Collaboration Is Key – Real-World Evidence for Decision-Making

As with recent previous ISPOR meetings, there was a very strong real-world evidence (RWE) stream at this year’s ISPOR Europe 2022 conference. In the context of the ongoing formalisation of RWE requirements brought about by the recent publication of guidance documents such as the National Institute for Health and Care Excellence (NICE) RWE framework, and the launch of initiatives including the Data Analysis and Real World Interrogation Network (DARWIN EU), there were several sessions exploring how RWE can be best utilised for the purpose of stakeholder decision-making.1-3

Definition of real-world data (RWD) and RWE

The exact definitions of RWD and RWE vary between different organisations. The US Food and Drug Administration (FDA) define RWD as data relating to patient health status and/or the delivery of health care routinely collected from a variety of sources.4 RWE is defined as clinical evidence regarding the usage and potential benefits or risks of a medical product and is derived from RWD analyses.4

Of key interest was the question of whether manufacturers can successfully navigate the differing remits and requirements of regulatory agencies, health technology assessment (HTA) bodies and payers to produce RWE that can be useful to all stakeholders. Given the varied perspectives of each stakeholder, there was a clear call for collaboration to best facilitate timely patient access to medicines through appropriate use of RWE. This view is aligned with the findings of a recent initiative conducted by RWE4Decisions; a multistakeholder initiative commissioned by the Belgian National Institute of Health and Disability Insurance (INAMI-RIZIV) whose mission is to agree what types of RWD could be collected for highly innovative technologies in order to generate high-quality RWE that can be used to inform decisions by healthcare systems, clinicians and patients.5 As such, cooperation between stakeholders (both between different types of stakeholder, and across geographies) to agree on appropriate standards and use-cases for RWD/E is key to facilitate the growing role of RWE in pharmaceutical decision-making, and to embolden manufacturers to invest in RWD/E as a core piece of their product evidence package.

The alignment of stakeholders with regards to RWE was explored within an issue panel titled ‘European Payer, Regulatory, and HTA Perspectives on RWE: Closely Aligned or Far Apart’.2

Payer Perspective

The payer perspective was provided by Wim Goettsch (Advisor; Zorginstituut Netherland). Based on experiences and survey results from his time acting as the payer representative for the DARWIN EU advisory board, Wim highlighted that although payers are often seen as the stakeholders who are most accepting of RWE, there remains a strong preference for randomised controlled trial (RCT) data for decision-making regarding pricing and reimbursement. Generally, payers tend to perceive RWE as a tool to supplement RCT data and address evidence gaps/uncertainties, rather than a replacement for RCT.2 A summary of potential use-cases for RWE highlighted by payers is presented in Figure 1.

Due to the differing national pricing and reimbursement process within individual European countries, payers can occupy differing roles with varied responsibilities. In some countries the regulatory, HTA, and coverage body (i.e. payer) functions are all performed by a single agency, whereas in others each function is performed by a separate agency.6 As such, obtaining a European payer consensus on the optimum use of RWE by payers is extremely difficult to achieve. Due to perceived utility of RWE by payers, those who have an ongoing responsibility for assessment after a health technology enters the market (e.g. as part of a managed access agreement) are more responsive to the use of RWE compared those payers whose remit is entirely focused on the initial assessment. This highlights a need for different stakeholders to collaborate and agree on suitable evidence standards rather than remaining siloed and looking at evidence through a narrow lens, and is particularly important for highly-innovative technologies where initial assessments may be associated with a high degree of uncertainty.2

Another session focused on the new evidence paradigm brought about by the evolving adoption of RWE in regulatory, reimbursement and other health care decisions. As payers are often the ‘last’ barrier to reimbursement, it is advisable for manufacturers to obtain payer insights throughout the clinical development programme, thus helping to shape the evidence package and ensure that the value of the product in the population of interest is clearly defined with high-quality supportive data.7 This early engagement would help manufacturers to ensure their evidence is relevant and acceptable to payers, however, alignment between stakeholders is also key to ensure evidence generation requirements are practical and actionable for manufacturers.

HTA Body Perspective

The HTA body perspective was provided by Dalia Dawoud (Associate Director; NICE) who highlighted that that a range of RWE was already widely used and accepted in HTA submissions, however, the use of RWE for comparative effectiveness purposes remains contentious.2 In 2021, 80% of NICE’s HTAs included at least one form of RWE, with the European average being 40%.2 Similarly, an analysis of IQVIA’s HTA accelerator platform demonstrated that between 2017–2021 the proportion of European HTA submissions that included at least one form of RWE increased by ~40%, with safety and epidemiology data being the most common RWE applications.8 Interestingly, effectiveness was ranked as the third most common application for RWE in HTA, suggesting that there is a growing appetite for the use of RWE for this purpose. Furthermore, a survey conducted as part of the HTx project found that when RWD was not used, the most common reasons for this were a lack of data or existing policy structures precluding the use of RWD.2

