Agreement about Availability of Alternative Treatments for Innovative Drugs Assessed by the EMA and HTA Organizations.

The European Medicines Agency (EMA) and European national/regional health technology assessment (HTA) organizations consider the availability of existing treatments when evaluating a new drug. Since disagreement about the availability of alternative treatments may impact patient access to new drugs, this study aimed to investigate whether the EMA and HTA organizations agreed on the availability of alternative treatments and whether a lack of alternative treatments was associated with HTA organizations' added benefit assessment outcomes. For 97 innovative drugs authorized in 2019-2021 (excluding vaccines and diagnostic tools), assessments by the EMA and AEMPS (Spain), AIFA (Italy), HAS (France), IQWiG/G-BA (Germany), NICE (England and Wales), and ZIN (the Netherlands) were identified. Until 1 June 2022, 429 HTA drug-indication combinations were identified for these 97 drugs, of which 205 exactly matched the EMA's indication. For those, the overall agreement between the EMA and HTA organizations on whether alternative treatments were available was 87%. The agreement of HTA organizations with the EMA on whether available treatments were either pharmacological on-label, pharmacological off-label, or non-pharmacological was 87%, 21%, and 57%, respectively. For all 429 HTA drug-indication combinations, absence of alternative treatments as considered by HTA organizations was associated with a higher chance to provide added benefit: risk ratio 1.8 (95%-CI 1.4-2.3). In conclusion, although there was high overall agreement between the EMA and HTA organizations about whether alternative treatments exist, there were differences in the types of treatment considered. Parallel joint scientific consultations could inform drug developers about relevant alternative treatments to facilitate patient access to innovative drugs.

Added benefit and revenues of oncology drugs approved by the European Medicines Agency between 1995 and 2020: retrospective cohort study.

OBJECTIVES: To evaluate the added benefit and revenues of oncology drugs, explore their association, and investigate potential discrepancies between added benefit and revenues across different approval pathways of the European Medicines Agency (EMA). DESIGN: Retrospective cohort study. SETTING: Oncology drugs and their indications approved by the EMA between 1995 and 2020. MAIN OUTCOME MEASURES: Added benefit was evaluated using ratings published by seven organisations: health technology assessment agencies from the United States, France, Germany, and Italy, two medical oncology societies, and a drug bulletin. All retrieved ratings were recategorised using a four point ranking scale to indicate negative or non-quantifiable, minor, substantial, or major added benefit. Revenue data were extracted from publicly available financial reports and compared with published estimates of research and development (R&D) costs. Finally, the association between added benefit and revenue was evaluated. All analyses were performed within the overall study cohort, and within subgroups based on the EMA approval pathway: standard marketing authorisation, conditional marketing authorisation, and authorisation under exceptional circumstances. RESULTS: 131 oncology drugs with 166 indications were evaluated for their added benefit by at least one organisation within the required timeframe, yielding a total of 458 added benefit ratings; 189 (41%) were negative or non-quantifiable. The median time to offset the median R&D costs ($684m, £535m, €602m, adjusted to 2020 values) was three years; 50 of 55 (91%) drugs recovered these costs within eight years. Drugs with higher added benefit ratings generally had greater revenues. Negative or non-quantifiable added benefit ratings were more frequent for conditional marketing authorisations and authorisations under exceptional circumstances than for standard marketing authorisations (relative risk 1.53, 95% confidence interval 1.23 to 1.89). Conditional marketing authorisations generated lower revenues and took longer to offset R&D costs than standard marketing authorisations (four years compared with three years). CONCLUSIONS: While revenues seem to align with added benefit, most oncology drugs recover R&D costs within a few years despite providing little added benefit. This is particularly true for drugs approved through conditional marketing authorisations, which inherently appear to lack comprehensive evidence. Policy makers should evaluate whether current regulatory and reimbursement incentives effectively promote development of the most effective drugs for patients with the greatest needs.

Pre-approval and post-approval availability of evidence and clinical benefit of conditionally approved cancer drugs in Europe: A comparison with standard approved cancer drugs.

AIMS: Cancer drugs are increasingly approved through expedited regulatory pathways including the European conditional marketing authorization (CMA). Whether, when taking CMA post-approval confirmatory trials into account, the level of evidence and clinical benefit between CMA and standard approved (SMA) drugs differs remains unknown. METHODS: We identified all CMA cancer indications converted to SMA in 2006-2020 and compared these to similar SMA indications with regard to pivotal trial and CMA post-approval confirmatory trial design, outcomes and demonstrated clinical benefit (per the European Society for Medical Oncology Magnitude of Clinical Benefit Scale). We tested for differences in clinical benefit and whether substantial clinical benefit was demonstrated. To account for the clinical benefit of unconverted CMA indications, we performed sensitivity analyses. RESULTS: We included 15 SMA and 15 converted CMA cancer indications (17 remained unconverted). Approval of 11 SMA (73%) and four CMA indications (27%) was supported by a controlled trial. Improved overall survival (OS) was demonstrated for four SMA indications (27%). Improved quality of life (QoL) was demonstrated for three SMA (20%) and one CMA indication(s) (7%). Of subsequent CMA post-approval confirmatory trials, 11 were controlled (79%), one demonstrated improved OS (7%) and five improved QoL (36%). After conversion, CMA indications were associated with similar clinical benefit (P = .31) and substantial clinical benefit as SMA indications (risk ratio 1.4, 95% confidence interval 0.57-3.4). CONCLUSION: While CMA cancer indications are initially associated with less comprehensive evidence than SMA indications, levels of evidence and clinical benefit are similar after conversion from CMA to SMA.

