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FDA opens dialogue on interim results of CV safety in diabetes drug trials
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The FDA has launched a dialogue on how to handle confidentiality of the interim results for cardiovascular outcomes in diabetes treatment trials while new trials are still ongoing.
Regulators, researchers, health care providers and representatives from the pharmaceutical industry and health care organizations convened to weigh the risks and benefits of revealing cardiovascular outcomes trials (CVOTs) data at early stages.
“General agreement was expressed that this is a balancing act,” said Lisa LaVange, PhD, director for the Office of Biostatistics, Office of Translational Sciences, Center for Drug Evaluation and Research at the FDA. “Balance is needed to give effective therapies to patients as soon as possible, but not jeopardizing our primary questions of interest about cardiovascular safety.”
To demonstrate a new diabetes therapy is not associated with an unacceptable increase in CV risk, guidance from the FDA has required that pre-marketing data show the incidence of events is no more than an 80% increase compared with the control group; this means the upper bound of the two-sided 95% CI for risk ratio is less than 1.8.
Further, if the risk ratio is determined to be between 1.3 and 1.8, and the remaining risk-benefit analysis supports therapy approval, a post-marketing trial is generally required to show the risk ratio is less than 1.3.
Safe dissemination
Viewpoints were put forth on how various groups involved in a trial could safely learn such detailed interim data without undermining the trial’s integrity and jeopardizing its continuation.
“People have to believe that the purpose of medical research is providing high integrity, high quality outcome results,” said Steven E. Nissen, MD, MACC, chairman of the department of cardiovascular medicine at Cleveland Clinic. “The most important thing here is to have standards about who gets to know and who doesn’t get to know and for what reasons they get to know.”
Steven E. Nissen
Groups discussed included: the sponsor, enlisted by the Agency to conduct post-marketing trials related to risks; the Data Monitoring Committee (DMC), established to review interim results and make recommendations to the sponsor; the drug company’s management; staff and trial participants; and the public.
“Any options that are likely to compromise the equipoise of the trial, that could irreversibly bias the investigators and subjects and could limit the likelihood of collecting the required number of CV events, are not really tenable or recommended,” said Matthew T. Roe, MD, MHS, a member of the American Heart Association (AHA) Mission Lifeline Scientific Task Force.
Previous FDA guidance on best practices for the DMC’s recommended procedures were established to “safeguard confidential interim data from the project team, investigators, sponsor representatives, or anyone else outside of DMC and the statistician(s) performing the interim analyses,” according to the Federal Register.
Raising concerns
Among the concerns raised about widespread disclosure of results was a change in recruitment or treatment administration, along with loss of objectivity in reporting safety events or managing the remainder of the trial. Conversely, knowing the results early could offer more timely marketing opportunities, providing patients access to new therapies sooner.
John Jenkins, MD, director for the Office of New Drugs, Center for Drug Evaluation and Research at the FDA, noted the diabetes field only deals with “full” approval — not “conditional” or “interim.”
“We accept HbA1c as a validated surrogate for approval of drugs to treat diabetes, assuming the benefits outweigh the risks,” Jenkins said. This means the interim analyses are used to assess CV safety as part of that equation, he added, with post-marketing requirements issued thereafter; to date, all therapies have met the 1.3 risk ratio.
For obesity therapies, Lee M. Kaplan, MD, PhD, of Harvard Medical School, representing The Obesity Society, pointed out the substantial time and cost burdens that would be incurred should trials be compromised by dissemination of interim results.
“Given the large unmet need for new safe-and-effective therapies — as is particularly true for obesity perhaps more so than diabetes — minimizing affordable barriers to development would be strongly beneficial,” Kaplan said.
At least one comment had been received to the public docket arguing for a policy of full disclosure, LaVange said, and one speaker suggested allowing more flexibility in releasing information about subgroups of patients or subsets of endpoints.
In response to a challenge by Steven P. Marso, MD, medical director of Interventional Cardiology at UT Southwestern Medical Center, for the FDA to have “courage of conviction” in possibly getting by with less information than it thinks it could, LaVange said it would be considered but that safety cannot be taken lightly.
“There are solutions, but there’s no easy fix — maybe some low-hanging fruit,” LaVange said. “The harder solutions are going to require more thought and more engagement.” — by Allegra Tiver
For more information:
Electronic or written comments on this subject will be accepted until Oct. 10.
Federal Register. Confidentiality of Interim Results in Cardiovascular Outcome Safety Trials; Public Hearing; Request for Comments.