Introduction
The increasing digitalization of healthcare data offers novel opportunities to leverage real-world data (RWD) to inform the evaluation of health technologies and advance our understanding of diseases and care pathways. The European Medicines Agency (EMA), and the Food and Drug Administration (FDA) encourage the use of RWD to generate real-world evidence (RWE) to support decision-making (Reference Arlett, Kjaer, Broich and Cooke1–4). Overall, the submission of RWE to regulators and health technology assessment (HTA) bodies is increasing (Reference Flynn, Plueschke and Quinten5, Reference Cave, Kurz and Arlett6).
Simultaneously, technological advances like genomic sequencing and its growing integration into healthcare systems contribute to better disease characterization, thereby increasing the diagnosis rates of rare and ultra-rare diseases (Reference Marwaha, Knowles and Ashley7–Reference Turnbull, Scott and Thomas13). These advancements enable the development of targeted and advanced therapy medicinal products (ATMPs), often aimed at addressing high unmet needs in rare diseases. Orphan and targeted therapies, including ATMPs, often face challenges in adhering to conventional randomized controlled trial (RCT) methodologies, with one key challenge being the recruitment of eligible patients (Reference Groft and Posada de la Paz14). Hence, implementing robust traditional RCTs suitable for regulators and HTAs may be unfeasible in this context (Reference Eichler, Pignatti and Schwarzer-Daum15). As a result, the number of new technologies using single-arm trials (SATs), instead of RCTs, has increased over the last decade (Reference Agrawal, Arora and Amiri-Kordestani16). In this context, leveraging RWE to reduce the uncertainty around SATs, such as through external control arms (ECAs), has become increasingly relevant. Still, in the context of assessing treatment effectiveness, RWE generated from RWD can also be leveraged to support label expansions (Reference Baumfeld Andre, Reynolds, Caubel, Azoulay and Dreyer17). Additionally, RWE can inform other aspects of the HTA process such as characterizing the size of the target population.
Despite the increasing integration of RWE into HTA, the acceptance and evaluation criteria for RWE vary between countries and often remain unclear. To date, most research examining the acceptability of RWE focuses on regulatory decision-making bodies, such as the FDA or EMA, rather than European HTA bodies (Reference Flynn, Plueschke and Quinten5, Reference Cave, Kurz and Arlett6, Reference Arlett, Kjaer, Broich and Cooke1 Reference Kumar-Sinha and Chinnaiyan8–Reference Hatswell, Baio, Berlin, Irs and Freemantle20). Although HTA bodies have recently published RWE guidance documents and position papers, the appraisal criteria remain vague and fail to address all potential uses of RWD (21–Reference Jaksa, Wu, Jónsson, Eichler, Vititoe and Gatto26). Hence, we conducted this study to inform the value of RWE for European HTA, and the criteria driving the acceptance and design of robust ECAs to support HTA decision-making.
Methods
This review implemented several approaches to unravel the value of RWE for European HTA decision-making focusing on five agencies: the Agencia Espanola de medicamentos y productos sanitarios (AEMPS) in Spain, the Gemeinsamer Bundersausschus (G-BA) in Germany, the Haute Autorité de Santé (HAS) in France, and the National Institute for Health and Care Excellence (NICE) in the United Kingdom (UK), and Agenzia Italiana del Farmaco (AIFA) from Italy. The information gathered to inform the acceptance criteria and the value of RWE for decision-making was extracted from three main sources: HTA documents containing RWE, HTA expert interviews, and RWE guidance documents published by the HTAs included in this study.
This study adhered to the definition of RWD provided by the EMA and the International Society for Pharmacoeconomics and Outcomes Research (ISPOR), as health data collected outside the context of RCTs and RWE as any meaningful and robust analysis of RWD (Reference Cave, Kurz and Arlett6, 2 Reference Marwaha, Knowles and Ashley7).
