When Blood & Guidance Go Bad: The Story of Bacteremia as an Indication

1. When Blood & Guidance Go Bad:The Story of Bacteremia as an Indication Janice Soreth, M.D. Director Division of Anti-Infective Drugs US Food & Drug Administration

2. Outline of Today’s Talks • The District, Rockville, and White Oak • Hollywood • The Washington Redskins • National Hockey League (NHL) Lockout • Monday Morning Quarterbacking • Credits

3. District of Columbia, pre- 1965 • Bacteremia, sepsis, bacteremic sepsis, septicemia, primary bacteremia, and secondary bacteremia discussions began a long time ago, since the FDA was located in the District of Columbia. • Org chart: Bureau of Biological and Physical Sciences, Division of Pharmacology, Branch of Antibiotics • My knowledge of this era is derivative.

4. Rockville: 1970s and 1980s • Language for “bacteremia”, “septicemia” made it into package inserts. • Org chart changed: Bureau of Biological & Physical Sciences/Div of Pharm → Bureau of Drugs & Biologics/Div of Anti-Infectives → Center of Drug Evaluation & Research/Div • Division of Anti-Infectives then regulated antibiotics, antiparasitics, topicals, dermatologics, ophthalmologics, antifungals, TB drugs, antivirals ↓ split Division of Anti-Viral Drugs (1988)

5. Rockville: 1990s to present

6. 2005: White Oak

7. Hollywood:Nothing Is Impossible “…every scientist should remove the word ‘impossible’ from his lexicon.”Christopher Reeve (1952-2004)

8. Hollywood:Nothing Is Impossible • …except maybe when it comes to breakdown of the skin, invasion of the bloodstream, and infection of the patient, followed by cardiac arrest, heart failure, coma, and death. • Superman was no match for a bloodstream infection .

9. AIDAC Meeting: October 14, 2004 It takes extraordinary individuals to recognize that investment and effort in the discovery of new antibiotics, and in treatments for serious infections like S. aureus bacteremia, are worth it in the long run.

10. The Washington Redskins and Catheter-Related Infections Guidance What do Joe Gibbs and the FDA have in common? Just like Joe Gibbs, we thought we had put all the right pieces together with the CRBSI guidance. Just like Joe Gibbs, we watched as the Monster just wouldn’t get up.

11. CRBSI Guidance • Discussed at AIDAC meeting 1999 • US stats: 200-400K episodes per year • Mortality 12-25% • Definable case definition Sponsors now tell us there are numerous reasons why they have hit the boards. Don’t blame it on my heart, blame it on my youth.

12. NHL Lockout and S. aureus Bacteremia • Success, beyond being tied to a salary cap, is determined not by knowing where the puck is… • …rather, knowing where the puck is going to be, sometimes unpredictable. • Increasing incidence of S. aureus bacteremia, paralleled by rise in infective endocarditis, foreshadows where major players need to position themselves to win.

13. Issues for Discussion • Should primary bacteremia due to S. aureus (PBSA) be an indication? What exactly would a healthy development program look like? • What patient populations would be included in such a program? • Should endocarditis due to S. aureus be a separate indication?

14. Issues for Discussion (continued) • Should we grant a CRBSI indication in its own right? Or fold it into a more general experience (PBSA or Complicated Skin Infections)? • If separate, what additional information would you suggest be collected on treating serious S. aureus infections?

15. Issues for Discussion (continued) • What role do preclinical and early clinical studies play in setting the stage for later, larger clinical trials? • Sweat the Small Stuff: How many positive blood cultures are required prior to study entry in a PBSA clinical trial?

16. Issues for Discussion (continued) • Screening patients for admission into clinical trials is complicated. Any thoughts as to a general approach?

17. Credits AC Staff: Shalini Jain Office: Mark Goldberger John Powers Edward Cox Leo Chan Division: Lillian Gavrilovich Sumathi Nambiar Janice Pohlman Fred Sorbello