Stellungnahme des IQWiG zum Entwurf eines Konzeptpapiers der EMA zur Erstellung eines Reflexionspapiers über den Einsatz externer Kontrollen zur Evidenzgenerierung in der regulatorischen Entscheidungsfindung
Das IQWiG begrüßt die Erstellung eines Reflexionspapiers über den Einsatz externer Kontrollen zur Evidenzgenerierung in der regulatorischen Entscheidungsfindung und betont die Notwendigkeit klarer methodischer Leitlinien. In diesem Zusammenhang verweist das IQWiG unter anderem auf Leitfäden der EU Health Technology Assessment Coordination Group, die Überlegungen und Empfehlungen zu Vergleichen unter Verwendung externer Kontrollen enthalten.
23.10.2025
Submission of comments on: Draft Concept Paper on the Development of a Reflection Paper on the Use of External Controls for Evidence Generation in Regulatory Decision-Making
| Name of organisation or individual* | General or Specific comment* | Line from*(line nr. or 0 for general comment) | Line to*(line nr. or 0 for general comment)2 | Comment and rationale(to go to next line within the same cell use Alt + Enter) | Proposed changes / recommendation (if applicable - to be used if you want to propose specific text changes) | Outcome (To be completed by the Agency) |
|---|---|---|---|---|---|---|
| IQWiG | General | 0 | 0 | IQWiG appreciates the opportunity to provide comments on the Draft Concept Paper on the Development of a Reflection Paper on the Use of External Controls for Evidence Generation in Regulatory Decision-Making. | ||
| IQWiG | Specific | 25 | 28 | We agree with the need for reflections on methodological reliability and operational aspects of external controls. Due to increasing numbers of single-arm trials in drug development programs we receive submissions to Health Technology Assessments using external controls. However, often basic methodological requirements for such comparisons are not met. Therefore, further clarification of appropriate methods for the use of external controls may be helpful. | ||
| IQWiG | Specific | 25 | 28 | We would like to refer to Guidance documents by the EU HTA Coordination Group which includes reflections and recommendations on comparisons using external controls: Methodological Guideline for Quantitative Evidence Synthesis: Direct and Indirect Comparisons (https://health.ec.europa.eu/publications/methodological-guideline-quantitative-evidence-synthesis-direct-and-indirect-comparisons_en ); Practical Guideline for Quantitative Evidence Synthesis: Direct and Indirect Comparisons (https://health.ec.europa.eu/publications/practical-guideline-quantitative-evidence-synthesis-direct-and-indirect-comparisons_en) | ||
| IQWiG | Specific | 29 | 30 | From our point of view, it is important to always specify the research questions for which an appropriate method should be used, which answers the research question and is feasible in the considered data situation. | ||
| IQWiG | Specific | 40 | 43 | Systematic identification of confounding variables followed by sufficiently complete collection and adjustment for identified confounders are key to generate reliable results using external controls for causal effect estimation. For the systematic identification of confounders Pufulete et al. 2022 provide a framework (Pufulete M, Mahadevan K, Johnson TW et al. Confounders and co-interventionsidentified in non-randomized studies of interventions. J Clin Epidemiol 2022; 148: 115-123.https://doi.org/10.1016/j.jclinepi.2022.03.018).This approach has been applied in an example project in MS and has been shown to be feasible. [GA23-02] Systematische Confounderidentifikation in der Indikation schubförmig remittierende multiple Sklerose (RRMS)https://www.iqwig.de/projekte/ga23-02.html | ||
| IQWiG | Specific | 40 | 43 | Un-anchored indirect comparisons to external controls are non-randomised comparisons for which the possibility of unmeasured confounding remains. Therefore, tests against a shifted null-hypotheses or quantiative bias assessment should be considered to account for remaining uncertainties. | ||
| IQWiG | Specific | 48 | 48 | Reliable adjusting for confounding variables is only possible using individual patient level data. There should be a strong recommendation against using aggregated data for adjusting un-anchored indirect comparisons to external controls. | ||
| IQWiG | Specific | 93 | 94 | We appreciate the information for the HTA Coordination Group and HTA bodies. |