DOSE SELECTION FOR ANTI-INFECTIVE DRUGS: INDUSTRY PERSPECTIVE

1. DOSE SELECTION FOR ANTI-INFECTIVE DRUGS: INDUSTRY PERSPECTIVE Dennis M. Grasela, PharmD, PhD Executive Director, Infectious Diseases Department of Clinical Discovery Bristol-Myers Squibb Pharmaceutical Research Institute FDA/IDSA/ISAP Workshop 15-16 April 2004

2. OUTLINE • Exposure-Response (PK/PD) approach to dose selection • Factors driving the use of PK/PD based drug development • Potential cost benefits

3. OUTLINE • Exposure-Response (PK/PD) approach to dose selection • Factors driving the use of PK/PD based drug development • Potential cost benefits

4. ELEMENTS OF PK/PD-BASED APPROACH TO DOSE SELECTION • Use in vitro MIC values to determine the height of the microbiological hurdle for key pathogen(s) • Use PK/PD data from in vitro hollow-fiber and in vivo animal models of infection to define PD-linked parameter and target values for key pathogen(s) • Use PK/PD modeling in ‘proof-of-principle’ studies to examine Exposure-Response relationship • Combine PK/PD-based knowledge and Monte Carlo simulations to define dose and schedule for Phase III studies

5. MIC DISTRIBUTION FOR S. pneumoniae • Data from the SENTRY Antimicrobial Surveillance Program • 1179 isolates (1998-2002), obtained from patients aged <7 years • MIC90 - 0.25 mg/L

6. 10 14 17 24 34 38 45 LEV USE OF IN VITRO MODELS TO DEFINE PD-TARGET for S. pneumoniae Log CFU/mL Time (hours) Lister D. AAC. 2002; 46: 69-74

7. USE OF IN VIVO ANIMAL MODELS TO DEFINE PD-TARGET for S. pneumoniae Mattoes HM et al. AAC. 2001; 45: 2092-2097

8. USE OF CLINICAL DATA TO CONFIRM PD-TARGET for S. pneumoniae Ambrose PG, et al. AAC. 2001; 45: 2793-2797

9. 0 200 300 Probability of Achieving Target AUC:MIC Ratio for S. pneumoniae Probability 0.05 0.045 0.04 0.035 0.03 0.025 0.02 0.015 0.01 0.005 0 94% 50 100 150 250 350 400 free AUC:MIC Ambrose PM, Grasela DM. Diagn Microbiol & Infect Dis. 2000; 38: 151-157. Bristol-Myers Squibb Company Ambrose PG, Grasela D. ICAAC 1999

10. OUTLINE • Exposure-Response (PK/PD) approach to dose selection • Factors driving the use of PK/PD based drug development • Potential cost benefits

11. DRIVERS FOR THE USE OF PK/PDInternal Factors • Knowledge-based decision making • Dose selection/confirmation • Examination of the effect of administering a dose not studied during development • Selection of target indication(s) • Enhanced understanding of the drug

12. DRIVERS FOR THE USE OF PK/PDInternal Factors • Use of population-based PK/PD analyses • Can help explain differences in response among individuals receiving the same dose (e.g., covariate analyses) • Can help identify at risk sub-populations and define risk-benefit ratios and/or risk management strategies • Can help guide the use of pharmacogenomics

13. DRIVERS FOR THE USE OF PK/PDExternal Factors • FDA Expectations/Opportunities • Guidances (http://www.fda.gov/cder/guidance) • Population PK guidance (1999) • Exposure-Response guidance (5April 2003) • FDA Modernization Act of 1997 (FDAMA) • Global Expectations • Data-driven responses to regulatory questions and/or ‘What if scenarios’ • Benefit-Risk assessment

14. DRIVERS FOR THE USE OF PK/PDExternal Factors Section 111 of FDAMA provides for: “use of PK bridging studies in Pediatric studies of new drugs” FDA Modernization Act of 1997 (FDAMA)

15. DRIVERS FOR THE USE OF PK/PDExternal Factors FDA Modernization Act of 1997 (FDAMA) Section 115 of FDAMA provides for: “new drug approval based upon evidence from a single adequate and well controlled trial, supported by confirmatory scientific evidence from other studies (e.g., Phase II PK/PD studies) in the NDA”

16. OUTLINE • Exposure-Response (PK-PD) approach to dose selection • Factors driving the use of PK-PD based drug development • Potential cost benefits

17. COST BENEFITS • Population PK can obviate the need for selected clinical trials (e.g., age-gender, renal impairment, etc..) • Position sponsor to utilize provisions in the ICH E5 guidelines for the use of PK bridging studies for submission in Japan, etc… • Position sponsor to utilize provisions in Sections 111 and 115 of FDAMA

18. COST BENEFITS • Selection of indications, based on PK/PD evaluation of antimicrobial spectrum • Smaller sample sizes associated with exposure-response vs. dose-response approaches • Selection of optimal dose may lower sample size requirements for non-inferiority trials

19. Sample Size Saving with Selection of Optimal Dose in Non-inferiority Trials Assume 90% power, with a delta of 10%, and all subjects enrolled are fully evaluable

20. COST BENEFITS • Higher quality submissions which could: • facilitate regulatory review • enhance relationship with regulatory authorities • minimize post-submission questions • Facilitate transition to novel dosage forms based on PK studies only, if PK/PD relationship is known • Provide basis for data-driven market differentiation

21. SUMMARY • Selecting the optimal dose(s) for the treatment of infection(s) is important in order to: • Maximize efficacy • Minimize toxicity • Minimize resistance development • Using an exposure-response approach to dose selection and drug development can: • Facilitate knowledge-based decision making • Optimize trial designs • Streamline development and related costs