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The Clinical Trials Track column is published periodically to provide updates on the clinical trials process and to summarize briefly some of the trials registered at www.ClinicalTrials.gov that are of interest to the cardiothoracic surgery community. This article highlights evolving issues in trial registration and reporting.

Many aspects of the clinical trials process have changed rapidly over the past 4 years, especially in the areas of registering and reporting, moving from industry self-regulation in 2005 to congressional fiat in 2007, to a new era of openness and accountability in 2009 inspired by the National Institutes of Health (NIH) public meeting, which addressed expanding the reporting process and increasing the utility of clinical trials.

Perhaps the most important catalyst for these changes was a September 2004 decision by the International Committee of Medical Journal Editors (ICMJE) to require that clinical trials be registered prior to patient enrollment as a prerequisite for publishing trial results in their member journals--including JAMA and the New England Journal of Medicine.

This mandate prompted the Pharmaceutical Research and Manufacturers of America and the International Federation of Pharmaceutical Manufacturers and Associations in 2005 to put forth a "Joint Position on the Disclosure of Clinical Trials Information via Clinical Trials Registries and Databases." The position statement proposed that all non-phase I trials initiated after July 1, 2005--"coincidentally" the deadline established by the ICMJE--be included in a clinical trials registry. The statement also included a requirement for timely posting of results, generally within 1 year after a drug was approved and commercially available in any country. The U.S. Web site www.ClinicalTrials.gov was proposed as the appropriate registry model.

This attempt at self-regulation did not prevent the U.S. Congress from stepping in and passing Public Law 110-85, Title VIII, in September 2007. The law expanded the types of clinical trials that must be registered at www.ClinicalTrials.gov to include devices and biologics, increased the number of data elements that must be submitted, and required the submission of results data. The law also established penalties for noncompliance, including civil monetary penalties for non-federally funded trials and the withholding or recovery of grant funds for federally funded trials. In addition, it stated that any application or report submitted to the Food and Drug Administration (FDA) for product approval must include certification of compliance with all of these applicable provisions.

According to Title VIII, the sponsor of the trial or the designated principal investigator (PI) is responsible for registering the trial in full no later than 21 days after the first patient is enrolled.

The registration must include descriptive, recruitment, and location and contact information, as well as the apppropriately designated administrative data (http://grants.nih.gov/grants/policy/hs/faqs_aps_clinical_trials.htm).

Descriptive information consists of a title and brief summary of the trial intended for the lay public; the primary purpose of the trial; study design, type, phase, and focus; the disease or condition addressed by the study; the start and expected completion dates; the target number of subjects; and the primary and secondary outcome measures.

The FDA was given a mandate to include several elements in a results database for the clinical trials of all drugs approved by the agency. These elements comprise demographic and baseline characteristics of the patient sample; primary and secondary outcomes; point of contact; and any agreements between a sponsor and the PI that would restrict the PI from discussing, reporting, or publishing the results of the trial after its completion.

Primary and secondary outcomes must be presented as a table of values for each arm of the clinical trial, including the results of "scientifically appropriate tests of the statistical significance of such outcome measures," according to the FDA Amendments Act (FDAAA), Title VIII, Section 801.

In July 2009, the NIH developed a "ClinicalTrials.gov 'Basic Results' Data Element Definitions" draft for comment, which designated and described information required or conditionally required by ClinicalTrials.gov or required to comply with the FDAAA (http://prsinfo.clinicaltrials.gov/results_definitions.html).

The requirements for summaries for the lay public and results reporting have led to concerns about the amount of labor involved on the part of industry, and about whether trial registry information and/or results reporting might be considered as potentially misleading corporate advertisements.

The NIH and industry discussed these concerns at the April 2009 public meeting on the implementation of Section 801, and it was suggested that these documents be submitted for FDA review before publication. A videocast of that meeting can be found online. (http://videocast.nih.gov/Summary.asp?File=15038).