To register and report is good for the science of endoscopy

Publication of scientific research is the fundamental mechanism for sharing experimental data. This is true whether it is a novel discovery of the mechanism of the disease or the practical and clinical application of a new endoscopic technique to treat gastrointestinal disorders. It has been widely recognized historically that investigators tend to publish more favorable, positive results than unfavorable and negative results; a phenomenon referred to as publication bias [1]. Publication bias, unfortunately, has been propagated by both publishers and investigators, as journals seek out the highest-impact studies and researchers are led to believe that only significant results have impact. This is quite concerning as it leads to a misperception of the benefits of certain procedures and interventions, and can directly lead to harm if interventions that are ineffective, but unpublished, are performed directly on patients. For this reason, there has been a broad international push to require publication of all clinical trial results whether positive or negative.

The requirement to register and report trials was formalized by the United States Food and Drug Administration Amendments Act (FDAAA) of 2007, also known as FDAAA-801. This regulation became active on 18 January 2017 and now requires US investigators to comply with any clinical trial performed in the USA. There are two parts of the requirement: the first is to register the trial typically before the trial begins, and the second is to report the results within 1 year of trial completion.

In this issue of Endoscopy, Garg et al. [2] report on their detailed analysis of compliance with reporting clinical trial results in the field of endoscopy. To do this they searched the ClinicalTrials.gov website to identify 923 trials in the field of endoscopy. The authors reported that approximately 81 % of the clinical trials had complied with reporting standards by reporting directly onto the ClinicalTrials.gov website (18 %) and/or in the form of a peer-reviewed publication (78 %). This is generally higher than other fields of gastroenterology where the compliance rate is approximately 75 % and other general fields of medicine where compliance ranges from 40 % to 63 % [2].

Garg et al. identified several factors that were associated with reporting. Interventional trials were more likely than observational trials to comply with reporting. Device trials, which often involve industry partners, were also more likely to comply than procedure-based trials, as were multicenter trials compared with single-center trials. Interestingly, trials registered from Europe and Asia were more likely to comply than North American trials.

The authors concluded that the field of endoscopy generally shows higher compliance with clinical trial reporting than other disciplines, with only approximately 20 % of trials not being reported, but there is still room for improvement. The authors performed a detailed analysis of current reporting requirements reflecting updated standards and should be commended on this important work.

“The observation that interventional trials, which typically involve an industry-sponsored device, and multicenter trials are all associated with high reporting compliance suggests that the more rigorous trials are likely to be compliant as there is federal oversight over approval of such devices.”

The observation that interventional trials, which typically involve an industry-sponsored device, and multicenter trials are all associated with high reporting compliance suggests that the more rigorous trials are likely to be compliant as there is federal oversight over approval of such devices. Industry sponsors of such trials naturally have an incentive to comply with federal rules. It was interesting, and somewhat counter-intuitive, that trials outside the USA were more likely to be compliant because the regulation was initiated by a US federal authority. We can only speculate as to why this is the case, but many device trials in previous years were initiated outside the USA, with the intent of later US approval. Thus, there could be some confounding between location and industry/device sponsorship. 

A limitation of the study is that it only focused on clinical trials that were previously registered on the same website. Trials that were not registered could not be tracked forward. It also did not evaluate registration sites other than the US-based ClinicalTrials.gov.

What can we learn from these data? First, it is encouraging that endoscopists around the world are aware of this requirement and increasingly report their results in either peer-reviewed publications or directly onto the ClinicalTrials.gov website. The 20 % of trials that were not reported do raise concerns and offer opportunities for improvement.

What can we do to further increase this number? First, journals and editors should be major sources of enforcement. Many journals already check for the registration of clinical trials before they consider them for final publication. In addition to the standard requirement for registering the trial and reporting the results, editors should check that the primary aim that was listed before the start of the trial was the same as the primary aim that was reported in the results. This is important because of the potential for bias if, for example, a primary aim was negative and the authors chose to report a secondary aim or, even more concerning, an exploratory aim, as the “primary” outcome. This is why registering the trial and its primary aims prior to enrolment of the first patient is so important. Journals and editors can also work toward reducing the stigma that fuels publication bias by considering the educational value and benefit of publishing negative studies despite their potential for lower impact.

Authors should also know the definitions of a clinical trial and what needs to be reported. This is clearly outlined on the ClinicalTrials.gov website, including who is responsible for registering clinical trials and submitting results, namely the study sponsor or a designated principal investigator.

The ClinicalTrials.gov website also defines which trials must be registered. This includes any “controlled clinical investigations other than phase 1 of any US FDA regulated drug or biologic product for any disease or condition” [3]. It also includes “any trial conducted under FDA investigational new drug application or investigational device exemption” [3] as well as “any trial involving a drug biological or device product that is manufactured in the United States or its territories.” These definitions are quite broad. One group of studies that are not necessarily included are retrospective case control or cohort studies. Of note, the precise definition of retrospective versus prospective is sometimes confused when an investigator begins to use a newly approved device but collects data on the use of that device with the intent of publishing it. In general, it is best to assume that if the investigator has the intent of publishing outcomes of any new device or drug, it should be considered a clinical trial and should be registered before the first patient is enrolled.

The International Committee of Medical Journal Editors (ICMJE) provides guidance on clinical trial registration requirements. The guidance defines a clinical trial as any research project that prospectively assigns people or a group of people to an intervention with or without a concurrent comparison or control group [4]. While ClinicalTrials.gov is one of the most common registration sites, multiple other national registration sites are acceptable.

In summary, Garg et al. have carefully assessed the current state of clinical trial registration and reporting of results. They have shown that endoscopy investigators are generally performing well with publication requirements. This is a glass mostly full, but there is still some room for improvement. Journals such as Endoscopy and their counterparts should continue to push for all clinical trials to be registered and reported in compliance with FDA and ICMJE regulations. This will continue to advance the field of science, reduce the publication bias against negative trials, and ensure the accurate reporting of primary outcomes.

Publikationsverlauf

Artikel online veröffentlicht:
16. September 2022

• References

• 1 Montori VM, Smieja M, Guyatt GH. Publication bias: a brief review for clinicians. Mayo Clin Proc 2000; 75: 1284-1288
• 2 Garg S, Rizvi A, Wee D. et al. Clinical trial transparency in gastrointestinal endoscopy research. Endoscopy 2022; 55: 36-41 DOI: 10.1055/a-1855-7870.
• 3 ClinicalTrials.gov. Accessed 26 July 2022. https://clinicaltrials.gov/
• 4 International Committee of Medical Journal Editors. Clinical trials registration. Accessed 26 July 2022. www.icmje.org/about-icmje/faqs/clinical-trials-registration/