Dataset Information

Effect Sizes Hypothesized and Observed in Contemporary Phase III Trials of Targeted and Immunological Therapies for Advanced Cancer.

ABSTRACT:

Background

We sought to compare the effect sizes hypothesized in the trial design, observed in the trial results, and considered clinically meaningful by the American Society of Clinical Oncology (ASCO) 2014 recommendations, in phase III trials of targeted and immunological therapies.

Methods

We studied phase III, superiority trials of targeted and immunological therapies in advanced cancers published from 2005 to 2015. We recorded the characteristics, design parameters, and observed results for the primary endpoint of each trial. The effect sizes hypothesized in the trial design were compared with the ASCO 2014 recommendation that phase III trials be designed to detect overall survival (OS) benefits that are clinically meaningful (hazard ratio??0.8).

Results

All critical elements of the trial design (effect sizes hypothesized, estimated survival in the control group, power, and significance level) were identified in 165 of 213 included trials (77%). Of trials with a statistically significant result for the primary endpoint, 16 of 30 (53%) with a primary endpoint of OS and 20 of 53 (38%) with a primary endpoint of progression free survival (PFS) had an observed effect size less extreme than hypothesized; and 7 of 30 trials (23%) reported an observed effect size for OS that was statistically significant but not clinically meaningful (HR?>?0.80) according to the ASCO 2014 recommendations.

Conclusion

Many trials were designed such that an observed benefit in OS or PFS that was not clinically meaningful would be statistically significant. Phase III trials should be designed to provide results that are statistically significant for observed effects that are clinically meaningful but not for observed results that are of dubious clinical importance.

SUBMITTER: Lawrence NJ

PROVIDER: S-EPMC6649714 | biostudies-literature | 2018 Oct

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Effect Sizes Hypothesized and Observed in Contemporary Phase III Trials of Targeted and Immunological Therapies for Advanced Cancer.

Lawrence Nicola Jane NJ Roncolato Felicia F Martin Andrew A Simes Robert John RJ Stockler Martin R MR

JNCI cancer spectrum 20181001 4

<h4>Background</h4>We sought to compare the effect sizes hypothesized in the trial design, observed in the trial results, and considered clinically meaningful by the American Society of Clinical Oncology (ASCO) 2014 recommendations, in phase III trials of targeted and immunological therapies.<h4>Methods</h4>We studied phase III, superiority trials of targeted and immunological therapies in advanced cancers published from 2005 to 2015. We recorded the characteristics, design parameters, and obser ...[more]

PMID: 31360867

Similar Datasets

Project description:BackgroundCardiovascular disease (CVD) has become an increasingly common limitation to effective anticancer therapy. Yet, whether CVD events were consistently reported in pivotal trials supporting contemporary anticancer drugs is unknown.ObjectivesThe authors sought to evaluate the incidence, consistency, and nature of CVD event reporting in cancer drug trials.MethodsFrom the Drugs@FDA, clinicaltrials.gov, MEDLINE, and publicly available U.S. Food and Drug Administration (FDA) drug reviews, all reported CVD events across latter-phase (II and III) trials supporting FDA approval of anticancer drugs from 1998 to 2018 were evaluated. The primary outcome was the report of major adverse cardiovascular events (MACE), defined as incident myocardial infarction, stroke, heart failure, coronary revascularization, atrial fibrillation, or CVD death, irrespective of treatment arm. The secondary outcome was report of any CVD event. Pooled reported annualized incidence rates of MACE in those without baseline CVD were compared with reported large contemporary population rates using relative risks. Population risk differences for MACE were estimated. Differences in drug efficacy using pooled binary endpoint hazard ratios on the basis of the presence or absence of reported CVD were also assessed.ResultsOverall, there were 189 trials, evaluating 123 drugs, enrolling 97,365 participants (58.5 ± 5 years, 46.0% female, 72.5% on biologic, targeted, or immune-based therapies) with 148,138 person-years of follow-up. Over a median follow-up of 30 months, 1,148 incidents of MACE (375 heart failure, 253 myocardial infarction, 180 strokes, 65 atrial fibrillation, 29 revascularizations, and 246 CVD deaths; 792 in the intervention vs. 356 in the control arm; p < 0.01) were reported from the 62.4% of trials noting any CVD. The overall weighted-average incidence was 542 events per 100,000 person-years (716 per 100,000 in the intervention arm), compared with 1,408 among similar-aged non-cancer trial subjects (relative risk: 0.38; p < 0.01), translating into a risk difference of 866. There was no association between reporting CVD events and drug efficacy (hazard ratio: 0.68 vs. 0.67; p = 0.22).ConclusionsAmong pivotal clinical trials linked to contemporary FDA-approved cancer drugs, reported CVD event rates trail expected population rates.

Dataset Information

Effect Sizes Hypothesized and Observed in Contemporary Phase III Trials of Targeted and Immunological Therapies for Advanced Cancer.

Background

Methods

Results

Conclusion

Publications

Effect Sizes Hypothesized and Observed in Contemporary Phase III Trials of Targeted and Immunological Therapies for Advanced Cancer.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets