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HIV IMMUNOTHERAPEUTICS STUDIES BASED ON "MINOR CLINICAL ENDPOINTS"

Executive Summary

HIV IMMUNOTHERAPEUTICS STUDIES BASED ON "MINOR CLINICAL ENDPOINTS" may be more effective than reliance solely on more general surrogate markers such as CD4 count or virological markers, Dennis Klinman, FDA's Laboratory of Retrovirus Research, suggested at a July 22 session of the VIII International Conference on AIDS in Amersterdam. Currently, "it's unclear whether CD4 count, virological markers, or progression to disease...is really the most appropriate marker," Klinman said. He argued that along with virologic markers and CD4 counts, researchers should look at the minor markers of disease progression and then continue a trial "past the point where [FDA] may be able to approve [the drug] on the basis of one of those minor markers, so that we eventually show that [the marker] does correlate with the progression of the more severe disease." Klinman said the appeal of "minor clinical endpoints," such as thrush, anergy, herpes zoster, minor opportunistic infections and hairy cell leukoplakia, is that they "affect anywhere from 30% to 50%" of patients with CD4 counts between 300 and 500. This means, he explained, that "if you use as your marker for disease progression -- or for effectiveness of immunotherapy -- the prevention of those minor aspects of disease, you can get approval based on that preventive aspect, and then continue the study to show that in fact you have a great and more important long-term effect on survival." Current data, Klinman noted, suggest that HIV immunotherapeutics may be most active when initially administered to subjects with CD4 counts above 500 per mm . Viral load measurements are "intuitively more appealing" to FDA as surrogate markers, Klinman continued, "since clearly, HIV infection and AIDS has to do with the amount of virus in the body, and clearly, if you can prevent virus from replicating, you should be able to have an impact on disease." But, he noted: "Sadly, we still have no evidence linking amount of viral load to eventual development of disease in the context of an immunotherapeutic." CD4 counts by themselves are not likely to be considered sufficient markers for immunotherapeutics, Klinman said. Antiviral agents like ddI and AZT do not directly affect the immune system by their mechanism of action, so any increase in CD4 count is a potentially useful marker of antiviral activity, Klinman explained. Immunological interventions, on the other hand, "are expected to directly affect the immune system, and can therefore alter CD4 count" without necessarily affecting disease. A second major strategy for speeding the evaluation of HIV immunotherapeutics, according to Klinman, would be to perform trials using populations that are more likely to progress faster to disease. For example, recent research shows that about one- quarter of all HIV-infected patients "proceed with decreasing CD4 counts about twice to four times more rapidly than the average HIV-infected population," he said. Individuals "with partial anergy" also appear to develop AIDS-defining diseases sooner. Pediatric studies could evaluate whether or not subjects "reach developmental landmarks at appropriate times," thereby providing a way to monitor "function without actually having to see the sequelae of infection," Klinman said. Finally, maternal- fetal studies could be performed "to judge whether or not an agent is really effective, either at preventing or slowing progression, or transmission of disease," he concluded. Klinman stressed that marker endpoints have the potential to be misleading "in that you can show a statistically significant difference between two patient populations which has no biological meaning whatsoever, which at best might mean a few days, weeks or months [of] difference before a patient actually succumbs to clinical disease." However, "that's not what we want to approve a drug on the basis of," he said.

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