1. Office of Drug Evaluation IV, CDER FDA/IDSA/ISAP Workshop 4/16/04 Overview of PK-PD in Drug Development Programs: FDA Perspective FDA/IDSA/ISAP Workshop April 16, 2004 John H. Powers, MD Lead Medical Officer, Antimicrobial Drug Development and Resistance Initiatives Office of Drug Evaluation IV Center for Drug Evaluation and Research FDA/IDSA/ISAP Workshop April 16, 2004 John H. Powers, MD Lead Medical Officer, Antimicrobial Drug Development and Resistance Initiatives Office of Drug Evaluation IV Center for Drug Evaluation and Research

2. Office of Drug Evaluation IV, CDER FDA/IDSA/ISAP Workshop 4/16/04 2 IntroductionIntroduction Background Discuss potential strengths and limitations of PK- PD in overall drug development program Applications in clinical trials –overall size of clinical development program –overall size of individual clinical trials Applications in prescription drug labeling Background Discuss potential strengths and limitations of PK- PD in overall drug development program Applications in clinical trials –overall size of clinical development program –overall size of individual clinical trials Applications in prescription drug labeling

3. Office of Drug Evaluation IV, CDER FDA/IDSA/ISAP Workshop 4/16/04 3 BackgroundBackground Previous discussions at prior meetings including workshops and advisory committee meetings November 2002 IDSA/PhRMA/FDA workshop began discussions on use of PK-PD in clinical development programs Further discussed in letter to FDA commissioner in November 2003 Suggestions to incorporate PK-PD to “shrink the size of clinical trials” Previous discussions at prior meetings including workshops and advisory committee meetings November 2002 IDSA/PhRMA/FDA workshop began discussions on use of PK-PD in clinical development programs Further discussed in letter to FDA commissioner in November 2003 Suggestions to incorporate PK-PD to “shrink the size of clinical trials”

4. Office of Drug Evaluation IV, CDER FDA/IDSA/ISAP Workshop 4/16/04 4 StrengthsStrengths PK-PD can be useful in overall drug development –Improper dose selection can increase size of database, time and expense of development program –Subjects patients to dangers of clinical treatment failure –Failure to show efficacy in clinical trials may require further studies –Lower success rates may impact on clinical utility of drug –Proper dose selection may limit dose-related adverse effects –May give clues as to which indications and which organisms to study and which to avoid PK-PD can be useful in overall drug development –Improper dose selection can increase size of database, time and expense of development program –Subjects patients to dangers of clinical treatment failure –Failure to show efficacy in clinical trials may require further studies –Lower success rates may impact on clinical utility of drug –Proper dose selection may limit dose-related adverse effects –May give clues as to which indications and which organisms to study and which to avoid

5. Office of Drug Evaluation IV, CDER FDA/IDSA/ISAP Workshop 4/16/04 5 Questions?Questions? Can PK-PD shrink the size of individual trials? –Sample size smaller if proper dose selection increases the success rate in the trial –Is PK-PD sufficiently accurate to predict relatively small differences in success rates between drugs? Is PK-PD best at predicting effective vs. ineffective drugs rather than differences between effective drugs –Do host and other effects predominate in affecting clinical outcomes? Can PK-PD shrink the size of individual trials? –Sample size smaller if proper dose selection increases the success rate in the trial –Is PK-PD sufficiently accurate to predict relatively small differences in success rates between drugs? Is PK-PD best at predicting effective vs. ineffective drugs rather than differences between effective drugs –Do host and other effects predominate in affecting clinical outcomes?

6. Office of Drug Evaluation IV, CDER FDA/IDSA/ISAP Workshop 4/16/04 6 Sample Size per Arm 80% power 

7. Office of Drug Evaluation IV, CDER FDA/IDSA/ISAP Workshop 4/16/04 7 Other Potential Uses Preliminary information to come up with hypotheses for potential susceptibility breakpoints –still requires clinical information for validate –requires further discussion at another time Potential to prevent development of resistance –What is clinical effect of preventing development of resistance? Does this prevent infection in that person or in other patients –Target pathogen vs. “collateral” organisms –Requires demonstration of clinical effects in clinical trials –Antimicrobial indications to treat or prevent disease Preliminary information to come up with hypotheses for potential susceptibility breakpoints –still requires clinical information for validate –requires further discussion at another time Potential to prevent development of resistance –What is clinical effect of preventing development of resistance? Does this prevent infection in that person or in other patients –Target pathogen vs. “collateral” organisms –Requires demonstration of clinical effects in clinical trials –Antimicrobial indications to treat or prevent disease

8. Office of Drug Evaluation IV, CDER FDA/IDSA/ISAP Workshop 4/16/04 8 LimitationsLimitations Typically, PK-PD in anti-infective drug development has focused on effects on microbiological outcomes In many situations, validity of microbiological outcomes as surrogates for clinical outcomes remains unclear –microbiological outcomes in some indications imputed from clinical outcomes as “presumed eradicated” Does effect of drug on organisms directly translate into clinical outcomes? Typically, PK-PD in anti-infective drug development has focused on effects on microbiological outcomes In many situations, validity of microbiological outcomes as surrogates for clinical outcomes remains unclear –microbiological outcomes in some indications imputed from clinical outcomes as “presumed eradicated” Does effect of drug on organisms directly translate into clinical outcomes?

