What can we learn from publishing endoscopy trial protocols?

Abstract

License terms Editorial E213 THIEME Clinical trials in medicine have come under public scrutiny as never before in the last decade with scandal after scandal about misrepresentation or misinterpretation of results leading to erroneous clinical conclusions. High-profile campaigns have been started by the British Medical Journal and others to allow access to original trial data, even down to the original case record forms, so that trials can be reanalyzed where foul play is suspected. In some cases, this has altered the primary outcome of the trial[1]; however, more subtle changes to trial analysis can occur during the study process. A common issue is that it is harder to publish negative trials than positive ones, which shouldn't be the case if the original trial was correctly designed to answer the clinical question with sufficient statistical precision. Nevertheless, it is not uncommon to see a secondary outcome or a per protocol analysis (rather than the more rigorous intention-to-treat analysis) that is statistically significant rise to prominence in the study report as the key finding, despite the trial being powered for a different primary outcome measure. The lack of correction for multiple testing of the data is another common omission, sometimes justified by describing such analysis as exploratory or hypothesis generating. While acceptable, clinical inference cannot be drawn for such uncorrected statistical presentation , nor should these results be presented as main trial outcomes. Endoscopic trials are certainly not immune from these phenomena, although the level of commercial input and drive has been less than seen with the millions of dollars that pharmaceutical companies have riding on a successful new drug. Endoscopic trials have often been single-center and often single-operator, with or without minimal funding, save for the time and enthusiasm of a committed endoscopic innovator. Such trials are often of very limited generalizability and essentially simply represent phase one safety studies. More recently much larger endoscopic studies have been developed that are multicenter, multi-operator and often international. These are phase two safety and efficacy studies, with some phase three regulatory studies now occurring and subsequent phase four post-marketing registries now also seen. This represents a maturing of endoscopic research approaches with grant funding for some of these larger trials, which entails formal peer review. Detailed peer review by grant funding bodies is to be commended, as it usually strengthens studies by making them more conservative in their assumptions, especially around recruitment, which makes completion of recruitment (and hence delivery of planned statistical power) more likely, requires patient involvement, and ensures the statistical analysis plan is rigorous and predefined, with a clear primary outcome measure. In many areas of the world there is an expectation that to secure grant funding, a clinical trials unit will be involved as part of the study team and help with trial design and ensure trial logistics can be delivered. Industry-delivered studies increasingly involve clinical trials units for endo-scopic studies as well a clinical research organizations to ensure delivery on the substantial investment that is required. As medical devices come under increasing scrutiny, and companies wish to make regulatory claims about devices, this is likely to become a bigger part of endoscopic research [2]. Transparency has already become part of publishing endoscopic studies with all major gastrointes-tinal and endoscopic journals requiring pre-recruitment trial registration to publish studies [3]. The purpose of this registration is mainly to publicly disclose study rationale and ethical considerations before recruiting subjects into the trial. Moreover, these registries minimize publication bias, since even high-quality studies may end up unpublished due to negative or unwanted results.