Real-world evidence in the reassessment of oncology therapies: payer perceptions from five countries

The US FDA defines real-world data (RWD) as data relating to patient health status and/or the delivery of healthcare routinely collected from a variety of sources other than clinical trials [1]. Examples of RWD include data derived from electronic health records, medical claims data, data from product or disease registries and data gathered from other sources (such as digital health technologies) that can inform health status. The FDA defines real-world evidence (RWE) as clinical evidence about the usage and potential benefits or risks of a medical product derived from analyses of RWD [1]. RWE has been used by regulators in market authorization decisions in limited cases, such as for indications with tremendous unmet need or when randomized controlled trials are not feasible. Regulators are more likely to consider RWE when included in historical or external control arms (ECAs), especially for conditions where randomization is less feasible [2,3]. Health technology assessment (HTA) agencies and payers, especially those outside the USA, may limit immediate coverage and reimbursement of some new therapies to better understand the safety, effectiveness and uptake of a new therapy and to consider the therapy in the context of other available treatments. Access decisions are complicated because data from registration trials may be deemed adequate for authorization but insufficient to support pricing and formulary decisions. Variations in assessment and funding models across countries and within countries at the regional or provincial level add to the complexity of planning and executing an evidence package to meet HTA and payer requirements [4,5].

HTA agencies and payers recognize that their coverage and reimbursement decisions must be based on the best available evidence, which will change over time and may require reassessments. A health technology reassessment is defined as a structured, evidence-based assessment of the clinical, social, ethical and economic effects of a technology currently used in the healthcare system, to inform optimal use of that technology in comparison to its alternatives [3,4]. Different payers and decision-making agencies have different triggers for reassessment. For example, reassessments may be scheduled at planned intervals, based on the expected availability of new data, dictated by laws or regulations, or initiated when changes to standard-of-care treatments occur. A managed access agreement provides access to a promising new therapy with high uncertainty, conditional on a reassessment when new data are available. Reassessments are especially important for oncology indications, for which considerable investment is yielding new and innovative therapies and the knowledge base is evolving rapidly.

At reassessment, HTA agencies and payers consider a more complete evidence package that includes updated information about the new therapy. Real-world evidence potentially offers insights on end points over a longer period of time and in a larger, more representative population compared with a traditional registration trial program. This more representative and longer-term data reduces some uncertainty for payers, especially when it includes country-specific or region-specific patient data.

This study summarizes the opinions of expert decision-makers when asked about the value of RWE; typical uses for RWE; and their expectations with respect to RWE design, methodology and communication in the reassessment of oncology therapies. Furthermore, we sought to understand similarities and differences across five countries in Europe and North America, which have different mechanisms for making coverage and reimbursement decisions.

Materials & methods

Study design

A web-based survey was conducted among current and former HTA and payer decision-makers using the Market Access Transformation Rapid Payer Response (RPR) online portal. The RPR portal is a research platform with a current enrollment of approximately 2000 individuals who are or have been involved in value assessment on behalf of HTA agencies or payer organizations from around the world.

For this study, experts were selected from countries representing different payer types. Participants from France, Germany, Spain, the UK and the USA were recruited based on their expertise in determining the coverage and reimbursement of oncology therapies at either a national or regional level. All participants were familiar with current HTA pricing and reimbursement mechanisms for oncology therapies in their country. All had a minimum of 5 years of experience in an HTA or healthcare payer organization and a minimum of 2 years of experience in assessing oncology therapies.

30 current and former payer decision-makers in France (n = 5), Germany (n = 5), Spain (n = 5), the UK (n = 5) and the USA (n = 10) were invited to complete the survey, and all accepted the invitation within 3 days. Of the 30 participants, 23 had experience at the national level and seven reported regional experience. Because any new therapy is assessed by country-specific decision-making agencies via a public procedure in France, Germany, Spain and the UK, participants were selected based on history of employment in relevant organizations at the national and regional decision-making level (Table 1). In the USA, all participants were employed by private insurers, such as managed care organizations, pharmacy benefit management firms and integrated delivery networks.