Literature Review
A targeted literature review was conducted to identify examples of technologies that used RWE in their regulatory evidence submissions. The search was limited to English, from 2015 to 2022 in the MEDLINE database using the following search string: (Real-world [ti] OR RWD [ti] OR RWE [ti] OR observational study [ti] OR External Control Arm [ti]) AND (Regulatory approval [ti] OR Regulatory Agencies [ti] OR European Medicine Agency [ti] OR EMA [ti] OR FDA [ti] OR food and drug administration [ti]). Only technologies that received marketing authorization from the EMA were included. The objective of the literature review was to identify examples of technologies using RWE in their submission package extracting insights regarding the criteria driving the acceptability and value of RWE. Systematically capturing all the technologies approved using RWE was out of scope, since after reviewing more than 10 technology reports, the insights extracted were considered redundant. Ten technologies spanning 12 indications were included to represent a wide range of RWE use cases and therapeutic areas (Reference Cave, Kurz and Arlett6, Reference Arlett, Kjaer, Broich and Cooke1 Reference Kumar-Sinha and Chinnaiyan8–Reference Hatswell, Baio, Berlin, Irs and Freemantle20,Reference Bolislis, Fay and Kühler27).
The HTA reports were retrieved and reviewed to assess the inclusion, acceptability, and potential impact of RWE on the final reimbursement decision. The reimbursement status and consequent availability of the technologies in their respective markets were also extracted and complemented with the NAVLIN database. For Italy, only the technology’s reimbursement status was retrieved from the Italian Gazzetta Ufficiale, as no HTA reports were available.
Differences exist in the criteria used by HTA bodies in the EU4 and UK to appraise technologies. The AEMPS and AIFA largely focus on budgetary impact analyses, whereas HAS and the G-BA prioritize clinical relevance over economic considerations. In contrast, the UK’s NICE places significant emphasis on cost-effectiveness analyses and incorporates quality-adjusted life years (QALYs) and incremental cost-effectiveness ratios (ICERs) to guide reimbursement decisions within the National Health Service (NHS).
Reimbursement status was categorized into (Reference Arlett, Kjaer, Broich and Cooke1) fully reimbursed when the reimbursed population matches the population indicated in the EMA label, (2) conditionally reimbursed, when post-marketing commitments to submit additional evidence are imposed, (3) restricted reimbursement, when the reimbursed population is narrower than that indicated in the EMA label and (4) not reimbursed when the technology is not approved by HTA bodies for funding.
The RWE acceptance status in each technology’s HTA assessment was determined based on references or appraisal of RWE and categorized into five groups: (1) RWE accepted to support efficacy, (2) RWE accepted as “disease background” (e.g., the burden of disease or natural history of the disease) (3) RWE “neutral connotation,” when the RWE was identified, however, no further evaluation of the evidence was found, (4) RWE is not included, and (5) RWE is not accepted when RWE was identified and appraised in the HTA report and a negative connotation(s) regarding the acceptability of the RWE was identified or inferred.
A set of best practices to support the design and implementation of an ECA was developed based on the RWE appraisal extracted from the HTA reports, complemented by the expert interviews and guidance documents reviewed.
Semi-structured expert interviews
Six online semi-structured 90-minute interviews with six country-specific HTA experts were conducted (two for the UK, and one expert each from France, Germany, Italy, and Spain) between September 2022 and December 2022. The experts recruited were selected for having at least 10 years’ experience in the HTA process of their respective country of expertise, such as being involved in dossier submissions and/or holding positions in the HTA body.
An interview guide (Supplementary Information) was developed that probed the perceptions, experiences, perceived obstacles to and factors driving the uptake, and preparedness to integrate RWE into HTA decision-making. Interviews were audio recorded and then transcribed. Information from both the literature review and supplemental interviews was reviewed by three researchers.
Results
Characterization of the selected technologies and RWE purpose
A total of 95 studies were identified in the literature review. After reviewing 17 technologies, ten technologies spanning 12 indications that met the inclusion criteria were selected to represent a wide range of RWE use cases across different therapeutic areas and to provide a comprehensive overview of the criteria and uses of RWE by HTAs. The selected technologies were divided into two groups: those using RWE to support efficacy claims (e.g., through ECAs or indication expansion) and those using RWE to inform the natural history of the disease (e.g., to characterize disease background or epidemiology) (Table 1). All the technologies included were targeted rare diseases and received orphan drug designation (ODD) by the EMA, except for atezolizumab in small cell lung cancer. The technologies using RWE to support efficacy claims included six ECAs, and two registry studies demonstrating the technology’s efficacy in subpopulations not included in the pivotal trials (Eculizumab in Atypical Hemolytic Uremic Syndrome [aHUS] for a pediatric line expansion, and in paroxysmal nocturnal hemoglobinuria [PNH] in patients without prior blood transfusions) (Table 1).
