A Comprehensive Comparison of Additional Benefit Assessment Methods Applied by Institute for Quality and Efficiency in Health Care and European Society for Medical Oncology for Time-to-Event Endpoints After Significant Phase III Trials—A Simulation Study
- The European Society for Medical Oncology (ESMO) and the German Institute for Quality and Efficiency in Health Care (IQWiG) use different methods for assessing additional benefit in cancer therapies, with ESMO considering both relative and absolute benefits, while IQWiG focuses on the upper limit of the hazard ratio confidence interval.
- There is currently no gold-standard method for determining the true additional benefit of cancer treatments, making this research valuable for comparing ESMO and IQWiG's approaches.
- ESMO's dual rule is generally more liberal than IQWiG's method, but measuring absolute benefit based on median survival differences can lead to unfavorable results in certain situations.
- Using the lower confidence interval limit for benefit assessment can result in a higher true-positive rate without increasing the false-positive rate, provided that the thresholds are appropriately chosen.
Pharmaceutical companies search for new drugs against specific diseases, for example cancer, which have to be investigated with respect to their quality, safety, and efficacy, preventing a nonbeneficial drug from getting on the market. Most efficacy endpoints in cancer trials are time-to-event endpoints such as overall survival or progression-free survival. Therefore, a statistically significant log-rank test result is usually one of many requirements for submission of a Marketing Authorization Application to an appropriate authority, which decides whether the drug is allowed to enter the market. Nevertheless, the degree of the added benefit from new and effective treatments with time-to-event endpoints derived from clinical trials remains unknown at this stage and needs to be assessed. Unfortunately, until now no clear definition and hence no gold standard for added benefit determination of a treatment exists. However, European authorities/societies have developed 2 different benefit assessment scores for time-to-event endpoints.
In Germany, the Federal Joint Committee defines the additional benefit of new drugs, which forms the basis of negotiations on the reimbursement price. For its decision, it commissions the Institute for Quality and Efficiency in Health Care (IQWiG) to evaluate the additional benefit of new drugs. Thus, the classification takes an important role in how much a new treatment is worth in economic terms. When evaluating time-to-event endpoints, the IQWiG makes use of the upper limit of the 95% hazard ratio (HR) confidence interval (CI), which is compared with specific thresholds categorizing the new treatment into 3 categories: major, considerable, and minor added benefit. The resulting categories can afterward still be adjusted to reflect other important endpoints such as toxicity and quality of life of the new treatment. Furthermore, the utilized thresholds were calculated assuming binomially distributed data using the relative risk (RR); ie, a true RR of 0.5 was defined as an effect of "major" extent for the outcome all-cause mortality. These RR-scaled thresholds are also used for time-to-event data, which are frequently present in oncology trials. To investigate the possible influence of differently scaled thresholds on the grading of added benefit for new treatments, we transformed the provided RR-scaled thresholds into HR-scaled thresholds using the conversion formula proposed by VanderWeele.
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