Leading Edge

http://neurology.thelancet.com Vol 5 July 2006 551

Establishing transparency to restore trust in clinical trialsPublic trust in clinical research has been shaken by high-profi le cases of drugs that have received approval for clinical use but have later been shown to have serious side-eff ects and by trials in which the patients’ safety has been compromised. Moreover, those involved in the running of trials and the dissemination of results are increasingly aware of the presently recondite nature of some aspects of clinical research.

Over the past few years, US legal requirements enforced by Food and Drug Administration (FDA) regulations and minimum standards set out by the International Committee of Medical Journal Editors (ICMJE) for clinical-trial registration have gone some way to ensure transparency in the conduct and reporting of clinical trials. On May 19, WHO launched the International Clinical Trials Registry Platform (ICTRP). Developed after consultation with academics, journal editors, industry representatives, patients’ organisations, and other stakeholders, the ICTRP encourages registration of all clinical trials with a minimum of 20 essential points of information before recruitment of the fi rst participant.

The essential requirements for registration set out by the ICTRP have been selected to ensure transparency of trial objectives for researchers, physicians, and members of the public. The main diff erence between the ICMJE’s requirements and the WHO ICTRP is that registration is required for all clinical studies, including phase I trials. The platform is not itself a registry, rather a baseline for registration, and trials will continue to be registered in established registries such as www.clinicaltrials.gov and www.current-trials.com.

Industry representatives raised concerns about the timing of disclosure of some commercially sensitive items on the list, which might allow competitors to rush through trials of similar treatments. However, WHO rightly concludes that none of these concerns is suffi cient to delay disclosure of any of the 20 items.

The impetus for the extension of registration to early phase trials has arisen from the recognition of a moral duty not only to patients participating in treatment trials but also to those healthy volunteers who participate in fi rst-in-man studies to investigate toxicity and pharmacokinetics of new drugs. These trials are not without substantial risks, as recently highlighted by the phase I trial of an immunomodulatory compound

(TGN1412) at Northwick Park in the UK, in which all volunteers receiving the active drug experienced severe and life-threatening adverse eff ects.

WHO’s goal is “to ensure that all clinical trials are registered and thus publicly declared and identifi able, so as to ensure that for all trials, a minimum set of results will be reported and made publicly available”. Complete registration of all trials will enable all parties to track the evidence supporting any one treatment for a particular disease. The establishment of the ICTRP by WHO itself is an important step in ensuring that these guidelines are recognised not only by sponsors, researchers, and journal editors conducting and publishing studies in more affl uent nations, but also by those involved in the running of clinical trials in developing countries.

But registration is only one half of the story. The ICTRP will form the basis for a minimum requirement of reporting for the results of trials. Some see the ICTRP as a step in the right direction in the restoration of public trust in clinical trials, but suggest that more radical changes are needed to ensure the fi delity of information used for clinical decision making.

An editorial by Richard Smith and Ian Roberts in the launch issue of PLoS Clinical Trials, a new open-access journal published by the Public Library of Science, urges that journals should no longer publish clinical trials because of publication bias favouring positive results created by pressures from sponsors, researchers, and journal editors. Rather, Smith and Roberts recommend that complete information for all registered trials—from protocols to individual patients’ data—should be archived in a publicly accessible database and that only systematic reviews of all the available evidence on an intervention should be used to inform treatment decisions.

In the light of recent controversies, all those involved in clinical trials must work hard to re-establish public trust in clinical research. The US FDA, ICMJE, and WHO have established legal, scientifi c, and ethical imperatives for transparency in trial registration and reporting. Whatever the future holds for the dissemination of trial results, the next step now is for all involved to ensure that these recommendations are upheld, not only to rebuild public trust, but also to improve the reliability of evidence that informs clinical decision making. ■ The Lancet Neurology

For the WHO Registry Platform see http://www.who.int/ictrp/en/

For the ICMJE declaration see Lancet 2005; 365: 1827

For Smith and Roberts’ editorial see PLoS Clin Trials 2006; 1: e6