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Executive Summary

N2 UNIVERSAL DATA DO NOT SUPPORT APPROVAL, FDA's DENTAL PRODUCTS PANEL concluded at its Feb. 12 meeting. The panel agreed that clinical studies submitted by N2 Products, Inc. to support approval of the root canal filling material and sealer do not meet the agency's standards for adequate and well-controlled studies. Committee member Julianne Glowacki, PhD, Brigham and Women's Hospital, remarked: "I have lingering problems based upon the package of material that was submitted by the sponsor that does not document adherence to an" FDA Medical Imaging, Surgical and Dental Drug Products Division Acting Director Paula Botstein MD, said that N2 Products' database, consisting of a clinical study of 109 root canals in 91 patients and case histories from 9,000 other patients, was "flawed" in several respects. The clinical trial was not performed using a "concurrent control group" but instead used a historical control "which was not well characterized," Botstein said. The case reports "were limited to one page...which contained all the data that were collected, including X-ray data" without accompanying analytic readings, Botstein said. "The outcome data on the principle group was sketchy and not very much analyzed." The case histories, Botstein said, "were not consecutive and were all chosen for successful outcome." FDA Biometrics Division Group Leader Darryl Harkin, PhD, commented that "there is some question as to whether or not the subjects were truly picked at random from the people who were presented to the 19 clinicians who participated in the study." Reflecting the concerns of the panel members, he also questioned the decision to use historical controls over an active control group. The panel voted "no" to the series of 14 questions addressed, ranging from "Are the criteria for effectiveness clearly defined in the study and in the historical controls?" to "Do the data presented demonstrate effectiveness and safety of N2 Universal?" At the conclusion of the meeting, Botstein remarked that the "scientific data presented were not enough" to prove the safety and effectiveness of the drug. N2 Universal is a root canal filler and sealer comprised of zinc oxide powder and liquid euginol components. Unlike other conventional sealers such as gutta purcha, N2 contains 6.5% paraformaldehyde. According to product literature, paraformaldehyde "achieves its disinfecting purpose through chemical action within the root canal." The presence of the potentially toxic ingredient led FDA to classify N2 as a drug requiring approval via the NDA process. Other root canal fillers are considered Class I medical devices. The safety and efficacy of N2 has been a subject of controversy for decades. In 1975, House Investigating Subcommittee Chairman Fountain (D-N.C.), devoted a hearing to the subject of FDA's classification of the filler. Fountain called N2 a "new drug which presents a health hazard and should be banned." FDA ultimately adopted Fountain's classification. Currently, the product is available only via pharmacy compounding. N2 Products' Alvin Arzt told the committee that the commercial availability of N2 Universal would allow dentists "to do root canals in one visit as opposed to the multiple visits" required when using comparable materials. Arzt declared that "the approval of the NDA application will provide general dental practitioners across the U.S. with the material necessary to provide safe, effective, and cost-efficient endodontic treatment to millions." N2 Products was formed in the late 1970s "to create and prosecute through FDA" an NDA for N2 Universal, the company's outside counsel Charles Raubichek (Piper & Marbury) told the committee. An NDA was filed Dec. 13, 1983. The company maintains that it "received a preliminary approval" of the clinical portion of its NDA in 1986, based on the 91-patient trial and "confirmatory data" from 375 case histories gathered from "a training program of a professional organization." After a change in raw material suppliers prolonged the review of the application, the company said, Botstein instructed the firm to gather an additional 9,139 case histories to supplement existing data in 1991. "We have to follow the standard of today," Botstein told the committee. N2 Products is presently "evaluating" the panel's decision, although no "next step" has yet been decided. The company said it will develop a plan of action in the next few months.

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