By Lisa Seachrist
GAITHERSBURG, Md. -- An FDA advisory panel voted 7-2 to recommend Advanced Tissue Sciences (ATS) Inc.'s wound healing aid, Dermagraft, for approval.
The General and Plastic Surgery Devices Advisory Committee decided to recommend Dermagraft on the condition that the La Jolla, Calif., company conduct a postmarketing study to provide short- and long-term efficacy data and engage in extensive physician training.
"We are quite familiar with the conditions of a postmarketing study," said Gail Naughton, chief operating officer for ATS. "We had them with the Dermagraft-TC product. Quite the contrary to slowing things down, it actually speeds things up. It allows us to have training in place earlier."
Unlike its FDA-approved predecessor, Dermagraft-TC, which contains no viable cells, Dermagraft is a bioengineered, living, metabolically active skin implant derived from discarded foreskin tissue. Dermagraft is essentially viable dermal fibroblasts cultured on a bioabsorbable scaffold that secretes vital matrix proteins, growth factors and glycosaminoglycans (a protein-polysaccharide complex needed for wound healing to occur.)
Currently available in Canada, the U.K., Ireland and Finland, Dermagraft is cryopreserved and delivered frozen to the treating physician, who thaws and implants the product into diabetic foot ulcers, which are responsible for up to 85 percent of the 60,000 foot and leg amputations that take place each year in the U.S.
ATS presented the committee data from a randomized, controlled pivotal Phase III trial and a 50-patient confirmatory study. The pivotal trial included 281 patients at 20 different centers. However, after completing the study, the company discovered that only a fraction of the Dermagraft implanted into the patients had the metabolic activity to promote healing, leaving the company with only 61 evaluable patients in the treated group.
As a result, the company initiated manufacturing procedures to produce Dermagraft that had a more uniform metabolic activity and conducted a 50-patient uncontrolled trial to add to the pivotal trial data. In both trials, all patients had standard care, which included weekly debridement of their wounds, general infection control with antibiotics and dressing with moist saline gauze.
Patients received Dermagraft once weekly for eight weeks. In addition, the patients were provided with custom-made shoes to take weight off their wounds when they walked or stood; however they were advised to use crutches and wheelchairs as much as possible.
Using the pooled data, the company found that 51 percent of the patients receiving Dermagraft had their ulcers completely healed in 12 weeks, compared with 32 percent of controls. At 32 weeks, 57.7 percent of the patients who received the metabolically active dose of Dermagraft had completely healed wounds, compared with 42.4 percent of the patients simply receiving the standard of care.
The panel, however, questioned the appropriateness of using the pooled data as the statistical base of approving the drug, noting that the effective formulation of the product was determined retrospectively and was never tested in a prospective fashion.
Clinical Benefit Outweighed Concerns
"The results presented are encouraging, but I am uncomfortable drawing a firm conclusion from this data at this point," said Thomas Mustoe, professor of surgery at Northwestern University, in Chicago. "I would like to see this tested prospectively. They have defined the study too narrowly for me to be convinced."
In addition, the panel was concerned that in the confirmatory study of 50 patients, the patients were slightly more likely to undergo surgery by the 12-week point than the controls from the pivotal trial. The company noted that the difference likely has to do with the participating physicians' tendency to treat the Dermagraft patients more aggressively.
The panel ultimately recommended Dermagraft because the company had convinced them the product aided in healing, irrespective of the statistical concerns.
"I think the product provides a clinical benefit," said Janine Janosky, assistant professor of biostatistics at the University of Pittsburgh. "We have been given a reasonable assurance of safety and a reasonable assurance of efficacy."
Mustoe, however, disagreed with the majority of the panel, arguing that the postmarketing clinical trial the panel recommended was more suited for a premarket study.
The company, however, is already looking to the day it will be marketing Dermagraft in the U.S.
"We anticipate that Dermagraft will bring us to profitability," Naughton said. "And that profitability will allow us to expand the indications where Dermagraft is applicable. This is what we did with Dermagraft-TC."
ATS is exploring Dermagraft for venous ulcers and bed sores. *