GAITHERSBURG, MD. — The possible approval of an injectable biologic treatment that breaks down collagen for treating advanced Dupuytren's disease raises the question of whether rheumatologists have enough training to administer it safely and effectively.
The Food and Drug Administration's Arthritis Advisory Committee voted 12-0 that the treatment (collagenase Clostridium histolyticum) should be approved for treating advanced Dupuytren's based on the available safety and efficacy data. The recommended approval came with a caveat calling for postmarketing studies to monitor safety and efficacy and to ensure that clinicians who provide the treatment have adequate training and experience to safely perform the procedure.
If approved, this would be the first nonsurgical therapy approved for Dupuytren's contractures, which are caused by cords and nodules that are formed from abnormal deposits of collagen in the hands. These contractures, which usually involve the metacarpophalangeal and/or proximal interphalangeal joints, are usually treated with fasciotomy or fasciectomy.
Because most of the clinicians in the trials were hand surgeons (only about 4% were rheumatologists), one of the main concerns raised by panel members and FDA reviewers was whether clinicians who are not hand surgeons would have adequate training and the expertise to safely administer this treatment with the same degree of safety and efficacy as seen in clinical trials.
Panel member Dr. Timothy McAlindon, the Natalie V. and Milton O. Zucker Chair of Rheumatology at Tufts University, Boston, said that he was concerned about limiting access to this treatment, and that he believed the physician-training program proposed by the manufacturer “is likely adequate” for physicians who are accustomed to regularly performing procedures on the hand. “There is an acute need for a nonsurgical intervention for Dupuytren's,” and the evidence indicates that collagenase clostridium is a “highly effective” treatment and has an acceptable safety profile for the disease, added Dr. McAlindon, who is also chief of the division of rheumatology at Tufts Medical Center.
The formulation, made up of two collagenases that are naturally produced by the bacterium Clostridium histolyticum, is injected into the cord at 4-week intervals for a maximum of three injections, according to the manufacturer, Auxilium Pharmaceuticals Inc. The enzymes are thought to result in lysis of the collagen in the deposits, with reduction of the contracture and improved range of motion. (If the contracture is not released 24 hours later, then each injection is followed by extension of the affected finger to help disrupt the cord.)
In randomized, double-blind, controlled studies of patients with advanced Dupuytren's (mean age was in the early 60s) and at least one affected joint with a palpable cord and contracture, significantly greater proportions of patients who were treated with collagenase clostridium had almost a complete reduction in contractures after up to three injections, compared with those who received placebo. In one of the two main studies, which enrolled 306 patients, 64% of those treated with collagenase clostridium had a contracture reduction of the primary joint to 0–5 degrees at 30 days after the last injection, compared with 7% among those in the placebo group. In the smaller trial of 66 patients, 44% of those treated with collagenase clostridium met this end point, compared with 5% who received placebo.
Treatment was associated with almost twice as many adverse reactions, but most were local. Serious adverse events in patients—including three tendon ruptures within a week of treatment among more than 1,000 patients who were treated with collagenase clostridium—were not common. Most patients developed autoantibodies to the two collagenases, but this did not appear to affect responses to treatment.
In the two main studies, most physicians (81%) were hand surgeons; the rest were orthopedic surgeons (about 15%) and rheumatologists (about 4%).
Although results among the different specialties were similar, the number of patients treated by non–hand surgeons was too small to make any conclusions, according to Dr. Eric Brodsky, medical officer in the Division of Anesthesia, Analgesia, and Rheumatology Products in the FDA's Center for Drug Evaluation.
Another issue was whether the results in the studies represented the best case scenario, as the procedures were performed by clinicians who were highly trained in the injection and finger-extension procedures, Dr. Brodsky said at the meeting.
Auxilium has developed a risk management plan that includes physician training, product labeling, patient education, and safety monitoring. The labeling would state that the product should be used only by physicians who are experienced in diagnosing and managing Dupuytren's disease (that is, hand surgeons, orthopedic surgeons, plastic surgeons, general surgeons with a hand focus, and rheumatologists), and would include precautions about avoiding injections into normal collagen-containing structures of the hand, with a warning that this could cause permanent injuries such as a ruptured tendon or ligament damage.
Clinicians would receive a training manual and a video describing the injection technique and finger-extension procedure, which were also provided to investigators in the two main studies. Clinicians in practice will not be able to get the product unless they sign a form stating that they understand the injection procedure and the associated risks, and that they have watched the video. But investigators in the trials also attended workshops and meetings, which is not part of the proposed training program.
The panel generally agreed that the training program was adequate, and that clinicians with the appropriate experience could safely administer this treatment, although opinions differed regarding whether rheumatologists were experienced enough.
Panelist Dr. William Swartz, a hand surgeon at the University of Pittsburgh, said that in his opinion, the proposed training program was adequate, and that any physician who had experience in treating hand patients and treated them regularly should be able to administer collagenase clostridium to patients. “What their board certification is is less important than their familiarity with the disease,” he added, noting that although the complications (such as tendon rupture) associated with collagenase clostridium are rare, they are “devastating” when they do occur. However, he said that it would be unusual for a rheumatologist to see a patient with Dupuytren's, which is a rare disease.
Short of extensive training in the technique, panelist Dr. Kenneth Saag of the division of clinical immunology and rheumatology at the University of Alabama at Birmingham said he would have “serious reservations” about rheumatologists performing this procedure. The average rheumatologist, he added, does not have enough knowledge of the anatomy of the hand to do so.
But panelist Dr. Nancy Olsen, a rheumatologist at the University of Texas, Dallas, said that she believed that “many of us could be trained to do this.” Measures to ensure safety, such as establishing a patient registry and limiting access, could make this treatment “available to the relatively small group of patients who need it,” added Dr. Olsen, professor of internal medicine and the McGee Foundation Chair in Arthritis Research at the university.
Dupuytren's is considered an orphan disease because it affects fewer than 200,000 people in the United States.
The FDA usually follows the recommendations of its advisory panels.
If the treatment is approved, Auxilium plans to markets the product as Xiaflex.
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