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Registration of Clinical Trials

Most clinical trials are undertaken in order to determine that one treatment produces a better result for the patient than another treatment or no treatment at all. Very early in the design of a study, before any patients are involved, the investigators must decide how many participants are needed to provide a reasonable possibility that they will detect a difference between the two interventions. They have to agree why Treatment A should be better than Treatment B or no treatment, how they are going to accurately and reproducibly measure it and how big a difference between the measurements is reasonable to expect if Treatment A was to be considered better than Treatment B (or no treatment). The measurement they choose is called the primary outcome and the difference between the interventions is examined using an appropriate statistical method to test the assumption that there is no difference in the primary outcomes between the two groups of patients (the null hypothesis). Historically, a statistically significant difference is considered to be present when the probability of the null hypothesis being true is less than 0.05. This is a completely arbitrary cut-off level at which we accept that, based on the data, we have a one in twenty chance of rejecting the null hypothesis when it is in fact true. Having gone through this process the investigators then have to seek the approval of an ethical committee, obtain funding, select, recruit and treat participants, collect, analyze and interpret the data. You can imagine the researchers’ disappointment when, despite all their careful planning and hard work, the analysis of the results is unable to determine any difference in the outcomes between the patients managed in different ways. They might consider that they have failed and be less motivated to publish the research. They might be tempted to look at outcomes other than the primary outcome and report only those that are statistically significant. Other interested parties, including those who funded the study, might also be disappointed, particularly if they have a vested interest in showing that one form of treatment is superior to another and may actively discourage the researchers from disseminating their findings more widely. Finally editors and reviewers of peer reviewed journals may be more reluctant to publish null findings. The possibility that studies with statistically significant findings are published more frequently than those with no statistically significant findings, also known as publication bias, has been recognized for some time. The psychologist Robert Rosenthal called this the ‘file drawer problem’. He suggested that journals might be filled with the 5% of studies which show Type I errors (rejecting the null hypothesis that there is no difference between two interventions when it is in fact true), whereas the file drawers are filled with the 95% of the studies that show no significant results. In addition to publication bias it has been shown that studies with positive findings are more likely to be published quickly (time lag bias), to be in English language journals (language bias), to be published more than once (multiple publication bias) and to be cited by others (citation bias). These types of bias are categorized under the heading of Reporting bias. This is a serious source of bias as it leads to a distorted view of the literature. The discerning clinician cannot decide how effective a treatment is by only reading or hearing about when a treatment works, without also being informed about the times when it did not work. This has led to the suggestion by the International Committee of Medical Journal Editors in 2004 that all clinical trials involving human subjects be registered in a publically available database before patients are recruited. The database will include details of the interventions, primary outcome and proposed sample size. It will then be possible to determine the proportion of studies involving a specific treatment that is not published. It will also help to ensure that researchers report the primary outcome they decided to measure at the start, rather than ignoring primary outcomes that are non-significant in favour of secondary outcomes, which are statistically significant. A recent study of the medical literature showed that out of 323 articles describing randomized controlled trials published in 10 high ranking medical journals less than half (45.5%) were adequately registered in an open access clinical trials database. An equally concerning Journal of Orthodontics, Vol. 38, 2011, 75–76