to look at who holds them... to ensure we are not reinforcing existing health inequalities.”

Collateral Findings 

Someone also must oversee collateral findings from PCTs unrelated to the primary research question, Morain stresses. “We need to anticipate and prospectively plan for what we might find and how we manage that downstream,” including the obligations of the research team and larger healthcare system. 

In a pragmatic trial like LIRE with 270,000 participants, the data analyst is not going to have a relationship with individual patients, she says. That reality is going to impact the ability to notify patients of unanticipated findings and, potentially, downstream management of those unforeseen issues. 

Radiologists or orthopedists may have the necessary clinical knowledge to manage collateral findings but also may have no preexisting relationship with study participants, Morain adds. Without an institutional point person for whom this is a defined responsibility, “it is very easy to assume someone else has picked up the ball.” 

The management of collateral findings is not a topic that has received much attention to date, says Morain. She proposes that PCT funders such as the NIH Collaboratory and the PCORI start requiring researchers and institutions to have a proactive plan in place as a condition of grant awards.