Effectively Leveraging RWD for External Controls: A Systematic Literature Review of Regulatory and HTA Decisions

Abstract

Real‐world data (RWD)‐derived external controls can be used to contextualize efficacy findings for investigational therapies evaluated in uncontrolled trials. As the number of submissions to regulatory and health technology assessment (HTA) bodies using external controls rises, and in light of recent regulatory and HTA guidance on the appropriate use of RWD, there is a need to address the operational and methodological challenges impeding the quality of real‐world evidence (RWE) generation and the consistency in evaluation of RWE across agencies. This systematic review summarizes publicly available information on the use of external controls to contextualize outcomes from uncontrolled trials for all indications from January 1, 2015, through August 20, 2021, that were submitted to the European Medicines Agency, the US Food and Drug Administration, and/or select major HTA bodies (National Institute for Health and Care Excellence (NICE), Haute Autorité de Santé (HAS), Institut für Qualität und Wirtschaftlichkeit im Gesundheitswesen (IQWiG), and Gemeinsamer Bundesausschuss (G‐BA)). By systematically reviewing submissions to regulatory and HTA bodies in the context of recent guidance, this study provides quantitative and qualitative insights into how external control design and analytic choices may be viewed by different agencies in practice. The primary operational and methodological aspects identified for discussion include, but are not limited to, engagement of regulators and HTA bodies, approaches to handling missing data (a component of data quality), and selection of real‐world endpoints. Continued collaboration and guidance to address these and other aspects will inform and assist stakeholders attempting to generate evidence using external controls.

Regulatory and HTA Considerations for Development of Real‐World Data Derived External Controls

“…These key takeaways are based on (i) guidance and frameworks put forward in recent thought leadership papers, 2,[21][22][23][24] (ii) guidance on the use of RWE published by regulatory and HTA bodies, [7][8][9][10][11][12][13][14][15][16][17] and (iii) a recent systematic literature review (SLR) we conducted and reported separately that examined regulatory and HTA submissions using RWD-derived external controls to identify feedback related to operational and methodological choices. 25 In the next section, we will explore each of these in sequence before moving to a discussion of key takeaways and case studies.…”

“…We recently conducted an SLR evaluating publicly available information on the use of RWD-derived external controls to contextualize outcomes from uncontrolled trials submitted to the EMA, the FDA, and/or HTA agencies for all indications. 25 The review summarized publicly available information, identifying several key operational and methodological aspects for which more detailed guidance and alignment within and between regulatory agencies and HTA bodies is necessary, including early engagement, methods for addressing missing data, and selection of real-world endpoints. Our review found that submission of the same RWE from the same data source often received different feedback when submitted to multiple agencies, suggesting that further international harmonization and standardization of RWE best practices is of value.…”

Application of the target trial emulation framework to external comparator studies

“…Although the concept of external controls was described in published literature as early as 1976, EC studies have received renewed attention within the drug development community over the last several years (Pocock, 1976). A recent systematic review identified 64 regulatory and 70 HTA submissions between January 2015 and August 2021 which included primary evidence from a SAT supplemented by an EC derived from RWD, for which the most common therapeutic areas were oncology, haematology, neurology (Sola-Morales et al, 2023).…”

“…A key benefit of the EC design is that it allows for broader contextualisation of pivotal trial results with reference to alternative treatments in RW settings (Carrigan et al, 2020;Sola-Morales et al, 2023). However, the strength of evidence generated from EC studies is often variable, and regulatory and HTA review committees have highlighted several biases as important limitations to the evidence generated from these studies (Jaksa et al, 2022;Sola-Morales et al, 2023). In light of this, regulatory and HTA bodies have released general guidance documents aimed at improving the quality of EC studies (National Institute for Health and Care Excellence, 2022; U.S. Food and Drug Administration, 2023).…”

Generalizability in real‐world trials

“…Regarding the generalizability of findings from RWE trials, there is currently a lack of transparency. It is worth noting that both the FDA and the European Medicines Agency (EMA) have established regulatory pathways for RWD, 21–24 which determine the design of RWE trials. In principle, standardized study protocols can be used to increase transparency along these pathways regarding the generalizability of findings from RWE trials.…”