Approximately 10–20% of individuals suffering from COVID-19 develop prolonged symptoms known as long COVID or post-COVID condition (LC). This review aimed to assess healthcare resource use (HCRU) and healthcare costs associated with LC. Because LC is not clearly defined and often remains undiagnosed, studies reporting on long-term follow-up of individuals with a COVID-19 diagnosis were also included. Among the 41 publications included, 36 reported on HCRU and 16 on costs. Individuals with LC had significantly elevated HCRU and healthcare costs vs. controls without a COVID-19 diagnosis over ≥15 months, with a 7.6–13.1% increase in total healthcare costs per person per month as assessed by difference-in-difference analysis. Among studies that did not specifically refer to LC, having a COVID-19 diagnosis was associated with a significant 4–10% increase in long-term total HCRU over 6–8 months and a 1.3- to 2.9-fold relative increase in total healthcare costs over 6 months. Due to the heterogeneity of the included studies, high-quality evidence is needed to better understand the economic burden of LC. In the absence of effective treatments, prioritizing the prevention of acute COVID-19, e.g., through vaccination, may be crucial for preventing LC and the associated long-term HCRU and medical spending.

The Joint Clinical Assessment (JCA) evaluates the relative effectiveness (RE) of interventions over comparators. While randomised control trials (RCTs) are considered the gold standard, single-arm trials (SATs) require an external control for accurate RE estimation. This study reviewed Health Technology Assessment (HTA) outcomes for medicinal products supported by SATs in France, Germany, Poland, and Spain, and simulated the JCA for these products based on evidence submitted in France. Among HTA evaluations published in France in 2019–2024, 16% were SAT-driven, and 5.6% of them included external controls. SAT-supported drugs had a high reimbursement approval rate (74%) and showed better HTA outcomes when controls were used. In Germany, 64% of SAT-based HTA outcomes indicated no added benefit and 30% a non-quantifiable benefit. In Poland and Spain, 63% and 72% HTA evaluations recommend reimbursement, respectively. Despite wide acceptance by Member States, experts determined that 94% of SAT-supported products would not qualify for JCA review due to insufficient evidence. Only 6% would qualify for JCA for a likely limited number of PICOs (Population–Intervention–Comparator–Outcome), but the certainty rating would be low. These findings suggest that SATs, as primary evidence, may not be suitable for JCA, potentially undermining HTA in EU Member States.

The Joint Clinical Assessment (JCA) evaluates the relative effectiveness (RE) of 4 interventions over comparators. While randomized control trials (RCTs) are considered 5 the gold standard, single-arm trials (SATs) require an external control for accurate RE 6 estimation. This study reviewed Health Technology Assessment (HTA) opinions for 7 medicinal products supported by SATs in France, Germany, Poland, and Spain, and 8 simulated the JCA assessment for these products based on evidence submitted in France. 9 Among HTA opinions published in France in 2019-2024, 16% were SAT-driven, and 5.6% 10 of them included external controls. SAT-supported drugs had a high reimbursement 11 approval rate (74%) and showed better HTA outcomes when controls were used. In 12 Germany, 64% of SAT-based opinions indicated no added benefit and 30% - non- 13 quatifiable benefit. In Poland and Spain, 63% and 72% opinions recommending 14 reimbursement, respectively. Despite wide acceptance by Member States, experts 15 determined that 94% of SAT-supported products would not qualify for JCA review due 16 to insufficient evidence. Only 6% would qualify for JCA for a likely limited number of 17 PICOs (Population-Intervention-Comparator-Outcome), but the certainty rating would be 18 low. These findings suggest that SATs, as primary evidence, may not be suitable for JCA, 19 potentially undermining HTA assessments in EU Member States.

The Joint Clinical Assessment (JCA) report on tovorafenib (Ojemda), the first assessment of an orphan oncology medicinal product completed under Regulation (EU) 2021/2282 [1], conformed closely to predictions made across our earlier work. This Perspective argues that the outcome was foreseeable from the framework’s design rather than from any feature of the product. We characterise the JCA as an audit that confronts developer-submitted evidence against a corpus of EUnetHTA methodological guidance whose scientific validity and development process have been widely contested. Four structural features explain the result: the referential cannot function as a settled gold standard; the assessment omits the interpretive, context-dependent judgment that gives evidence meaning, on the assumption — specific to one national tradition — that assessment can be separated from appraisal and conducted free of judgment; products supported only by single-arm trials are predictably assessed negatively, as Ojemda illustrates; and the framework departs from the tripod of evidence-based medicine by marginalising clinicians and patients. By multiplying PICOs, subgroups and outcomes and then criticising the resulting analyses as post hoc, the JCA generates its own limitations and ultimately cannot state a degree of certainty of relative effectiveness. We conclude that single-arm-supported products should fall outside the JCA’s remit and that the framework requires a transparent route from documented uncertainty to a stated certainty.