Table 1.

Summary of key challenges in presenting the value of IOs in HTA submissions

Challenge	Considerations for researchers
Mechanism of action
Representation of the underlying biological model	Has the underlying biological model and how it links with any survival analysis/statistical modeling been clearly explained?
Possibility of cure underlying the long-term survival	Have published external data or additional clinical trial data been presented as supportive evidence of long-term survivorship?
Addressing pseudo-progression	Has pseudo-progression been raised as an issue? If yes, were any outcome measures used in the trials that take into account this phenomenon?
Model structure and survival extrapolation methodology
Use of non-standard model structure to capture immunotherapy effect	Have the methods used been explained, and any previous uses of the methods incorporated?
Capturing heterogeneity in treatment effect and outcomes	Has heterogeneity in treatment effect been explored and were any subgroup analyses based on mechanism of actions and clinical plausibility?
Availability and use of early response biomarkers to predict long-term survival	Have any biomarker data been presented as the predicate for considering heterogeneity?
Shape of the survival curve/plateau and smoothing estimators of the hazard function	Has the survival analysis/statistical modeling been presented and justified not just in terms of statistical performance, but how it reflects the underlying biological model?
Clinical plausibility and validation of the extrapolation using real-world evidence or other data	Have real-world data been sourced and included to support estimates of long-term survival?
Limited clinical trial evidence at HTA submission
Duration of follow-up and maturity of OS and PFS	Have the trial end points been presented within the context of completeness—for example, censoring, numbers at risk?
Availability and use of intermediate and/or surrogate end points (TFI, DFS, response)	Have the surrogate end points been presented, and their relationship to long-term survival demonstrated?
HTA submission
Linking central points with payer, clinician, and patient perspectives on immunotherapy: this is not necessarily a question that can be used as a proxy for a submission requirement, but it is in place for manufacturers to consider that they have sought out expert opinions from these important stakeholders.

DFS, disease-free survival; HTA, health technology assessment; IOs, immuno-oncologics; OS, overall survival; PFS, progression-free survival; TFI, treatment-free interval.