#HEORInsights

Systematic literature reviews (SLRs) are classically conducted with an aim of mapping the complete evidence base of a particular healthcare intervention, which enables an impartial evaluation of the evidence and lays the foundation for strong recommendations. The initial step in achieving this aim, while carrying out an SLR, is to conduct an extensive literature search in bibliographic databases, such as PubMed and EMBASE. However, just this step may not be enough, since these databases usually contain only articles published in scientific journals, except occasional abstracts from conferences. (1,2)

Systematic literature reviews are of great importance when it comes to the level and quality of evidence, which is why they are extensively used by clinical policy-makers, granting health agencies, and journal editors alike. (3,4) Identifying all relevant randomized controlled trials (RCTs), irrespective of their publication status, poses a great challenge in the conduct of SLRs. (5,6) To state the fact, findings from half of these RCTs never get published, which may affect the publication status and  direction of results. This may further cause bias in the systematic review results. (7)

Trial registries, set up for a hypothetical registration of trials, have proven to be an effective tool to reduce their selective publication. (80 Since the initial computerized registries in the US in 1960s, various national and international, public and private registries have been generated. However, just the registration of a trial may not yield any information about a particular healthcare intervention, since a complete information about methodology and results of a trial can be achieved only through its unbiased assessment. (1) Registration of clinical trials in public trial registers (for e.g. ClinicalTrials.gov) has become mandatory since July 2005, as per the recommendations from International Committee of Medical Journal Editors (ICMJE). (9) Additionally, the ‘Amendments Act’ (2007) by the USFDA recommends posting of clinical trial results on ClinicalTrials.gov within one year of final data collection for the pre-defined primary outcome, for all phase II to IV trials of drugs, biological treatments as well as devices. (4,10,11)

The specifications warranted by authorities like USFDA, ICJME as well as National Institutes of Health Policies during registration of trials are – trial type, name of the intervention, trial phase, sponsors, outcomes, and types of data among other variable parameters. There also exist explanations about the information to be included in ClinicalTrials.gov in order to ensure compliance and well-timed submission of appropriate data. The regulators believe that the role of registry platforms, such as ClinicalTrials.gov, would facilitate propagation of aggregated results amongst researchers, clinicians as well as study participants. Registry platforms improve transparency by means of a list of studies either in progress or have been completed. (12)

Today, searching trial registries is regarded as an essential tool while conducting an SLR. Evidence from literature also shows that the addition of data from unpublished trials logged in the registries, such as ClinicalTrials.gov, may change the magnitude of the effect size or, in some cases, the statistical importance of SLRs as well as meta-analyses. It may also help in achieving more precision. Findings of a recent systematic review, estimating the effect of under-reporting of adverse events (AEs) in SLRs, report that the information from such unpublished trials may lessen the inaccuracy of pooled effect estimates while reporting of AEs. (4) Furthermore, information from ClinicalTrials.gov can also aid planning an SLR and offer valuable updates, since the registries enlist not only ongoing, but also soon to be completed trials. (1)

While searching ClinicalTrials.gov can be helpful in obtaining precise information on unpublished trials, it is not observed to be implemented thoroughly. (4) Information from trial registries can significantly encourage value-addition in SLRs through identification of additional trials. This search should be promoted and applied; while listing of trials on these registries should also be encouraged.

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References

1. Potthast R, Vervolgyi V, McGauran N, et al. Impact of Inclusion of Industry Trial Results Registries as an Information Source for Systematic Reviews ncbi. PLoS One 2014; 9(4):e92067. 
2. Hopewell S, McDonald S, Clarke M, et al. Grey literature in meta-analyses of randomized trials of health care interventions. Cochrane Database Syst Rev 2007; MR000010.
3. Bastian H, Glasziou P, Chalmers I. Seventy-five trials and eleven systematic reviews a day: how will we ever keep up? PLoS Med 2010; 356:e1000326. 
4. 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:j448.
5. Chalmers I, Glasziou P. Avoidable waste in the production and reporting of research evidence. Lancet 2009; 356:86-9.
6. Chan AW, Song F, Vickers A, et al. Increasing value and reducing waste: addressing inaccessible research. Lancet 2014; 356:257-66. 
7. 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.
8. Simes RJ. Publication bias: the case for an international registry of clinical trials. J Clin Oncol 1986; 4:1529–1541.
9. De Angelis C, Drazen JM, Frizelle FA, et al. International Committee of Medical Journal Editors. Clinical trial registration: a statement from the International Committee of Medical Journal Editors. N Engl J Med 2004 Sep 16; 351(12):1250–1.
10. United States Congress. (2007) Food and Drug Administration Amendments Act (FDAAA) of 2007: public law no 110-85.
11. Groves T. Mandatory disclosure of trial results for drugs and devices. BMJ 2008; 356:170.
12. 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(1):59.

Written By: Ms. Tanvi Laghate