In a research letter published on 6 December 2018 in the JAMA Oncology, Eitan Amir and colleagues alerted on changes in trials design upon the onset of patient accrual. In particular, they tried to quantify such changes in trials that supported anticancer drug approvals by the US Food and Drug Administration (FDA).
The study team searched the FDA website for clinical trials that supported approval of new drugs for treatment of solid tumours from 1 January 2010 to 31 December 2016. They compared the ClinicalTrials.gov entries at trial initiation with entries for the same trials effective on 1 April 2018, thereby identifying modifications in trial design. Then they identified the publication of the registered studies and assessed the reporting of these changes.
Among 101 included trials in the analysis, 56 (55.4%) had modifications in planned sample size, 34 (33.7%) in inclusion criteria, and 27 (26.7%) in primary outcome. They also found that 39 of 56 studies (69.6%) with changes in the pre-planned sample size, 19 of 34 studies (55.9%) with changes in the inclusion criteria, and 10 of 27 studies (37.0%) with changes in the primary outcome definitions were reported in the matching publication.
A breakthrough therapy designation was associated with more changes in inclusion criteria (odds ratio [OR], 2.73; 95% CI, 1.01-7.39; p = 0.048) and primary outcome definitions (OR, 3.95; 95% CI, 1.11-14.13; p = 0.03).
Accelerated approval was associated with more changes in inclusion criteria (OR, 2.84; 95% CI, 1.12-7.21, p = 0.03) and sample size (OR 2.71; 95% CI, 1.00-7.34; p = 0.049).
A single-arm trial design was associated with more changes in sample size (OR, 4.00; 95% CI, 1.33-12.50; p = 0.01).
Tumour and drug types and other regulatory pathways were not associated with modifications in study design.
Although the study has some limitations (e.g. most journals do not make serial versions of protocols available publicly or small number of studies included in the analysis), the authors concluded that among trials supportive for FDA approval of anticancer drugs, modifications in study design after patient accrual has begun are common, often unreported, and associated with breakthrough therapy designation, accelerated approval, and single-arm trials.
Shepshelovich D, Tibau A, Molto C, et al. Assessment of Frequency and Reporting of Changes in Cancer Trial Design After Initiation of Patient Accrual. JAMA Oncol. Published online December 6, 2018. doi:10.1001/jamaoncol.2018.5877