All U.S. Clinical Trials Must Now Be Registered

Registering before a clinical trial begins and reporting basic results after the trial are now mandatory, thanks to the Food and Drug Administration Amendment Act of 2007 (FDAAA).

ClinicalTrials.gov, the free, searchable, and open online registry administered by the National Library of Medicine (NLM) will begin to post clinical trial results as early as this September, according to Rebecca Williams, Pharm.D., an assistant director at ClinicalTrials.gov.

Williams presented an overview of the implications of the new law and specific timelines for implementing the FDAAA mandates during the annual meeting of the New Clinical Drug Evaluation Unit (NCDEU) conference in May in Phoenix. The meeting was sponsored by the National Institute of Mental Health and American Society of Clinical Psychopharmacology.

Previous legislation had required public registration for trials of drugs to treat life-threatening diseases. After the International Committee of Medical Journal Editors began to require clinical trial registration in 2005 as a condition for consideration for publication in prominent medical journals, most researchers or sponsors have registered their clinical trials on ClinicalTrials.gov. Nevertheless, the process remained voluntary. The legislation enacted in September 2007 imposed legal requirements that mandate registering trials before they begin as well as reporting their results at their end.

Prospective trial registration is intended to reduce the underreporting of trials with negative results, especially such trials sponsored by drug companies. Recent analyses showing that underpublication of negative trial results may have inflated the perception of the effectiveness of antidepressants and other medications, which has generated demands from the research community for more transparent reporting and open access to industry-sponsored trial data. Making trial results open to public access will increase the transparency of industry data and allow researchers to have easier access to more complete clinical evidence.

Since December 26, 2007, all phase 2 through phase 4 drug trials and medical-device trials conducted for all diseases are required to be registered prospectively with ClinicalTrials.gov before enrolling patients.

“[The new law] not only expanded the types of trials that should be registered but also added data elements required to be registered,” Williams explained. Clinical trial protocols posted on the Web site must contain specific study elements consistent with the standards issued by the World Health Organization and International Committee of Medical Journal Editors, including primary outcome measures.

In addition, the FDAAA requires that the sponsor or investigator report the results of some of these trials within 12 months after the estimated or actual date of trial completion, whichever is earlier. This requirement does not apply to drugs or devices that have not been approved by the FDA. Once the FDA approves or issues an approvable or not approvable letter, the results of clinical trials conducted previously must be posted within 30 days of the regulatory action.

The NLM is currently expanding the registry database and building the results database, Williams said. She encouraged meeting attendees to review the proposed data presentation formats and submit comments and suggestions. A public meeting will be held by March 2009 to help develop specific rules and processes.

The reporting of “basic results” will begin on September 27, as required by the legislation. In these datasets, the public and researchers can find trial participants' demographic and baseline characteristics, primary and secondary outcomes, point of contact (personnel from whom scientific information can be obtained), and main statistical analyses in clear and standardized tables.

According to Williams, the database for trial results will include links to“ existing results” such as FDA approval packages, advisory committee information, and journal publications.

On September 27, 2009, the reporting of safety results will become mandatory and include at least the following data summaries: rates of all serious adverse events, adverse events that occurred in more than 5 percent of subjects in any treatment arm, and adverse events in the active-treatment group that are at least twice as frequent as those in the placebo arm.

Protocol registration and reporting of results are required for not only industry-sponsored trials but also for academic and publicly funded trials. Although ClinicalTrials.gov will become the central repository for all clinical trials conducted in the United States, it remains unclear whether the NLM will have the resources and authority to monitor and enforce the accuracy of trial registration information and results data posted on the Web site. At present, it is the responsibility of sponsors and/or investigators to ensure that all information submitted to the databases is correct.

The NLM does not restrict the submission of information, and clinical trials conducted outside of the United States are encouraged to register as well.

The complete set of final rules about clinical trial registration and results reporting, including the data format, guidelines, and enforcement, will be released by the director of the National Institutes of Health (NIH) by September 27, 2010.

In a separate presentation, Jean Baum from the National Institute of Mental Health's Office of Communication, pointed grant-receiving investigators to assistance provided on the Web sites of NIH and her agency on registering and reporting their studies.

Additional information about ClinicalTrials.gov and instructions for submitting comments are posted at<prsinfo.clinicaltrials.gov/fdaaa.html>. The text of the FDAAA 2007 is posted at<www.fda.gov/oc/initiatives/hr3580.pdf>. Guidance for researchers funded by NIMH grants can be accessed at<www.nimh.nih.gov/health/trials/researchers/index.shtml>.▪