The Benefits and Risks of Receiving Investigational Solid Tumor Drugs in Randomized Trials : A Systematic Review and Meta-analysis

Renata Iskander; Hannah Moyer; Dean Fergusson; Sean McGrath; Andrea Benedetti; Jonathan Kimmelman

doi:10.7326/M23-2515

The Benefits and Risks of Receiving Investigational Solid Tumor Drugs in Randomized Trials : A Systematic Review and Meta-analysis

Ann Intern Med. 2024 Apr 30. doi: 10.7326/M23-2515. Online ahead of print.

Authors

Renata Iskander¹, Hannah Moyer¹, Dean Fergusson², Sean McGrath³, Andrea Benedetti⁴, Jonathan Kimmelman¹

Affiliations

¹ Department of Equity, Ethics and Policy, McGill University, Montreal, Quebec, Canada (R.I., H.M., J.K.).
² Department of Medicine and School of Epidemiology and Public Health, University of Ottawa, Ottawa, Ontario, Canada (D.F.).
³ Department of Biostatistics, Harvard T.H. Chan School of Public Health, Harvard University, Boston, Massachusetts (S.M.).
⁴ Departments of Medicine and of Epidemiology, Biostatistics and Occupational Health, McGill University, Montreal, Quebec, Canada (A.B.).

PMID: 38684102
DOI: 10.7326/M23-2515

Abstract

Background: Many patients participate in cancer trials to access new therapies. The extent to which new treatments produce clinical benefit for trial participants is unclear.

Purpose: To estimate the progression-free survival (PFS) and overall survival (OS) advantage of assignment to experimental groups in randomized trials for 6 solid tumors.

Data sources: ClinicalTrials.gov was searched for trials of investigational drugs with results posted between 2017 and 2021.

Study selection: Investigational drugs were defined as those not yet having full approval from the U.S. Food and Drug Administration for the study indication. Trials were included if they were randomized and tested drugs or biologics.

Data extraction: Data extraction was completed by 2 independent reviewers. Data were pooled using a random-effects model.

Data synthesis: The sample included 128 trials comprising 141 comparisons of a new drug and a comparator. These comparisons included 47 050 patients. The pooled hazard ratio for PFS was 0.80 (95% CI, 0.75 to 0.85), indicating statistically significant benefit for patients in experimental groups. This corresponded to a median PFS advantage of 1.25 months (CI, 0.80 to 1.68 months). The pooled hazard ratio for OS was 0.92 (CI, 0.88 to 0.95), corresponding to a survival gain of 1.18 months (CI, 0.72 to 1.71 months). The absolute risk for a serious adverse event for comparator group patients was 29.56% (CI, 26.64% to 32.65%), with an increase in risk of 7.40% (CI, 5.66% to 9.14%) for patients in experimental groups.

Limitations: Trials in this sample were heterogeneous. Comparator group interventions were assumed to reflect standard of care.

Conclusion: Assignment to experimental groups produces statistically significant survival gains. However, the absolute survival gain is small, and toxicity is statistically significantly greater. The findings of this review provide reassuring evidence that patients are not meaningfully disadvantaged by assignment to comparator groups.

Primary funding source: Canadian Institutes of Health Research.

Publication types

Review