Article
Evaluation of adverse events in early benefit assessment (Part II): current and possible future strategies for time to event analyses and zero events
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Authors
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Anke Schulz
- Institut für Qualität und Wirtschaftlichkeit im Gesundheitswesen (IQWiG), Köln, Germany
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Guido Skipka
- Institut für Qualität und Wirtschaftlichkeit im Gesundheitswesen (IQWiG), Köln, Germany
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Lars Beckmann
- Institut für Qualität und Wirtschaftlichkeit im Gesundheitswesen (IQWiG), Köln, Germany
| Published: | September 15, 2023 |
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Outline
Text
This is the second part of a tandem presentation on the topic of the evaluation of adverse events by the Cox proportional hazards regression in early benefit assessment. The first part will have been presented at the CEN2023 conference in Basel, Switzerland, 2023.
For the early benefit assessment of drugs in Germany by the institute for quality and efficiency in health care (IQWiG), the pharmaceutical company must describe the extent of an added benefit of the drug to be assessed compared with an appropriate comparator therapy [1]. The confidence interval of a significant effect must lie completely outside a certain corridor around the null effect for the extent of the effect to be regarded as major, considerable, minor, or non-quantifiable. The corridors are defined by different thresholds depending on outcome category (e. g. all-cause mortality, quality of life, or non-serious adverse events). For adverse events, frequently no events in one of the arms are observed, and while the log rank test provides appropriate p-values, the standard Cox proportional hazard regression does not provide valid effect estimates with corresponding confidence intervals. Thus, in the case of a statistically significant effect according to the log rank test, the extent of the effect cannot be determined. Consequently, the overall assessment of the early benefit might be hampered. In fact, in almost all these situations there is no estimate for a hazard ratio submitted by the pharmaceutical company.
In the first part of the tandem presentation, a simulation study of time to event analyses with zero events, based on an adoption of the Firth correction [2], will have been discussed.
In this second part of the tandem presentation, we will present several past examples of time to event analysis with zero events in one arm, together with the derived certainty of conclusions (proof, indication or hint) and the extent of the added benefit. We will show exemplarily how the application of the Firth correction could change the inference of the extent. The possible contribution of the Firth correction to the early benefit assessment, primarily for adverse events, will be discussed.
The authors declare that they have no competing interests.
The authors declare that an ethics committee vote is not required.
