Protocol for the development of a tool (INSPECT-SR) to identify problematic randomised controlled trials in systematic reviews of health interventions.

INTRODUCTION: Randomised controlled trials (RCTs) inform healthcare decisions. It is now apparent that some published RCTs contain false data and some appear to have been entirely fabricated. Systematic reviews are performed to identify and synthesise all RCTs that have been conducted on a given topic. While it is usual to assess methodological features of the RCTs in the process of undertaking a systematic review, it is not usual to consider whether the RCTs contain false data. Studies containing false data therefore go unnoticed and contribute to systematic review conclusions. The INveStigating ProblEmatic Clinical Trials in Systematic Reviews (INSPECT-SR) project will develop a tool to assess the trustworthiness of RCTs in systematic reviews of healthcare-related interventions. METHODS AND ANALYSIS: The INSPECT-SR tool will be developed using expert consensus in combination with empirical evidence, over five stages: (1) a survey of experts to assemble a comprehensive list of checks for detecting problematic RCTs, (2) an evaluation of the feasibility and impact of applying the checks to systematic reviews, (3) a Delphi survey to determine which of the checks are supported by expert consensus, culminating in, (4) a consensus meeting to select checks to be included in a draft tool and to determine its format and (5) prospective testing of the draft tool in the production of new health systematic reviews, to allow refinement based on user feedback. We anticipate that the INSPECT-SR tool will help researchers to identify problematic studies and will help patients by protecting them from the influence of false data on their healthcare. ETHICS AND DISSEMINATION: The University of Manchester ethics decision tool was used, and this returned the result that ethical approval was not required for this project (30 September 2022), which incorporates secondary research and surveys of professionals about subjects relating to their expertise. Informed consent will be obtained from all survey participants. All results will be published as open-access articles. The final tool will be made freely available.

To guide future practice, perinatal trials should be much larger, simpler and less fragile with close to 100% ascertainment of mortality and other key outcomes.

The Australian Placental Transfusion Study (APTS) randomised 1,634 fetuses to delayed (≥60 s) versus immediate (≤10 s) clamping of the umbilical cord. Systematic reviews with meta-analyses, including this and similar trials, show that delaying clamping in preterm infants reduces mortality and need for blood transfusions. Amongst 1,531 infants in APTS followed up at two years, aiming to delay clamping for 60 s or more reduced the relative risk of the primary composite outcome of death or disability by 17% (p = 0.01). However, this result is fragile because nominal statistical significance (p < 0.05) would be abolished by only 2 patients switching from a non-event to an event, and the primary composite outcome was missing in 112 patients (7%). To achieve more robust evidence, any future trials should emulate the large, simple trials co-ordinated from Oxford which reliably identified moderate, incremental improvements in mortality in tens of thousands of participants, with <1% missing data. Those who fund, regulate, and conduct trials that aim to change practice should repay the trust of those who consent to participate by doing everything possible to minimise missing data for key outcomes.