Results from over half of all conducted randomized controlled trials (RCTs), especially those with negative or unfavorable results, never get published. This means, searching only electronic databases that index published literature does not provide the entire spectrum of information; additionally, a bias is induced, since most trials having negative results get omitted. This is extremely crucial while doing literature search for informing a systematic review (SR).(1) Any kind of information bias, such as publication bias, selective outcome reporting bias, selective analysis bias, and time-lag bias, can result in an SR with a biased result, which can significantly hamper the validity and applicability of an SR.(2)
Identification of all the previous relevant research, along with its informative quality, is an essential tool that validates the SR findings. This has led to the development of certain methods to identify all the literature to avoid publication bias. These methods, such as those based on funnel plots, are now regularly performed and are a part of the SR reporting guidelines.(3) However, these methods are found to be inadequate, since they can only suggest the presence of unpublished studies, assuming that the largest studies on the subject are published, which might not always be the case.(4,5) Furthermore, findings from empirical analyses have shown these methods to not consistently detect publication bias.(5,6)
There are two approaches preferred by the systematic reviewers to deal with the information bias. One is detecting (and perhaps correcting results for) the bias based only on the identified studies (e.g., applying funnel-plot-based methods(7) or sensitivity analyses to represent possibly missing information(8) or comparing outcomes listed under Methods and Results sections in published manuscripts.(9) The second one is assessing trial registries, survey researchers, and scrutinize the gray literature to identify missing information from unpublished study results or ongoing studies.(2)
Clinical trial registries basically enable clinical researchers, physicians, as well as the general public, to learn about clinical studies/trials being conducted on a subject, irrespective of the publication of findings of those studies. The International Committee of Medical Journal Editors (ICMJE) has, since 2005, made it mandatory for all the prospective human trials to undergo registration prior to commencing study enrollment. This requirement also makes for the condition ICMJE has put forth for publication in member journals.(10) Prospective registration of trials has also become a requirement under United States law for several interventional studies after the United States Food and Drug Administration Amendments Act (FDAAA) was passed in 2007.(11) Therefore, clinical trial registries are an all-inclusive storehouse of recently initiated clinical trials. Policy-makers and regulators believe that pre-registration of studies, if done consistently, will help all the healthcare stakeholders justify publication bias and other forms of selective reporting.(5,10)
Clinical trial registries not only make available the findings from prospectively registered studies, but they also have result summaries (e.g., the National Library of Medicine ClinicalTrials.gov registry and registry networks), which can account for a lot of unpublished information. Policies that mandate prior registration often comprise of requirements for registering studies that include documentation of the study type, intervention, trial phase, information on the funding source, and outcomes, and the kind of information to be included within a study record. These steps have evolved after the launch of ClinicalTrials.gov in 2000. Explanations on what information to include in ClinicalTrials.gov have been provided to the research community to warrant compliance and timely submission of appropriate data to the registry.(12) The Clinical Trial Registry of India (CTRI) does a similar function with respect to clinical trials conducted in India, and it is now mandatory for RCTs performed in India to prospectively register with CTRI.(13) Researchers in favor of clinical trial registration underline the role of registry platforms to broadcast gathered results to researchers, clinicians, and study participants. Clinical trial registries improve transparency by providing a record of studies, which are in progress or have been completed.(2)
Clinical trial registries have been developed essentially to reduce waste in research, as well as publication bias. Even policy makers and editors have emphasized on their use. Furthermore, the use of registries have shown to provide greater transparency, thus improving the value of research. Therefore, searching clinical trial registries should be promoted and mandated while conducting SRs.(14)
- Schmucker C, Schell LK, Portalupi S, et al. OPEN consortium. Extent of non-publication in cohorts of studies approved by research ethics committees or included in trial registries. PLoS One 2014; 356:e114023.
- Adam GP, Springs S, Trikalinos T, et al. Does information from ClinicalTrials.gov increase transparency and reduce bias? Results from a five-report case series. Syst Rev 2018; 7(59).
- Liberati A, Altman DG, Tetzlaff J, et al. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration. J Clin Epidemiol 2009; 62(10):e1-e34.
- Jones CW, Handler L, Crowell KE, et al. Non-publication of large randomized clinical trials: cross sectional analysis. BMJ 2013; 347:f6104.
- Jones CW, Keil LG, Weaver MA, et al. Clinical trials registries are under-utilized in the conduct of systematic reviews: a cross-sectional analysis. Syst Rev 2014; 3(126).
- Lau J, Ioannidis JP, Terrin N, et al. The case of the misleading funnel plot. BMJ 2006; 333:597-600.
- Rucker G, Carpenter JR, Schwarzer G. Detecting and adjusting for small-study effects in meta-analysis. Biom J 2011; 53:351–68.
- Copas JB, Shi JQ. A sensitivity analysis for publication bias in systematic reviews. Stat Methods Med Res 2001; 10:251–65.
- Dwan K, Altman DG, Clarke M, et al. Evidence for the selective reporting of analyses and discrepancies in clinical trials: a systematic review of cohort studies of clinical trials. PLoS Med 2014; 11:e1001666.
- De Angelis C, Drazen JM, Frizelle FA, et al. Clinical trial registration: a statement from the International Committee of Medical Journal Editors. N Engl J Med 2004; 351(12):1250-1251.
- Food and Drug Administration Amendments Act of 2007. US Public Law 110–85. (2007, Sept 27); 21 USC 301.
- Zarin DA, Tse T, Sheehan J. The proposed rule for U.S. clinical trial registration and results submission. N Engl J Med 2015; 372:174–80.
- Vardhana Rao MV, Maulik M, Gupta J, Panchal Y, Juneja A, Adhikari T, Pandey A. Clinical Trials Registry – India: An overview and new developments. Indian J Pharmacol. 2018 Jul-Aug;50(4):208-211.
- Baudard M, Yavchitz A, Ravaud P, et al. Impact of searching clinical trial registries in systematic reviews of pharmaceutical treatments: methodological systematic review and reanalysis of meta-analyses. BMJ 2017; 356.