New report explores health technology assessment body and regulator collaborations to address evidence challenges and uncertainty for timely patient access 

A newly published position paper, ‘Joint HTAb-regulatory perspectives on understanding evidence challenges, managing uncertainties and exploring potential solutions,’ outlines how European HTA bodies and regulators can reduce uncertainty at market entry through early collaboration, improved trial design, and better use of data. The findings aim to support more aligned decision-making and accelerate patient access to innovative treatments. 

The paper outlines key findings from a series of workshops between Health Technology Assessment bodies (HTAbs) and regulatory authorities. The discussions focused on improving mutual understanding of evidence needs and addressing shared challenges at the time of market entry. 

Using three case studies on onasemnogene abeparvovec (Zolgensma) for spinal muscular atrophy, amivantamab (Rybrevant) for non-small cell lung cancer, and axicabtagene ciloleucel (Yescarta) for aggressive B-cell lymphomas, participants examined the types of uncertainty commonly encountered in assessments. These included the lack of comparative evidence, immature data, and limited relevance of surrogate endpoints. Additional challenges were noted around intercurrent events, trial recruitment in small or rare populations, limited knowledge of disease pathways, and the complexity of evaluating multiple therapies being developed in parallel. As the report notes, these issues often result in, “limitations in the ability to obtain adequate additional evidence when new treatments have become available.” 

Michael Berntgen (Head of Scientific Evidence Generation, European Medicines Agency) stated on LinkedIn that: 

“Clinical evidence needs to address the needs of different decision-makers to enable access to innovation for patients.”  

A central theme across the workshops was the importance of early and ongoing collaboration between HTAbs and regulators, from initial trial design through to post-launch evidence generation. The report also highlighted, “a strong preference for randomized evidence from both regulators and HTAbs when assessing benefit/risk and comparative effectiveness.” When standard randomized controlled trials (RCTs) are not feasible, particularly in rare or pediatric diseases, novel designs such as adaptive or platform trials are seen as important alternatives. As the Institut für Qualität und Wirtschaftlichkeit im Gesundheitswesen (IQWiG) noted on LinkedIn;  

“For challenging situations such as small patient populations, novel randomized study designs are seen as a promising alternative to single-arm studies.” 

To address remaining uncertainties, participants also highlighted the value of pragmatic and registry-based randomized trials, which can complement pre-licensing clinical data. Conducted in real-world settings, pragmatic RCTs can provide evidence on effectiveness in broader patient populations and help compare treatments not previously studied. Registry-based RCTs offer efficient platforms for recruitment and data collection, particularly post-launch. The timely availability of individual participant data (IPD) from such trials is also seen as critical to support robust evidence synthesis, indirect comparisons, and meta-analyses.  

The estimand framework was highlighted as a valuable shared language for aligning trial design with the evidence needs of both regulators and HTAbs. Since each may require different estimands for decision-making, trials should be designed to estimate multiple estimands in parallel, supported by appropriate sensitivity analyses. Harmonizing estimands across studies can improve treatment comparisons and support consistent conclusions about efficacy and effectiveness. 

While real-world data (RWD) can provide valuable context, such as understanding treatment patterns or informing trial design, the report highlights significant concerns when RWD is used for effect estimation in indirect comparisons. These analyses are often conducted post hoc, without sufficient planning or adjustment for confounding, and are not considered suitable as confirmatory evidence. Reliable use of RWD requires a well-designed approach and access to high-quality, granular data. 

Ultimately, both HTAbs and regulators emphasized the need for structured, transparent approaches to decision-making under uncertainty. Developing shared methodologies and integrating measures such as health utility data into clinical trials may support better-aligned assessments. The report concludes that proactive evidence planning, starting early in development and informed by both regulatory and HTA needs, can improve the robustness of decision-making and help ensure timely access to innovative treatments.