Participants completed the English-language, web-based survey in the 10-day period from 5 May 2022 to 15 May 2022. Participants were asked to reflect on their experience related to oncology therapies. The questions were based on information obtained from a targeted literature review of primary research focused on HTA agencies and payers and the information they used to inform decisions. Thus, questions were asked on the following issues: sources of evidence important to pricing and reimbursement decisions at reassessment; common uses of RWE by HTA agencies/payer decision-makers; and considerations related to RWE design, methods (including end points) and communications. Participants responded to the questions with answers in multiple-choice, open-text, Likert-type scale, or ranked-choice formats. The questions were designed to collect the opinions of the participants and variations of interpretation were expected. The results are not intended to capture the formal guidelines or the official positions of the organizations from which the participants gained their experience.

Ethics

Participants were compensated in line with a service-level agreement developed by the independent market research agency. Informed consent was obtained in the online questionnaire, which included a statement of voluntary participation and notification that the research was sponsored by a pharmaceutical company for market research purposes and was not promotional. The research was carried out within the Market Research codes of conduct and complied with the European Union (EU) General Data Protection Regulation (GDPR EU 2016/679) [6], the UK Data Protection law [7], and relevant laws for the conduct of market research [8–10].

Statistical analyses

Descriptive analyses of the participants' survey responses were performed. Categorical variables were summarized using frequencies and percentages. Continuous variables were summarized using means.

Results

This paper explores insights related to the reassessment of oncology therapies in three categories: opinions about the current uses of RWE that are important to pricing and reimbursement decisions; perceived value of RWE and country-specific preferences for RWE design, methods and communications.

When asked to rank different sources of evidence by importance to pricing and reimbursement decisions at the time of reassessment, most participants confirmed that clinical evidence from randomized controlled trials is most important. Overall, 23 of 30 participants (77%) ranked clinical evidence from trials as the most important source, including all ten participants from Germany and Spain, four of five in France, one of five in the UK and eight of ten in the USA. After clinical evidence from trials, RWE that provided new data on treatment effectiveness and characterized treatment patterns ranked higher than all other types of evidence, including systematic literature reviews, indirect treatment comparisons, budget impact analyses, cost–effectiveness analyses and patient/physician preference studies. RWE on effectiveness was ranked first or second by three of five participants in Germany, three of five in Spain, two of five in France, one of five in the UK and three of ten in the USA. Payers in the UK expressed a preference for cost–effectiveness analyses compared with other types of evidence for decision-making in their market (three of five participants ranked cost–effectiveness analysis first).

Participants agreed that payer decision-makers most commonly use RWE to confirm whether efficacy and safety results from randomized controlled trials are reflected in real-world outcomes and to confirm the projected utilization of an oncology therapy. Most participants reported that RWE can support the reassessment of oncology therapies by demonstrating long-term effectiveness (27 of 30 [90%]) and addressing safety questions and concerns (24 of 30 [80%]). All participants from France, Spain and the UK and most from Germany (4 of 5 [80%]) and the USA (8 of 10 [80%]) reported that RWE can be used to confirm the effectiveness of an oncology therapy during the reassessment review. When asked if RWE can confirm safety data, all participants from France and Spain and 80% of participants from Germany (four of five) and the USA (eight of ten) agreed. In the UK, two of five participants (40%) responded that RWE could be used to confirm safety results (Table 2).

While the study found agreement across countries related to use of RWE for confirming effectiveness and safety, there was considerable geographic variability when considering other uses of RWE in reassessment. For example, all French and most Spanish and US participants found RWE useful in confirming the level of treatment utilization, but only one of five German participants and two of five UK participants agreed. Similarly, four of five participants in Spain and in the UK would use RWE at reassessment to confirm the cost or economic benefit of an oncology therapy, while half of US, three of five French and no German participants would do so. Similar results were found when participants were asked about the value of RWE in assessing healthcare resource use. Four of five UK participants (80%) agreed that RWE could be useful in assessing resource use, but only one of five German participants (20%) agreed. All five German participants (100%) agreed that RWE could confirm the patient perspective in terms of quality of life and patient-reported outcomes. In contrast, only one participant each in France and the USA reported that RWE could confirm the patient perspective in a way that would be useful for oncology reassessment (Table 2).

How RWE documents were presented mattered to study participants. Most participants ranked peer-reviewed publications ahead of value dossiers, conference abstracts and other forms of communication (29 of 30 [97%]). However, payers from Germany (four of five) expressed a slight preference for value dossiers (Figure 1).

