Composite event-free-survival as an endpoint in oncology drug evaluation: Review and guidance perspectives from the Haute Autorité de Santé (HAS)

Abstract

Background: The use of right-censored composite endpoints, such as progression-free survival, has been questioned in haemato-oncology trials due to potential bias in estimated treatment effect. This may impact the accuracy of health technology evaluations. We hypothesized that there is heterogeneity and potential sources of bias in the reporting of composite endpoints to health technology assessment (HTA) bodies.

Methods: We reviewed the submissions for reimbursement of oncology drugs in 2021 and 2022 that used a composite endpoint in the pivotal trial, after appraisal by the French HTA body. The retrieved information included the clinical study report, protocol, and statistical analysis plan submitted by the industry. All events of the composite endpoint and all causes of censored observations were measured. The design characteristics and treatment effect estimates were recorded.

Findings: Seventy-six submissions were selected, including seven without a right-censored endpoint and four evaluating associations, resulting in 65 analysed records: 17 for haematological and 48 for solid tumours. Out these 65 submissions, 47 (72·3%) used a randomized controlled design, and 18 (27·7%) a non-comparative design. The most frequently used composite endpoint was progression-free survival, used in 54 (83·1%) of the submissions. Censoring was possibly informative in 51 (92·7%) cases, mostly due to the onset of new treatment (44/51, 86·3%) and/or discontinuation of follow-up (33/51, 64·7%). In contrast, 38 (58·5%) trials reported a quantification of censored observations, with only 12/51 (23·5%) quantifying the informative ones. The estimated treatment effect on the composite outcome increased with the amount of censoring, suggesting a higher benefit of the drug, but remained below that on survival with poor evidence of surrogacy (R-squared=0·23).

Interpretation: Clinical study reports should be improved in terms of reporting censoring, while stakeholders should be aware of this potential source of bias. At a minimum, sensitivity analysis that ignores intercurrent events should be requested.

Keywords: Clinical trial; Health technology assessment; Informative censoring; Progression-free survival; Regulation.