Investigator Choice Comparator Arms in Oncology Clinical Trials: Implications for HTA/Reimbursement Assessments

OBJECTIVES: There rise in the use of investigator-choice comparator (ICC) arms in clinical trials is driven by issues including the routine use of multiple treatment options and the lack of a clear single comparator. Although ICCs are accepted by regulators, they may be challenged by health technology assessment (HTA) agencies. This study aimed to identify the criticisms of agencies in several countries.

METHODS: A published literature review conducted in 2021 identified 92 oncology trials with an ICC arm. Associated HTAs from the UK, France, Germany, and Canada were identified and critically reviewed to identify payer concerns and criticisms.

RESULTS: A total of 37 trials supported European regulatory approval and 11 drugs underwent HTA in the UK (by NICE) between 2016 and 2023. Of those, 11 had also been reviewed in Canada, 9 in France, and 5 in Germany. All agencies recommended treatments supported by trials with ICC arms.

Concerns noted by payers included misalignment of ICC components with clinical practice (e.g., inclusion of treatments, use of dosages not used in current practice, or omission of relevant treatments). Another criticism was around assumptions of clinical equivalence of ICC components.

As both issues could impact estimates of overall treatment effect, efforts were made to minimize this impact, including by conducting post hoc analyses by treatment component of the ICC, or excluding components of the ICC from analyses.

CONCLUSIONS: The increasing use of ICCs is driven by the availability of multiple treatment options and lack of a clear single comparator. However, challenges specific to HTA are evident, with implications for the analyses required to support HTA assessments. Market-specific generalizability issues will be exacerbated with the introduction of European Joint Clinical Assessments and subsequent market assessments. Manufacturers conducting trials with ICCs will need to anticipate potential objections.