Medical Device Daily Washington Editor

GAITHERSBURG, Maryland 151; Wednesday's meeting of the FDA Gastroenterology and Urology Devices panel maintained a trend of advisory committee hearings that render either a landslide or a unanimous vote in favor of approvability.

The beneficiary of this unanimous panel vote was Medical Enterprises Group (Amsterdam, the Netherlands), maker of the Synergo, a radio frequency (RF) ablation catheter deployed with the anticarcinogenic mitomycin (MMC) to treat bladder cancer.

While FDA was concerned about the construct and conduct of the trials used to support the PMA, the fact that a PMA made it this far through the FDA gauntlet based entirely on studies conducted outside the U.S. was remarkable, to say the least.

The Synergo system, a combination product, heats the tumor site with RF energy while monitoring the temperature of the bladder. The system circulates cooled MMC into and out of the bladder.

Transurethral resection of bladder cancers allows a rate of recurrence of 95%, and while concomitant use of MMC and Bacillus Calmette-Guerin (BCG) cuts the rate of recurrence, those improved recurrence rates are still daunting, 43% for BCG and 55% for MMC. Both agents also impose substantial side effects, including a 4% rate of potentially lethal sepsis for BCG, a vaccine for tuberculosis prepared from bovine serum.

In his remarks on behalf of the sponsor, Michael O'Donnell, director of urological oncology at the University of Iowa Hospitals and Clinics (Iowa City, Iowa), reminded the panel that "the problem with doing surgery is that most patients recur" within two years, which he said is the justification for the two-year follow-up used by the company in its trials.

O'Donnell also said that the average age of onset of bladder cancer is 65 and noted that the pivotal trial did not include patients at low risk of recurrence, which is about half of all bladder cancer patients. Medium- and high-risk patients, he said, make up 35% and 15% of all patients, respectively.

"Unfortunately, the best treatments we have" are not very effective, O'Donnell said, adding that "the average cost of treatment is estimated to be between $100,000 and $200,000" at present. He made the case that "there's a real need there for alternative advancements," and noted that FDA has approved no new treatments for the disease since BCG got the nod in the early 1990s.

As for the Synergo system, O'Donnell said, "What impresses me is the consistency, the safety and the efficacy of this device."

Yagel Koren, MD, the company's medical director, led off the Medical Enterprises presentation by pointing out that the Synergo is not an utterly new device. "In 2000, Synergo received a CE mark" and has seen "routine use" in Europe, he said, noting that the device's development began in 1994 as a collaborative work among three investigators working at different centers.

Fred Witjes, MD, of Radboud University Hospital (Nijmegen, the Netherlands), said he has been treating European subjects with the device for seven years, and that at first, the sample size calculation was designed to power the study to catch a 50% rate of reduction in treated patients vs. controls, leading to an enrollment of 158 patients.

That number came down to 84 because the protocol forced an interim analysis at the completion of two-year follow-up on 80 patients. When the returns on those patients showed a recurrence rate of 11% for the study arm compared to 62% for controls, the trial was halted for ethical reasons.

However, there were also five randomization errors, "which the sponsor was not aware of until after the study had closed," Witjes said. Another five were disenrolled for various reasons, but the numbers were pared down a bit further. "After two [were rejected due to] protocol deviations, you are left with 35 patients in the protocol arm and 40 in the control arm," he said.

Witjes also acknowledged that for the first three years of the study, hospital records were not directly transcribed to case report forms (CRFs), but he said that an audit by FDA "confirmed CRFs were an adequate reflection of source documentation," and adequately captured safety and efficacy data.

He also said, "I think the treatment is very well tolerated," a statement based on data from six trials encompassing more than 200 patients on the treatment.

John Baxley, a biomedical engineer at the Office of Device Evaluation, told the panel that none of the studies offered as evidence were initially designed as pivotal trials. He noted that Medical Enterprises first submitted the PMA in 2001, and FDA conducted in-depth reviews the following year and in 2004. FDA decided in 2005 that it needed more data to make any decision.

Robert Kane, MD, a medical officer at the Office of New Drugs at the Center for Drug Evaluation and Research, said that while MMC "is not approved" for prevention of bladder cancer recurrence, "it has wide use in this indication." He also acknowledged that two-year recurrence is a common endpoint. "Long-term outcomes have not been systematically studied for this indication," he said.

Kane said that one of the supporting studies, "a randomized comparison, was a study of Synergo and MMC versus BCG alone." He also said that the study "the applicant has identified as a pivotal study ... began as a research collaboration."

In discussing the application, the panelists universally cited the magnitude of effect, with Robert Markovich, PhD, assistant professor at the University of Texas Health Science Center (San Antonio), saying, "I certainly don't think this is a perfect study, but the magnitude of the effect" reassured him of the device's safety and efficacy.

Bruce Redman, DO, professor of medicine at Southwest Oncology Group (Ann Arbor, Michigan) said "I don't think there are that many biases" in the supporting data despite FDA's concerns, adding that "the treatment effect is substantial."

The panelists unanimously voted that both safety and efficacy were reasonably well established by the data, and voted for approvability based on one year of follow-up.