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April 7, 2004 11 Primary bloodstream infection as an indication: Regulatory perspective FDA/IDSA/ISAP Workshop April 15, 2004 David Ross, M.D., Ph.D. Outline Regulatory history Defining anti-infective (AI) indications Primary bloodstream infection as an AI indication Bloodstream infection (BSI): history 10 drugs indicated for bacteremia or septicemia All labeled prior to 1992 Labeling based on variable or unspecified clinical manifestations in different studies Includes bacteremia associated with focal infection and bacteremia of unknown origin Patients pooled from trials of other indications 9/93 Anti-Infective Drugs AC meeting Bacteremia did not affect outcome in a large NDA dataset Bacteremia is due to infection at a primary site Bacteremic SIRS patients form a heterogeneous population Unclear if bacteremic SIRS patients were sicker than nonbacteremic patients 9/93 AC conclusions Bacteremia less important than site of infection for classifying infections Study of ‘bacteremic sepsis’ as a separate indication not feasible given heterogeneity of patient population Labeling should include bacteremia in the context of site-specific infections, e.g., “pneumonia with associated bacteremia” Reconsidering BSI as an indication Increased incidence of BSI: with resistant pathogens (e.g., VRE, MRSA) without identifiable primary source Issues in measuring drug effect in BSI . . . Patient heterogeneity Differences in natural history for different pathogens Differences in pathogen epidemiology/virulence Need to define an identifiable clinical syndrome . . . before considering as an indication Does bacteremia equal destiny? 28 yo female with patchy infiltrate in one lobe. No comorbidities. HR 80, RR 16. SCx → S. pneumoniae BCx → S. pneumoniae. Mortality risk 0.1% 52 yo male with multilobar pneumonia. Chronic renal failure, uncontrolled DM HR 130, RR 35. Intubated. SCx → S. pneumoniae BCx → negative Mortality risk 27% Not all bacteremias are the same A 76 yo nur