Selected technologies, corresponding disease areas, and RWE descriptions
Abbreviations: INN: International Nonproprietary Name; aHUS: atypical hemolytic uremic syndrome; ALL: acute lymphoblastic leukemia; EC: European Commission; ECA: external control arm; EMA: European Medicines Agency; ES-SCLC: Extensive-stage small-cell lung cancer; GEP NET: gastroenteropancreatic neuroendocrine tumor; HTA: health technology assessment; MCC: Merkel cell carcinoma; N: sample size; ODD: Orphan Drug Designation; PNH: paroxysmal nocturnal hemoglobinuria; QoL: quality of life; R/R DLBCL: relapsed or refractory diffuse large B-cell lymphoma; RWD: real-world data; RWE: real-world evidence; and SMA: spinal muscular.
Acceptance status of RWE and ECA by each HTA body
The overall acceptance of RWE and reimbursement status across selected technologies from 12 indications are captured for each HTA body, illustrated in Figure 1. Additionally, the specific acceptance status of the submitted RWE and the reimbursement status for each technology per HTA are outlined in Table 2. Despite all technologies being approved by the EMA, not all secured reimbursement from the assessed HTAs; some were only reimbursed for subpopulations of the labeled population. Only onasemnogene abeparvovec and eculizumab (for aHUS) received reimbursement in all markets within the study scope. Overall, the NICE (UK) and AEMPS (Spain) had the highest acceptance rate, accepting RWE from nine and seven of 12 indications, respectively. In contrast, the HAS (France) and the G-BA (Germany) accepted RWE from six and two of the 12 indications, respectively (Table 2). Several technologies (e.g., avelumab, blinatumomab, tisagenlecleucel, axicabtagene ciloleucel, and velmanase alfa) had their RWE rejected by some HTA bodies; however, they still received reimbursement in the respective countries.
Overview of the RWE acceptance status and reimbursement decision among the selected 12 technologies.
RWE Acceptance and reimbursement status of each technology per HTA
Abbreviations: 1 L: first-line; 2 L: second-line; AEMPS: Agencia Española de Medicamentos y Productos Sanitarios; aHUS: atypical hemolytic uremic syndrome; AIFA: Agenzia Italiana del Farmaco; ECA: external control arm; G-BA: Gemeinsame Bundesausschuss; HAS: Haute Autorité de Santé; HTA: health technology assessment; NICE: National Institute for Health and Care Excellence; PNH: paroxysmal nocturnal hemoglobinuria; and RWE: real-world evidence.
*No distinction in the Gazzetta Ufficiale between first-line and second-line Avelumab.
For Lutetium Lu 177 dotatate no assessment was made by the G-BA (Germany) as Lutetium Lu 177 dotatate is expected to impose a negligible cost on the healthcare system.
*** No information could be found regarding reimbursement restrictions or post-marketing commitments for AIFA.
Best practices for ECA design and implementation
In this study, six technologies using an SAT with a supportive ECA were included. Critical analyses of the technology’s HTA reports, expert interviews, and guidance documents published by HTAs led to the development of best practices for designing and implementing an ECA to supportan SAT. Eight key categories were identified for consideration in the design of an SAT + ECA. For each recommendation, an excerpt from HTA reports supporting the recommendation is presented (Table 3).
