The General and Plastic Surgery Devices Panel met on May 8, 2000 in Salons F&G of the Gaithersburg Marriott Washingtonian Center at 9751 Washingtonian Boulevard in Gaithersburg, Maryland, to provide advice and recommendations to the Agency for two premarket application submissions.
The Panel Meeting began at approximately 8:00 am with Mr. Stephen Rhodes updating the Panel Members on events related to the Panel that had occurred since the Panel last met in March of 2000. In his update, Mr. Rhodes indicated that the FDA is working to bring closure to the review of the Saline-filled Breast Prostheses premarket approval applications, which were the subjects of last March’s Panel Meeting.
The morning session of the Panel Meeting concerned a PMA for Focal, Inc.’s FocalSeal-L Synthetic Absorbable Sealant. The FocalSeal-L Synthetic Absorbable Sealant molecule is comprised of a water soluble poly(ethylene glycol) group modified with acrylic ester endgroups, which are connected to each other by lactic acid-trimethylene carbonate, biodegradable segments. The material is applied to tissue in a non-polymerized form and chemically and photo-polymerized on the lung tissue into an absorbable hydrogel polymer that is intended to seal air leaks over suture or staple lines following lung surgery or trauma. The Panel was asked to provide recommendations and advice for the FocalSeal-L Synthetic Absorbable Sealant (P990028).
The sponsor presentation focused attention on a product overview and preclinical data summary and the clinical study design and results. Preclinical testing, in accordance with ISO 10993, demonstrated that the sealant was non-cytotoxic, non-sensitizing, a slight irritant, non-toxic, non-hemolytic and non-pyrogenic. Also, the sealant was non-mutagenic in the Ames Bacterial Mutation Test, the Chromosomal Aberration (CHO cells) Test and in the standard (4 hour) Mouse Lymphoma Assay. However, the result was weakly positive in the modified (24 hour) Mouse Lymphoma Assay. The clinical study was designed as an open label, prospective, randomized (2:1), multicenter study. The protocol compared standard tissue closure procedures to standard closure procedures plus the application of FocalSeal-L Sealant. Patients were stratified into high and low risk strata based on preoperative and intraoperative (air leak) risk factors. The study was performed at 4 research centers with the first two patients at each center considered pilot patients who were assigned to the treatment group. These patients were excluded from the efficacy analyses but included in the safety analyses. The primary efficacy endpoint was a between-group comparison of the percent of patients that were air leak-free from the time of skin closure through the time of hospital discharge. Secondary endpoints were the time to air leak cessation and the percent of patients that were air leak-free at the time of skin closure. The study also assessed the time to chest tube removal, the time to hospital discharge for each patient in each group and the incidence of air leak recurrence.
A total of 180 patients were enrolled into the clinical study (8 pilot patients, 117 patients randomized to FocalSeal-L and 55 patients randomized to Control). The percentage of patients that remained air leak-free before randomization were comparable between groups: 24% (30/125) FocalSeal-L; 29% (16/55) Control. Based on the total number of patients randomized, the percentage of patients that remained air leak free from skin closure through hospital discharge were 39% (108/117) for FocalSeal-L and 11% (6/55) for Control. The number of patients with air leak recurrence after skin closure was comparable between groups: 57% (62/108) FocalSeal-L; 63% (10/16) Control. Based on the number of patients who were air leak free at the time of skin closure, the percentage of patients that remained air leak free from skin closure through discharge were 43% (46/108) FocalSeal-L 37% (616) Control. The mean time to air leak cessation was 30.9 h for FocalSeal and 52.3 h for Control while the proportion of patients that were air leak-free at the time of skin closure was 92% in the FocalSeal-L group and 29% in the Control group. The mean time to chest tube removal was 4.5 days for FocalSeal-L patients and 5.2 days for Control patients, however, the median was 4.0 for both groups of patients. A similar pattern was noted for days to hospital discharge, which was 7.4 days for the FocalSeal-L patients and 10.1 days for the Control patients when looking at the means, but 6.0 days for both groups when looking at the median.
