European and national legislation clearly specify the mandatory structure and content of a clinical trial protocol, e.g. for a randomised, controlled phase II human drug study [1-4]. The same applies to the structure and content of a clinical study report [5]. One should assume that a publication of a given clinical trial fulfilling these legal requirements is a high-quality and complete mirror of the trial protocol and the study report. The reality is different. Read on to learn more and discover what measures are being taken by the scientific community to avoid distorting public perception and reporting bias by implementing new rules on publishing results of clinical trials.
Many reviews, have pointed out insufficient and inaccurate reporting of clinical trials. Analyses of PubMed-indexed trial reports in 2006 revealed that information on participants’ assignment to comparison groups was provided in no more than 34% of the cases. Only 53% of reports defined a primary endpoint, and only 45% reported a sample size calculation [6]. This led to an update of the CONSORT (Consolidated Standards of Reporting Trials) statement [7], an evidence-based, minimum set of recommendations for reporting randomised controlled trials (RCTs). It includes a 25-essential-items checklist with a focus on trial design, analysis and interpretation – and a flow-diagram to display the progress of all trial participants through the trial [7]. The primary objective of CONSORT is to provide guidance to authors how to improve reporting of their trials, and to assist readers, peer reviewers and editors to critically appraise and interpret reports of RCTs [8].
Meanwhile, extensions to the CONSORT statement have been published in order to cover a wider range of trial designs, such as, non-inferiority and equivalence -, cluster - and pragmatic trials [9-11]. Another extension deals with the reporting of abstracts [12]. Additional statements are available including reporting of observational studies (STROBE) [13], systematic reviews and meta-analyses (PRISMA; PRISMA-IPD) [14, 15], and diagnostic accuracy studies (STARD 2015) [16]. Reporting of harms and adverse events has been shown still to be inadequate [17, 18] – this has led to two further statement extensions: the CONSORT for harms checklist [19] and the PRISMA harms checklist [20]. The SPIRIT 2013 Explanation and Elaboration Paper [21] extends guidance to clinical trial protocols. The AGREE Reporting Checklist comprises a tool to improve reporting of clinical practice guidelines [22]. The list could still be continued. The EQUATOR (Enhancing the QUAlity and Transparency Of health Research) network, which was formed to support the development and dissemination of all these guidelines, currently includes 313 reporting guidelines on its website [23].
The Cochrane Collaboration published its tool for assessing risk of bias in randomised trials and specified six bias domains: selection bias, performance bias, detection bias, attrition bias, reporting bias and other bias [24].
Sources of selection bias (= biased allocation to interventions) include inadequate random sequence generation and allocation concealment. Performance bias could be due to non-blinding of participants and personnel, and detection bias due to knowledge of the allocated interventions by outcome assessment – to be avoided by blinding of outcome assessment. Attrition bias refers to incomplete outcome data and could be caused by their amount, nature or handling. Reporting bias implies selective outcome reporting and other bias could be due to problems not covered elsewhere. In order to judge a given trial or manuscript each of the above mentioned potential sources of bias should be classified as ”low risk” / “high risk” /”unclear risk” [24].
Reporting bias due to unpublished clinical trial results, delayed publication or under-reporting of adverse event data - in case of negative or unfavorable results - may distort the real effect of an intervention or a new drug, may harm patients and is in contrast to the ethical principles set in the Declaration of Helsinki [25, 26]. It is a challenge to search for unpublished clinical trial evidence [27], and there is an ongoing request to register all trials and publish the results [28, 29].
The European Medicines Agency (EMA) has adopted a policy on publication of clinical data [30], and The International Committee of Medical Journal Editors (ICMJE) recently made a proposal concerning data-sharing requirements and asked for feedback by April 18, 2016 [31]. They propose to require authors to share with others the de-identified individual-patient data (IPD) underlying their trial results – for transparency and reproducibility reasons - and would like them to include a data sharing plan as a component of trial registration. ClinicalTrials.gov has already added a respective element to its registration platform [31].
In summary, some lessons have already been learnt concerning improved reporting of clinical trial results – and tools how to do so are available. A lot more, however, still needs to be done to achieve transparent, accurate and complete publications of each clinical trial including sharing of data with other researchers. Continuous careful observation of this process - accompanied by further publications on which next steps have been reached and what has failed – will be necessary.
References
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