The Role of Regulator-Imposed Post-Approval Studies in Health Technology Assessments for Conditionally Approved Drugs.

BACKGROUND: The European Medicines Agency (EMA) aims to resolve uncertainties associated with conditionally approved drugs by imposing post-approval studies. Results from these studies may be relevant for health technology assessment (HTA) organizations. This study investigated the role of regulator-imposed post-approval studies within HTA. METHODS: For all conditionally approved drugs up to December 2018, regulator-imposed post-approval studies were identified from EMA's public assessment reports. The availability for and inclusion of study results in relative effectiveness (re)assessments were analyzed for 4 European HTA organizations: NICE (National Institute for Health and Care Excellence, England/Wales), HAS (Haute Autorité de Santé, France), ZIN (Zorginstituut Nederland, the Netherlands) and the European Network for Health Technology Assessment (EUnetHTA, Europe). When study results became available between an HTA organization's initial assessment and reassessment, it was evaluated whether and how they affected the assessment and its outcome. RESULTS: For 36 conditionally approved drugs, 98 post-approval studies were imposed. In total, 81 initial relative effectiveness assessments (REAs) and 13 reassessments were available, with numbers of drugs (re)assessed varying greatly between jurisdictions. Study results were available for 16 initial REAs (20%) and included in 14 (88%), and available for 10 reassessments (77%) and included in all (100%). Five reassessments had an outcome different from the initial REA, with 4 (2 positive and 2 negative changes) relating directly to the new study results. Reassessments often cited the inability of post-approval studies to resolve the concerns reported in the initial REA. CONCLUSION: Results from regulator-imposed post-approval studies for conditionally approved drugs were not often used in REAs by HTA organizations, because they were often not yet available at the time of initial assessment and because reassessments were scarce. When available, results from post-approval studies were almost always used within HTA, and they have led to changes in conclusions about drugs' relative effectiveness. Post-approval studies can be relevant within HTA but the current lack of alignment between regulators and HTA organizations limits their potential.

Associations between uncertainties identified by the European Medicines Agency and national decision making on reimbursement by HTA agencies.

We aimed to determine whether uncertainties identified by the European Medicines Agency (EMA) were associated with negative relative effectiveness assessments (REAs) and negative overall reimbursement recommendations by national health technology assessment (HTA) agencies. Therefore, we identified all HTA reports from Haute Autorité de Santé (HAS; France), National Institute for Health and Care Excellence (NICE; England/Wales), Scottish Medicine Consortium (SMC; Scotland), and Zorginstituut Nederland (ZIN; The Netherlands) for a cohort of innovative medicines that the EMA had approved in 2009 to 2010 (excluding vaccines). Uncertainty regarding pivotal trial methodology, clinical outcomes, and their clinical relevance were combined to reflect a low, medium, or high level of uncertainty. We assessed associations by calculating risk ratios (RRs) and 95% confidence intervals (CIs), and agreement between REA and overall reimbursement recommendation outcomes. We identified 36 medicines for which 121 reimbursement recommendations had been issued by the HTA agencies between September 2009 and July 2018. High versus low uncertainty was associated with an increased risk for negative REAs and negative overall reimbursement recommendations: RRs 1.9 (95% CI 0.9-3.9) and 1.6 (95% CI 0.7-3.5), respectively, which was supported by further sensitivity analyses. We identified a lack of agreement between 33 (27%) REA and overall reimbursement recommendation outcomes, which were mostly restricted recommendations that followed on negative REAs in case of low or medium uncertainty. In conclusion, high uncertainty identified by the EMA was associated with negative REAs and negative overall reimbursement recommendations. To reduce uncertainty and ultimately facilitate efficient patient access, regulators, HTA agencies, and other stakeholders should discuss how uncertainties should be weighed and addressed early in the drug life cycle of innovative treatments.

Weighing of Evidence by Health Technology Assessment Bodies: Retrospective Study of Reimbursement Recommendations for Conditionally Approved Drugs.

This study assessed whether five Health Technology Assessment (HTA) bodies in Europe were more negative about drugs with a Conditional Marketing Authorization (CMA) that are approved without controlled studies compared to CMA drugs that are approved based on controlled studies. The HTA recommendations were categorized into positive, restricted, and negative. A total of 92 HTA recommendations were available for 27 drugs. Thirty of 62 (48%) and 17 of 30 (57%) of the recommendations were negative for drugs with and without controlled studies, respectively. Overall, only 12 (13%) recommendations were positive. In all jurisdictions, recommendations between drugs with and drugs without controlled data were comparable, which suggests that the presence of controlled data is not decisive in HTA evaluations. The small proportion of unrestricted positive recommendations highlights difficulties with recommending the drugs in this cohort, which may be caused by scientific uncertainty or other factors. Earlier collaboration between stakeholders is advised in order to improve patient access.