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MILES GAMIMUNE N IVIG USE IN HIV-INFECTED CHILDREN

Executive Summary

MILES GAMIMUNE N IVIG USE IN HIV-INFECTED CHILDREN to prevent bacterial infections was recommended for approval by a joint meeting of FDA's Antiviral Drugs and Blood Products Advisory Committees May 11. "I think the drug has been demonstrated to be efficacious and I think it belongs in the clinical armamentarium," antiviral committee member Deborah Cotton, MD, Harvard Medical School, said. A majority of committee members agreed with Cotton's assessment that the new indication for the human intravenous immune globulin (IVIG) product should be approved. Miles Medical Research Director James Pennington, MD, presented results from a 28-center randomized, placebo-controlled study conducted by the National Institute of Child Health and Human Development. The study began in 1988 and was halted in January 1991. A total of 383 patients aged one month to 12 years were enrolled with an average follow up of 17 months, generating a database of 369 patients evaluable for efficacy. Primary endpoints were survival, reduction in laboratory-proven or clinically diagnosed serious infections, and hospitalizations. Gamimune N showed a reduction in the number of patients with at least one infection from 47% in the placebo group to 30% in the treatment group. The rate of infections per 100 patient years was reduced from 56.7 on placebo to 33.1 on Gamimune N, Pennington said. IVIG showed no effect on survival; the mortality rate in both arms was about 20%. Committee members expressed concern that the cost and inconvenience of therapy outweighed the benefit shown in clinical trials of IVIG. Gamimune N requires monthly four-hour infusions, a regimen which some committee members noted was especially inconvenient for children. Other members argued that the cost of infusions is not worth the benefit. A dose of 400 mg/kg was studied in the trials; the recent Gamimune N price is $60 per gram AWP. "The number of children who stand to benefit from this drug are relatively small," John Modlin, MD, Dartmouth/Hitchcock Medical Center, said. "By relatively small, I would guess in the range of 20%-30%." Modlin compared the situation to that faced by the antivirals committee when reviewing Burroughs Wellcome's application to use Zovirax to treat chicken pox. While the committee expressed concern that the benefit from Zovirax therapy might not justify the increased cost, the group recommended approval ("The Pink Sheet" Nov. 18, 1991, p. 15). Mark Smith, MD, Henry J. Kaiser Family Foundation, commented: "If I ran an insurance company, I wouldn't pay for this. If I were writing practice guidelines, I wouldn't approve it...But I'm being asked, 'Is it safe and effective?'...I don't see any alternative but to say 'yes.'" The Miles database may allow the company to demonstrate cost effectiveness on the strength of reduced hospitalizations. Gamimune showed a reduction in the percentage of patients hospitalized during the study from 62% in the placebo group to 45.4% in the Gamimune group. Gamimune also reduced the average annual number of days hospitalized and increased the median time to first hospitalization from 300 days to 500 days, Pennington said. The committees did not agree on specific wording for the new indication. The showing of overall efficacy for Gamimune N was confused by seemingly contradictory results from a second trial. The second study, AIDS Clinical Trials Group protocol 051, was presented to the committee by University of California-San Diego researcher Stephan Spector, MD. The recently completed trial compared IVIG to placebo in 260 children three months to 12 years of age at 30 centers. Miles did not sponsor the trial, and the data have not yet been submitted to FDA. The study showed trends in favor of IVIG but did not show a clear treatment effect in terms of bacterial infections, Spector said. Hospitalizations were significantly reduced, with the average number of hospital days reduced from 15.6 in the placebo group to 9.3 in the IVIG group. In both the NICHD and ACTG trials, no effect was seen in a subset of patients with CD4 cell counts below 200 per mm. Use of trimethoprim/sulfamethoxazole for Pneumocystis carinii pneumonia prophylaxis confounded results of the ACTG trial but appeared to have no effect in the NICHD study. Miles proposed an indication restricting use of IVIG to patients with CD4 counts above 200 where the efficacy data were strongest. FDA medical reviewer Julia Barrett, MD, noted that "for most of the efficacy endpoints, the overall population [regardless of CD4 counts] also showed a statistically significant improvement." The committee agreed that the indication should not be restricted by CD4 counts. The committee consensus appeared to be that the effect of TMP/SMX therapy was significant and should be reflected in labeling. Miles' Pennington argued that patients taking TMP/SMX may simply have been the sicker population. Committee members, however, suggested that TMP/SMX may have had a broader antibacterial effect. Since TMP/SMX is not approved for general bacterial prophylaxis, however, the committee was uncertain what labeling should state. Gamimune N is approved for primary humoral immunodeficiency and idiopathic thrombocytopenic purpura. Gamimune N was recommended for approval for prophylaxis of bone marrow transplant complications in April ("The Pink Sheet" April 12, T&G-7). Miles filed a PLA (92-0747) for the pediatric AIDS indication in September. The company said it is "hopeful of continued fast-track response from FDA" following the advisory committee.
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