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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. OUTLINE.

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dose selection for anti infective drugs industry perspective

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

outline
OUTLINE
  • Exposure-Response (PK/PD) approach to dose selection
  • Factors driving the use of PK/PD based drug development
  • Potential cost benefits
outline3
OUTLINE
  • Exposure-Response (PK/PD) approach to dose selection
  • Factors driving the use of PK/PD based drug development
  • Potential cost benefits
elements of pk pd based approach to dose selection
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
mic distribution for s pneumoniae
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
use of in vitro models to define pd target for s pneumoniae

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

use of in vivo animal models to define pd target for s pneumoniae
USE OF IN VIVO ANIMAL MODELS TO DEFINE PD-TARGET for S. pneumoniae

Mattoes HM et al. AAC. 2001; 45: 2092-2097

use of clinical data to confirm pd target for s pneumoniae
USE OF CLINICAL DATA TO CONFIRM PD-TARGET for S. pneumoniae

Ambrose PG, et al. AAC. 2001; 45: 2793-2797

probability of achieving target auc mic ratio for s pneumoniae

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

outline10
OUTLINE
  • Exposure-Response (PK/PD) approach to dose selection
  • Factors driving the use of PK/PD based drug development
  • Potential cost benefits
drivers for the use of pk pd internal factors
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
drivers for the use of pk pd internal factors12
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
drivers for the use of pk pd external factors
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
drivers for the use of pk pd external factors14
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)

drivers for the use of pk pd external factors15
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”

outline16
OUTLINE
  • Exposure-Response (PK-PD) approach to dose selection
  • Factors driving the use of PK-PD based drug development
  • Potential cost benefits
cost benefits
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
cost benefits18
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
sample size saving with selection of optimal dose in non inferiority trials
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

cost benefits20
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
summary
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