NIH & TACT: Lessons learned?

The TACT trial, and by association its investigators, came under fire with publication of results that found the cardiovascular benefits of chelation therapy to be modest at best. But its sponsor, the National Institutes of Health (NIH), should shoulder a hefty portion of the criticism.

The National Heart, Lung, and Blood Institute and the National Center for Complementary and Alternative Medicine allocated $31 million to fund the 10-year Trial to Assess Chelation Therapy, a multicenter, randomized, double-blind, placebo-controlled clinical trial to determine if the use of the drug disodium EDTA reduced cardiovascular events in patients with a prior MI. Problems and irregularities plagued the trial, including allegations of noncompliance with federal standards, difficulties with enrollment and discontinuation of therapy and withdrawal of consent in both arms.

One typical standard of funding through the NIH is that the study meets a significant need in the community. Chelation practitioners and some patients increasingly had embraced the therapy to treat cardiovascular diseases, despite its unknown risks and benefits, Lamas et al explained in the Journal of the American Medical Association. A trial such as TACT appeared to be highly relevant.

But was TACT investigator-initiated or in response to a request from the NIH? The distinction matters. If it is the former, then key TACT investigators were responsible for its study design, execution and other matters. If not, then the NIH set the parameters of the study and then selected the proposal that best matched its goals at an acceptable price point.

In either case, the two NIH bodies vetted the study proposal. Their members and reviewers should have scrutinized the study design and research plan, including the proposed processes for protecting human subjects, recruiting enrollment sites and investigators and contingencies if problems arose.

At the risk of Monday morning quarterbacking, one challenge that stood out was the duration and frequency of the drug infusion, which averaged three hours and under the study protocol required weekly infusions over 30 weeks and then 10 more infusions at two- to eight-week intervals. Twenty-four percent of participants failed to complete the first 30 infusions, and only 65 percent completed all 40. Adverse events were cited in both arms but “the most common reason for discontinuation was patient refusal to continue treatment,” according to the study authors.

In an accompanying editorial, Steven E. Nissen, MD, of the Cleveland Clinic, observed that NIH policy allows sponsors access to unblinded trial data. “This gave them access to confidential data during each of the 11 interim analyses,” he wrote. The NIH invested $31 million into the trial and was far from a disinterested observer. “These agencies made major financial commitments and may intentionally or inadvertently influence study conduct if inappropriately unblinded during the study.”

The NIH and other federal funding agencies have contributed greatly to the advancement of medicine. But was TACT worth $31 million? It may be an expensive lesson learned, but only if the NIH acknowledges its role in the troubled trial.    

Candace Stuart

Cardiovascular Business, editor