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This article was originally published in The Gray Sheet

Executive Summary

Cambridge Biotech Corp.'s HTLV-I enzyme immunoassay cross- reactivity to the HTLV-II virus is an insufficient basis for allowing the product to be labeled as a diagnostic assay for HTLV- II, FDA's blood products advisory panel concluded at a March 16 meeting in Bethesda, Maryland. The panel voted seven to two against allowing an indication for HTLV-II. Cambridge is seeking FDA approval of a product license application supplement to add the HTLV-II claim to its HTLV-I assay. The company modified its microplate solid-well test by adding antigen derived from HTLV-I recombinant p21e protein. Based on the fact that the p21e sequence is relatively homologous in both HTLV strains, CBC's modified test is intended to detect antibodies common to both viruses rather than separate antibodies that are unique to the two types of HTLV. The panel did not address the approvability of the PLA because FDA has not yet come to the point in the review process where such a recommendation is needed. Steve Alexander, PhD, CBC's associate director of product technology, presented clinical data on the ability of the modified HTLV-I test to detect HTLV-II antibodies. In a trial of 1,082 confirmed HTLV-II positive samples, results demonstrated a 99.2% sensitivity rate for the new CBC test compared to 88.4% sensitivity of a currently licensed HTLV-I assay. (Although no assay has yet been licensed for HTLV-II, HTLV-I tests identify some type-II positive samples). In a separate trial, the test also maintained 100% sensitivity to HTLV-I with specificity of 99.98%, Alexander stated. Panel members, however, expressed discomfort with recommending a test for HTLV-II screening based on cross-reactivity. The concern was due primarily to the lack of a reliable HTLV-II confirmatory test and also to a lack of precedence for a cross- reactivity claim. Committee member Chantal Harrison, MD, University of Texas Health Science Center, San Antonio, commented: "There is still a lot to be done as far as being able to define and confirm HTLV-I and HTLV-II." She also expressed concern because she did not "think it's ever been done before, that we allowed a product claim [based] purely on cross-reactivity." Panel industry representative Frederick Gates III, PhD, director of regulatory affairs at Genetics Institute, Inc., felt that the only problem is lack of a standard HTLV-II test. "There is nothing wrong with labeling an assay because it is cross reactive," he stated. "The problem here is you don't know the true incidence of HTLV-II. Until you solve that problem, I think its difficult to label any test as capable of detecting HTLV-II." Panel member Louis Katz, MD, Mississippi Valley Regional Blood Center, agreed that "without a 'boss' test, I have a real hard time supporting" claims for HTLV-II. In April 1992, the Centers for Disease Control and Prevention addressed the need for confirmatory tests that distinguish HTLV-I and HTLV-II in its Morbidity and Mortality Weekly Report ("The Gray Sheet" April 20, 1992, p. 8). In a separate presentation, Abbott Laboratories' Retrovirus Research and Development Section Manager Susan Stramer announced Abbott's plans to commence clinical trials on a "test currently completing development...that will use lysates for both HTLV-I and HTLV-II in a combination test." The trials are slated for "the summer of this year," Stramer said. Stramer also presented data on studies which compared a modified version of Abbott's HTLV-I EIA to the original version and to an investigational p21e-enhanced HTLV-I assay. In a sample of 2,873 high-risk specimens tested for HTLV-I or II, Abbott's modified test had "the best sensitivity," detecting 511 of 528 true positives compared to 490 detected by the p21e test and 483 for the current Abbott assay. The committee also discussed, but eventually tabled for future consideration, an FDA request for a recommendation on the need for HTLV-II blood donor screening. "I don't think we have the data to be able to answer this question....We need to know whether there really is a disease that's transmitted by HTLV-II," Harrison said, adding: "I don't even think we have the data to show that we would pick up a significant number of donors for HTLV-II" with type-II screening. Panel member Michael Busch, MD, PhD, Irwin Memorial Blood Centers, San Francisco, said he believed HTLV-II screening would be "worth doing, but not if it costs a lot, particularly in terms of false positives. I would urge manufacturers not to push for [HTLV-II] sensitivity at the expense of specificity."

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