FDA orthopedic panel votes against bringing single-injection HA gel to market

Members of the U.S. Food and Drug Administration Orthopaedic and Rehabilitation Devices Advisory Committee panel voted 6-1 yesterday to not recommend approval of a single-injection hyaluronic acid (HA).

The device, indicated for knee pain due to osteoarthritis (OA) in those who fail to respond to conservative therapies, is similar to other products sold in the United States and has been used in about 350,000 treatments worldwide.

At the end of the day, panel members who voted against approving Durolane, a nonstabilized HA injectable gel, said it did not show enough superiority vs. injectable methylprednisolone acetate (MPA), the control device used in a 26-week pivotal clinical trial.

Device manufacturer Q-Med AB of Uppsala, Sweden, sought marketing approval via premarket approval (PMA) application P060013. Smith & Nephew markets Durolane outside the United States and would also market it domestically, if approved.

Noninferiority trial

The Durolane vs. MPA noninferiority trial (study #3), which included 442 randomized patients, was the third of three studies on which the sponsor based its PMA application. The other two compared a single 3-ml intra-articular injection of Durolane to saline injection. One, with 6-month outcomes, included 347 patients, including some from the United States. The second trial included 218 patients who were followed for 6 weeks.

Panel members deliberated extensively about statistical analyses performed on the trials’ data, including a propensity score analysis and other efforts to deal with data extracted from the first two studies to provide a stronger defense for Durolane’s efficacy at 12 weeks in study #3.

However, panel members remained unconvinced of Durolane’s effectiveness, but agreed it was safe. Some indicated they would like to see new data on its clinical performance, while others noted the device would benefit from being studied in a better-designed, placebo-controlled trial, perhaps with saline injection as a second comparator along with MPA. Meanwhile, others suggested that the sponsor should clearly delineate certain subgroups with knee OA for whom Durolane is indicated.

The pivotal trial included patients whose knees were Kellgren-Lawrence grades 2 and 3 without clinically detectable effusion or polyarticular pain. However, an indication was sought that would extend Durolane use to those with milder or more severe symptoms.

“Based on the pivotal study alone, you can say that this is possibly inferior to the corticosteroids at 12 weeks,” said panel member Sanjiv Naidu, MD, PhD, of Mechanicsburg, Pa., who seconded the nonapprovable motion.

Michael Mayor, MD, of Dartmouth-Hitchcock Medical Center in Lebanon, N.H., the only panel member who favored approving the device, said he was willing to let the marketplace decide its best application.

“Supportive” results

Michael Weisman, MD, of Cedars-Sinai Medical Center in Los Angeles, a consultant to the FDA Arthritis Drugs Advisory Committee and temporary voting member of the orthopedic panel, said, “What we saw was a positively controlled trial with results that were supportive. However, there were serious questions raised about the validity of the [positive] control group and the fact that there were two other studies in a larger population that were negative studies compared to a saline control.

“In spite of the fact that the sponsor has given us outside evidence and clinical experience supporting the efficacy of the comparator in study #3, that did not outweigh the difficulties that we have encountered in interpreting the results of study #3,” he added.

In study #3, the sponsor used the response rate to a single intra-articular knee injection — Durolane or MPA — at 12 weeks as the primary endpoint based on a 40% relative reduction in WOMAC pain scores from baseline, or an absolute 5-point reduction in scores. Responder rates were 44.6% for Durolane vs. 46.2% for MPA, according to Cindy Wong, MD, Q-Med chief medical officer.

Q-Med and Smith & Nephew officials said in a press release they are committed to providing the clinical evidence of Durolane’s efficacy needed to bring it to the U.S. market.