1. IDSA / ISAP / FDA Workshop on Antimicrobial Drug Development Update 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 4 th and 5 th, 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. Drug Y Evaluating Cross-Resistance Drug X S, S S, I S, R I, S I, I I, R R, S R, I R. R MIC

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 5 Total n = 5387

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 4 th and 5 th, 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 1.Limited available therapies due to multi-drug resistance of the organism 2.Organism causes serious and severe disease 3.Drug to which organism is resistant is commonly used in disease under study 4.Organism of sufficient prevalence in population with disease under study 5.Drug used to control spread of disease in population 6.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 4 th and 5 th, 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