Overcoming Hesitancy to Include Real-World Evidence (RWE) in Reimbursement Submissions

Boasting at the top of the list of ISPOR’s Top 10 HEOR Trends since 2020, “leveraging the power of RWE” continues to be a hot topic in the field and was a major theme of plenaries, short courses, and breakout sessions alike at ISPOR International 2024 in Atlanta.

The short course that I attended focused exclusively on developing decision-grade RWE, highlighting the RCT-DUPLICATE trial which investigated the ability of database studies to generate similar causal conclusions about the effectiveness of medications as RCTs.¹ The study found a high level of agreement between the two, particularly when study design allows for closer emulation of an RCT. However, it also identified that this close emulation can be difficult to obtain due to confounding and incomplete information on design and analysis implementation.¹

HTA bodies have recognised target trial emulation (TTE) as a best practice when generating RWE. Similar to what was employed in the RCT-DUPLICATE study, this methodological approach is used in observational research to emulate the hypothetical design of an RCT.² The goal is to reduce bias and confounding that are often present in observational studies, and thus produce more reliable and causally interpretable results.²

Despite published literature and endorsements from both HTA bodies and the US FDA through the release of RWE frameworks to guide the quality of evidence included in submissions, RWE remains underutilised.² While there is broad consensus on the potential power of RWE, the practical challenges of fully leveraging it, especially in the context of evidence for reimbursement, have created a gap between expectations and reality.

So, what is the reason for this gap? ISPOR discussions highlighted current issues in the development and submission of decision-grade RWE to HTA bodies. A poll in one session indicated that 40% of the audience were sceptical regarding HTA bodies’ acceptance of RWE and another 40% self-reported that they had a lack of in-depth understanding of TTE and other robust methodologies to make RWE decision-grade.² Scepticism around the inclusion of RWE in HTA was also a topic widely discussed at ISPOR EU 2023, as outlined in our post-conference commentary.

However, at ISPOR International 2024, there was direct encouragement from representatives of HTA bodies along with other session hosts that in the appropriate context, RWE can and should be a supportive addition to an HTA submission. Multiple breakout sessions and short courses discussed ways to overcome hesitations, highlighting common mistakes or examples of poor reporting, key components of a successful HTA submission through case studies, and details on methodologies that can be used to improve the quality of evidence.^1-4

Three ways to improve the robustness of RWE to make it decision-grade were shared:

1. Clarifying Trade-offs and Uncertainties: Manufacturers should explicitly address the trade-offs involved in study design, including the choice of eligibility criteria, treatment strategies, and the handling of uncertainties within the study framework. If employing TTE, the hypothetical RCT being emulated should be clearly defined
2. Demonstrating Suitability of RWE Sources: Selection of real-world data sources is critical. Submissions should detail the relevance of the data to the context, the rationale behind dataset selection, patient inclusion criteria in the database, and the extent to which relevant confounders were captured. Discussing missing data and imputation methods is also paramount
3. Adapting Complex Analytical Methodologies: Powerful causal inference methods such as Augmented Inverse Probability of Treatment Weighting and Targeted Maximum Likelihood Estimation can be applied to help account for confounding factors in RWE studies while resulting in narrower confidence intervals and more precise effect estimates⁴

In summary, when conducted well, the inclusion of RWE in a reimbursement submission can provide a more robust evidence package. However, in order to leverage the power of RWE and ensure it is decision-grade, manufacturers should be meticulously prepared to address potential concerns of HTA bodies and be clear in their description of the methodology used. As the landscape evolves, the role of RWE and best practices such as TTE are poised to become increasingly central, necessitating a comprehensive understanding and strategic application of these methodologies.