Published on January 9, 2008
Challenges in AntibacterialDrug Development: Challenges in Antibacterial Drug Development Francis P. Tally M.D. Cubist Pharmaceuticals, Inc. Francis P. Tally M.D.Background: Francis P. Tally M.D. Background Tufts/New England Medical Center 1975-1986 Infectious Disease, Senior Physician Principal Investigator – 7 New Antimicrobials Lederle/Wyeth 1987-1995 Executive Director, Infectious Disease Research Registered Zosyn (piperacillin sodium & tazobacam sodium) – 1993 Involved with discovery of tigecycline Cubist Pharmaceuticals, Inc. 1995 – present Currently working to develop daptomycin Challenges in AntibacterialDrug DevelopmentCharacteristics of the Drug: Challenges in Antibacterial Drug Development Characteristics of the Drug Broad Spectrum vs. Narrow Spectrum Oral and/or IV Modification of Existing Class vs. Novel Class Challenges in AntibacterialDrug Development: Challenges in Antibacterial Drug Development Challenges in AntibacterialDrug DevelopmentCharacteristics to Justify Development: Challenges in Antibacterial Drug Development Characteristics to Justify Development Microbiological Superiority Inhibit resistant organisms Pharmacological Advantage Frequency of dosing Ease of administration Safety Advantage Challenges in AntibacterialDrug DevelopmentClassification of New Antibacterial Drugs: Challenges in Antibacterial Drug Development Classification of New Antibacterial Drugs Broad Spectrum – Existing Classes Carbapenem – oral; qd Penicillin / ß-lactamase inhibitor Cephalosporin – MRSA activity Narrow Spectrum – Gram+ Susceptible and Resistant Organisms New Drug Class – Covers Resistant Organisms Challenges in AntibacterialClinical Protocol Development: Challenges in Antibacterial Clinical Protocol Development Spectrum and Drug Distribution Defines the Clinical Indications to Be Studied PK/PD Guide to Dose Selection Preclinical Safety Profile Influences Patient Selection Clinical Trial Design Superiority Noninferiority Challenges in AntibacterialDrug DevelopmentTrial Design: Challenges in Antibacterial Drug Development Trial Design Clinical Indications and Organisms Encountered Monomicrobial – S. aureus – cSST Mixed infection – intra-abdominal Potential Pathogens Dictate Selection of Comparative Agents Narrow – UTI, SST Divergent – CAP, nosocomial pneumonia, intraabdominal infection Bacterial Causes of Pneumonia: Bacterial Causes of Pneumonia Challenges in AntibacterialDrug DevelopmentTrial Design: Challenges in Antibacterial Drug Development Trial Design Type of Controlled Trial to Prove Noninferiority Blinded double or investigator open label – microbiology endpoint Sample Size “delta” 95% Confidence Interval projected efficacy rate End Points – Clinical vs. Microbiological Challenges in AntibacterialDrug DevelopmentChallenges of Selecting Delta for Clinical Trial: Challenges in Antibacterial Drug Development Challenges of Selecting Delta for Clinical Trial Is Drug Therapy Better Than Placebo – Superiority Placebo controlled requires monitoring board Seriousness of the Infection – Affects Delta Mild: Impetigo, UTI, gonorrhea Moderate: Bacteremia/Nosocomial pneumonia Severe (rare): Endocarditis/Meningitis Is Drug Equal to Standard of Care “Biocreep” in mild infections Serious infection – select best therapy Challenges in Antibacterial Drug Development“Biocreep”: Challenges in Antibacterial Drug Development “Biocreep” Historically, drugs with lower efficacy rates than standard of care can be approved with wider deltas Theoretically, one could sequentially compare and approve slightly inferior products relative to an approved standard of care “Biocreep” – over time a product could be approved as noninferior that would not be better than placebo Challenges in Antibacterial Drug DevelopmentDelta – Related to Efficacy Rates in 1992: Challenges in Antibacterial Drug Development Delta – Related to Efficacy Rates in 1992 Challenges in AntibacterialDrug DevelopmentImpact of Small Delta: Challenges in Antibacterial Drug Development Impact of Small Delta Number of Patients to Be Enrolled is Greatly Increased Time to Complete Enrollment Measured in Years Enrollment Outside U.S. Patient population differs Control for study variables Cost of Drug Development Big Pharma Biotech / Specialty Pharma Challenges in AntibacterialDrug DevelopmentOpinion: Challenges in Antibacterial Drug Development Opinion “Biocreep” Should Be Stopped Selection of comparative agent in collaboration with academic societies’ cited guidelines Infectious Disease Society of America American College of Pediatrics Society for Critical Care Medicine American College of Surgeons Challenges in AntibacterialDrug DevelopmentOpinion: Challenges in Antibacterial Drug Development Opinion Oral Drugs for Common Community Diseases Skin and skin structure Sinusitis Otitis media Bronchitis Urinary tract infection Gonorrhea 10% Delta Appropriate Challenges in AntibacterialDrug DevelopmentOpinion: Challenges in Antibacterial Drug Development Opinion IV Drug for Serious Infections Delta Should be Based on Clinical Knowledge of the Infection Challenges in Antibacterial Drug DevelopmentProblems With IV Only Drugs: Challenges in Antibacterial Drug Development Problems With IV Only Drugs Serious Infections – Limited Subjects for Enrollment – cSST, Pneumonia, Intraabdominal Selection of Comparative Agent (Stop Biocreep) Inpatient Hospital Requirement vs. Home IV Therapy Criteria for oral switch – small delta magnifies the challenges to perform adequate studies Challenges in AntibacterialDrug DevelopmentOpinion – Paradox of Higher Mortality Infections: Challenges in Antibacterial Drug Development Opinion – Paradox of Higher Mortality Infections Widest Delta in Severe Disease such as Meningitis and Bacterial Endocarditis – because sterilization of blood or CSF are hard end points Challenges in Antibacterial Drug DevelopmentOverall Conclusions on Delta: Challenges in Antibacterial Drug Development Overall Conclusions on Delta Community-acquired common infections are where the most “Biocreep” has occurred. Therefore a small delta is appropriate and the best comparative agent should be selected. Intravenous therapy for serious infections are the main problem in clinical development where physicians will select the best therapy. The delta should be based on statistical and clinical considerations and comparative therapy should represent the standard of care. Challenges in Antibacterial Drug DevelopmentOverall Conclusions on Delta: Challenges in Antibacterial Drug Development Overall Conclusions on Delta Severe infections (e.g. meningitis and bacterial endocarditis) require the widest deltas because microbiology end points are firm and incidence of infection is low.