Multi-indication Evidence Synthesis in Oncology Health Technology Assessment: Meta-analysis Methods and Their Application to a Case Study of Bevacizumab

Background Multi-indication cancer drugs receive licensing extensions to include additional indications, as trial evidence on treatment effectiveness accumulates. We investigate how sharing information across indications can strengthen the inferences supporting health technology assessment (HTA). Methods We applied meta-analytic methods to randomized trial data on bevacizumab, to share information across oncology indications on the treatment effect on overall survival (OS) or progression-free survival (PFS) and on the surrogate relationship between effects on PFS and OS. Common or random indication-level parameters were used to facilitate information sharing, and the further flexibility of mixture models was also explored. Results Treatment effects on OS lacked precision when pooling data available at present day within each indication separately, particularly for indications with few trials. There was no suggestion of heterogeneity across indications. Sharing information across indications provided more precise estimates of treatment effects and surrogacy parameters, with the strength of sharing depending on the model. When a surrogate relationship was used to predict treatment effects on OS, uncertainty was reduced only when sharing effects on PFS in addition to surrogacy parameters. Corresponding analyses using the earlier, sparser (within and across indications) evidence available for particular HTAs showed that sharing on both surrogacy and PFS effects did not notably reduce uncertainty in OS predictions. Little heterogeneity across indications meant limited added value of the mixture models. Conclusions Meta-analysis methods can be usefully applied to share information on treatment effectiveness across indications in an HTA context, to increase the precision of target indication estimates. Sharing on surrogate relationships requires caution, as meaningful precision gains in predictions will likely require a substantial evidence base and clear support for surrogacy from other indications. Highlights We investigated how sharing information across indications can strengthen inferences on the effectiveness of multi-indication treatments in the context of health technology assessment (HTA). Multi-indication meta-analysis methods can provide more precise estimates of an effect on a final outcome or of the parameters describing the relationship between effects on a surrogate endpoint and a final outcome. Precision of the predicted effect on the final outcome based on an effect on the surrogate endpoint will depend on the precision of the effect on the surrogate endpoint and the strength of evidence of a surrogate relationship across indications. Multi-indication meta-analysis methods can be usefully applied to predict an effect on the final outcome, particularly where there is limited evidence in the indication of interest.