FDA Advisory Panel Calls for More Data on HIFU Treatment

Larry Hand

October 02, 2014

A US Food and Drug Administration (FDA) advisory committee voted October 1 not to recommend approval, at least for now, of a high-intensity focused ultrasound (HIFU) device to treat some patients with recurrent prostate cancer.

Members of the Gastroenterology and Urology Devices Panel of the FDA's Medical Devices Advisory Committee encouraged the device manufacturer to continue to conduct research but to come back when the ongoing pivotal trial at 20 sites in the United States and Canada is completed, not halfway through.

SonaCare Medical Devices of Charlotte, North Carolina, had requested FDA approval of its Sonablate 450, a computer-controlled device with a probe that clinicians can use to deliver HIFU energy through thermal ablation to the prostate. The proposed indication was for treatment of biopsy-proven recurrent cancer in patients, low to high risk, who have failed primary external beam radiation therapy and have prostate-specific antigen (PSA) readings lower than 10 ng/mL.

SonaCare based its request on an interim analysis of results from a nonrandomized, single-group clinical trial involving the first 100 of a planned 200 patients. Patient ages ranged from 53 to 83 years (mean, 69.7 years), they were mostly white (76%), and they had pretreatment PSA readings ranging from 0.4 to 14 (mean, 4.9).

Of the first 100 patients enrolled at 16 sites, 78 completed 12 months of follow-up and had a biopsy, and 22 did not.

Adverse events included seven rectal fistulas in five patients (5% rate compared with an expected 3% rate), three of whom required medical management and two of whom required surgery. Urinary incontinence occurred 55 times in 44 patients after Sonablate treatment.

Two Analyses, One Problem

SonaCare reported results based on both the 100 intention to treat (ITT) population and the 78 per protocol (PP) population.

In the ITT group, 50 (50%) patients obtained local control, defined in the trial as achieving a PSA nadir of 0.5 ng/mL or lower and having a negative prostate biopsy at 12 months, with the lower bound of a 97.06 confidence interval 39% falling slightly below a targeted 40% performance goal.

However, the company reported that the PP group of 78 patients achieved better than 40% success, and that if only one more patient in the ITT group had done so, that group would have met its overall goal.

That set the stage for a robust discussion about the use of performance goals in clinical trials and what percentage constitutes success.

SonaCare representatives said the overall success in the ITT group showed a clinically meaningful benefit in a trial in which endpoints are unique for the new technology and not comparable to other salvage treatments for recurrent prostate cancer. However, FDA representatives said the study missed the success criteria in the ITT group, and the claim to success in the PP group "should be considered ancillary."

Jonathan P. Jarow, MD, from the FDA's Office of Hematology and Oncology Products, told panel members that the analysis was missing significant data regarding PSA follow-up and underestimating failures and that the PP analysis was not a true PP method because it just dropped the 22 patients who failed to meet the 12-month follow-up.

When asked why SonaCare brought the case up for approval at this time, rather than waiting for trial end, Mark Carol, MD, chief development officer, said the request was based on the whole body of evidence and that the study was just a single patient shy of the planned performance goal. "We believe that justified this opportunity," he said.

For Which Patients

Dr. Carol added that with a lack of literature for comparison, the proposed treatment should be considered as an early technology that will ultimately provide a therapy that will benefit a subset of patients with prostate cancer.

However, panel member Mark Garnick, MD, from Harvard Medical School in Boston, Massachusetts, said the information presented lacked in defining just which patients would be likely or unlikely to benefit from the treatment, and that the information provided did not justify market approval.

He emphasized that for prostate cancer, which is typically a slow-growing disease, 12 months "is a very, very short time," and that the FDA should have 5-year data. Other panel members echoed that sentiment.

Panel members varied on what a proper performance goal should be, with some arguing a lower than 40% goal over 5 years would be sufficient and others calling for 50% or more.

The Vote

For 3 voting questions, panel members voted:

  • 7 to 3 against (1 abstention) recommending that the treatment was safe if used as intended,

  • 9 to 2 against recommending that the treatment was effective if used as intended, and

  • 10 to 0 (1 abstention) against recommending that the benefits outweigh the risks.

Panel member Jason Connor, PhD, an adaptive trials expert based in Orlando, Florida, said, however, that his no vote on the second and third questions was "not a terminal no," and he encouraged SonaCare to continue the trial and get to 200 patients.

Panel member Susie Q. Lew, MD, from the George Washington University, Washington, DC, added, "I think there's a niche for this device. I think we have insufficient data at this point."

In July, the panel voted against recommending another HIFU treatment.

No panel members reported any relevant financial relationships.


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