Hundreds of public and private clinical trials registries have been created in the last few decades, and the worth of such efforts has been discussed in meetings and in the pages of scientific journals. But clinical trials registration received newfound attention about a year ago when several pharmaceutical companies were accused of suppressing clinical trial data that raised questions about the safety of some popular antidepressants when used in children.
Registration is now viewed as the best way to prevent this from happening again. But with many different organizationsincluding medical journals, the U.S. Congress, and the World Health Organizationdeveloping their own plans for how and when registration should happen, it is not clear whether or exactly how the goal of greater transparency in the clinical trials system will be achieved.
The allegations of suppressed data make headlines, but the larger implications of a suppressed or unregistered trial are often reported only anecdotally. However, in 1986, R. John Simes, M.D., of the University of Sydney, showed that trial registration could eliminate publication biasthe likelihood that only positive results are published. He compared results of published versus registered (both published and unpublished) trials of chemotherapy drugs for ovarian cancer. Published trial results showed a benefit for a combination drug regimen over a single drug regimen, whereas results of registered trials showed no difference. A second example, using multiple myeloma trials, found similar results.
Early Registries
The National Cancer Act of 1971 spurred the creation of one of the first registries, one that contained cancer trials and that eventually became part of the National Cancer Institute's Physician Data Query (PDQ). The U.S. Food and Drug Administration Modernization Act of 1997 created the U.S. government's first general trial registry, ClinicalTrials.gov, which is run by the National Library of Medicine. The law required that clinical trials of drugs for which an investigational new drug application has been filed be registered if the drug is for a "serious or life-threatening" disease or condition and the trial is testing the effectiveness of that drugthat is, phase II, III, or IV trials.
Despite the mandate, many trials have not been registered, in part because there is no enforcement mechanism for the law. An analysis of protocols submitted to the FDA in 2002 found that only 48% of trials of cancer drugs that should have been registered actually were. "AIDS was the only [disease] that was better than cancer," said Terry Toigo, director of the Office of Special Health Issues at the FDA, who has worked on the analysis.
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Part of the problem may be the interpretation of the definition of "serious or life-threatening diseases." "We heard some statements that [ClinicalTrials.gov] was only for AIDS and cancer," Toigo said. This may account for why registration rates in the federal database are as high as they are for cancer and AIDS compared with other diseases.
The cancer community has also been aided by the existence of the PDQ, said Richard E. Manrow, Ph.D., chief of the International Cancer Research Databank Branch at NCI. PDQ and ClinicalTrials.gov now share all data from cancer trials submitted to either database. Registration in either database is not required for NCI-sponsored trials, but the PDQ staff is trying to increase registration by gathering data submitted to NCI from cancer centers and from the cancer Biomedical Informatics Grid (caBIG) project. In addition, about 30% of protocol summaries in the database now have literature citations that tie in published results with the trial descriptions, Manrow said. Many of the new plans for trial registries call for results to be included in some manner.
Pharmaceutical Support
In January, four pharmaceutical industry organizationsthe European Federation of Pharmaceutical Industries and Associations, the International Federation of Pharmaceutical Manufacturers and Associations, the Japanese Pharmaceutical Manufacturers Association, and the Pharmaceutical Research and Manufacturers of America (PhRMA)committed their members to several principles of clinical trials registration. They promised that all clinical trials, except for exploratory trials, would be registered in a database such as ClinicalTrials.gov within 21 days of the start of patient accrual.
The organizations also require that the results of all clinical trials, other than exploratory trials, conducted on an approved drug be publicly disclosed within 1 year of the drug's approval or, for trials completed after the initial approval, within 1 year of trial completion.
At the moment, ClinicalTrials.gov does not provide links to published results of clinical trials. However, PhRMA has created a site, ClinicalStudyResults.org, for pharmaceutical companies to publish summaries of trial results, both positive and negative. As of mid-January, the database had summaries for 33 major drugs, according to Jeff Trewhitt, PhRMA's spokesman. "Companies continue to enter summaries slowly but surely into the database," he said.
Some critics have expressed concern that databases managed by pharmaceutical companies will be transient and that they will disappear once the issue fades from its current level of interest. "PhRMA has made it clear that we're in it for the long haul," Trewhitt said. He pointed out that the registry plan has been approved by the PhRMA board of directors, which comprises senior executives from many of the major pharmaceutical companies.
However, the plans of PhRMA and the other three organizations make registration voluntary. Mandatory registration may not be effective without some kind of enforcement, which even the FDA Modernization Act lacks. For more trials to be registered, "registration must be done at inception, by law, and be mandatory," and there must be penalties for failure to register trials, said Drummond Rennie, M.D., professor of medicine at the University of California at San Francisco and deputy editor of the Journal of the American Medical Association.
In the United States, failure to register clinical trials may carry a price if the Fair Access to Clinical Trials (FACT) Act, introduced into Congress last year, becomes law. The act would require registration at the beginning of a trial and the reporting of results at the conclusion. Registration would be enforced by making it a condition for institutional review board approval.
Refusal to submit results could result in fines of up to $10,000 per day or, for federally funded research, a restriction in future funding, according to the legislation. However, the act died with the end of the last Congressional session, and it has not yet been reintroduced.
Not all trials would be covered by the legislationonly the 60% or so that are drug trials. "To focus on drugs is somewhat of a disappointment," said Kay Dickersin, Ph.D., a professor in the Department of Community Health at Brown University in Providence, R.I. Trials that compare other types of treatment, such as lumpectomy versus mastectomy for breast cancer, or devices would be left out, she said.
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Worldwide Standardization?
The World Health Organization has started an effort to standardize the information collected in clinical trials registries. The WHO has proposed creating a virtual registry, a single portal to existing clinical trials registriesin countries where they exist that would rely on a unique number assigned to the trial called the International Standard Randomized Controlled Trial Number (ISRCTN) to identify trials. The WHO would also help countries that do not have a registry to create them.
The WHO is now forming a steering committee for the program, and the plan must still be presented to the World Health Assembly in May, said Dickersin, who has been working on the plans. Leadership from the WHO is needed, she said, because there is no standardization across registries and registries are not comprehensive across countries or topics.
Clinical Trials Registration Web Sites http://www.clinicaltrials.gov (coordinated by the National Library of Medicine) http://www.nci.nih.gov/search/clinicaltrials/ (coordinated by the National Cancer Institute) http://www.clinicalstudyresults.org (coordinated by the Pharmaceutical Research and Manufacturers of America) http://www.controlled-trials.com (owned by BioMedCentral; official site to obtain an International Standard Randomized Controlled Trial Number)
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Dickersin was also involved last September in the creation of a set of international standards called the Ottawa Statement, which will be published in The Lancet later this year. Among the standards are requirements for a unique identification numberthe ISRCTNto be assigned to each trial and be included in any publications about the trial. In addition, the statement delineates the responsibilities for registration for trial sponsors, investigators, and institutional review boards and sets a timeline for these activities.
The ultimate goal of all of these plans is greater transparency in the clinical trials system. "Unless a trial is registered at the start, later on someone can pretend that it never existed," Rennie said.
Despite efforts at organization and simplification, patients and physicians who are looking for information about ongoing trials may still face a daunting list of hundreds of databases run by pharmaceutical companies, advocacy groups, and government organizations. "The problem of multiple databases isn't going to go away," Manrow said.
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