NEWS

Multinational Effort Aims to Record All Clinical Trials

Tom Reynolds

Oncologists put their faith in the findings of randomized clinical trials, especially in the sum of evidence from many trials, in determining how best to treat their patients.

But they have to wonder, along with other clinicians, how complete, and how reliable, is the record of published results. For a variety of reasons, the results of many trials never get published, while those of others may be published several times, perhaps in different languages with different authors.

Most troubling is that trials with positive results—evidence for superior efficacy of a new treatment—are more likely than others to be published. This casts doubt on the basis for clinical decision-making and the validity of reviews and meta-analyses attempting to weigh the balance of accumulated evidence (see sidebar, next page). Indeed, some argue that failure to submit a trial for publication is tantamount to fraud because of the bias introduced to medical practice.

To address this problem, a U.K.-based company, Current Controlled Trials Ltd., (CCT) is mounting an ambitious effort to build a comprehensive international "metaRegister" of Controlled Trials in all areas of health care. The metaRegister (http://controlled-trials.com) was launched in October 1998 after a meeting earlier that year, at which a group of publishers, medical charities, research funders, and pharmaceutical companies agreed on the need for prospective registration of clinical trials.

CCT funds and maintains the metaRegister, which the company designed with help from the British government’s Medical Research Council and the National Health Services’ National Research Register. It includes trials from major existing registries such as those maintained by the U.K. Coordinating Committee for Cancer Research (UKCCCR), the Canadian HIV Trials Network, GlaxoWellcome, and Schering Healthcare. Others will shortly be added, including the new register from the U.S. National Institutes of Health and the Veterans Affairs Cooperative Studies Program. CCT also plans to set up specialized registries in cancer and other major medical specialties.

The Cochrane Collaboration, a Oxford-based not-for-profit group that performs, maintains, and disseminates systematic reviews of health care issues, is working with independent cooperative groups and countries that do not have their own registries, and together with CCT is seeking to enlist global cooperation of researchers, funding agencies, and journals. Research agencies from the United States, Canada, Spain, The Netherlands, South Africa, Hong Kong, and Brazil are among many who have expressed interest in cooperating, said CCT managing director Anne Greenwood.

"For it to work, you have to register trials at the beginning—you can’t let people decide halfway through, ‘it’s looking interesting, let’s register it,’" noted Chris Williams, M.D., coordinator of the Cochrane Cancer Network (part of the Cochrane Collaboration), who will direct CCT’s Cancer Register of Randomized Controlled Trials.

Part of the strategy is to persuade journals and societies to adopt a policy—phased in over 5 years or so—making prospective registration a prerequisite for publication or presentation of trial results. Although he called this "a radical idea," Williams hopes to follow the example of protocol approval by ethics committees—a practice that fast became de rigueur thanks to the insistence of funding bodies and journals.

The metaRegister and Cancer Register will include as much information as trialists provide, but the minimal data set will be enough to let users know what the trial is about and whom to contact for further information. Each trial will be assigned an International Standard Randomized Controlled Trial Number (ISRCTN) that will identify it in every published citation or other reference. (Not always the simple task it might seem: NIH database administrators said some trials inevitably get duplicate entries, which are eliminated as identified. And meta-analyses have been discovered to include the same trial more than once, skewing the results.)

The ISRCTN has been designed to be compatible with NIH’s numbering system. While NIH trials have the prefix NCT followed by eight digits, the ISRCTNs will be RCT plus eight digits.

"The goal over the next several years is for the Cancer Register of Randomized Controlled Trials to link the NIH, UKCCCR, and other databases into a single portal where you can access the world’s database of current trials in cancer," Williams said. This will help research planners determine the need for new trials while avoiding redundancy. It will also allow scientists performing meta-analyses to ensure they have data from all trials (or at least are aware of them). It will make it easier to track treatment data over the long term.

Eventually, Greenwood said, CCT hopes to fund the metaRegister through subscriptions to its new range of print and online journals that will publish protocols, trial results, and even data from the trials themselves. Peer-reviewed original research articles published in these journals will be available free of charge at the Controlled Trials Web site and in PubMed Central, NIH’s central research repository. A subscription fee will be charged to access reviews, meta-analyses, and other secondary articles.



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The Current Controlled Trials Web site (http://controlled-trials.com) allows users to search several registries for clinical trial information.

 
Major U.K. journals have expressed strong support for trial registration. "The registration of trials is of value not only to those clinicians and investigators wanting to be sure that they have access to all available evidence, but also to patients who may want to know of trials in which they might wish to take part," editors Richard Horton, M.D., of The Lancet and Richard Smith, M.D., of the British Medical Journal wrote in an editorial, versions of which appeared in both journals last October. "And research funding agencies need to ensure that their decisions are made in the full knowledge of current work, planned or in progress, to prevent duplication and to promote collaboration."

At a conference last October, Smith suggested that registration should be enforced by law. Others suggested instead inculcating health professionals with the ethical responsibility of registration.


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