AT AN FDA ADVISORY COMMITTEE MEETING
SILVER SPRING, MD. – Expanding the approval of the Radiesse dermal filler to include cosmetic improvement of the hands was supported by the majority of a Food and Drug Administration Advisory Panel, whose confidence in the risk-benefit profile was bolstered in part by wide off-label use in the United States and approval of this indication in other countries.
At a meeting of the FDA’s General and Plastic Surgery Devices Panel on Feb. 27, the panel voted 9-4, with one abstention, that the benefits of the dermal filler, marketed as Radiesse by Merz North America , outweighed its risks for the proposed indication, “hand augmentation to correct volume deficit in the hands.” Despite some issues with the US pivotal study, and the unavailability of data some panelists said would have been helpful, such as X-rays of treated hands to determine if the filler obscured imaging of bone, most of the panel also voted that there was “reasonable assurance” that it was effective (12-2) and that it was safe (11-3) for this use.
Issues raised by panelists included the need to better define patients who should not receive this treatment, further evaluation of possible adverse effects of treatment on hand function and strength, and evaluation of the filler in patients with severe volume deficit in the hands, who were not included in the study.
Voting in favor of approval, Dr. Karen Burke, a dermatologist at Mt. Sinai Medical Center, New York City, cited the long history of Radiesse use for the hands in many countries and in many patients in the United States. “I believe it is safe and that efficacy was demonstrated,” and that FDA approval is necessary so this use can be properly regulated and “we can teach people openly how to use it,” she said.
If approved, Radiesse – a semisolid dermal filler made of synthetic calcium hyroxyapatite suspended in a gel – would be the first dermal filler approved for hand augmentation. Merz describes it as a “durable” filler that is not permanent, and is broken down over several months.
Radiesse was approved in 2006 for subdermal implantation for correction of moderate to severe facial wrinkles and folds, and for restoration and/or correction of facial lipoatrophy that occurs in people with HIV. It has been approved for hand augmentation in 52 countries, including in Europe and Canada, and like other fillers, has been used off-label in the United States for this use. Fillers are regulated by the FDA as devices.
The US study, a prospective, 12-month study at 6 sites, randomized 85 patients to Radiesse (who received a maximum of 3 cc injected per hand), and 29 initially to no treatment, who served as controls. Responses were evaluated by clinicians who could not see the patient, using the Merz Hand Grading Scale (MGHS), a 5-point scale ranging from 0 (no loss of fatty tissue) to 5 (very severe loss of fatty tissue, marked visibility of veins and tendons), with an improvement of at least 1 considered clinically meaningful, according to Merz, which validated the scale before the pivotal study. Most hands at baseline were rated as 2 or 3 on the MGHS scale (moderate or severe loss of fatty tissue with mild or moderate visibility of veins or tendons); most were women, their mean age was 53-54 years, and most were white.
At three months, 75% in the Radiesse group had at least a 1 point improvement on the MGHS scale, the primary effectiveness endpoint, vs. 3.4% of controls, a statistically significant difference. Based on the Global Aesthetic Improvement Scale (GAIS) at three months, a secondary endpoint, 76% of treated hands were rated as “much “ or “very much improved” in appearance; none were rated as worse and 2% were rated as having not changed. Among those who did not have a second treatment, the effect was durable through 12 months
Patients recorded adverse events in a diary. The most common adverse event among treated patients, which included controls who opted for treatment after the three month period, was swelling, in 99%. Other common adverse events included pain (92%), redness and bruising (74%), difficulty performing activities (46%), and loss of sensation (18%); 6% had nodules.
Most of the adverse events were mild (61%) or moderate (35%); and most resolved without sequelae. Severe events included swelling, pain, and redness. No intervention was reported for 98% of adverse events, which lasted a mean of about 8 days, with 89% resolving within 14 days, according to Merz. There were no unanticipated events. (Over 12 years of experience with the use in the hand, swelling has been the most common adverse effect of treatment, according to Merz.)
In the study, 13 patients developed lumps, bumps and nodules, most were mild and none were severe and they resolved without intervention or sequelae. At the end of the study, no patients had a persistent granuloma. In three studies of 234 patients evaluating Radiesse in the hands, no granulomas have been reported, according to the company.
There were 8 severe recurrent adverse events in 7 patients: 5 reports of swelling, 1 report pf pain, 1 report of difficulty in performing activities, and 1 report of bruising.
FDA reviewers agreed that the clinical study appeared to meet the primary effectiveness endpoint, but pointed out that the amount of improvement varied between study sites. Among other issues they raised was the increased rate, severity, and duration of adverse events associated with treatment, particularly pain and swelling, which seemed to be higher and lasted longer than when Radiesse was used for the two facial indications. In addition, they indicated that the results of hand function tests were difficult to interpret.
Panelist Dr. Murad Alam, professor of dermatology, otolaryngology, and surgery, Northwestern University, Chicago, said there were some significant issues with the pivotal study, “but they do not undermine the overall conclusions” that treatment appeared to be safe and effective. The significant off-label use and experience elsewhere “was sufficient to sway me,” he added.
One of the panelists voting no on the risk-benefit question, Dr. Clayton Peimer, an orthopedic surgeon at Michigan State University, said he simply did not have enough information to support approval. He added that there were still unanswered questions, such as what would happen if the filler ends up next to synovial tissue, or if it was used in patients with systemic sclerosis, or calcinosis cutis. “I respect that board-certified plastic surgeons, dermatologists, and hand surgeons are using this safely” in the hands, he said, but added that he was concerned that FDA approval could lead to widespread use by cosmetologists and mid-level practitioners.
FDA usually follows the recommendations of its advisory panels. The panelists had no disclosures.
If approved, Merz has plans for a postapproval, open-label study that would follow at least 100 patients after they receive hand augmentation with Radiesse for three years after their initial treatment, monitoring for adverse events and satisfaction with treatment.