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Journal editors and legislators expand the scope of clinical trial registration and results disclosure.
There will be more information available to patients and health professionals about ongoing clinical trials and the results of those studies under new disclosure policies established by Congress and medical journal publishers.
Provisions to expand registration of active clinical trials have been included in legislation to renew prescription drug user fees (PDUFA) and to promote drug safety. The policymakers also seek to link trial registration to stronger requirements for posting study results. At the same time, leading medical journals are expanding their trial registration requirements for sponsors and investigators that hope to publish articles on their research findings.
Under these new policies, sponsors of studies involving a broader range of drugs and medical products will have to submit more detailed information on trial design and enrollment. Clearer links may be established between registries and sources of information on trial results and outcomes. This data aims to help patients and health professionals make appropriate prescribing decisions, as well as inform clinical trial participants of the outcomes of their voluntary efforts.
Many of these initiatives build on registration requirements authorized by Congress a decade ago, followed by the policy set in 2005 by the International Committee of Medical Journal Editors (ICMJE). The editors of 12 leading journals said they would not publish articles on the results of research studies unless sponsors and investigators register these trials in any of five recommended registries. In addition to better informing patients of clinical research opportunities, the policy establishes a system for tracking safety and efficacy issues related to clinical research.
In 1997, Congress called for registration of trials involving drugs to treat critical diseases, but the program was very slow getting started and many pharmaceutical companies failed to comply. Sponsors were reluctant to make public what they considered competitive information, such as study design, controls, inclusion and exclusion criteria, and primary and secondary outcomes. Many pharmaceutical companies also withheld the company name, product name, and other important information.
The journal editors appear to have been more successful. In June, the Journal of the American Medical Association (JAMA) published a two-year evaluation of the program, reporting that "the research community has embraced trial registration." Listings on ClinicalTrials.gov, the largest registry operated by the National Library of Medicine (NLM) at the National Institutes of Health (NIH), has jumped from about 13,000 prior to the ICMJE policy to more than 40,000 trials today. This surge reflects similar registration policies adopted by many medical journals. At the same time, more local and regional trial registries have been established, many linked to the World Health Organization's International Clinical Trial Registry Platform.
To facilitate registration, the ICMJE now aims to make compliance easier for sponsors by accepting registration in a larger number of primary registries that meet WHO-specific criteria. These primary registries usually are managed by not-for-profit entities and accept information from partner registries that tend to cover a specific disease, company or geographic region. All combined, these registries provide a coordinated network and "one-stop search portal" for patients and researchers to list and locate trials all over the world.
The ICMJE also is expanding registration requirements to apply to more early clinical trials, a change that fits WHO policy more closely. The ICMJE initially did not seek registration of preliminary studies designed to test pharmacokinetics or toxicities. Now the group has decided that Phase I studies can provide useful information for patients, prescribers, and researchers on a drug's safety and efficacy.
Therefore, ICMJE will require as of July 1, 2008, the registration of all trials that meet the WHO definition: a research study that prospectively assigns human participants or groups of humans to one or more health-related interventions to evaluate the effects on health outcomes. Covered interventions include drugs, surgical procedures, devices, behavioral treatments, dietary interventions, and process-of-care changes. Purely observational studies still do not require registration.
An important clarification from the ICMJE is that posting limited trial results to meet disclosure requirements will not preclude later journal publication of articles on that study—an issue that had raised concern among sponsors and investigators. The editors specify that summaries of results posted in a standard abstract format in the same trial registry will not prevent publication in a peer-reviewed journal. However, editors may consider more detailed information on trial results in publicly available registries as prior publication.
While sponsors and investigators do not have to comply with the ICMJE recommendations, they will have to submit more information about ongoing clinical trials under registration requirements included in the PDUFA/drug safety legislation. The legislators agree that sponsors are doing a better job of listing more complete information on the ClinicalTrials.gov Web site, and they aim to support this trend.
The legislation expands the information included in registration listings to include the WHO 20 minimal data points, plus the address of each trial site, a toll-free number for obtaining additional information, time frame for study completion, and information on expanded access to not-yet-approved test treatments. The measure also wants to know if the sponsor has placed any restrictions on the ability of an investigator to discuss or publish information on a study.
Congress emphasizes that the registration system should make it easy for patients to search for trials based on disease or condition, intervention, trial location, age group, study phase, recruitment status, and study identifier. Sponsors will need to update enrollment status every 30 days and report when the trial is completed.
In addition to requiring registration for all studies submitted to the Food and Drug Administration, Congress extends the policy to clinical trials supported by grants from NIH. Sponsors of some studies for generic drugs, biotech therapies, and medical devices also will have to register.
A key goal of the new policy is to link the clinical trials registry to results information. Many sponsors do that now voluntarily, but the legislators want a more comprehensive approach. They specify that such listings should include information posted about the drug at FDA advisory committee meetings, any FDA health advisories or notifications related to the product, and the action package used by FDA to approve the application. The results also would include Medline citations to publications reporting study results, along with information in the NLM structured product labels database of FDA-approved medicines. Policymakers want sponsors to provide summaries of study results that are written for a lay audience, as well as more technical summaries for scientists and health professionals.
One issue to be determined is whether this expanded results database builds on or replaces the ClinicalTrials.gov Web site and just how to link a trials registry to a results database. NLM staffers have long expressed concerns that a results-posting system requires much more vetting and oversight than straight registration. To address the complexities of establishing an NLM drug results database, policymakers first may conduct a feasibility study on how best to make the results of clinical trials publicly available. If the experts conclude that a public results data bank makes sense, officials at NIH, NLM, and FDA then would develop regulations for submitting trial information based on an appropriate format, time frame, and procedures.
A thorny issue is how sponsors can comply with registration and results disclosure policies without drawing charges of illegal promotion. Posting information about the indication and study design of a test product could bring up unapproved uses. And requiring sponsors to provide a non-technical summary of a study in lay language could expose a company to liability for off-label promotion and false claims. Pharmaceutical companies believe that such summaries are of limited value and that clinical trial results should be written primarily for a medical and scientific audience.
The trial registration and results disclosure provision fit the broader legislative goals of ensuring drug safety. The PDUFA bill provides FDA with authority to require more extensive clinical trials following product approval and to impose new labeling requirements within a set time frame. Applications for new drugs will have to spell out a range of pharmacovigilance activities for sponsors to undertake in order to manage the risks associated with the use of a new drug by patients and prescribers. While there was considerable debate on these and many topics covered in the broad bill, proposals for making public more information on clinical research activities and results were relatively uncontroversial, reflecting the rise in public acceptance of these programs.
Jill Wechsler is the Washington editor of Applied Clinical Trials, (301) 656-4634 email@example.com