Biometrische Entscheidungsunterstützung in Zulassung und Nutzenbewertung am Beispiel der Implikationen von heterogenen Ergebnissen in Untergruppen der Studienpopulation

Abstract

In the context of both drug licensing and reimbursement, the target population is sometimes restricted to a specific subgroup. In the setting of drug licensing the discussion concerns a negative benefit/risk assessment in a relevant subgroup. For reimbursement the debate involves the detection of an additional benefit compared with standard treatment, which can in some situations not be accepted for the overall study population. In their Methods Paper, the Institute for Quality and Efficiency in Health Care (IQWiG) refers to published articles that name criteria for the evaluation of credibility to claim a therapeutic effect on the basis of results in the subgroups of a study population (BMJ 340:850-854, 2010). A number of these criteria have found their way into the regulatory debate, which was recently published in a draft guideline of the European Medicines Agency (EMA). However, the significance of the interaction/heterogeneity test has been mentioned as one criterion for the credibility of a finding in a subgroup of the study population. This aspect is critically challenged in our paper. In our estimation, the application of this criterion hinders the critical discussion of whether a global treatment effect is applicable to relevant subgroups of a study population and the potential implications of this. We feel that biostatistical support for decision-making strategies should be the same in both worlds, even though in some instances the outcomes in a specific situation may be different, depending on the objective to be demonstrated.

Subgroup analysis and interpretation for phase 3 confirmatory trials: White paper of the EFSPI/PSI working group on subgroup analysis

“…Conversely, clinical trials are generally not designed for detecting subgroup heterogeneity, so statistical tests may miss important interactions due to low power . This is particularly challenging as approaches need to account for both issues simultaneously, as illustrated by Gonnermann who also concluded that further work was needed to understand alternative statistical approaches in this area. Despite these issues, potential subgroup differences cannot be ignored, so it is still necessary to understand potential subgroup heterogeneity, and as such, consideration needs to be given for how such effects are to be analysed and interpreted.…”