Best practices for the design of an SAT with an RW-ECA with illustrative quotes from the selected HTA reports
Abbreviations: AEMPS: Agencia Española de Medicamentos y Productos Sanitarios; ALL: acute lymphoblastic leukemia; DLBCL: diffuse large B-cell lymphoma; ECA: external control arm; ERG: Evidence Review Group; G-BA: Gemeinsame Bundesausschuss; HAS: Haute Autorité de Santé; HSCT: hematopoietic stem cell transplantation; HTA: health technology assessment; KOL: key opinion leader; MCC: Merkel cell carcinoma; NICE: National Institute for Health and Care Excellence; QoL: quality of life; RCT: randomized controlled trial; RW: real-world; RWD: real-world data; RWE: real-world evidence; SAT: single-arm trial; SMA: spinal muscular atrophy; and TC: Transparency Commission.
Country profile: use and acceptance of RWD and RWE
Finally, country profiles based on three main themes – common usages of RWE, RWE supporting efficacy, and early advice on the RWE plan – are summarized in Table 4, illustrating how RWE is employed, its goals, level of acceptance, and value across each country. The data were primarily gathered from the expert interviews, complemented by HTA reports and HTA-specific guidance, which supported the interview findings (Table 4).
Use and acceptability of RWD and RWE in the EU4 + UK across a range of use cases
Abbreviations: ACT: appropriate comparator therapy; AEMPS: Agencia Española de Medicamentos y Productos Sanitarios; ASMR: Amélioration du Service Médical Rendu; CEPS: Comité Economique des Produits de Santé; CPRD: Clinical Practice Research Datalink; ECA: external control arm; ERG: Evidence Review Group; EMR: Electronic Medical Records; G-BA: Gemeinsame Bundesausschuss; HAS: Haute Autorité de Santé; HTA: health technology assessment; NHS: National Health Service; NICE: National Institute for Health and Care Excellence; PRO: Patient-reported Outcomes; P&R: Pricing and Reimbursement; QoL: quality of life; RCT: randomized controlled trial; RW: real-world; RWD: real-world data; RWE: real-world evidence; SACT: Systemic Anti-Cancer Therapy; SAT: single-arm trial; SNDS: Système National Des Données De Santé; SoC: Standard of Care; and TC: Transparency Commission.
Representativeness of the RWD source was highlighted as a key criterion, driving the evaluation and acceptance of RWD. Most HTA experts who were interviewed mentioned a preference for national data, followed by Europe, the United States (US), and the rest of the world. However, experts agreed that while representativeness is crucial for informing economic models, identifying the standard of care (SoC), and estimating the size of the target population, the similarity between the trial and the external patient characteristics is more relevant for assessing comparative effectiveness. RWD used to characterize the natural history of the disease, humanistic and clinical burden, and the unmet need is also acceptable from non-national sources if clinical and treatment practices are similar to those of the country in question.
Transparency in RWD collection and analysis was the second most-cited criterion driving acceptability and trust in RWD. The NICE (UK) RWE Framework and the HAS (France) RWD study guidance both recommend publishing the protocol before conducting the study to raise confidence in RWD (22, 2 3). The recommended platforms for the publication of RWD studies include the EMA RWD Catalogues (28), the RWE Registry, endorsed by the ISPOR RWE Transparency Initiative, and the Clinical Trial.gov registry (29–33).
Regarding the common uses of RWE, these include informing the natural history of the disease, characterizing the epidemiology, the clinical unmet need, identifying the national SoC, and informing the safety of newly introduced technologies. The identification of the appropriate SoC is particularly relevant in Germany, as the G-BA evaluates new technologies against the pre-defined appropriate comparative therapy (ACT). Robust RWE can be used to challenge the G-BA-endorsed ACT, which can have a strong impact on the final benefit assessment and price of the technology being evaluated. Similarly in France, the new technology is evaluated in the context of a selected appropriate comparator. In Italy and in the UK, RWE can also help to identify the SoC; whereas, at the national level in Spain, the SoC is often defined by specialized physicians consulted by the AEMPS (Spain) (Table 4).
