By Jill Waldbieser

For decades, clinical trials—and specifically, randomized controlled trials (RCTs)—have been the backbone of clinical pain research. These experiments are the best way to determine whether a given treatment leads to a specific outcome, while reducing noise from other contributing factors.

But RCTs, which randomly select some participants to receive the studied therapeutic and others to receive a control treatment such as the current standard of care or a placebo, are not without limitations. Pain researchers are increasingly looking outside the lab for answers that these trials alone cannot provide.

The widespread availability of patient data, and the ability to analyze it more efficiently, has made it possible to use real-world data to generate what is termed real-world evidence (RWE). Much of the information informing RWE is provided by patients themselves. The use of this evidence to complement traditional scientific findings is changing the landscape of pain research and influencing health care decision-making.

What is real-world evidence?

RWE explores the impact of promising interventions in real-world settings as opposed to in controlled clinical trials. That concept isn’t entirely new, says Robert Kerns, PhD, professor emeritus and senior research scientist of psychiatry at Yale School of Medicine, and a longtime pain researcher: “People in the field have been doing survey research and observational cohort studies forever for this purpose.”

In the past, however, accessing data wasn’t nearly as easy as it is today. The advent of electronic health records, which are rife with measurable patient data, has accelerated the use of RWE in research, Kerns says.

For instance, he has been active in a work group that studies clinical and administrative data from the Veterans Health Administration to draw insights about opioid therapy and potential long-term effects.

In addition to electronic health records, RWE can come from:

—Insurance claims

—Patient registries

—Pharmacy and prescription data

—Wearable health monitors, fitness trackers, or symptom-tracking apps (collectively called patient-generated health data)

—Online health communities

New data sources continue to emerge, especially with the rapid growth of artificial intelligence tools. “We can now train computers to read narrative progress notes and extract information from written narratives,” shares Kerns.

What’s more, he notes, much of the research can be conducted non-intrusively and without additional patient participation and burden, using already-existing data.

Picking up where trials leave off

While RWE alone can’t determine a treatment’s efficacy, it often supplements clinical findings by providing useful information that can’t be obtained in a structured lab experiment.

Controlled trials allow researchers to determine causality to a reasonable degree of certainty by isolating variables, says John Farrar, MD, PhD, a clinical researcher and professor at the Center for Clinical Epidemiology and Biostatistics at the University of Pennsylvania, focusing on pain therapeutics and clinical trial processes.

If one randomized group receives a new medication while another takes a placebo, and only the first group shows improvements—with all other factors held constant—it’s plausible to conclude the new medication can be credited for the improvement. Additional experiments may then try to replicate the results, and to control for other variables such as comorbidities or nutrition.

But not everything can be controlled—take the efficacy of a medication across varying levels of radiation exposure. You can’t expose half your study participants to radiation, but you can search for clinically important patterns in existing data from individuals who have already been exposed.

“There are lots of things we cannot randomize in patients,” Farrar says. “Real-world data helps us study the things it’s not possible or ethical to study in a randomized controlled trial.”

Benefits and opportunities

RWE can help:

—Assess treatment use in daily life. Research environments are deliberately precise—but real life rarely is. Seeing how people actually use a treatment (or fail to) as part of their normal routine informs approaches to improve adherence.

—Shed light on long-term effects. Trials tend to be relatively small and short-lived. RWE can offer substantial data on how a treatment works over time.

—Show treatment variations in diverse populations. There’s often limited data on how a treatment addresses pain across different age groups, ethnicities, or other populations. RWE can provide more of those insights.

—Highlight possible new indications of existing medications. RWE may suggest that a medication is effective in an area other than its originally approved use.

—Guide future clinical trial design. Analyzing already-existing data from people living with complex pain can help inform which studies are conducted next, and how to design them for the most effective results.

—Address scenarios that trials can’t capture. Clinical trials rarely account for every use case. That’s particularly true for those that are uncommon or whose manipulation may be impractical, unethical, or legally challenging—such as studying medical cannabis. RWE can help fill in those gaps.

—Reduce costs and participant impact. The cost of large-scale, multi-site clinical trials can be significant—and clinical trials generally require more involvement from patient participants compared to real-world data tracking.

The road ahead

To facilitate the actionable integration of RWE into the broader pain research landscape, quality measures must be consistently applied. Farrar co-authored a paper that underscores the value of RWE as a tool to expand evidence beyond clinical trials, while noting that “rigorous quality standards need to be set to maximize the validity of RWE studies.”

RWE creates pathways for broader research involvement. Most patients, says Farrar, “want to be part of the solution.”

“Pain research so heavily relies on people’s reports of their experiences,” adds Kerns. And through real-world evidence, each patient’s individual experience becomes part of a data set that may eventually help inform care and lead to improved treatment approaches for others.