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

Regulators and Health Technology Assessment (HTA) bodies are increasingly familiar with, and publishing guidance on, external controls derived from real-world data (RWD) to generate real-world evidence (RWE). We recently conducted a systematic literature review (SLR) evaluating publicly available information on the use of RWD-derived external controls to contextualize outcomes from uncontrolled trials submitted to the European Medicines Agency (EMA), the US Food and Drug Administration (FDA), and/or select HTA bodies. The review identified several key operational and methodological aspects for which more detailed guidance and alignment within and between regulatory agencies and HTA bodies is necessary. This paper builds on the SLR findings by delineating a set of key takeaways for the responsible generation of fit-for-purpose RWE. Practical methodological and operational guidelines for designing, conducting, and reporting RWD-derived external control studies are explored and discussed. These considerations include: (i) early engagement with regulators and HTA bodies during the study planning phase; (ii) consideration of the appropriateness and comparability of external controls across multiple dimensions, including eligibility criteria, temporality, population representation, and clinical evaluation; (iii) ensuring adequate sample sizes, including hypothesis testing considerations; (iv) implementation of a clear and transparent strategy for assessing and addressing data quality, including data missingness across trials and RWD; (v) selection of comparable and meaningful endpoints that are operationalized and analyzed using appropriate analytic methods; and (vi) conduct of sensitivity analyses to assess the robustness of findings in the context of uncertainty and sources of potential bias.

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

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.

Healthcare resource utilization and costs among psoriasis patients treated with biologics, overall and by disease severity.

AIMS: To describe healthcare resource utilization (HCRU) and costs among biologic-treated psoriasis patients in the US, overall and by disease severity. MATERIALS AND METHODS: IQVIA PharMetrics Plus administrative claims data were linked with Modernizing Medicine Data Services Electronic Health Record data and used to select adult psoriasis patients between April 1, 2010 and December 31, 2014. Eligible patients were classified by disease severity (mild, moderate, severe) using a hierarchy of available clinical measures. One-year outcomes included all-cause and psoriasis-related outpatient, emergency department, inpatient, and pharmacy HCRU and costs. RESULTS: This study identified 2,130 biologic-treated psoriasis patients: 282 (13%) had mild, 116 (5%) moderate, and 49 (2%) severe disease; 1,683 (79%) could not be classified. The mean age was 47.6 years; 45.4% were female. Relative to mild psoriasis patients, patients with moderate or severe disease had more median all-cause outpatient encounters (28.0 [mild] vs 32.0 [moderate], 36.0 [severe]), more median psoriasis-related outpatient encounters (6.0 [mild] vs 7.5 [moderate], 8.0 [severe]), and a higher proportion of overall claims for medications that were psoriasis-related (28% [mild] vs 37% [moderate], 34% [severe]). Relative to mild psoriasis patients, patients with moderate or severe disease had higher median all-cause total costs ($37.7k [mild] vs $42.3k [moderate], $49.3k [severe]), higher median psoriasis-related total costs ($32.7k [mild] vs $34.9k [moderate], $40.5k [severe]), higher median all-cause pharmacy costs ($33.9k [mild] vs $36.5k [moderate], $36.4k [severe]), and higher median psoriasis-related pharmacy costs ($32.2k [mild] vs $33.9k [moderate], $35.6k [severe]). LIMITATIONS: The assessment of psoriasis disease severity may not have necessarily coincided with the timing of biologic use. The definition of disease severity prevented the assessment of temporality, and may have introduced selection bias. CONCLUSIONS: Biologic-treated patients with moderate or severe psoriasis cost the healthcare system more than patients with mild psoriasis, primarily driven by higher pharmacy costs and more outpatient encounters.