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SMITHKLINE BEECHAM’s ANTI-MALARIAL HALFAN IS SAFE AND EFFECTIVE -- FDA ADVISORY CMTE.; AGENCY REVIEWERS UNVEIL NEW ADR STATISTICAL ANALYSIS SYSTEM

Executive Summary

SmithKline Beecham's Halfan (halofantrine) is safe and effective for the treatment of mild to moderate acute malaria, FDA's Anti-Infective Drugs Advisory Committee concluded at its June 11 meeting. Halfan, which was originally discovered by the Walter Reed Army Institute of Research (WRAIR) and then codeveloped by the Army and SmithKline Beecham, is currently approved in over 50 countries. SB filed the NDA for the anti-malarial on Jan. 3 of this year. FDA Division of Anti-Infective Drugs Director Murray Lumpkin, MD, explained that FDA classified the application as a "priority NDA" based on evidence of efficacy and an improved safety profile, as well as the knowledge "of the emergence of resistance to malaria [treatments] throughout various parts of the world and the increased travel of Americans to these various areas." SmithKline Beecham Group Director of Regulatory Affairs Stella Jones, MD, also emphasized the growing threat of malaria. Quoting estimates from the World Health Organization, Jones said that about 490 mil. people live in countries where malaria is endemic, and that the global incidence is approximately 110 mil. cases per year with at least 2 mil. people dying annually from the disease. "Up to 1 mil. children die in Africa" each year, Jones added, "and the incidence of imported malaria in nonendemic areas such as Europe and North America is increasing due to more people traveling to the tropics." SmithKline and WRAIR presented the committee with data from 42 trials involving over 2,000 patients. Ellen Bourdeau, MD, of the statistical consulting firm Pharmaceutical Systems, Inc., concluded that "Halfan had a 92% overall efficacy against p. falciparum" malaria and a "99% efficacy against p. vivax" strain at the recommended regimen of 500 mg administered three times at six hour intervals. The efficacy of Halfan for treatment of the p. vivax strain has been studied in a very small patient population. After some discussion the committee agreed that a presumption of efficacy in treating p. vivax can be extrapolated from data gathered in studies of patients infected with the p. falciparum strain. The committee voted unanimously that FDA should request Phase IV postmarketing studies of Halfan targeted towards a pediatric population and encourage the sponsor to develop an indication for children. While many of SmithKline Beecham's controlled tests were performed on children, SB is not applying for a pediatric indication in the U.S. at this time. Committee consultant Richard Steketee, MD, Centers for Disease Control malaria branch, agreed that the pediatric population should be studied, saying: "I think we have an ethical responsibility both from private industry and for this committee to pursue studies and approval in children as rapidly as we pursue studies in adults." Steketee also stressed the need for an anti-malarial drug that can be used in pregnant women. Preclinical data of Halfan has shown no teratogenicity but has displayed some embryo toxicity, leading FDA to list the drug as Class C. Despite the findings of embryo toxicity, Steketee suggested that Halfan may have potential as a treatment for pregnant women, and the committee expressed interest in receiving more information. Finally, the committee urged SB to produce data on Halfan's efficacy as a prophylactic treatment for malaria. WRAIR's Brian Schuster, MD, said that the Army is finishing a "two-year chronic toxicity study and then will be going into a prophylactic regimen." One of the questions FDA asked the committee to consider about the Halfan data, which are mostly from a "semi-immune" population that has been exposed to malaria, is how those data "apply to the non-immune American population." Of the 2,376 patients involved in Halfan trials, only 80 non- immune European individuals were tested in a controlled study. Although committee member Judith Dunn, PhD, Baylor College of Medicine, thought that the number "is way too few," Russell Steele, MD, Louisiana State University School of Medicine, said the company's postmarketing information "gives me more confidence." For non-immune patients, Pharmaceutical Systems' Bourdeau explained, "the cure rate can be optimized with a repeat course [after] seven days." SB has requested that U.S. labeling follow European labeling in indicating that a second course of treatment at day seven is recommended for non-immune patients. Committee member Theresa Shapiro, MD/PhD, Johns Hopkins University Hospital, expressed concern whether a second course of therapy "is the best choice of dosing regimens since it raises the specter of non- compliance." Other committee members worried that studies of the two-dose regimen were not extensive enough to show possible toxicities resulting from separate courses. SB representative John Halton, MD, noted that most patients would still be in the hospital after seven days, thus eliminating the issue of non-compliance, and he pointed to the extensive postmarketing surveillance of non-immune patients as evidence that the two-course regimen is not toxic. Shapiro agreed that "the risk/benefit [ratio] of the second course is clearly indicated," but encouraged the company to study a simpler regimen. Horton also noted that Halfan has been used in over 2 mil. treatments, and postmarketing surveillance has shown only 20 adverse reports. There have been no deaths reported. During FDA's presentation, agency reviewers Richard Lizambri and Janice Soreth unveiled a new statistical tool that allows reviewers to define their own safety parameters in determining the frequency of adverse effects. Using raw data supplied by the company and a Lotus computer program that utilizes a Macro -- a general solution for analyzing laboratory safety data based on specific criteria -- reviewers can locate individual adverse events and then determine the percentages of these occurrences. While this re-analysis did not have a significant impact on the review of Halfan, Lizambri emphasized that the Macro "is modular and...can easily be recreated to adapt to various presentation formats among different drugs."

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