In the context of accelerated regulatory processes which are being put in place to facilitate accelerated access to innovative treatments, data (particularly RCT data) may be limited at the time of HTA assessment, and thus there is likely to be an increasing need for high-quality RWE which can address data gaps within HTA submissions. With this in mind, there is a need for manufacturers to carefully plan and engage with HTA bodies as early as possible, to establish evidence expectations and requirements. In order to build trust in RWE, manufacturers could seek to proactively address likely data gaps with well-planned and high-quality studies, moving away from reactive post-hoc analyses conducted during the HTA process. However, heterogeneous evidence requirements from different HTA agencies currently make it challenging to use the same evidence package across markets. For this vision to be viable, there is a need for HTA bodies to put systems in place to properly evaluate RWE, and for different HTA bodies to align as much as possible on the acceptable use of RWE. Furthermore, given that HTA assessment follows regulatory approval, better alignment on regulatory and HTA requirements is needed to enable RWD collection and RWE generation that can meet the needs of both processes.

Regulatory Perspective

The regulatory perspective was provided by Peter Arlett (Head of Data Analytics and Methods Task Force; EMA). RWE is a key aspect of the EMA clinical evidence vision for 2030, and the EMA is aiming to enable the use, and establish the value, of RWE for regulatory decision making. Peter explained that to establish the use of RWE in the regulatory setting, it is important for regulators to understand the demand for RWE from their committees in order to determine appropriate use-cases for RWE (see Figure 1). To manage the supply of high-quality RWD, the EMA are setting up DARWIN EU, which is a federated network of data, expertise and services that generates reliable evidence from RWD. As part of this, the EMA are collaborating with HTA bodies and payers to best understand their RWE needs and define clear use-cases for DARWIN EU. Regulators from different geographies are also collaborating internationally to converge on RWD and RWE guidance and best practices, which would simplify the RWE landscape for manufacturers.9

Figure 1: The potential applications for RWE throughout the regulatory and reimbursement process are distinct but overlapping

Figure 4


Generally, across sessions there was a consensus that manufacturers should endeavour to be driven by their evidence needs and should allow their research question to determine the most appropriate study choice. Where RWE is deemed the best solution, stakeholders should continue to formalise requirements and outline clear expectations regarding RWD standards, data analytic methods and study transparency/reproducibility to enable manufacturers to develop RWE that meets the expectations of all stakeholders. It is also important that RWD collection is both comprehensive and consistent to ensure that generation of appropriate RWE is not limited by missing or incomplete data.

Despite having differing functions and priorities, stakeholders should seek to collaborate and develop common standards and expectations for RWE usage. The roll-out of DARWIN EU will serve to increase the generation of RWD in Europe. As part of the set-up of DARWIN EU, the EMA have held workshops with both HTA bodies and payers to raise awareness of RWE generation possibilities via DARWIN EU, and better understand HTA, payer and regulator questions of mutual interest suitable for RWE analysis. These workshops aimed to identify possible use-cases for DARWIN EU pilot studies, which demonstrates a growing willingness of stakeholders to collaborate and align on the topic of RWE.2

These activities should serve to drive the generation of high-quality RWE, which is able to add value to product evidence packages and address uncertainties and data gaps in the clinical evidence. Higher quality RWE is likely to instil a greater confidence amongst stakeholders and lead to increased acceptance for RWE where it can add value. More efficient and effective use of RWE will facilitate timely patient access, particularly to highly innovative technologies or in rare conditions when traditional clinical assessments may be particularly challenging.


  1. Session 138.2: Generating High Quality Real-World Evidence for Regulatory Decision Making in Europe. ISPOR Europe 2022, Vienna, Austria.
  2. Session 124: European Payer, Regulatory, and HTA Perspectives on RWE: Closely Aligned or Far Apart? ISPOR Europe 2022, Vienna, Austria.
  3. Session 010: Developing Decision Grade Real-World Evidence. ISPOR Europe 2022, Vienna, Austria.
  4. US Food & Drug Administration. Framework for FDA’s Real-World Evidence Program. Available here. Last accessed: 8 December 2022.
  5. Facey KM, Rannanheimo P, Batchelor L, et al. Real-world evidence to support Payer/HTA decisions about highly innovative technologies in the EU—actions for stakeholders. International Journal of Technology Assessment in Health Care 2020;36:459-468.
  6. Allen N, Pichler F, Wang T, et al. Development of archetypes for non-ranking classification and comparison of European National Health Technology Assessment systems. Health Policy 2013;113:305-12.
  7. Session 230: Generating Payer Insights and Evidence: Meeting the Challenges of The New evidence paradigm. ISPOR Europe 2022, Vienna, Austria.
  8. Session 202: Use of RWE to Support Health Technology Assessment in United States, Europe, and Japan. ISPOR Europe 2022, Vienna, Austria.
  9. ICMRA statement on international collaboration to enable RWE for regulatory decision making. Available here. Last accessed: 28 November 2022.

If you would like any further information on the themes presented above, please do not hesitate to contact Declan Summers, Consultant (LinkedIn). Declan is an employee at Costello Medical. The views/opinions expressed are their own and do not necessarily reflect those of Costello Medical’s clients/affiliated partners.