Participants were asked to rate several RWE study design/methodology options based on the potential impact on their decision-making using a scale from 1 to 7, where 1 was no value and 7 was highest value. A mean score from 5.0 to 7.0 was considered high value. Prospective observational studies were rated high value by participants from France (mean score = 6.0), Germany (5.0), Spain (5.6) and the UK (6.0). Product/disease registries were rated high value by payers from France (mean score = 6.0) and the UK (5.6). Participants from the USA did not consider any specific study design to be high value (Figure 2). The preferred end points for inclusion in RWE studies were overall survival, adverse event rates, discontinuation rates and progression-free survival (Figure 3).

Discussion

The results of this survey suggest that payer decision-makers support the idea that RWE plays an important role in informing the reassessment decisions made by HTA agencies and payers when considering oncology therapies. The participants agreed that RWE has a place in evidence generation, but they had differing views on how best to use it. HTA agencies and payers value RWE that confirms clinical evidence from registration trials. The application of stringent methodological requirements is a key determinant of the value of RWE in reassessment decisions. Most participants reported that RWE was useful for confirming treatment utilization, economic impact and healthcare resource use.

Our study confirmed that when RWE measures the impact of a treatment on survival, it can influence payer decision-making. Additionally, the participants in this study agreed that RWE provides more patients than registration trials for evaluating the incidence of adverse events, which can lead to a better understanding of the safety of new therapies. The participants in this study valued safety data from RWE even for cancer therapies. RWE that captures the impact of a treatment on patient-reported outcomes and provides updated estimates for cost–effectiveness models has the potential to inform decision-makers in markets where that information is valued. Results from quality-of-life questionnaires have been shown to predict survival in patients with cancer [11]. The potential exists for decision-makers to consider patient-reported outcome data as part of a larger body of evidence.

Regulatory agencies have issued guidance documents [12,13] and accepted evidence from RWE to fill evidence gaps. In 2021, the FDA approved a modified dosing regimen for cetuximab based on RWE from Flatiron Health, an electronic health record-derived database [14]. Additionally, the FDA and European Medicines Agency (EMA) shared high-level guidance documents describing the characteristics of ECA design [15,16]. Also, several agencies have included data from ECAs in their evaluation of oncology therapies, but lacked alignment in their assessments of the same evidence [3].

We believe that with the availability of resource use data, a larger patient population, and potentially longer follow-up periods, RWE will provide an important source of information for payer decision-makers and reimbursement agencies as well as for regulatory agencies [17]. Some researchers have expressed concern that over-reliance on observational data at the expense of randomized controlled trials could fail to fill the information gaps that are critical to evaluating oncology therapies [18,19]. The results of our questionnaire suggest that payer decision-makers see a place for RWE when the reassessments of oncology therapies are needed.

For all of the countries represented in this study, the availability of new evidence or changes in the market could trigger a reassessment of an oncology therapy [4,20–26]. National agencies in France, Germany and Spain schedule reassessments based on the expected availability of results from additional and ongoing clinical trials [4,26], or reassessments could be triggered if the budget impact of a new therapy exceeds expectations [27].

In France, the Transparency Committee conducts a formal reassessment of all therapies every 5 years or when significant new information becomes available [4,26]. The drug manufacturer may request a reassessment of a therapy [4]. Payers in France emphasized the need for RWE to confirm the safety of an oncology therapy during the reassessment review. RWE can be used to validate the risk-benefit ratio in resubmission dossiers and to confirm long-term effectiveness versus the standard of care [26].

In Germany, data from randomized controlled trials are preferred, and RWE must come from well-designed studies to be considered useful. If those conditions are met, RWE could be used to demonstrate comparative clinical benefit in a target patient population or subpopulation for some therapies that require additional data. Use of RWE in reassessment is possible; however, German decision-making bodies, including Gemeinsamer Bundesausschuss (G-BA) and Institut für Qualität und Wirtschaftlichkeit im Gesundheitswesen (IQWiG), require evidence to meet robust methodological standards [24,25,28]. Reassessments are not mandatory but may be requested by the G-BA or the manufacturer and typically occur at least 12 months after the initial assessment. The payer decision-makers in our study who stated a preference for value dossiers over abstracts may have been interested in seeing more detail on the research than is provided in a conference abstract. In Germany, value dossiers must be submitted for approval as German payers expect to see dossiers and analyze the evidence themselves in advance of a decision.