RWE extends beyond initial technology assessments. In the UK, Italy, and Francecollecting RWD during the post-marketing phase is crucial for re-evaluating technologies. This practice is well-established, as evidenced by initiatives such as the Cancer Drug Fund (CDF) in the UK, post-marketing authorization studies in France, and the AIFA registries in Italy. Notably, in France, the use of RWD in technology re-evaluation is a primary focus outlined in the HAS (France) RWD Guidelines (“RWD studies for the evaluation of drugs and medical devices, 2021”) (23) and is already well-established with 11 post-marketing RWD studies requested in 2022 concerning 10 technologies (34). The collection of RWD for re-evaluation of technologies is critical for maintaining reimbursement, confirming the added benefit of technologies conditionally approved due to uncertainties in areas of high unmet need, and assessing the impact of integrating the technology into the healthcare system (23) (Table 4).
The practice of requesting RWE for re-evaluation has spread to Germany and Spain (36, 3 Reference Marwaha, Knowles and Ashley7). In Germany, a new law was introduced in 2019 which allows the G-BA to request RWD collection following the initial assessment of technologies with conditional approval or approval in an orphan disease (36). Historically, the G-BA and IQWiG have been critical of including RWE in decision-making; however, the law states that any additional RWE mandated by the G-BA must be used in the reassessments by both the G-BA and IQWiG. In 2021, onasemnogene abeparvovec became the first technology to undergo this process. The G-BA mandated the collection of RWD to monitor the real-world effectiveness and safety of onasemnogene abeparvovec. Novartis, the manufacturer, is using the RESTORE registry, which will include nearly 500 children with SMA from the US and Europe, to collect this data over 15 years (Reference Simpson and Ramagopalan37, 38).
In Spain, VALTERMED was introduced by the Spanish National Health System in 2019 as a national registry designed to devaluate the therapeutic value of high-impact medicines in real clinical practice. The initiative aims to enhance transparency and optimize healthcare decisions by collecting and analyzing RWD on the effectiveness of medicines with significant clinical and economic impacts, as well as supporting pay-for-performance agreements (Reference Patsopoulos49). As of December 2022, VALTERMED has included 22 drugs, most of which are orphan drugs (63 percent) and ATMPs (40). Due to privacy concerns, data from the VALTERMED registry is only available to the Spanish Minister of Health (MoH) Table 4).
In Italy, the AIFA oversees 283 therapeutic indication-based registries. Among these, 182 registries focus solely on drug utilization, while 35 registries include additional financial-based agreements, and 60 registries utilize performance-based risk-sharing agreements (Reference Capuozzo, Celotto, Zovi, Langella and Ferrara41, 4 4). Although supporting the achievement of economic sustainability the registries represent a significant operational burden that can delay access to treatments, according to the expert interviewed (Table 4).
The NICE (UK) RWE Framework highlights the ambition to create “dynamic, living clinical guideline recommendations,” (22) where the agency aims to regularly update its guidance documents with the latest RWE. An example of the use of RWE to update clinical guidelines can be found in the uptake of injectable long-acting antipsychotics, where multiple RWE studies showed that these treatments result in better adherence and therefore, are more effective compared with their oral comparators (42–Reference Tiihonen, Mittendorfer-Rutz and Majak44) (Table 4).
Discussion
This study provides evidence that the utilization and scrutiny of RWE vary by its specific application and among different HTA bodies. Additionally, the use of RWE in HTA decision-making is increasing, as evidenced by Germany’s new law enabling the G-BA to request RWE and the establishment of VALTERMED in Spain.
Overall, the NICE (UK) and AEMPS (Spain) had the highest acceptance rate of RWE, accepting RWE from nine and seven of 12 indications, respectively. In contrast, the HAS (France) and the G-BA (Germany) accepted RWE from six and two of the 12 indications, respectively. The non-acceptability of RWE was not correlated with the reimbursement decision since several technologies were reimbursed despite the rejection of RWE. In Germany, new pharmaceuticals are reimbursed by default, however, the level of reimbursement and price are dictated by the level of added benefit versus the ACT.
The use of RWE to characterize the natural history of the disease, epidemiology, and identification of SoC is widely accepted. However, some uses of RWE are more established than others, such as supporting economic models in the UK and France, or post-marketing studies to support payer agreements in Italy. Our findings indicate that the quality of the data, relevance, methodological robustness, and disease context (e.g., rare disease, high unmet need) are key determinants of its acceptance, which is consistent with previous findings (Reference Grimberg, Asprion, Schneider, Miho, Babrak and Habbabeh45, 4 Reference Alvarellos, Sheppard and Knarston9). Additionally, this study demonstrates that transparency is key to establishing trust in the methodological validity of an RWE study, as highlighted by the latest NICE RWE framework (22).
