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Executive Summary

Carter-Wallace's mucolytic expectorant Organidin (iodinated glycerol) should remain on the market while FDA reviews efficacy data to determine benefit versus potential carcinogenicity, FDA's Pulmonary-Allergy Drugs Advisory Committee recommended in a six- to-three vote at its March 23 meeting. Because iodinated glycerol is a DESI drug, no NDA has ever been filed. Carter-Wallace began marketing Organidin in 1975. The product currently is labeled for use in "bronchitis, bronchial asthma, pulmonary emphysema, cystic fibrosis, chronic sinusitis, or after surgery to prevent atelectasis." The panel asked FDA to focus particularly on data from a large, double-blind, placebo-controlled investigation called the "National Mucolytic Study." Results from the trial, which involved 367 chronic bronchitis patients, were published in the December 1990 issue of the journal Chest by Petty, et al. The study was undertaken because previously available data "did not clearly support the effectiveness of Organidin," FDA Pulmonary Drugs Group Leader Eileen Leonard, MD, said. The National Mucolytic Study reported statistically significant improvements in cough severity and frequency, chest discomfort, sputum production and overall patient comfort after eight weeks. The panel asked FDA to review the data "because we are basing our decision [to allow Organidin to remain on the market] on this being a meaningful study," committee Chairman Leonard Bernstein, MD, University of Cincinnati Medical Center, said. Several panel members questioned the efficacy findings. Committee member Richard Rosenthal, MD, Fairfax, Va., said that "clinically there is not a lot of overwhelming evidence of efficacy." Barbara Gothe, MD, Case Western Reserve University, agreed, saying "I'm not convinced at all that it works." Both FDA and committee members agreed that FDA review may provide more vigorous scrutiny than has yet been accorded to the study: peer reviewers for a medical journal "wouldn't use a fine tooth comb like an NDA [review would]," Bernstein said. Leonard stated that "if you observe the magnitude of actual changes in the symptoms on study...we are a little bit perplexed as to how the statistical findings could appear so strong." The committee voted five to four that if the reanalysis of the National Mucolytic Study does not yield proof of efficacy, it will recommend another pivotal trial to prove effectiveness. Bernstein emphasized that "we have to make a quick decision" and that a reanalysis of the efficacy data "should be done forthwith." He estimated that the data could be submitted and reviewed within "six months to a year." The committee also discussed animal carcinogenicity data on iodinated glycol. A National Toxicology Program study published in March 1990 concluded that Organidin causes mononuclear cell leukemia and thyroid follicular cell carcinoma in male Fisher 344 rats and pituitary adenoma and Harderian gland adenoma in female B6C3F1 mice at rates statistically significantly higher than control groups. Carter-Wallace VP-Preclinical Research Duane Sofia, PhD, criticized the NTP study, citing "technical study conduct deficiencies which we believe invalidate the scientific usefulness of these studies." Sofia maintained that mononuclear cell leukemia often occurs spontaneously in Fisher 344 rats and argued that the appearance of both this tumor and thyroid follicular cell carcinoma showed "no dose-response relationship" in the study. He also argued that the pituitary adenoma demonstrated "at best equivocal evidence of carcinogenicity" and discounted the Harderian gland adenoma because "we know of no counterpart in man." Wallace Labs VP-R&D James Costin, MD, said that the company has just begun a carcinogenicity study of its own; data will not be available until "four or five years from now." The company's study expands on the NTP study by using additional species of rodents. Pending the FDA review, Carter-Wallace should send a "Dear Doctor" letter to alert physicians to the potential carcinogenicity of Organidin, the committee unanimously recommended. Carter-Wallace already includes a carcinogenicity warning in the package insert. However, the panel concurred with member Leslie Hendeles, University of Florida, that "doctors only read labeling once until they know how to prescribe a drug." Several panel members recommended that the warning be highlighted in the labeling as well. Several committee members suggested that Organidin's indications should be curtailed. Committee member Joann Blessing- Moore, MD, Palo Alto, Calif., who voted to remove the drug from the market, said she had "questions" about Organidin's efficacy "in cystic fibrosis and chronic sinusitis." Hendeles said the drug's use in asthma or cystic fibrosis "is below the standard of care." Harold Nelson, MD, National Jewish Center for Immunology and Respiratory Medicine, Denver, concurred that "most of the indications are inappropriate," but felt Organidin should remain on the market for chronic bronchitis.

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