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. 2 Soreth October 15, 2004 Outline of Today’s Talks The District, Rockville, and White Oak The District, Rockville, and White Oak Hollywood Hollywood The Washington Redskins The Washington Redskins National Hockey League (NHL) Lockout National Hockey League (NHL) Lockout Monday Morning Quarterbacking Monday Morning Quarterbacking Credits Credits

3. Soreth October 15, 20043 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. Soreth October 15, 20044 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. Soreth October 15, 20045 Rockville: 1990s to present Anti- Infectives Ur-Division of Anti-Infectives Special Pathogens & Immunologics Anti-Virals

6. Soreth October 15, 20046 2005: White Oak

7. 7 Soreth October 15, 2004 Hollywood: Nothing Is Impossible “…every scientist should remove the word ‘impossible’ from his lexicon.” Christopher Reeve (1952-2004)

8. Soreth October 15, 20048 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. Soreth October 15, 20049 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. 10 Soreth October 15, 2004 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. Soreth October 15, 200411 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. Soreth October 15, 200412 NHL Lockout and S. aureus Bacteremia Success, beyond being tied to a salary cap, is determined not by knowing where the puck is…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.…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.Increasing incidence of S. aureus bacteremia, paralleled by rise in infective endocarditis, foreshadows where major players need to position themselves to win.

13. Soreth October 15, 200413 Issues for Discussion Should primary bacteremia due to S. aureus (PBSA) be an indication? What exactly would a healthy development program look like? 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? What patient populations would be included in such a program? Should endocarditis due to S. aureus be a separate indication? Should endocarditis due to S. aureus be a separate indication?

14. Soreth October 15, 200414 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)? 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? If separate, what additional information would you suggest be collected on treating serious S. aureus infections?

15. Soreth October 15, 200415 Issues for Discussion (continued) What role do preclinical and early clinical studies play in setting the stage for later, larger clinical trials? 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 ? Sweat the Small Stuff: How many positive blood cultures are required prior to study entry in a PBSA clinical trial ?

16. Soreth October 15, 200416 Issues for Discussion (continued) Screening patients for admission into clinical trials is complicated. Any thoughts as to a general approach? Screening patients for admission into clinical trials is complicated. Any thoughts as to a general approach?

17. 17 Soreth October 15, 2004Credits AC Staff:Shalini Jain Office:Mark Goldberger John Powers Edward Cox Leo Chan Division:Lillian Gavrilovich Sumathi Nambiar Janice Pohlman Fred Sorbello