RWE Is Growing Up, And Here's Why That Matters
By Dan Schell, Chief Editor, Clinical Leader
Until recently, I knew ISPOR — The Professional Society for Health Economics and Outcomes Research — mostly by name. When I sat down with the group’s Chief Science Officer, Laura Pizzi, MPH, PharmD, it was my first deep dive into the organization and its role in shaping how we think about health economics and outcomes research (HEOR). What I found was a pragmatic, global-minded view of real-world evidence (RWE); one that’s both hopeful and candid about where the field still needs work.
Pizzi, who has been a member of ISPOR since 1996 and joined its leadership four years ago, sees RWE moving from the margins of drug development to the mainstream. But she’s also quick to note that the field’s challenges — data quality, trust, and regulatory clarity — aren’t going away anytime soon.
WHY RWE’S “MOMENT IN THE SUN” HAS ARRIVED
When I asked Pizzi why this is RWE’s time, she pointed first to the pipeline. “We continue to have a biomedical innovation pipeline dominated by rare disease drugs,” she said. That creates an obvious problem for traditional randomized controlled trials: too few patients. RWE can help fill those gaps, particularly through the use of external control arms designed from real-world data sources. Regulators in both the U.S. and Europe are starting to accept these approaches. (For more on how synthetic control arms function, I’ve written about the concept here.)
It isn’t just rare diseases driving demand for RWE. The volume and variety of available data have exploded, far beyond the billing claims datasets that once defined the field. EHRs, patient registries, and linked databases now offer insights into treatment patterns, costs, and outcomes. “On the technical side of things, there’s more data [than just claims data], and it’s becoming more reasonable to answer more complex scientific questions with it,” Pizzi noted.
PRAGMATIC TRIALS BLUR THE LINES
One of the biggest shifts she highlighted is the move toward pragmatic, or adaptive, trials that embed real-world data (RWD) directly into study design. These trials don’t just compare RWD to clinical data, they integrate it.
For example, she described a current project on medically tailored meals for patients with diabetes in Philadelphia. The trial tracks clinical endpoints like blood glucose and A1C levels, but also pulls in RWD on ER visits and outpatient healthcare utilization. The benefit, Pizzi said, is a richer, more inclusive picture of impact. The downside? Complexity. “In some ways, it becomes two studies you’re running at the same time; one with clinical data and one with real-world data,” she said.
Still, the inclusivity benefits are significant. Pragmatic trials can reach patients who might otherwise be excluded, which opens the door to addressing health equity and reducing disparities in care.
TRUST AND QUALITY REMAIN STICKING POINTS
Globally, regulators understand they need RWE. The challenge is figuring out how to use it for high-stakes questions like effectiveness and safety. Pizzi pointed to “target trial emulation” as a promising method . In this approach, researchers formally design an RWE study as if it were a traditional trial — with prespecified hypotheses, design, intervention, outcome measures, and analysis plans — then apply it to a real-world dataset. Harvard’s ongoing RCT Duplicate project with FDA is one large-scale example.
But even the best methods fail if the data are flawed. “We don’t really have much information on the traceability of most real world datasets,” Pizzi said. Regulators want confidence in who collected the data, how it was processed, and what quality checks were applied. ISPOR is currently launching a project to help researchers ask the right questions of data providers before building studies.
And while regulators may be cautiously open, payers and health technology assessment (HTA) bodies are less convinced. Many still see RWE as inconsistent or insufficient to fill evidence gaps. Pizzi suggested the problem lies not just with the data but with trust. “Maybe the future is one where they’re partners in building RWE, not just recipients of it,” she said.
ISPOR’S TRANSPARENCY INITIATIVE
One of ISPOR’s signature efforts in RWE has been its Transparency Initiative, now more than a decade old. At its core is a simple idea: make protocols and methods openly available before studies begin.
The Harper Template, ISPOR’s most widely cited guidance, provides a standard way to prespecify RWE protocols. CMS has adopted it for medical device work, and international regulators have also cited it. ISPOR also runs a free public protocol registry through the Center for Open Science, which regularly receives new submissions .
More recently, the organization introduced a “badging” system in its Value in Health and Value in Health Regional Issues journals. Authors can earn badges for their paper if they have pre-registered their RWE protocol, shared methods, or made datasets publicly available. It’s a small step, but Pizzi sees it as a powerful way to signal credibility: “When that paper is used by a decision-maker down the line, having a badge is like a seal of approval.”
A SEA OF GUIDANCE
With so many groups releasing RWE guidelines, harmonization is another growing need. Pizzi described today’s environment as a “sea of guidance” — well-intentioned but overwhelming for companies trying to navigate different standards across different regulators, HTA bodies, and countries.
Some progress has been made on the regulatory side, including recent moves within the International Council for Harmonisation (ICH). But HTA bodies are still largely fragmented. New collaborations, like the Health Economics Methods Alliance (involving NICE, Canada’s CDA, and ICER in the U.S.), may eventually be in a position to support cross-country RWE methods harmonization.
ISPOR, for its part, doesn’t aim to add to the noise. Instead, the organization focuses on “good practices” in emerging areas where guidance is thin, such as feasibility assessments for RWE. As Pizzi put it, “We’ emphasize earlier stages of the guidance pipeline — identifying scientifc gaps and setting the foundation to address them.”
Talking with Pizzi left me with the impression of a field in adolescence: no longer experimental, but not yet fully mature. Regulators are cautiously embracing RWE, payers remain skeptical, and researchers are still wrestling with questions of quality, transparency, and feasibility.
But ISPOR’s role is clear — to set standards, promote trust, and build bridges between the scientists generating RWE and the decision-makers relying on it. If the next decade delivers on even half the promise Pizzi outlined, RWE could move from “moment in the sun” to a mainstay of the evidence hierarchy.