The utilization of RWE in combination with clinical trials to demonstrate treatment effects results in increased scrutiny. Our research highlights that HTA bodies tend to be skeptical of the need for and validity of SATs with RWE-based ECAs, as this study design is prone to bias and confounding. Traditional RCTs remain the gold standard for demonstrating the safety and efficacy of new technologies. Consequently, the rationale supporting the non-feasibility of a comparative trial is a key driver for the acceptability of such a study design. While regulators and HTAs may hold different perspectives on what constitutes a valid rationale for accepting an SAT, which is assessed on a case-by-case scenario, there is a consensus that under special conditions (e.g., rare and ultra-rare diseases where there may be violations of equipoise), traditional RCTs may be infeasible or unethical, and SATs with ECAs may provide the best available evidence. This is also recognized by the EMA when stating that RCTs may “need to be complemented by other methodologies to address research questions where a traditional RCT may be unfeasible or unethical.” (Reference Eichler, Pignatti and Schwarzer-Daum15) Similarly, the AEMPS (Spain) accepts that certain situations are not amenable to RCTs, such as in the case of onasemnogene abeparvovec in SMA, where “the rapidly progressive and fatal nature of the forms studied makes the use of placebo unfeasible.” (46) Additionally, Traditional RCTs have limitations, including stringent inclusion and exclusion criteria that enhance internal validity but may result in findings that are not representative of the broader population, as the included subjects tend to be less severe and more homogenous in terms of comorbidities, ethnicity, and socio-economic background. Hybrid trial designs, such as pragmatic trials that combine RCT characteristics with real-world conditions, are gaining attention; however, their acceptance by regulators and HTAs remains debatable (Reference Kostis and Dobrzynski47–Reference Sanson-Fisher, Bonevski, Green and D’Este51).
While the criteria cited by HTAs for rejecting evidence derived from ECAs are similar, the acceptance of the same evidence package varies widely across the evaluated countries. High-quality RWD allowing for robust statistical analyses are very important for HTA bodies when appraising RW-ECA. The impact of the quality of the RWD used in the ECA may be illustrated in the case of axicabtagene ciloleucel and tisagenlecleucel, where both technologies used the same data source for their ECA SCHOLAR-1 (an international retrospective research study pooling data from two randomized trials and two academic databases) (Reference Crump, Neelapu and Farooq52), but only axicabtagene ciloleucel’s manufacturer had access to the individual patient data. While the ECA data from axicabtagene ciloleucel was accepted by the AEMPS (Spain), G-BA (Germany), and NICE (UK), tisagenlecleucel’s ECA was only accepted by the AEMPS and NICE. The increased level of robustness of axicabtagene ciloleucel’s ECA, given the access to patient-level data, may have contributed to a more favorable appraisal such as the acceptance of the ECA data by the G-BA, and achievement of ASMR III in France (indicating a moderate improvement in the medical benefit), while tisagenlecleucel’s ECA was not accepted by the G-BA, and tisagenlecleucel received an ASMR IV in France, (indicating a minor improvement).
The risk of bias was cited by HTAs as one of the main criteria for rejecting data from ECA; however, neither the sponsors nor the evaluating committee has attempted to evaluate or quantify the presence and impact of bias, highlighting the importance of the systematically using quantitative bias analysis methods to enable a more objective assessment of bias in RWE studies (Reference Lash, Fox, Cooney, Lu and Forshee53, Reference Flynn, Plueschke and Quinten5 Reference Kumar-Sinha and Chinnaiyan8).
Overall, this study demonstrates differences in the degree of RWE acceptance among the included HTAs. This represents a challenge that the future European Joint Clinical Assessment (JCA) will bring (Reference Drummond, Tarricone and Torbica54). For a harmonized evaluation of RWE, particularly RW-ECA, member states and their respective HTA bodies should align on the requirements and acceptability of such data across various use cases.
