Health-related quality-of-life as co-primary endpoint in randomized clinical trials in oncology

Abstract

Overall survival (OS) has been considered as the most relevant primary endpoint but trials using OS often require large numbers of patients and long-term follow-up. Therefore composite endpoints, which are assessed earlier, are frequently used as primary endpoint but suffer from important limitations specially a lack of validation as surrogate of OS. Therefore, Health-related quality of life (HRQoL) could be considered as an outcome to judge efficacy of a treatment. An alternative approach would be to combine HRQoL with composite endpoints as co-primary endpoint to ensure a clinical benefit for patients of a new therapy. The decision rules of such design, the procedure to control the Type I error and the determination of sample size remain questions to debate. Here, we discusses HRQoL as co-primary endpoints in randomized clinical trials in oncology and provide some solutions to promote such design.

Keywords:

• clinical trial
• composite endpoint
• co-primary endpoint
• endpoint
• health-related quality of life
• methodology

Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.

Key issues

• Composite endpoints combine multiple events (called components) into a single endpoint.

• There is heterogeneity of the definitions of composite endpoints like PFS.

• Most of composite endpoints have not been validated as a surrogate endpoint for OS. Nevertheless, PFS is frequently used as the primary outcome in other types of cancer and many trials have demonstrated improved PFS with no improvement of OS.

• A trial with co-primary endpoints is a trial with two or more primary efficacy endpoints.

• Over the last decade, a tremendous growth in the incorporation of HRQoL in cancer clinical trials has been observed. The US FDA considers HRQoL as an endpoint that assesses direct clinical benefit for the patient.

• Implementation of HRQoL as co-primary can provide a useful measure of the impact of intervention in a way that it is relevant to clinicians and patients.

• The decision rules of trials with HRQoL as co-primary endpoint remains a question to debate. If an intermediate endpoint and HRQoL are co-primary endpoints, we can presume that the investigator might want to give equal importance to the endpoints. Therefore, a decision rule could be that the intermediate composite endpoint must be positive (e.g., PFS) and at least one dimension of HRQoL must be positive without deterioration of the other. The decision rules must be clearly described in the protocol.

• The procedure to control the type I error must be clearly reported and the determination of sample size, taking into account the adjustment of the type I error, is mandatory.