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BURROUGHS WELLCOME’s RETROVIR SHOULD BE APPROVED FOR USE IN CHILDREN

Executive Summary

BURROUGHS WELLCOME's RETROVIR SHOULD BE APPROVED FOR USE IN CHILDREN with AIDS or an advanced stage of HIV infection, FDA's Antiviral Drug Products Advisory Committee recommended by an eight-to-one vote on March 30. The committee agreed that "pediatric AIDS/advanced HIV infection is sufficiently similar to the disease in adults, and that there are adequate...data to justify a waiver of the requirement for separate adequate and well-controlled clinical trials in pediatrics to support labeling for pediatric use." The committee recommended approving Retrovir in the pediatric AIDS population despite finding that the amount of clinical data submitted in support of the pediatric NDA was insufficient to support approval. However, the panel took into account clinical data from AZT studies in adults to support its recommendation. Under FDA regulations for pediatric drug approvals, data from studies in adults may be sufficient to waive the need for significant data in children, provided that the progression of disease in children is sufficiently similar to adults. If FDA follows the approval recommendation, it would be the first time the agency has waived the requirement for adequate and well-controlled studies in children based on data in adults. AZT has been approved for use in patients 13 years of age or older since March 1987. Children with AIDS or advanced AIDS infection have been able to receive the drug since October 1989 under a collaborative Treatment IND protocol between Burroughs Wellcome and the National Institute of Allergy and Infectious Diseases. The company's presentation of clinical data focused on a Phase I/II multicenter study of 124 children with AIDS or advanced HIV disease. The Phase I open label study evaluated pharmacokinetics and safety using three dose regimens, while the Phase II safety and efficacy study used a single dosing regimen. Summarizing the study results, Burroughs Wellcome's Nathaniel Brown, MD, said: "Children are experiencing prolonged survival with proportions of patients surviving on therapy that exceed most of the available estimates for advanced pediatric HIV disease." Brown noted that there has been a "low probability of opportunistic infections on therapy." FDA Center for Drug Evaluation and Research Medical Officer Steven Gitterman, MD, expressed concern that the Phase I/II studies were difficult to evaluate without a concurrent control group. He suggested that AZT is "of benefit to certain children, especially for growth." However, he added: "It is uncertain whether there were survival benefits for the cohort in these trials, although [AZT] has prolonged survival in adults." Commenting on the safety profile, Gitterman characterized AZT use in children as "reasonably safe with a toxicity profile similar to that in adults at the dose proposed." He pointed out, however, that the treatment population will not receive "the same level of care or be as carefully selected" as the patients in the clinical studies. He noted that toxicity "was primarily hematologic and in most all cases manageable with dose modification or interruption." Regarding dosing regimens, most of the committee went along with the pediatric dose of 180 mg/mm four times daily recommended by Burroughs Wellcome. However, the committee also suggested that the language in the labeling allow for flexible dosing by physicians to allow them to make decisions on a case-by-case basis. Burroughs Wellcome VP David Barry, MD, reported that the drug has been studied in doses up to 240 mg/mm in children. Several members went a step further and suggested that the committee consider approving AZT for use in asymptomatic HIV-infected children with laboratory evidence of severe immunodeficiency. Several committee members suggested that additional targets for study include: comparative dosing studies; further retrospective natural history studies; prevention of infection from perinatal transmission using therapeutic agents; children with established neurological disease; combination chemotherapy; fetuses in infected mothers, and infants younger than six months.
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