How And When Should Data From Clinical Trials For Heart Disease Medications Be Shared?

Increasingly, clinical trials are monitored by independent, external groups called Data and Safety Monitoring Committees (DSMCs), charged with protecting the safety of trial participants and preserving trial integrity and credibility. These committees are the only groups that can know results of blinded trials (trials in which participants and investigators are not aware of treatment assignments) while the trials are ongoing. The proper function of DSMCs is subject to discussion and debate.

"Several situations exist in which it is reasonable and appropriate for the DSMC to share interim data from a blinded trial with operational study personnel and sponsors. These situations might include the need for 'mid-course corrections,' when the number of outcome events -- like deaths and heart attacks -- is substantially lower in the untreated group than was expected in a trial to reduce such problems," says Dr. Jeffrey S. Borer, article co-author and director of Cardiovascular Pathophysiology and co-director of The Howard Gilman Institute for Valvular Heart Diseases at NewYork-Presbyterian/Weill Cornell, and the Gladys and Roland Harriman Professor of Cardiovascular Medicine at Weill Cornell Medical College.

"If this happens," Dr. Borer continues, "the total number of patients slated to participate in the trial may be inadequate to test the therapy's effectiveness. In this case, the DSMC might notify the sponsor and suggest an increase in the number of subjects to be recruited into the study. However, the DSMC would not tell the sponsor the number of events that had occurred in each treatment group."

While sharing some data would be reasonable and appropriate in several other situations, Dr. Borer stresses that "the DSMC should share patient treatment assignments related to interim outcome/event data with the sponsor in only one situation -- when recommending premature termination of the study."

Reasons the DSMCs recommend termination include:

• The committee perceives a rising toll of adverse events that appears to outweigh any possible benefit from the treatment.
• No evidence of benefit is apparent, and statistical analysis suggests that continuation is highly unlikely to produce such benefit (called "futility analysis").
• Evidence of benefit is so overwhelming and important (example: reduction in death rate) and risks sufficiently low, that the benefit/risk relation is highly likely to be maintained if the trial continued to its planned conclusion. It would be unethical to withhold the good treatment, not only from all trial participants, but also from other members of society who might benefit. According to the authors, this decision must be undertaken with great caution because of the well-known variability of results over time, even in large trials.

The article notes that while there are differences in data-sharing procedures between industry-sponsored and government-sponsored trials, all sponsors "own" their data, and can demand unblinded information even if this is considered unwise by the DSMC.

The authors recommend that before doing so, the sponsor should consider the long-term consequences of such action, which can affect regulatory acceptability, future analyses and publication of the data.

"In such settings, if the DSMC is concerned that trial credibility or validity will be compromised by the release of interim data, there are few avenues open to the committee except formal protest or resignation," says Dr. Borer, since no legally constituted regulatory body has provided relevant guidance or regulation to deal with the issue of interim data release.

The authors note that discussion and debate will continue regarding the appropriate sharing of interim data as society increasingly depends on clinical trials for advancing medical treatments.

The article is based on presentations by the authors and subsequent discussion held during the Ninth Cardiovascular Clinical Trialists (CVCT) Workshop in Paris, France, in 2006.

This issue is explored in the April 9 Journal of the American Medical Association (JAMA) in a commentary article authored by Dr. Jeffrey S. Borer of NewYork-Presbyterian Hospital/Weill Cornell Medical Center and Drs. David J. Gordon and Nancy L. Geller -- both of the National Heart, Lung and Blood Institute (NHLBI).