IJD(®): Consorting with CONSORT 2010.

Why does IJD embrace CONSORT?

Much like a living organism, the Indian Journal of Dermatology (IJD) continues to evolve with the ever-changing developments of scientific research in clinical dermatology. One particular area, that of encouraging better design and reporting of randomized controlled clinical trials, is worthy of special mention given that the IJD has adopted a requirement that all trial reports should adhere to the latest Consolidated Reporting of Trials (CONSORT 2010) statement.[1]

The primacy of randomized controlled clinical trials (RCTs)

While many different study designs are appropriate for answering different sorts of clinical questions, the randomized controlled trial (or a systematic review of RCTs) is the gold standard for assessing the potential for therapeutic benefit because of its ability to reduce selection, performance, response, and attrition bias.[2] For decades, empirical reasoning based upon partially explained mechanisms was the cornerstone for justifying certain treatments.[3] Thus, at one time, thalidomide was being increasingly used to treat toxic epidermal necrolysis (TEN) based on the premise that TEN is associated with raised levels of tumor necrosis factor-alpha (TNF-α) and that thalidomide inhibits the effects of TNF-α. When a formal trial was initiated, it had to be stopped early as 10 out of 12 patients in the thalidomide group died compared with 3 out of 10 on placebo. Moreover, it was also found that TNF-α levels in the thalidomide group had actually increased during treatment.[4] The current trend of using intravenous immunoglobulin in TEN in the absence of high quality evidence may be cited as another example of hangover from the empiricist tradition.[5] Such examples teach us that while basic science and surrogate outcome studies help identify interventions of promise, it is the RCTs that determine whether clinical benefit really matches such promise. Thus, IJD has now prepared the way for being the vehicle for important RCTs.

It has been our experience while editing this journal that the term ‘clinical trial’ is being used by authors far too loosely and far too often to mean just any kind of clinical study. The International Committee of Medical Journal Editors defines a clinical trial as research that prospectively assigns human participants to intervention and concurrent comparison groups to study the cause-and-effect relationship between a medical intervention and a health outcome.[6] Explanatory trials are designed to answer the question. ‘Can this intervention work’? These are carried out under conditions so controlled as to be ideal, with highly selected patients, drug doses, and placebo or vehicle groups, and typically contain short-term efficacy or surrogate efficacy measures.[2] Pragmatic trials, in contrast, aim to answer the question: ‘Does this treatment work in real clinical practice?’[7] These are usually larger and include participants who are much more similar to those encountered in day-to-day clinical practice, and control groups typically include those using any of the existing treatments. All RCTs belong to this explanatory to pragmatic continuum.[8]

So what exactly is CONSORT?

Many past and present trials do not include any descriptions of essential items such as method of randomization or drop outs. Absence of such features renders the methodology opaque and, consequently, the evidence base for treatment recommendations is considerably weakened. Missing information ensures that readers cannot adequately assess the validity of the study, and those conducting systematic reviews (SRs) are forced to exclude the study because of insufficient information. Such inadequate reporting of trials, even if done inadvertently, amounts to research waste.[9] Other problems such as covert duplicate publication, post hoc highlighting of positive subgroups or minor time points, failure to perform an analysis on those originally randomized (intention to treat) and failure to declare potential conflicts of interest may indicate attempts to show a particular intervention in a more favorable light.

The CONSORT statement took shape in order to address these issues. The major features of the CONSORT 2010 statement are shown in Table 1.[10] Many of these are self-evident while some (viz., a clear statement on the mechanism of allocation concealment) are more subtle yet critical in ensuring an unbiased estimate of treatment effects. Unless a checklist is used, these points may be missed by authors reporting even good quality studies. The “new” features of CONSORT 2010 when compared with older versions include: a sub-item that asks the author to explain any post hoc changes in the methods; a fuller description of the interventions ensuring greater replicability; a clearer elucidation of the mechanism of allocation concealment instead of facile statements assuring that allocation was concealed; a more complete description of what was meant by intention to treat; a requirement that the interpretation of study findings is consistent with the results; a requirement for registration of the trial; and finally, a query on whether a protocol is publicly available, essential for ascertaining whether the authors have really done what they had set out to do.[11]

Table 1

Major features of the CONSORT 2010 statement for clinical trial reporting (modified from Cox and Williams, 2000[10])