9. Office of Drug Evaluation IV, CDER FDA/IDSA/ISAP Workshop 4/16/04 9 QuestionsQuestions PK-PD can differentiate ineffective drug or dose from effective drug or dose Can PK-PD differentiate between various effective drugs when each dosed optimally? Are other factors as important or more important than PK-PD in overall outcomes in a given disease –mortality in severe community-acquired pneumonia has not changed despite more “active” drugs in vitro PK-PD can differentiate ineffective drug or dose from effective drug or dose Can PK-PD differentiate between various effective drugs when each dosed optimally? Are other factors as important or more important than PK-PD in overall outcomes in a given disease –mortality in severe community-acquired pneumonia has not changed despite more “active” drugs in vitro

10. Office of Drug Evaluation IV, CDER FDA/IDSA/ISAP Workshop 4/16/04 10 QuestionsQuestions Does PK-PD take into account various aspects of drug-host-organism interaction? –pH at site of infection, log vs. static growth phase, microbial load of organisms –direct immunological effects of drug on host –immunological effects on host by organism lysis and inflammatory mediators e.g. acute bacterial meningitis Does PK-PD give information on non-dose related adverse effects? Still need clinical trials to determine effects of drug on clinical outcomes in a given disease Does PK-PD take into account various aspects of drug-host-organism interaction? –pH at site of infection, log vs. static growth phase, microbial load of organisms –direct immunological effects of drug on host –immunological effects on host by organism lysis and inflammatory mediators e.g. acute bacterial meningitis Does PK-PD give information on non-dose related adverse effects? Still need clinical trials to determine effects of drug on clinical outcomes in a given disease

11. Office of Drug Evaluation IV, CDER FDA/IDSA/ISAP Workshop 4/16/04 11 ApplicationsApplications Question of role in “follow-on” indications –presume this means demonstrating clinical efficacy in one indication and then receiving approval for a different indication based on PK-PD alone without clinical trial information Presumes safety and efficacy of drugs are identical across various diseases –different cure rates in various diseases, e.g. acute bacterial meningitis vs. acute bacterial sinusitis –differences in safety outcomes across indications Question of role in “follow-on” indications –presume this means demonstrating clinical efficacy in one indication and then receiving approval for a different indication based on PK-PD alone without clinical trial information Presumes safety and efficacy of drugs are identical across various diseases –different cure rates in various diseases, e.g. acute bacterial meningitis vs. acute bacterial sinusitis –differences in safety outcomes across indications

12. Office of Drug Evaluation IV, CDER FDA/IDSA/ISAP Workshop 4/16/04 12 ApplicationsApplications Still need clinical data from each indication Discussions at March 2003 Anti-Infective Drugs Advisory Committee meeting regarding clinical data from one indication supporting another “Supportive” presumes still at least one trial in each indication since “supporting” implies there is some data to support in each disease Need data on resistant pathogens in each indication Still need clinical data from each indication Discussions at March 2003 Anti-Infective Drugs Advisory Committee meeting regarding clinical data from one indication supporting another “Supportive” presumes still at least one trial in each indication since “supporting” implies there is some data to support in each disease Need data on resistant pathogens in each indication

13. Office of Drug Evaluation IV, CDER FDA/IDSA/ISAP Workshop 4/16/04 13 Prescription Labeling Clinicians often do not have information needed to make PK-PD assessments –cultures not commonly done in some diseases (uUTI) in clinical practice or organism not isolated (CAP) –drug concentrations not available either in blood or at site of infection Is “one size fit all” for PK-PD parameters sufficiently accurate to make individual treatment decisions for patients e.g. target PK-PD index of 100 for all Gram-negative organisms in all diseases in all hosts? Clinicians often do not have information needed to make PK-PD assessments –cultures not commonly done in some diseases (uUTI) in clinical practice or organism not isolated (CAP) –drug concentrations not available either in blood or at site of infection Is “one size fit all” for PK-PD parameters sufficiently accurate to make individual treatment decisions for patients e.g. target PK-PD index of 100 for all Gram-negative organisms in all diseases in all hosts?

14. Office of Drug Evaluation IV, CDER FDA/IDSA/ISAP Workshop 4/16/04 14 Prescription Labeling Would providing PK-PD information in labeling imply superiority for one drug over another that has not been demonstrated in clinical trials? Would PK-PD information in labeling spur clinicians to use a higher, unstudied dose that may not be safe in hopes of improved efficacy? How would this information in labeling help practicing clinicians to use the drug appropriately in patients? Would providing PK-PD information in labeling imply superiority for one drug over another that has not been demonstrated in clinical trials? Would PK-PD information in labeling spur clinicians to use a higher, unstudied dose that may not be safe in hopes of improved efficacy? How would this information in labeling help practicing clinicians to use the drug appropriately in patients?

15. Office of Drug Evaluation IV, CDER FDA/IDSA/ISAP Workshop 4/16/04 15 Today’s Discussion Focus on dose selection in clinical trials to streamline development process Requires discussion among all parties as to what constitutes an adequate PK-PD database for drug development program Future discussion on other issues such as breakpoint selection warranted and necessary Focus on dose selection in clinical trials to streamline development process Requires discussion among all parties as to what constitutes an adequate PK-PD database for drug development program Future discussion on other issues such as breakpoint selection warranted and necessary