Payers in Spain may accept RWE and pay-for-performance schemes to corroborate long-term effectiveness and mitigate some safety concerns [29]. RWE may be used to demonstrate the generalizability of efficacy results to local or real-world populations. Reassessments are initiated at the national or regional level, although there is not a clearly defined formal process [4]. Officially, regional agencies are not supposed to deny access to medicines with centrally approved reimbursement, but in practice, within their role of managing and paying healthcare providers, some regional payers apply further criteria [30]. For this study, three of the five participants from Spain had experience in regional HTA roles.

For UK payers, RWE has been used to provide data to populate cost–effectiveness analyses [31]. A recent guideline was published to help researchers develop RWE studies to meet the requirements of the National Institute for Health and Care Excellence (NICE) [32]. NICE has the option to recommend a managed access agreement called the Early Access to Medicines Scheme (EAMS) that allows patients to receive a new therapy while additional data are collected.

The UK acknowledged that a higher threshold for cost–effectiveness was required for oncology therapies compared with other medications to meet the needs of patients, and the Cancer Drug Fund (CDF) was established in 2011. The CDF provided a separate reimbursement path for oncology therapies that did not meet the cost–effectiveness standards for NICE. In 2016, the CDF was reformed to take a more sustainable approach to funding medicines and collecting data. A lack of survival data at the initial assessment of oncology therapies has been identified as an information gap for payer decision-makers in the UK. The CDF has been tasked with using the Systemic Anti-Cancer Therapy (SACT) database to answer some of these questions. The SACT is a UK-specific RWE dataset consisting of routinely collected data from cancer patients. Evidence suggests that this resource has not been fully realized in recent reimbursement decisions [33].

In the UK, the CDF generally reassesses new therapies after 2 to 3 years. NICE typically initiates a review up to 3 years post-approval, especially with changes in the technology/evidence base or clinical practice [4]. In the UK, a reassessment could be triggered if a new therapy is not as cost-effective as expected [4].

The US FDA recently released a guidance document for the use of RWD and RWE to support regulatory decision-making that encouraged sponsors to engage with the agency early in the drug development process [12]. US payers highlight the value of RWE in understanding long-term clinical effectiveness, safety and durability of effect versus standard of care and in helping understand the patient journey beyond registration trials [34,35]. US payers are more likely to use RWE in the reassessment of oncology therapies accepted under accelerated FDA approvals, as well as for cell and gene therapies with high average wholesale prices. In the USA, payers rely heavily on the results of clinical practice guidelines, such as those from the National Comprehensive Cancer Network^® (NCCN^®), to inform coverage decisions [34]. Reassessments are generally conducted annually but could be triggered by other factors, such as changes to the product label, updated guidelines, approval of other therapies, new safety data, unexpectedly high utilization, opportunities for value-based pricing or risk-based contracting or a request from clinicians and patient advocacy groups [34].

While payer decision-makers agree that RWE can contribute to the reassessment of oncology therapies, the wide range of opportunities and diverse needs of different payers creates a challenge for drug developers [17]. Even large registration trials are unlikely to produce or report data from a sufficient number of patients in an individual country or region. RWE can provide decision-makers with the local data that they need and enhance the relevance of information by providing longer-term follow-up and context for local treatment patterns, as well as patient characteristics and end points of special interest.

One recent example of RWE gathered from country-specific data to support the results from registration trials is from the UK. Nivolumab was made available to patients with gastric/gastroesophageal junction cancer in the UK under EAMS. Nivolumab had demonstrated clinically meaningful anti-tumor activity with favorable overall survival and safety results in two clinical trials (ATTRACTION-2 [36] and CheckMate-032 [37]). An RWE study was designed to capture disease progression, overall survival and health-related quality of life in the patients who received the therapy under the EAMS [38]. The 6-month results aligned with the results of the registration trials [39].

