CDU Washington Editor

How do you do a randomized controlled trial (RCT) when the product you are testing seems to be such a great potential advancement that you can't talk patients into enrolling into control groups?

That's the barrier that companies developing device treatments for atrial fibrillation and seeking from the FDA some help — perhaps by providing guidance concerning a definitive alternative. The need is pressing, given that several device systems have been developed for cardiac ablation but none approved for the specific AF application. the problem: lack of sufficient data to support approval.

The FDA seems unable to provide either an answer to this conundrum or provide the direction that eventually will define an answer. The agency has held discussions with industry regarding alternatives to the standard RCT, and the agency's circulatory systems advisory panel met last month to consider allowing greater flexibility in conducting these trials.

But the panel consensus was that an RCT is still the only appropriate means for testing safety/efficacy in these devices.

Lesley Ewing, a contract employee at the Office of Device Evaluation, described AF as "an important public health problem," with medical treatment usually palliative and not effective for maintenance. The gold standard for surgical treatment is the Cox-Maze procedure, she said, now usually performed as the modified RF Cox-Maze. Ewing said there are "many approaches to catheter ablation," with efficacy rates in the literature ranging from 28% to 100%. But complications of catheter ablation, including death, stroke, tamponade, and pulmonary vein stenosis, are "inconsistently reported," she said.

Part of the agency's dilemma, Ewing said, is very basic: "What is an appropriate method to characterize effectiveness?"

Among the proposed measures are absence of AF and absence of symptomatic AF. Another question still up in the air is how to define a reduction of AF burden.

Felipe Aguel, an engineer at the FDA's Office of Science and Engineering Laboratories, said that an alternative design - one that allowed a one-arm study with objective performance criteria - would make it "potentially easier to enroll patients" and might pull down the sample size of the study population, but also that "it is unclear whether suitable data are available" to aid in the design of such a study.

Aguel said that a device maker and FDA might be able to agree on a hybrid design, one that would randomize patients into both a control and study arm, but the patients in the control arm would get ablation by another device.

In such a scenario, both primary efficacy and primary safety comparisons would be based on data for the alternative ablation method. However, the data from the study arm would also be stacked up against the OPC standard.

While such an approach was likely to ease enrollment problems at least somewhat, Aguel said, "the use of multiple catheters" in some procedures "makes it difficult to standardize procedures." The resulting pooled data would likely be confounded by the presence of such mixed data.

During the open public hearing portion of the meeting, Albert Waldo, MD, professor of cardiology at Case Western Reserve University (Cleveland), said he was participating in the NaviStar ThermoCool catheter trial, which is "widely used," including for AF. Biosense Webster (Diamond Bar, California), maker of the NaviStar, "recognizes the importance and value" of examination of safety and efficacy, he said, but the trial for paroxysmal AF is "encountering major challenges."

Waldo said that the trial, which randomizes to drug therapy, "has taken three-plus years" to fulfill enrollment objectives. He said that of all the prospective participants screened, only 3% were enrolled and that 11% refused to participate due to reluctance to end up in the control arm. However, the majority of the screened prospects, 62%, flunked inclusion/ exclusion criteria.

The company's efforts to recruit were apparently uneven in terms of cost and benefit. In one surge of recruiting, involving ads on television and the web as well as through doctor's offices, the company spent about a half-million dollars and netted only three patients for the trial.

"We would suggest that greater flexibility is needed in trial design," and companies need to be able to tailor inclusion/exclusion criteria, he said. He also made a case for allowing clinical investigators some flexibility in deciding on adjunctive catheters to be used in the procedure, saying that "the issue is not what's best — the issue is what works."

The panel hashed out a number of questions, including what might serve as a standard outcome for successful treatment of AF as well as what duration of follow-up might be appropriate to track adverse events for drugs used to treat AF. Another dilemma is that the number of patients whose electrocardiograms display tracks that are typical of AF, but who never experience physical symptoms.

In the end, the panel concluded, with little dissent, that RCTs remain the standard.