Methods and Designs of Modern Breast Cancer Confirmatory Trials.

Julien Péron,Benoît You,Gilles Freyer,Thibaut Reverdy,Colette Smenteck,Marion Cortet

doi:10.3390/cancers13112757

Abstract

Simple SummaryThe benefit–risk assessments of new drugs for breast cancer (BC) face several challenges, as all stakeholders do not agree on the evidence bar required for market authorization, and by the fragmentation of breast cancer diagnosis. In this study, we describe the methods and designs of breast cancer confirmatory trials published between 2001 and 2020. We found that the quality of the evidence supporting new breast cancer drugs was improving over time, but that patient-relevant endpoints such as survival and quality of life remained unfrequently used as primary endpoints.Background: The benefit–risk assessments of new drugs for breast cancer (BC) face several challenges, as all stakeholders do not agree on the evidence bar required for market authorization, and by the fragmentation of breast cancer diagnosis. The aim of this study was to describe the changes in methods and designs of breast cancer confirmatory trials. Methods: All phase III randomized trials published between 2001 and 2020 and assessing systemic BC therapies were included. Trials’ main characteristics, endpoints, and statistical methods were collected using a standardized data extraction form. Results: A total of 347 randomized controlled trials (RCTs) met the inclusion criteria. While most older trials (79%) included all subtypes of breast cancer, most recent trials populations were limited to one large intrinsic BC subgroup (69%). The use of gatekeeping testing strategies increased dramatically from 9% to 71%. The use of overall survival (OS) as an endpoint in the trials increased over time, but its use as a primary endpoint remained infrequent. The inclusion of OS testing in a hierarchical sequence in case of positive testing of a tumor-centered or composite endpoint appeared to have become the new standard. Conclusion: Our findings indicate some improvements in the quality of the evidence-base supporting new breast cancer drugs. The rigorous assessment of patient-relevant endpoints has increased over time, but this improvement is mainly related to the analysis of OS as a secondary endpoint analyzed in a hierarchical sequence.

Highlights

Introduction distributed under the terms andBreast cancer (BC) is the most common malignancy diagnosed in women worldwide, and so the development of new drugs and new therapeutic strategies is a public health priority
The review of most recent clinical trials in our study shows that the overall survival (OS) has been very infrequently used as a primary endpoint, and there was no sign of any relevant increase in its use over time
Our findings indicate some improvements in the quality of the evidencebase supporting new breast cancer drugs

Summary

Introduction

Introduction distributed under the terms andBreast cancer (BC) is the most common malignancy diagnosed in women worldwide, and so the development of new drugs and new therapeutic strategies is a public health priority. Clinical endpoints, such as overall survival, quality of life or patient-reported outcomes for assessing the new drugs’ benefit–risk has regularly been emphasized by most HTA bodies and international scientific societies [2,3] Such an aim requires at least one high-quality randomized placebo-controlled trial investigating a clinical endpoint of interest, such as overall survival (OS), as a primary endpoint. The use of tumor-centered surrogate or intermediate endpoints have led to faster access to the market, but these endpoints have inconsistent clinical relevance It resulted in a wide distribution in the therapeutic benefits associated with approved anticancer drugs, suggesting a wide variation in the value that they bring to society [4,5]. The rigorous assessment of patient-relevant endpoints has increased over time, but this improvement is mainly related to the analysis of OS as a secondary endpoint analyzed in a hierarchical sequence

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