During the Panel deliberations, the Panel was asked to discuss the adequacy of the preclinical testing performed on FocalSeal-L and on the safety profile obtained during the preclinical testing. The Panel was also asked to comment on the fact that thoracic wound infections and empyema were 7.2% and 3.2%, respectively, in the FocalSeal-L group and only 3.6% and 0%, respectively, in the Control group and that cancer progression was 10.4% in FocalSeal-L patients and 7.3% in Control patients. Finally, the panel was asked to comment on the safety and effectiveness of the FocalSeal-L Synthetic Absorbable Sealant in light of the 21 CFR 860.7 definition of safety and effectiveness. Following Panel deliberations, the panel voted unanimously (8-0) to recommend approvable with conditions. The majority of the Panel Members indicated that they felt that the sponsor had shown clinical effectiveness and relative safety of the device in the target population. The conditions of approval included that the Package Insert should contain a maximum number of product applications per patient, information regarding the possible increased rate of infection and empyema with product usage, a warning that the product has not been tested with any types of additives (antibiotics, etc.) and that the sponsor should undertake a post-market study that captures the rates of tumor progression and infection.
The afternoon portion of the Panel Meeting dealt with the safety and effectiveness of Organogenesis Inc.’s Apligraf® product when used on diabetic foot ulcers. In their presentation, the sponsor pointed out that Apligraf® is presently indicated for use with standard therapeutic compression for the treatment of non-infected partial and full-thickness skin ulcers due to venous insufficiency of greater than one month duration and which have not adequately responded to conventional ulcer therapy. The sponsor would like to extend this indication for use to include the treatment of full-thickness neuropathic diabetic foot ulcers of greater than 2 weeks duration that extend through the dermis but without tendon, muscle, capsule or bone exposure.
The sponsor presentation and panel discussion focused on the multicenter, prospective, randomized, controlled clinical trial that compared the use of standard therapy plus Apligraf® to the use of standard therapy alone. Standard care for this type of foot ulcer consists of extensive debridement of nonviable tissue, the application of saline-moistened dressings and the off-loading of weight from the foot to decrease pressure on the damaged areas of skin. In order to participate in the trial, patients needed to have Type 1 or Type 2 diabetes, be between the ages of 18 and 80 years and have full-thickness neuropathic ulcers of at least 2 weeks duration that were between 1 and 16 cm2 in size. In the standard care plus Apligraf® group, Apligraf® would be applied between 1 and 5 times in a four week period. The additional applications would be made at weekly intervals if there was less than 100% wound closure and the wound did not appear to be progressing to healing. Off-loading was achieved by placing the patient on crutches or a wheelchair for the first 6 weeks of the study and then by applying customized pressure-relieving footwear for study duration.
The study was performed at 24 investigational sites and randomized 277 patients of which 208 were treated, 112 in the Apligraf® group and 96 in the Control group. Patient demographics and baseline ulcer characteristics were comparable. The primary effectiveness endpoint was complete wound closure on or by week 12. Complete wound closure was defined using the Wound Healing Society definition of full epithelialization of the wound with the absence of drainage. The frequency of complete wound closure observed was 56% in the Apligraf® group and 38% in the Control group (p = 0.0082). The other primary effectiveness endpoint was the median time to complete wound closure, which was 65 days for the Apligraf® group and 90 days for the Control group (p = 0.0026). There were no significant differences in secondary endpoints; durability of response and ulcer recurrence.
During the panel deliberations the FDA asked the Panel to comment on the clinical use of Apligraf® on patients with Charcot’s foot disease and to discuss the impact of ulcer location on Apligraf® performance. Also, the Panel was asked to comment on the safety and effectiveness of Apligraf® in light of the 21 CFR 860.7 definition of safety and effectiveness. Following Panel deliberations, the panel voted unanimously (6-0) to recommend approvable with conditions for the device. The majority of the Panel Members indicated that they felt that the sponsor had shown clinical effectiveness and relative safety of the device in the target population. The conditions of approval included only some adjustments to the labeling. The panel recommended that the sponsor include in the label statements that the use of the device be limited to use after failure of standard therapy, that FDA should carefully examine how effectiveness is described in the label and that the labeling state that Apligraf® has not been compared to human skin autograft.
David Krause, PhD
General and Plastic Surgery Devices Panel
(301) 594-3090, x141
Transcripts may be purchased from Neal R. Gross & Company, 1323 Rhode Island Avenue, NW, Washington, DC 20005, 202-234-4433 (voice) or 202-387-7330 (facsimile); or from the Food and Drug Administration, Freedom of Information Staff (FOI), 5600 Fishers Lane, HFI-35, Rockville, MD 20852, 301-827-6500 (voice) or 301-443-1726 (facsimile).