Our study is not without limitations. The results presented in this paper focus on the reassessment of oncology therapies. The target markets were selected to capture a range of healthcare payer types. However, the number of participants per country was small. For the countries on the European continent, only five payers with expertise in each market were surveyed. The USA has a more diverse mix of payers, so twice as many payers from the USA were included. Thus, the overall survey results are not equally representative of the countries of interest. Some questions may have been interpreted differently by different participants. The results of this exploratory analysis of survey data provide an indication of the opinions of experienced payer decision-makers based on practices from different regions. Response bias is a potential concern for survey studies. For example, the participants may have felt obligated to respond more positively to some questions to please the researcher. However, the surveys were emailed instead of conducted in person to reduce response bias due to the presence of a researcher.

High-quality RWE is required to minimize the risk of bias so decision-makers can trust the results. The application of rigorous research methods will improve the viability of RWE [40]. Higher-quality RWE will use standardized methods and procedures to harmonize study designs and outcomes (e.g., STaRT-RWE template [41], EQUATOR network [42], PICOTS framework [43] and International Consortium for Health Outcomes Measurement [ICHOM] indicators [44]). Developing international standards for RWE data collection and data sharing has been identified as an important component of collecting meaningful RWE [45]. The International Society for Pharmacoepidemiology (ISPE) and the Professional Society for Health Economics and Outcomes Research (ISPOR) recently published a consensus statement by their joint task force that describes a harmonized protocol template for RWE studies designed to evaluate a treatment effect and inform decision-making, called the HARmonized Protocol Template to Enhance Reproducibility (HARPER) [46]. A survey of decision-makers in central European countries identified international collaboration and political support as potential solutions for overcoming the barriers to the use of RWE in HTA assessments [47].

RWE studies that are conducted with input from payers and key opinion leaders can close the gap between what is known at initial assessment and the comprehensive informational needs of stakeholders [48]. National and international organizations are forming to establish standards for developing, conducting, and reporting RWE that aim to address changing market dynamics and pharmaceutical innovations, including the entry of new competitors [12,49,50]. A partial list from the countries considered in this study is included in the supplemental material (Supplementary Table).

When standard study designs/methodologies for collecting RWE develop, studies can be replicated and validated across countries. Decision-makers in individual countries and markets will be more confident that the results of RWE studies describe their population, reflect the standard of care in their country, and cover a timeframe that is relevant to their patients of interest.

Researchers should consider the areas of uncertainty that are of concern to payer decision-makers at the time of the initial assessment and design RWE studies that can help fill the information gap [51].

Improvements in electronic medical record data capture will provide additional opportunities for developing RWE studies [52,53]. With the creation of disease-specific registries, randomized prospective RWE studies should be designed and implemented in specific patient populations. Research objectives, well-designed hypotheses and statistical protocols should be developed in advance of the studies [54,55]. If RWE is used to support reassessment of a new or conditionally approved oncology therapy, transparency is key to acceptance of the results. Creating a scientific committee that includes international and national experts to advise on publication strategy (e.g., sequence of topics, journals) is important for sharing both the plan for the research and the results. Protocols for RWE studies should be publicly posted to clinicaltrials.gov or other publicly available sources [12,32,56].

Researchers must generate RWE to the highest possible standards to build trust and deliver credible information that provides value to payers, providers and patients. Researchers and manufacturers should work with key opinion leaders and payers to develop a comprehensive plan to provide information for reassessments at the appropriate intervals. The goal should be to identify the information that is lacking, develop RWE assessments to best fill the information gap, publicly share the study plans and results, and prepare the data package to deliver an up-to-date view of the therapy. The provision of consistently valuable and reliable RWE will help stakeholders better understand the role of RWE and increase its value in decision-making. Because of rapid market changes and opportunities for combination treatments, oncology therapies are well suited to lead the way on this important initiative to highlight the need for comprehensive RWE.

Conclusion

RWE can play an important role in informing HTA and payer oncology therapy reassessment decisions. However, organizations generating and communicating RWE need to ensure that their RWE plans recognize the heterogeneity in how different HTA agencies and payers perceive the value of such evidence. A comprehensive RWE generation plan will be responsive to how different types of HTA agencies and payer organizations view the acceptability of RWE. Using a range of information to improve access to the most effective oncology therapies at approval and reassessment provides options for patients and providers but requires a comprehensive approach to collecting and communicating RWE.