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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.

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.

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.

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. ispartof: CTS-CLINICAL AND TRANSLATIONAL SCIENCE vol:14 issue:4 pages:1566-1577 ispartof: location:United States status: published

Background: Prior studies investigated regulatory actions that reflected a negative impact on drug risks. We aimed to evaluate occurrence of regulatory actions that reflected a negative or positive impact on benefits or risks, as well as relations between them. Research design and methods: We followed EMA-approved innovative drugs from approval (2009���2010) until July 2020 or withdrawal to identify regulatory actions. We assessed these for impact on benefits or risks and relations between actions. Additionally, we scrutinized drug lifecycles for time-variant characteristics that may contribute to specific patterns of regulatory actions. Results: We identified 14 letters and 361 label updates for 40 drugs. Of the label updates, 85 (24%) reflected a positive impact, mostly concerning indications, and 276 (76%) a negative impact, mostly adverse drug reactions. Many updates (54%) occurred simultaneously with other updates, also if these reflected a different impact. Furthermore, levels of patient exposure, innovativeness, needs for regulatory learning and unexpected risks may contribute to patterns of regulatory actions. Conclusions: Almost a quarter of regulatory actions reflected a positive impact on benefits and risks. Also, simultaneous learning about benefits and risks suggests an important role for drug development in risk characterization. These findings may impact regulatory analyses and decision-making.

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.

Study Objective. To develop and evaluate a peer review group (PRG) meeting using feedback data on a patient level to improve the quality of drug therapy for prevention of recurrent myocardial infarction. Design. Prospective follow-up study. Data Source. General practitioners' computerized patients records (intervention patients) and the PHARMO record linkage system (controls). Patients. Forty patients in the intervention group and 1030 control patients; both groups had documented myocardial infarction. Intervention. The intervention, which was based on the principles of group academic detailing, consisted of scoring current cardiovascular treatment on separate forms for each patient, presenting an overview of, and discussing, evidence-based treatment after myocardial infarction, defining the target population, formulating a binding consensus, and identifying patients who were eligible for improvement of pharmacotherapy. Measurements and Main Results. Drug therapy and adherence to the newly formulated PRG consensus were assessed at baseline and 1 year after the intervention. Of the patients who received the intervention and were not treated according to the PRG consensus at baseline, 40% received treatment according to the consensus 12 months after the PRG meeting. In the control group, the proportion of patients was 9.5% (prevalence ratio 4.2, 95% confidence interval 1.8–9.7). Conclusion. Peer review group meetings can be a valuable tool for improving pharmacotherapy after myocardial infarction.

OBJECTIVE: To examine the use of oral antithrombotics (i.e., antiplatelet agents, oral anticoagulants) after myocardial infarction (MI) in the Netherlands from 1988 to 1998. METHODS: Retrospective follow-up of 3800 patients with MI, using data from the PHARMO Record Linkage System. RESULTS: From 1988 to 1998, oral antithrombotic treatment increased significantly from 54.0% to 88.9%. In 1998, only 75.8% of patients who experienced a MI in the late 1980s received oral antithrombotic treatment compared with 94.4% of those who experienced a recent MI. CONCLUSIONS: Oral antithrombotics were considerably underused in patients with a past history of MI. Therefore, these patients should be reviewed for antithrombotic therapy to assess whether their failure to use oral antithrombotics was right or wrong, and whether treatment should be initiated if possible.