Registering a trial protocol before recruitment begins in a publicly accessible trial registry approved by the World Health Organization (http://www.who.int/ictrp/en/) is a simple form of honest good practice, which will help to minimize publication bias (the tendency to conceal or delay publishing negative results), and selective reporting of outcome bias (choosing to highlight only those outcomes that look good). In tune with CONSORT 2010, the IJD will make registration of trials mandatory in 2014 in order to be considered for publication. The malign effects of reporting bias should not be underestimated, leading to wastage of resources of the physicians, patients, and health systems, and possible serious harms.[12]

What CONSORT can and cannot do

Quality of trial reporting is not the same as trial quality. In fact, these are two different domains. As illustrated in Table 2, four categories are formed when these two domains are combined into a four-celled matrix. One is a clearly reported well-designed study that is useful in clinical practice. Another is a clearly reported flawed study – not ideal, but at least the shortcomings are transparent and one can make a judgment about such a report. Both these kinds of trial reports are possibilities when CONSORT is adhered to during reporting. The remaining two cells consist of the nonCONSORted reports – the well-designed or flawed study that is poorly reported. Both lie in a gray zone of uncertainty and are, thus, of limited utility. They may be sparkling diamonds in a pile of rubble or simply rubbish, but they are difficult to distinguish from each other because of opaque reporting.[11] Ideally, a CONSORTed RCT report will contain a flow diagram as illustrated in Figure 1, so that readers can see exactly how many people were approached, how many were randomized, and how many were included in the final analysis.[13]

Table 2

Quality of trial reporting is not the same as trial quality (Source: Williams 2010[11])

Figure 1

An example of a participant flow diagram of a CONSORTed RCT, taken from an RCT on ion-exchange water softeners in the management of eczema in children[13]

It is clear therefore that simple adoption of CONSORT might not lead to an automatic improvement in the quality of clinical trials reported in IJD, but at least the job of weeding out the poorly designed trials will be much easier and more objective. Researchers who would wish to have a guide toward the planning and execution of proper studies may find CONSORT only partially helpful. Specific recommendations in this regard are to be found in a publication by the Committee on Publication Ethics (COPE) that was set up in 1997 by a group of editors of biomedical journals.[14]

Other than not being able to fully influence trial quality, other issues that CONSORT cannot fully address include the goal of achieving fully representative publications. CONSORT does not specifically touch upon the potential for getting all negative results onto the public view. Preregistration and a published protocol – two of the newly added features in CONSORT 2010 – can help to plug this loophole. Outcome measure is another area that requires more attention in dermatology. Outcomes for chronic diseases that are too short-term are a typical problem. A large systematic review of treatments for atopic dermatitis (AD) conducted in 2000 thus found that most of the 272 included studies were of short duration, that is of less than 6 weeks.[15] None of these short-term studies could give any information regarding long-term assessment of disease control such as duration of remission or number of flares that is of critical clinical relevance in a chronic disease like AD that lasts for years. Similarly, in a systematic review of interventions in melasma in 2010, again a chronic and relapsing disease, most of the 20 studies were of short duration.[16] Too many outcome measures are also problematic. For example, at least 20 named outcome measures have been published in AD, yet few have been tested rigorously and even fewer pass those tests.[17]

Patient and public involvement in the design, recruitment, and dissemination of clinical trials is a neglected facet that requires development if dermatological trials are to reflect issues that are important to patients.[18] Running independent trials professionally in collaboration with academic clinical trial units provides another opportunity to improve the conduct of dermatology trials.[19] Working together more collaboratively through national and international dermatology trial networks is also vital if large numbers of patients with relatively rare skin disorders are to be meaningfully studied. All these concerns in improving trial quality have led to the formation of the International Federation of Dermatology Clinical Trial Networks (IFDCTN), an independent collaboration of 34 scientists from 20 countries who will work together to share good practice and encourage the formation of country-wide independent dermatology clinical trial networks.

What will CONSORT mean for IJD contributors and readers?

Trial authors will have to fill up an additional CONSORT 2010 checklist when submitting an RCT. This might seem like a burden to those who are encountering it for the first time, yet it is to be hoped that once more authors become accustomed to the CONSORT statement and its essential requirements, the checklist will became a universal standard that will be followed as a matter of course. CONSORT 2010 is not an instrument to saddle the researcher with a host of prescriptive reporting formats; it is simply a tool to ensure that a trial report contains all the key information. Readers in contrast, and indeed other researchers such as those preparing and maintaining systematic reviews in the Cochrane Skin Group (http://skin.cochrane.org/), will quickly be able to see the architecture of the trial and make an assessment of its quality. Other top dermatology journals have adopted CONSORT and prospective trial registration and it is time that the IJD played its part in minimizing bias in published clinical research and for upholding the highest standards for the benefit of our patients.