Navigating indirect comparisons in health technology assessments: Insights from German AMNOG evaluations
The acceptance criteria for ICs are stringent, with success often hinging on special circumstances. Methodological limitations, such as heterogeneity across studies and inherent biases in the evidence on the comparator side, can introduce uncertainty to the comparative assessments. It is essential for researchers and evaluators to transparently address these limitations and employ robust methodologies to enhance the validity and reliability of IC results. Methods guidance regarding the requirements for ICs is provided by the Institute for Quality and Efficiency in Health Care (IQWiG). In addition, drug developers can schedule an additional advice meeting with the G-BA to gain further insights on the appropriate methodology. This article explores the findings from recent analyses of ICs in German AMNOG assessments, highlighting the stringent criteria for acceptance and the implications for various therapeutic fields.
Methods
Results
Figure 1. ICs in German benefit assessments by therapeutic field

Key: IC – indirect comparison.

The G-BA’s rigorous criteria ensure that only robust and reliable ICs are accepted. This emphasis on methodological rigor is crucial for maintaining the integrity of HTA processes. As a rule, the G-BA requires adjusted comparisons, such as the IC according to Bucher. However, both adjusted and unadjusted comparisons were identified among the accepted ICs, whereas other methods, such as network meta-analyses or propensity score matching, were not considered methodologically appropriate. Consequently, the database analysis showed that unadjusted comparisons may also be deemed acceptable under certain circumstances, such as in highly vulnerable populations or when facing significant challenges within the therapeutic field.
Figure 2. Acceptance of ICs by the G-BA

Key: G-BA – Federal Joint Committee; IC – indirect comparison.

For instance, in the case of chronic hepatitis C virus infection, interferon-containing combination therapies were defined as ACT prior to 2014. Interferons are associated with significant side effects, including depression and suicidal thoughts. Given the treatment success that can be achieved with the newer drugs sofosbuvir and elbasvir/grazoprevir, along with the potential for shorter therapy durations and the avoidance of severe interferon-related side effects, it was deemed necessary for ethical reasons to consider uncontrolled, single-arm studies in which these newer drugs were compared with historical controls. Thus, an adjusted comparison was not feasible, and, in this case, an unadjusted comparison was accepted by the G-BA.
Special considerations are also given to highly vulnerable populations, such as pediatric patients or those with rare diseases. In those cases, RCTs may not be ethically feasible to conduct. In the context of lysosomal acid lipase deficiency, for instance—a rare disease that typically results in increased mortality within the first year of life with no available treatment alternatives at the time of assessment—the manufacturer provided ICs with historical controls to overcome the lack of direct comparative evidence. The G-BA accepted this methodology and concluded that the results of the IC ruled out the possibility that the demonstrated gain in overall survival could only be explained by methodological uncertainty. Therefore, the G-BA granted a hint of a non-quantifiable additional benefit to sebelipase alfa. This is an example of the acceptance of an unadjusted IC under additional exceptional circumstances.
Figure 3. Reasons for rejection of ICs by the G-BA

Key: ACT – appropriate comparator therapy; G-BA – Federal Joint Committee; IC – indirect comparison; SmPC – summary of product characteristics.


Conclusion
Authors

Sources
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Bucher HC, Guyatt GH, Griffith LE, et al. The results of direct and indirect treatment comparisons in meta-analysis of randomized controlled trials. J Clin Epidemiol. 1997;50(6):683-691. https://dx.doi.org/10.1016/s0895-4356(97)00049-8
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Federal Joint Committee (G-BA). 2014. Frühe Nutzenbewertung: Beträchtlicher Zusatznutzen für Wirkstoff gegen chronische hepatitis C. Accessed 31 October 2024. https://www.g-ba.de/presse/pressemitteilungen-meldungen/546/
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Federal Joint Committee (G-BA). 2017. AM-RL-XII Elbasvir-Grazoprevir. Accessed 31 October 2024. https://www.g-ba.de/downloads/40-268-4429/2017-06-15_AM-RL-XII_Elbasvir-Grazoprevir_D-268_TrG.pdf
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Federal Joint Committee (G-BA). 2021. AM-RL-XII Sebelipase alfa. Accessed 31 October 2024. https://www.g-ba.de/downloads/40-268-7570/2021-06-03_AM-RL-XII_Sebelipase-alfa_D-606_TrG.pdf
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Federal Joint Committee (G-BA). 2024. Benefit assessments database. Accessed 31 October 2024. https://www.g-ba.de/
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Institute for Quality and Efficiency in Health Care (IQWiG). 2023. General Methods Version 7.0. 19 September 2023. https://www.iqwig.de/methoden/general-methods_version-7-0.pdf
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Warmbold B, Scharrenbroich J, Teich K, Ingendoh-Tsakmakidis A, Löpmeier-Röh J, Kulp W. Indirect comparisons in German AMNOG assessments: keep the faith. Presented at: ISPOR Annual European Congress; Barcelona, Spain; 2024.
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