Medicis/Q-Med plan to conduct a 100-patient, Phase IV study to evaluate Restylane non-animal stabilized hyaluronic acid-based wrinkle gel in "people of color," in accordance with FDA panel recommendations.

Voting 6-3 in favor of PMA approval, the General & Plastic Surgery Devices Panel suggested Medicis alter the description of the patient cohort for its proposed postmarket study, which originally included only "African-Americans."

Enrollment will end six months after the first Restylane injection, allowing one year for the study to conclude, Medicis execs said at the panel meeting in Gaithersburg, Md. Nov. 21.

In questions to the panel, FDA noted the pivotal study population's apparent homogeneity. In a 137-subject, randomized trial to support the Restylane PMA, 89% of participants were Caucasian.

"Only two African-American patients were enrolled in the Restylane clinical study," and 10 were listed as "'other,'" FDA notes, asking: "Is specific labeling needed to address potential use in minorities that may be at a higher risk for adverse clinical outcome?"

Panelists subsequently agreed Restylane's proposed labeling should be changed to note that controlled clinical studies have not been conducted on "people of color" and patients with a rating of 5 and 6 on the Fitzpatrick scale of skin type.

In Medicis/Q-Med's pivotal study, each subject served as his or her own control, with Restylane application in one nasolabial fold, and, in the other, Inamed's Zyplast bovine collagen implant. Baseline was established as when an optimal cosmetic result was obtained, with follow-up visits at two, four and six months.

In Q-Med's clinical submission, the manufacturer maintains that the Wrinkle Severity Rating Score at six months was "clinically significantly (1 unit, minimum) higher for Restylane than control in 59.7% of patients, but less than clinically significantly higher (0.6 unit) for the overall cohort."

FDA's statistical summary elaborates that while Restylane was superior to Zyplast in 78 cases (56.9%), it was equal to the control in 46 cases (33.5%). Meanwhile, Zyplast was rated superior to Restylane in 13 subjects (9.5%).

"In total, the overall percentage of patients for which Zyplast was equivalent or better was 42.9%," the FDA document concludes, warning that a superiority claim over Zyplast is "problematic." The statistical summary also cites "the lack of an effective masking procedure."

Addressing those concerns, panelists suggested that training in surgical technique could vastly improve Restylane performance. Although Medicis already has engaged a CME consulting firm, and is proposing Restylane workshops in 50 U.S. cities, the panel requested "confirmation of education" before use.

The panel also agreed that the word "superiority" should be stricken from Medicis' proposed labeling.

Inamed/Genzyme's Hylaform , another injectable facial wrinkle treatment, was reviewed by the panel on the same day. Although, like Restylane, it obtained a 6-3 vote in favor of approval, the accompanying conditions may prove onerous.

Because Genzyme's pivotal study excluded patients allergic to avian materials composing the HA gel, the panel stipulated that assessment of avian protein allergies should be required before injection, either through a test or confirmation of history.

As a further requirement, the panel recommended Hylaform labeling should state that clinical data reflects safety and effectiveness only for one injection. This condition could present a problem, as the biomaterial is understood to degrade in approximately 12 weeks, and repeat injections may be necessary.

In other conditions, the panel said labeling should state that safety and effectiveness of lip augmentation has not been established. As with Restylane, the panel said the PMA sponsor should conduct a postmarket study in "people of color," and that a lack of data for various skin types should be addressed in the labeling.

Approximately 80% of Genzyme's pivotal study subjects were white. In the trial, 133 subjects were injected with Hylaform along the nasolabial fold and 128 subjects with Zyplast. At two weeks, 38.2% of Hylaform subjects' folds returned to pre-treatment status, compared with 21.9% of Zyplast patients. At four weeks, those numbers rose to 56.1% and 26.3%, respectively. At the final, 12-week follow-up period, 73.3% of Hylaform folds returned to pre-treatment status, compared with 65.1% for Zyplast.

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