Most people believe that daily multivitamin and mineral supplements are important for one’s health, particularly during autumn and winter when more people tend to develop colds. The unsuspecting populace are sold on the “antioxidant” and “immune-boosting” properties of these supplements, which claim to prevent and treat a variety of human afflictions from the common cold to the aging process. Even people who are not entirely convinced of the effectiveness of these supplements will consume these tablets “just in case” it is necessary and because “even if they do no good they are not likely to do any harm”. Results of a recent Cochrane Systematic Review, assessing the effects of antioxidant multivitamin and mineral supplements on death, suggest that this might not necessarily be the case. The combined results of 47 randomised controlled trials of sound methodological quality involving 180938 participants showed that antioxidant supplementation, in particular beta carotene, vitamin A and vitamin E, was associated with an increased risk of death. So what has this got to do with clinical trials and clinical trial registration?

A clinical trial is a research study in which human participants are prospectively assigned to an intervention or comparison group in order to evaluate the safety and effectiveness of a new treatment or health intervention. An important aspect of a good clinical trial is the presence of a control or comparison group in which individuals receive either a placebo pill or no treatment. This group accounts for any natural changes that may occur during the course of a disease as well as the fact that some people will recover from an illness without any treatment. It is also important that the participants of a clinical trial are randomly assigned to the treatment and comparison group. This will ensure as far as possible that the groups are similar at baseline and therefore sufficiently comparable throughout the trial. As a result of the random assignment of participants to the various experimental groups as well as the presence of a control or comparison group, the results of clinical trials provide the best evidence for the effectiveness of various health care interventions.

How can the results of clinical trials be used to ensure that all citizens receive the best possible healthcare?
Ideally the results from clinical trials investigating a particular health care intervention should be incorporated into and summarised by a systematic review. The results of the systematic review should be used to inform both healthcare practice and policy. When and only when, this happens will the most effective and best possible healthcare be provided to all citizens.

There is a general tendency in both the pharmaceutical industry as well as the academic environment to favour the publication (make public) of clinical trial results that show that the treatment outcomes are significantly better than the comparison outcomes. This is known as publication bias. If only the “good” trial results are made public then people will, incorrectly, be lead to believe that the treatment is more effective than it really is. Furthermore, failure to publish results deemed “unfavourable”, such as adverse effects of a treatment, can cause considerable harm (even death in some cases) to patients. The “hype” surrounding multivitamin and mineral supplementation and their antioxidant and immune-boosting properties are most likely as a result of publication bias in that only the trials showing a positive effect of supplementation are more likely to be published and so brought to the attention of the media and consequently the public. The registration of all clinical trials will allow policy makers, clinicians, researchers and the public to keep track of what treatments are being investigated as well as if all the results of these trials are being made public in some form. Clinical trial registers will also facilitate the incorporation of these results into systematic reviews, for future translation and implementation.

There are also important ethical reasons to support the registration of clinical trials. Individuals who volunteer to participate in clinical trials expect their contributions to be made use of in improving health care for everyone. The registration of all clinical trials (ideally before the trial commences) in databases that are freely and easily accessible to everyone will help to satisfy the ethical obligation to trial participants and will promote greater trust and public confidence in clinical research.

Trial registration in open access registries will not only reduce publication bias and satisfy the ethical obligations to trial participants; it will also serve to a) decrease wasteful duplication of research, b) promote international research collaboration and c) ensure more efficient allocation of research funds.

Recent global developments
While the registration of clinical trials is not a new concept, a number of recent developments have revived interest in the idea. In October 2003, the World Health Organization (WHO) committed itself to a global initiative to promote access to research information. This led to a discussion about the WHO’s potential role in coordinating the establishment of an international prospective registry of all clinical trials. Six months later the WHO announced that as a condition of approval by the WHO ethics review board all clinical trials would henceforth have to be registered at inception and assigned a unique number.

Adding to the push towards trial registration were two other important developments. In the United States, the New York Attorney General filed a lawsuit against pharmaceutical company GlaxoSmithKline for suppressing clinical trial data on the negative effects of the antidepressant paroxetine in children. This case generated widespread discussion on the potential value of prospectively capturing data on on-going trials.

Furthermore, the International Committee of Medical Journal Editors (ICMJE) recently decided that all trials enrolling patients after July 2005, will be considered for publication in the ICMJE member journals only if they have been registered with an acceptable prospective trials registry (NEJM 2004, 351:12:1250-1251). An acceptable register has to meet the following criteria:  it must be accessible to the public at no charge; it must be open to all prospective registrants and managed by a not-for-profit organization; there must be a mechanism in place to ensure the validity of the registration data; it should be electronically searchable and it must contain a minimal data set of information for each registered trial.

While a number of clinical trial registries are already in existence none are comprehensive, there is no standardization of content or processes involved and the information contained in the registries is often not freely accessible. The WHO aims to address this problem through establishing an international clinical trials registry platform with the following objectives:  1) increase transparency, accessibility and accountability of trials registries; 2) standardize and clarify registration worldwide; 3) increase capacity for trials registration globally; 4) build consensus on processes for existing and future registries; and 5) ensure scientific and ethical integrity. To achieve these goals coordination among a range of stakeholders such as regulators, funders, investigators, consumers, policy makers, journals, and others will be necessary. Advocacy will be needed at both global and national levels to explain the benefits of trial registration and to promote the implementation of the registration system.

WHO ICTRP
The WHO’s International Clinical Trials Registry Platform is taking the lead in setting international norms and standards for trial registration and reporting. The Registry Platform consults with relevant stakeholders worldwide to produce consensus-based policies that uphold scientific and ethical principles on clinical trials but that are also practical and feasible.

The Registry Platform's primary objectives is to ensure that all clinical trials are registered and thus publicly declared and identifiable, so as to ensure that for all trials, a minimum set of results will be reported and made publicly available. Specific goals of the Registry Platform include:

• Establishing standards on the scope and content of trial registration
• Establishing a network of Member Registers that satisfy criteria for internationally acceptable registers
• Establishing and assigning a Universal Trial Reference Number to globally unique trials
• Defining minimum standards for the reporting of trial results
• Launching a one-stop Search Portal for searching registers worldwide.

ATM Clinical Trials Registry
In an effort to support this worldwide initiative and to ensure that the issues and health concerns relevant to people living in sub-Saharan Africa are advanced/included, the South African Cochrane Centre (SACC), the European and Developing Countries Clinical Trials Partnership (EDCTP) and the Cochrane Infectious Disease Group have established the international registry for HIV/AIDS, TB and Malaria clinical trials (ATM Registry) to be conducted in sub-Saharan Africa.

The ATM registry, created for researchers, clinicians, policy makers and the lay public, aims to provide information on all prospectively (clinical trials to be conducted) and retrospectively (clinical trials already completed) registered HIV/AIDS, Tuberculosis and Malaria trials. The ATM Registry promises to:

• Provide a source of reliable information on the efficacy and safety of prevention and treatment measures
• Identify research gaps that should be addressed in future trials
• Provide a ‘laboratory’ for studying the scope, quality and funding patterns of trials
• Keep track of on-going trials