IDSA / ISAP / FDA Workshop on Antimicrobial Drug Development Update 2004

1. IDSA / ISAP / FDA Workshop on Antimicrobial Drug DevelopmentUpdate 2004 Edward Cox, MD MPH ODE IV Center for Drug Evaluation and Research US Food and Drug Administration April 15, 2004

2. Update 2004 - Outline • Scientific meetings • Guidance development • Work with Focus Technologies database • Criteria for resistant pathogens of public health importance • Critical path initiative • Preserving the utility of existing antimicrobial agents

3. Scientific Meetings - 1 March 4th and 5th, 2003 - FDA Anti Infective Drug Products Advisory Committee • Patterns of antimicrobial resistance in Streptococcus pneumoniae and drug labeling • Science-based resistant pathogen claims • Use of data from Focus Technologies contract • High rate of cross resistance between penicillin resistant strains and other classes of drugs – multi-drug resistant Streptococcus pneumoniae (MDRSP) • Developing criteria for resistant pathogens of public health importance • Relating clinical data from one disease to another

4. Evaluating Cross-Resistance S, R R. R I, R Drug Y I, I S, I R, I S, S I, S R, S MIC Drug X

5. Correlations in MIC Distributions between Penicillin and Cefuroxime Tested against S. pneumoniae (2000 – 2002) Total n = 9,779 Levo R isolates: n = 87; 26.4% Pen S; 42.5% Pen I; 31.0% Pen R Total n = 5387 5

6. Correlations in MIC Distributions between Levofloxacin and Penicillin Tested against S. pneumoniae (2000-2002) Total n = 9,779 Levo R isolates: n = 87; 26.4% Pen S; 42.5% Pen I; 31.0% Pen R 6

7. Scientific Meetings - 2 March 4th and 5th, 2003 - FDA Anti Infective Drug Products Advisory Committee • Patterns of antimicrobial resistance in Streptococcus pneumoniae and drug labeling • Developing criteria for resistant pathogens of public health importance • Criteria refined for resistant pathogens of public health importance in a particular indication • The pros and cons of a list were discussed • Relating clinical data from one disease to another

8. Criteria for Resistant Pathogen/ Indications of Public Health Importance • Limited available therapies due to multi-drug resistance of the organism • Organism causes serious and severe disease • Drug to which organism is resistant is commonly used in disease under study • Organism of sufficient prevalence in population with disease under study • Drug used to control spread of disease in population • Clinical correlation of in vitro resistance with poor clinical outcomes

9. How to Use the Criteria • Pathogen would not need to fulfill all of criteria to be a resistant pathogen of public health importance in a particular indication • Drug sponsors would need clinical data on treatment of resistant pathogens in the indication of interest • differences in patient characteristics of those with resistant organisms vs. susceptible organisms • Priority review based upon results of clinical trials • Note that a drug may still be approved but not garner resistant pathogen claim until sufficient clinical data on the resistant pathogen of interest have been accrued

10. Previously Granted Resistance Claims • Methicillin resistant S. aureus (MRSA) • vancomycin in serious infections • linezolid in HAP and cSSSI • Vancomycin resistant E. faecium (VRE) • linezolid • dalfopristin-quinupristin in bacteremia • Penicillinase-producing staphylococci • nafcillin in serious and severe infections • Beta-lactamase producing H. influenzae and Moraxella catarrhalis • number of infections with cephalosporins • Penicillin resistant S. pneumoniae (PRSP) • levofloxacin and moxifloxacin in CAP • Multi-drug resistant S. pneumoniae (MDRSP) • gemifloxacin, telithromycin in CAP

11. Scientific Meetings - 3 March 4th and 5th, 2003 - FDA Anti Infective Drug Products Advisory Committee • Patterns of antimicrobial resistance in Streptococcus pneumoniae and drug labeling • Developing criteria for resistant pathogens of public health importance • Relating clinical data from one disease to another • Discussion of the role of using data from one indication to support another indication • Similar microbial etiologies • Similar tissue distribution • Consider severity disease of one illness to another • Consideration of host factors

12. Scientific Meetings - 4 • September 2003 - BAMSG/FDA workshop on fungal drug development • Clinical trial design for empiric antifungal therapy in febrile neutropenic patients • Clinical trial design for investigating combination antifungal therapy • October 2003 FDA AIDP Advisory Committee • Acute Bacterial Sinusitis • Diabetic Foot Infections

13. Scientific Meetings - 5 • September 2003 - BAMSG/FDA workshop on fungal drug development • October 2003 FDA AIDP Advisory Committee • Clinical trial design for Diabetic Foot Infections • Defining the condition • Microbiologic diagnosis in patients with DFI • Measuring outcomes • Clinical trial design in Acute Bacterial Sinusitis • Enriching the population for patients with bacterial sinusitis • Role of microbiologic diagnosis • Superiority trial designs – active + other symptomatic therapies vs. symptomatic therapies or dose-response

14. Guidance Development • Updating and Developing New Guidance Documents • Acute Bacterial Sinusitis • Acute Bacterial Exacerbation of Chronic • Bronchitis • Acute Otitis Media • Acute Bacterial Meningitis • Drug Development for Resistant Pathogens

15. Critical Path Initiative • Critical Path white paper issued March 2004 • Recognizes the advances in the basic biomedical sciences and the high costs of bringing a new medicine to market • Calls for advances in the applied sciences in medical product development – A better product development toolkit • Tools for assessing safety • Tools for demonstrating medical utility • Tools for characterization and manufacturing • Addressing the critical path initiative will require the joint efforts of academia, industry, and FDA http://www.fda.gov/oc/initiatives/criticalpath/whitepaper.pdf

16. Preserving the Utility of Existing Antimicrobial Drugs - 1 • Final rule - Labeling Requirements for Systemic Antibacterial Drug Products Intended for Human Use • Issued February 6, 2003 • Effective February 6, 2004 • Includes statements in labeling about using systemic antibacterial drugs in a way that will reduce the rate of development of antimicrobial resistance and to encourage physicians to counsel their patients about the use of antibacterial drugs • Estimated to impact 669 systemic antibacterial drug product labels http://www.fda.gov/OHRMS/DOCKETS/98fr/03-2969.pdf

17. Preserving the Utility of Existing Antimicrobial Drugs - 2 • FDA is a co-sponsor of the GetSmart Program with CDC • Education/Outreach Program • Includes television, radio and print public service announcements • Goal is to better inform Americans about when antibiotic treatment is warranted • Campaign launched fall 2003 at ICAAC http://www.fda.gov/cder/consumerinfo/antibiot-resist-brochure.htm http://www.cdc.gov/drugresistance/community/default.htm#campaign

18. Summary - Update 2004 • Scientific meetings on labeling issues and clinical trial design for a number of indications • Drug labeling for resistant S. pneumoniae • Criteria for resistant pathogens of public health importance • Relating clinical data from one disease to another • Trial design for studies of empiric antifungal therapy for febrile neutropenic patients and combination antifungal therapy • Trial design for DFI and ABS • Guidance development • Critical path initiative • Preserving the utility of existing antimicrobial agents