A method for identifying causal effects from heterogeneous clinical trials in the absence of a common control group: an individual participant data meta-analysis and validation study

BACKGROUNDThe advent of clinical trial data sharing platforms has created opportunities for making new discoveries and answering important questions using already collected data. However, existing methods for meta-analyzing these data require the presence of shared control groups across studies, significantly limiting the number of questions that can be confidently addressed. We sought to develop a method for meta-analyzing potentially heterogeneous clinical trials even in the absence of a common control group. METHODSThis work was conducted within the context of a broader effort to study comparative efficacy in Crohns disease. Following a search of clnicaltrials.gov we obtained access to the individual participant data from nine trials of FDA-approved treatments in Crohns Disease (N=3392). We developed a method involving sequences of regression and simulation to separately model the placebo- and drug-attributable effects, and to simulate head-to-head trials against an appropriately normalized background. We validated this method by comparing the outcome of a simulated trial comparing the efficacies of adalimumab and ustekinumab against the recently published results of SEAVUE, an actual head-to-head trial of these drugs. This study was pre-registered on PROSPERO (#157827) prior to the completion of SEAVUE. FINDINGSUsing our method of sequential regression and simulation, we compared the week eight outcomes of two virtual cohorts subject to the same patient selection criteria as SEAVUE and treated with adalimumab or ustekinumab. Our primary analysis replicated the corresponding published results from SEAVUE (p=0{middle dot}9). This finding proved stable under multiple sensitivity analyses. INTERPRETATIONThis new method may help reduce the bias of individual participant data meta-analyses, expand the scope of what can be learned from these already-collected data, and reduce the costs of obtaining high-quality evidence to guide patient care. FUNDINGNIH; UCSF Division of Gastroenterology and Bakar Computational Health Sciences Institute; University of San Francisco