OTC HEMORRHOID PRODUCTS CONTAINING LYCD MUST BE REFORMULATED

OTC HEMORRHOID PRODUCTS CONTAINING LYCD MUST BE REFORMULATED by Sept. 2, 1994 under a final rule published by FDA in the Sept. 2 Federal Register. The decision primarily affects Whitehall's Preparation H -- the market leader in the category with about a 50% market share as of August, according to Nielsen data. As recently as 1991, the product line generated over $ 80 mil. in sales for the American Home Products subsidiary. Whitehall said it plans to submit additional studies to support the efficacy of live yeast cell derivative as a treatment for hemorrhoids. The company said that clinical studies are "already under way to answer the questions FDA raised" in the final rule. The company said it "believes" the studies "will demonstrate the effectiveness of LYCD with the goal of having LYCD included in the Anorectal Drug Products Monograph." LYCD is one of the active ingredients in Preparation H cream, ointment and suppositories, which also include protectant ingredients covered in the monograph. Preparation H cream and ointment have shark liver oil and petrolatum as active ingredients while the Preparation H suppository formula includes shark liver oil and cocoa butter. Other OTC hemorrhoid products containing LYCD include G&W's Formulation R and Goldline's Prompt Relief, according to FDA. FDA had placed LYCD in Category III (data insufficient to support effectiveness) in the anorectal products tentative final monograph published in August 1988. The agency published the final rule for OTC anorectal agents in August 1990 but delayed a final decision at that time on LYCD efficacy pending a review of two clinical studies (WBI-1987 and WM-444B) submitted by Whitehall in 1989. In reaching its nonmonograph decision on LYCD, FDA questioned the study methodology and the reliability of the data from the two Whitehall studies and rejected the company's argument that studies supporting the efficacy of LYCD as a wound-healing agent also have a bearing on the ingredient's status as a hemorrhoidal treatment. FDA had notified Whitehall in March 1992 of its evaluation of the two clinical studies (WBI-1987 and WM-444B) and its finding that "they are unacceptable to demonstrate the effectiveness of LYCD for relief of hemorrhoidal symptoms of pain." The first study, WBI-1987, was designed as a double-blind, randomized, parallel group comparison of LYCD versus an ointment vehicle for the relief of hemorrhoid discomfort. Under the study protocol, patients were asked to assess their hemorrhoidal "burning" and "irritation" immediately prior to treatment and 5, 15, 30, 45 and 60 minutes after treatment using a six-category scale ranging from "no relief" to "complete relief." Based on the subjective ranking system, LYCD appeared to be significantly more effective than the control in improvement from baseline for both "burning" and "irritation" and for mean total pain relief -- 3.8 with LYCD versus 2.8 for the control. In addition, the test subjects were asked to fill out a global assessment of the treatments at the end of the one-hour study using a scale of one ("poor") to ten ("excellent"). The mean global assessment rating for LYCD was 9.6 compared to 7.3 for the control. "While these results seem to infer effectiveness," FDA noted in the final rule, "it does not appear that the case report forms . . . were in fact contemporaneously filled out by the subjects" and that the markings on the forms "were all of two easily distinguishable types." FDA concluded that the study personnel filled out the forms, which, the agency declared, "is a clear violation of the protocol and which raises major questions as to the blinding and integrity of the study." FDA decided that "the significant discrepancy between the reported and the actual method of data collection does not allow the agency to conclude that bias on the part of the investigator or analyst has been shown to be minimized." Regarding WM-444B, FDA pointed out that the 100-patient study was similar in design to WBI-1987 but with the subjective assessment period extended to two hours. That study also showed a "significantly" greater effect with LYCD, FDA noted. However, the agency found that the tear-off portions of the label could easily be removed to reveal the identity of the medication and then replaced. In addition, FDA said that the tubes used in the study did not have lot numbers so there "is no assurance that the drug product used in the clinical trial was the same formulation as the drug product proposed for marketing." FDA concluded that it "does not consider either study capable of demonstrating the effectiveness of LYCD for anorectal uses." The agency also reported in the final rule that "the conduct" of the two studies "was independently inspected by agency field investigators who found evidence that the data submitted were unreliable." In response to Whitehall's submission of data supporting LYCD's effectiveness as a skin protectant wound-healing agent, FDA cited the OTC panel's recommendation that "studies to test the effects of agents on wound healing must be designed with the use site in mind." The panel, according to FDA, "further pointed out that although the wound-healing process may be similar in the anorectal and other areas, the natural impediments are not and thus an experimental design germaine to the anorectal area must consider these impediments." Noting that Whitehall's data for LYCD as a skin protectant wound-healing agent was from studies in burn patients and subject with surgically induced abrasions, FDA ruled that these studies "are not acceptable to support the use of LYCD as a wound-healing agent in the anorectal area." In a prepared statement on the final rule, Whitehall said it has been advised by FDA that the agency "has accepted a study demonstrating that LYCD is an effective wound-healing agent" and that the ingredient would be accepted in the skin protectant monograph "upon acceptance of one additional confirmatory study that is now under way." Whitehall said "it believes that with its current studies, it will be able to demonstrate to FDA that LYCD is effective in relieving hemorrhoidal symptoms, as well as confirm its ability to heal wounds." The final rule relating to antifungal claims was one of four OTC monograph documents published by FDA in the Sept. 2 Federal Register. Those monograph documents along with four other published on Aug. 26 brings to eight the number of monograph documents published in the last seven days. The Office of Management Budget notified FDA in early August that it had cleared for publication 14 OTC drug monograph documents ("The Tan Sheet" Aug. 16, p. 1). The documents still outstanding include final monographs on ingrown toenail relief products, topically applied hormone products, boil treatment drug products and topical antifungal drug products. Also expected is a proposed rule on cosmetic products containing hormone ingredients and an amendment to the antacid monograph for a revised neutralization test.