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ANTIMICROBIAL LABELING CHANGES IN PROPOSED FDA POLICY SEEK TO DISCOURAGE SUPERIORITY CLAIMS BASED ON INADEQUATE CLINICAL DATA AND IN VITRO STUDIES

Executive Summary

FDA is considering changes of antimicrobial drug labeling in order to minimize comparative claims based on inadequate clinical data and in vitro studies, the Division of Anti-Infective Drug Products indicated in a recently-issued draft policy statement. The division reported that it plans to propose labeling changes for antimicrobial agents to more accurately reflect the efficacy of products against certain microorganisms. In addition, the division said it "will work closely with the Division of Drug Marketing, Advertising, and Communications to eliminate any advertising that implies greater efficacy of one compound versus another based solely on in vitro microbiologic data." FDA's advertising division has expressed a growing concern about the use of in vitro study data in promoting the efficacy of anti-infective drugs against certain organisms. The advertising division is currently drafting a letter to manufacturers of antimicrobial agents that will warn them against the use of such data to bolster clinical comparative claims. FDA said the proposed policy is intended to complement the new anti-infective guidelines being developed by the Infectious Disease Society of America for the agency ("The Pink Sheet" May 21, 1990, T&G-5). Those guidelines, discussed last year at the Nov. 1-2 meeting of FDA's Anti-Infective Drugs Advisory Committee, provide advice on the conduct of trials and the extent of data required for approval. The policy statement concept is apparently being looked at by other drug review divisions at FDA. Reportedly, the Division of Oncology and Pulmonary Drug Products is considering a policy statement on indications for different tumor types. The draft policy statement was prepared by Division of Anti- Infective Drug Products Director Murray Lumpkin, MD, and Office of Drug Evaluation II Deputy Director Bruce Burlington, MD. The draft will be considered at FDA's Anti-Infective Drugs Advisory Committee on Oct. 31 and Nov. 1, and will be subject to a 30-day comment period beginning Nov. 4. Under the policy, the division would abandon the use of asterisks in the indications and usage section of antimicrobial labeling. The asterisks, which currently appear next to organism listings, call attention to the fact that efficacy of the antimicrobial agent against the specific organism has been studied in fewer than 10 infections. Under the new policy, FDA would allow in the indications and usage section of labeling "only those organisms thought by the medical reviewer to be the etiologic agent (pathogen) in at least 10% of the evaluable cases of the infection successfully treated with the investigative agent." In questions for public and industry comment accompanying the policy statement, FDA indicated that the use of asterisks may have contributed to inappropriate claims of superiority of one product over another. The agency asks whether the practice of placing asterisks beside certain organisms actually satisfies any clinical need "or has this become simply another area for clinically irrelevant 'one-upsmanship' in the commercial exploitation of Product A and Product B?" FDA also is asking whether in vitro data for certain organisms "corroborate certain clinical data and allow extrapolation of efficacy claims?" The agency wants to know if the "listing of organisms in the in vitro microbiology subsection of the labeling furnish[es] the clinician with relevant data, or has it simply become a de facto license for the product to be promoted for implied clinical indications?" FDA's position in the policy statement is that organisms with clinical and in vitro data should be listed separately from organisms for which there is only in vitro data. The draft policy proposes that antimicrobial product labeling list those organisms for which there is clinical data supporting efficacy preceded by the statement that the drug "has been shown to be active against most strains of the following organisms both in vitro and in clinical infections." An "in vitro only list" would be preceded by a statement informing physicians that "the following in vitro data are available; however, their clinical significance is unknown." The organisms included in the in vitro list would be required to have "a minimum of 100 isolates tested." The draft document notes, however, that for "more fastidious organisms or those with difficult growth/testing methodologies, lesser numbers will be allowed." Firms also would be required to use more than one laboratory in the testing process. FDA added that if clinical data exist "which cast doubt on the potential efficacy of the compound to treat infections due to an organism at the labeled dosing regimen at a given body site, the organism will not be included in this list, even if the in vitro microbiologic data fulfill the criteria" of inhibiting greater than 90% of the strains of the organism. Company promotions for antimicrobials would be restricted only to those infections listed in the indications and usage portion of labeling, the draft policy states. FDA said that a labeled indication would describe the treatment and/or prevention of a site-specific infection, instead of a general infection due to certain organisms. On this point, the agency poses the question: If infections are not identified according to a site in the body, "how do we maintain a scientifically sound approach to labeling that furnishes clinicians with valid information yet restrains misleading or disinformative marketing campaigns?" FDA's approach to the indications section in antimicrobial labeling has evolved over time, the agency noted, from a broader interpretation to the greater specificity of such indications as "community-acquired pneumonia" or "acute bacterial exacerbation of chronic bronchitis." While more specific indications have led to a more accurate assessment of the efficacy of products, they have "also resulted in gross inequities in the promotion of some older products as opposed to some new products," FDA said. "The wording of these older products' indications, rather than the scientific data in their submitted studies has become the important element in product promotion," the agency maintained. "In many cases, ironically, a marketing advantage has been created for some more broadly labeled, more poorly studied older products in comparison to some more definitively labeled, more scientifically studied newer products," FDA noted. In support of an indication, a company would be required to perform at least two "statistically adequate" and well-controlled trials, the draft policy states. A statistically adequate study is defined as "a trial with numbers of evaluable patients in each arm of a study to establish equivalence or superiority to an approved comparator agent, or in special circumstances, an approved efficacy standard." FDA stated that firms may consult with the agency concerning the selection of an appropriate agent to use in comparative trials before beginning the studies. The agency said it is concerned about a phenomenon called "bio-creep," which results in the "selection of successively less effective products, which individually fit a statistical confidence interval relative to the product to which it was compared," Over time the practice may lead to implied efficacy for "inherently statistically and clinically unequivalent products," FDA maintained. Included in the draft policy statement are proposals for clinical requirements for 24 specific infections. Many of the indications require only one adequate and well-controlled multicenter trial on the assumption that a sponsor would generally develop a drug for more than one indication and that there would be safety data from at least two studies. Several indications that would require at least two trials are: complicated urinary tract infections, including pyelonephritis; community-acquired pneumonia; acute bacterial exacerbation of chronic bronchitis; otitis media; sinusitis; bacterial meningitis; gonococcal and non-gonococcal urethritis/cervicitis; and uncomplicated intra-abdominal infections.
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