Objectives: The challenges associated with single-arm trial (SAT) oncology submissions to health technology appraisal (HTA) bodies are well documented. Previous research has extensively described the type of evidence submitted to build the external control (EC) arm. However, there is limited research behind the rationale of the EC source selection. We aimed to understand how the selection of EC source was justified by manufacturers, how it matches the decision problem, and the critique associated with this justification and its influence on decision making.

Methods: A search for oncology submissions to the National Institute for Health and Care Excellence (NICE) and Pharmaceutical Benefits Advisory Committee (PBAC) between 2016 and 2021 was conducted to identify pharmaceutical submissions using SAT as the pivotal evidence base to support the technology under appraisal. Data from these submissions were extracted and synthesized.

Results: 29 and 19 submissions to NICE and PBAC, respectively, were identified. Most submissions (55% [NICE], 67% [PBAC]) considered multiple sources (previous trials, RWE) to build the EC arm. This selection was rarely justified. HTA bodies were concerned about closeness of EC population to the decision problem, representativeness to clinical practice and biases about the EC source. However, HTA bodies did not critique the lack of justification of the EC source selection. The use of proxy EC data, although limited in the submissions, was considered plausible by HTA bodies when based on clinical grounds.

Conclusion: Besides the type of EC considered, we found that the justification of the EC source selection is rarely documented. Given the strong emphasis by HTA bodies on unbiased selection of evidence to support decision making, more transparent rationale should be provided. Further guidance is also needed from HTA bodies on explicit weighting criteria for EC preferences such as the use of quality assessments for evaluating population differences between EC sources.