Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2023 Feb 8;115(2):174-180.
doi: 10.1093/jnci/djac210.

Design and reporting of phase III oncology trials with prospective biomarker validation

Fei Liang  1   2 , Ling Peng  3 , Zhengyu Wu  4 , Georgios Giamas  5 , Justin Stebbing  6   7
Affiliations

Design and reporting of phase III oncology trials with prospective biomarker validation

Fei Liang et al. J Natl Cancer Inst. .

Abstract

Background: Phase III trials with prospective biomarker validation are essential to drug development in the era of personalized oncology. However, concerns have emerged regarding the design and reporting of phase III trials with prospective biomarker validation.

Methods: We searched MEDLINE for phase III oncology trials with prospective biomarker validation published in high-impact medical journals from 2011 to 2020. Information regarding trial design and reporting were extracted. Descriptive methods were used to summarize the results.

Results: We identified 45 phase III trials with prospective biomarker validation. There was a trend for increasing use of biomarker validation phase III trials (from 1 trial in 2011 to 12 trials in 2020). For 39 (86.7%) trials, results in biomarker-negative population were either listed as an exploratory subgroup analysis (62.2%) or not mentioned in the methods (24.4%). Twenty-one (46.7%) trials were originally designed without biomarker validation but were then apparently modified to incorporate prospective biomarker validation after trial commencement, albeit only 15 (33.3%) trials reported this change. Treatment effect and primary outcome values in biomarker-negative patients were not reported in 24.4% and 40.0% trials, respectively. For 18 trials with statistically significant results in the overall population, only 7 trials reported a hazard ratio less than 0.8 in the biomarker-negative population.

Conclusions: Although biomarker validation in phase III trials have been increasingly used in the past decade, issues regarding changes in trial design after commencement without disclosure, underreporting of results in biomarker-negative groups, and recommending treatment in biomarker negative groups despite modest effects require substantial improvement.

PubMed Disclaimer

Figures

Figure 1.
Figure 1.
Number of phase III trials with biomarker validation per year between 2011 and 2020.
Figure 2.
Figure 2.
Comparison of treatment effect in biomarker-positive population with that in biomarker-negative population among trials reporting positive results in overall population. CI = confidence interval; IV = inverse variance. Error bars indicate the 95% confidence intervals.
See this image and copyright information in PMC

Comment in

References

    1. Freidlin B, Sun Z, Gray R, et al. Phase III clinical trials that integrate treatment and biomarker evaluation. J Clin Oncol. 2013;31(25):3158-3161. - PMC - PubMed
    1. Hu C, Dignam JJ.. Biomarker-driven oncology clinical trials: key design elements, types, features, and practical considerations. J Clin Oncol Precis Oncol. 2019;3:1. - PMC - PubMed
    1. Mandrekar SJ, Sargent DJ.. Clinical trial designs for predictive biomarker validation: theoretical considerations and practical challenges. J Clin Oncol. 2009;27(24):4027-4034. - PMC - PubMed
    1. Matsui S, Crowley J.. Biomarker-stratified phase III clinical trials: enhancement with a subgroup-focused sequential design. Clin Cancer Res. 2018;24(5):994-1001. - PubMed
    1. Sargent DJ, Conley BA, Allegra C, et al. Clinical trial designs for predictive marker validation in cancer treatment trials. J Clin Oncol. 2005;23(9):2020-2027. - PubMed