Optimizing Patient-Reported Outcomes for HTA Success: Lessons from German Early Benefit Assessments

Use and relevance of patient-reported outcomes (PROs) in health technology assessment (HTA) has increased, reflecting a shift toward patient-centered evaluation. Germany's HTA benefit assessment process, including initial assessment by the Institute for Quality and Efficiency in Health Care (IQWiG) and final resolution by the Federal Joint Committee (G-BA), has driven this shift by prioritizing patient-relevant endpoints such as PROs. However, guidance on optimally designing and positioning PROs in clinical trials to support HTA remains limited. Using Germany as a reference, this study reviewed HTA reports to identify methodological expectations and guidance for PRO evidence generation.

A targeted review of German benefit assessments from January 2019 to August 2024 was conducted. Assessments including PROs in oncology, cardiovascular, immunology/dermatology, and neurology were reviewed. Quantitative and qualitative analyses examined HTA feedback, critiques, and recurring themes related to PRO design, conduct, and analysis.

A total of 249 benefit assessments (283 datapoints) were reviewed. Common PRO critiques reflected nonadherence to IQWiG General Methods such as response (i.e., compliance) rates < 70%, failure to apply the 15% scale-span responder definition, open-label design, and statistical analysis issues. A framework linking methodological critiques to PRO rejection and bias showed that the frequency of a critique did not necessarily correspond to rejection of PRO data. PRO rejection was most strongly associated with inadequate instrument validation, low or imbalanced response rates, differing observation periods across treatment arms, and incomplete follow-up.

Early optimization of PRO selection, trial design, and analyses may enhance PRO acceptance in German HTA and may strengthen access in other markets. Nonacceptance of PRO results was driven primarily by methodological and operational design misalignment rather than by lack of patient relevance. While several factors can be addressed through early PRO strategy development, operational challenges, particularly related to data completeness, remain difficult to mitigate.