Study limitations
One limitation of this study is the limited number of technologies covered, as well as the representation of each HTA body by a single expert (except for the UK where two experts were interviewed), which may limit the generalizability and completeness of the findings. However, selecting a restricted number of technologies allowed a more granular analysis of the HTA reports that may be generalizable to similar RWD types and disease contexts (e.g., rare diseases).
Another limitation is that it is challenging to pinpoint the specific impact of the submitted RWE for the final HTA reimbursement decision. Velmanase alfa in Spain represents an example where the submitted RWE was accepted and used to inform the epidemiology of the disease; however, the technology was not reimbursed by the AEMPS (Spain) due to the lack of statistically significant changes in the trial’s functional outcomes, which is unrelated to the quality of the RWE (55). Several technologies (e.g., avelumab, blinatumomab, tisagenlecleucel, axicabtagene ciloleucel, and velmanase alfa) had their RWE rejected by the HTA bodies; however, they still received reimbursement (most cases, conditional reimbursement with mandatory post-marketing studies) despite the rejection of the RWE. Highlighting the multitude of factors that influence the final HTA decision, such as cost-effectiveness, the disease’s unmet need, disease prevalence, patient engagement, and political pressures, which are challenging to capture and evaluate. In some cases, interpreting the acceptability of ECA data from HTA reports is challenging, as seen in the AEMPS report for avelumab in first- and second-line MCC. While it is stated that “the comparison of avelumab with the chemotherapy presents large methodological problems,” the comparative data from the observational studies are presented at length and compared with the results of the SAT, which itself received criticism. In the first-line setting, the conclusion was that the efficacy results, although preliminary, present a “duration of response not achievable with chemotherapy,” which was derived from the ECA. While in second-line Merkel Cell Carcinoma (MCC), the lack of a comparator arm “prevents us from being certain about the magnitude and relevance of the benefit.” Thus, we considered that the ECA data were accepted in the first line (where the conclusion refers to challenges associated with the clinical trial and not the ECA) but not in second line (where the lack of an appropriate comparator is specifically mentioned in the conclusion) (56).
Conclusion
Based on the RWE guidelines reviewed, HTA reports, and expert interviews, this study highlights that RWE is becoming an integral component of evidence submitted to HTA bodies alongside clinical trials. RWE is used for various purposes, including estimating disease epidemiology, characterizing standard of care, assessing the safety of new technologies post-marketing, supporting economic models, and payer agreements in some regions. It is particularly crucial in the re-evaluation of technologies following conditional approvals. When RWE is used to support efficacy claims, HTA bodies apply stringent scrutiny. Methodological rigor, population comparability between clinical trials and external controls, along with transparency, are key factors influencing RWE acceptance. As the number of registered SATs grows annually, developing robust RWE strategies aligned with regulatory and HTA requirements becomes increasingly essential. Enhanced collaboration and transparency among stakeholders are needed to create integrated evidence-generation plans that address the needs of patients, healthcare professionals, regulators, and HTA bodies.
Supplementary material
The supplementary material for this article can be found at http://doi.org/10.1017/S0266462324004720.
Acknowledgments
We would like to acknowledge the following individuals for reviewing specific sections of the manuscript and providing valuable feedback: Chus Castillo, Andrea Mantovani, Claudia Leopaldi, Anne-Line Couillerot, and Emmanuelle Préaud. This work was funded by Alira Health.
Author contributions
Catia C Proenca designed the study, wrote the manuscript, performed the research, and analyzed the data. Oscar Dumoulin contributed to the writing of the manuscript, performed the research, and analyzed the data. Alexa Vidalis contributed to the writing of the manuscript, performed the research, and analyzed the data. Mrunmayee Godbole contributed to writing the manuscript and the qualitative analyses.
Funding
This project was funded by Alira Health.
Competing interest
Oscar Dumoulin, Alexa Vidalis, Catia C Proenca, and Mrunmayee Godbole were all employed by Alira Health while contributing to this project. Alira Health is a healthcare consulting company providing services to pharmaceutical and MedTech companies. The work conducted in this project was fully funded by Alira Health and was not associated with any external organization.
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