Medical Device Daily Washington Editor

GAITHERSBURG, Maryland – The PMA for Durolane, a hyaluronic acid product intended for use as a single-injection treatment for osteoarthritis-induced pain in the knee, tanked in Wednesday's hearing of the orthopedic and rehabilitative devices advisory committee due to the failure to convince the panel of the device's efficacy. The panel grew a case of the jitters regarding efficacy in part because of the use of three trials the company conducted in support of the application, but the last of the three trials used a corticosteroid injection for controls, a move FDA went along with then criticized during the panel hearing.

During the portion of the hearing dealing with FDA's questions to the panel, several panel members indicated that they saw the device as offering at least a modicum of efficacy (safety in and of itself was not seen as an issue), but the panel voted 6-1 against approvability.

Made by Q-Med (Upsalla, Sweden), Durolane faces a stiff climb to get to market should it resurface via another PMA, given the success of Synvisc One, made by Genzyme (Cambridge, Massachusetts). Synvisc One has in common with Durolane that they are both hyaluronic acid products and are both developed for the same condition and frequency of treatment, but Genzyme won FDA's approval in February and hence is expanding its lead in the U.S. market (Medical Device Daily, Feb. 27, 2009), although Durolane has been available outside the U.S. since 2001. Genzyme won the panel's nod for approvability in December (MDD, Dec. 11, 2008), but the application for Synvisc One represented a PMA supplement to the Synvisc PMA, which is labeled for a three-shot regimen.

Speaking on behalf of the sponsor, Courtenay Whitman, MD, of Hugh Chatham Memorial Hospital (Elkin, North Carolina) said he sees about 200 patients each month with osteoarthritis of the knee and that he treats with injectable corticosteroids as well as hyaluronic acid products. He said his patients testify that corticosteroid injections are effective for up to 24 weeks, but said he worries "about systemic adverse events ... which are unique" to this class of anti-inflammatories. He noted further that the substance is contraindicated for diabetics (excess serum levels of corticosteroids are known to suppress insulin's action on serum glucose).

The Durolane study, Whitman said, satisfied him. "Single injection with long-term relief? To me, that's a home run," he said, adding that he would like to be able to use the product and that "my patients would really appreciate it as well."

The comparison of Durolane with methylprednisolone acetate (MPA), which employed the Western Ontario MacMaster (WOMAC) scoring system, worked fairly well for the sponsor, Q-Med (Uppsala, Sweden) at the six month follow-up in the pivotal trial, and the sponsor was of the view that the test article demonstrated non-inferiority at 12 weeks. All the same, many on the panel were of the view that MPA's duration of action falls off after 12 weeks.

During the FDA question period, panelist Sanjiv Naidu, MD, of Pinnacle Health System (Mechanicsburg, Pennsylvania), took the most dour view of the matter, stating that it is "difficult for me to believe that anyone who has significant arthritis in the knee will have sustained effect" from MPA at three months. "After about three to four weeks, there is no efficacy," he argued. Another panelist called MPA "a weak control."

Panel chairman Jay Mabrey, MD, of Baylor University Medical Center (Dallas), who served his last day on the panel after four years, summarize: "The panel is somewhat evenly divided as to whether methylprednisolone is an appropriate control at 12 weeks," but he concluded that there was "no overwhelming opinion."

The firm had argued that the American Academy of Orthopedic Surgeons (AAOS; Washington) had included MPA's use for short-term relief of knee osteoarthritis (OA) in guidelines published in December 2008 and according to company documents, AAOS's definition of short-term relief "was defined to include 16-24 weeks." The sponsor also noted that corticosteroids typically cannot be used repeatedly on musculoskeletal tissues due to long-term degradation.

Regarding the statistical analysis of the MPA trial, FDA asserted that Q-Med's data did not clearly demonstrate non-inferiority at 12 weeks because the hypothesis test employed a non-inferiority margin of 15% based on a two-sided confidence interval of 95%, which the agency asserted the trial did not meet. The firm's rebuttal was that the data indicated a difference of -1.6% (favoring MPA) when a one-sided confidence interval of 97.5% is applied, which was said to have hit the efficacy endpoint.

When FDA asked the panelists whether they were satisfied with the safety data, Brett Blumenstein, PhD, of Trial Architecture Consulting (Washington) responded, "I don't accept any level of risk" given what he said is a lack of efficacy, but the other panelists indicated no misgivings on the subject.

Compared to the final vote, the panel's response to FDA's question regarding efficacy seemed to offer a somewhat mixed message. Michael Weisman, MD, of Cedars Sinai Medical Center (Los Angeles), said the MPA study "was a positive study and I feel with reasonable assurance ... this device is approvable." Panelist Allan Gibofsky, MD, of Weill Cornell Medical College (New York) said the first two studies did not help the third study. "I am troubled by the fact that it's just one study that demonstrated effectiveness," he said, but he declined to take a firm stand either way. Panelist Michael Mayor, MD, of Dartmouth-Hitchcock Medical Center (Lebanon, New Hampshire) said, "I think there's reasonable assurance that this device is moderately effective."

All the same, Mayor got no backing when he proposed a vote for approvability, and a subsequent motion to recommend that FDA not approve the application quickly lined up the other six voting members of the panel. In responding to a question as to his vote, Mayor replied that he is "not sure corticosteroids are an unalloyed benefit," adding that he is "happy to let the marketplace decide" if the device has a valid use.

In an Aug. 20 statement posted at the Q-Med web site, the firm's CEO and founder Bengt gerup said the company is "continuing the clinical development of Durolane ... to provide satisfactory clinical evidence of Durolane's performance" and that the firm remains "committed to our goal of providing U.S. physicians and patients access to a non-animal, single-injection product."

Mark McCarty, 703-268-5690;