Clinical Trials Considerations in Primary Bacteremia due to Staphylococcus aureus Clinical Trials Considerations in Primary Bacteremia due to Staphylococcus aureus John H. Powers, MD Lead Medical Officer Antimicrobial Drug Development and Resistance Initiatives Office of Drug Evaluation IV Center for Drug Evaluation and Research U.S. Food and Drug Administration

2Introduction  Defining the indication  Place of this potential indication in clinical development program  pre-clinical development  prior clinical trials data  Issues in clinical trials of study of this indication  selecting appropriate patient population  endpoints with focus on metastatic disease  selection of duration of therapy  selection of control drugs  statistical considerations

3 Defining the Indication  Should Primary Bacteremia due to S. aureus (PBSA) constitute a separate indication?  Indication and patients studied should be clearly defined disease entity  clinicians should be able to appropriately select patients for treatment  allow for adequate description in product labeling  Primary bacteremia due to S. aureus (PBSA)  evidence of systemic signs and symptoms with positive blood cultures for S. aureus and no identified source of infection at time of enrollment  signs and symptoms part of definition given previous AIDAC discussions that bacteremia alone is not a disease

4 Defining the Indication  Should one differentiate from secondary bacteremia with a known source of infection?  differential efficacy of drugs based on site of infection  previous discussions of AIDAC regarding importance of primary site of infection  bacteremia related to intravascular catheter often diagnosis of exclusion so may be logical to include in category  Would this indication provide useful information to clinicians?  Would data from this indication add to data from clinical trials of patients with a known source of infection?  Does this indication provide opportunity to study patients not included in clinical trials of patients with a known source of infection (e.g. endocarditis)

5 Defining the Indication  Does efficacy in PBSA imply efficacy in endocarditis?  Clinical concern in patients with PBSA is occurrence of endocarditis or other metastatic site of infection that may be occult at time of initial diagnosis  Implies different outcomes and  different duration of therapy  Can drugs be studied without examining efficacy in endocarditis?  Are there differences between right and left sided disease?  Can drugs be studied in “staged” approach of first studying uncomplicated disease, then right sided, then left sided disease? Can this be reflected in labeling?

6 Clinical Development Program  April 2004 FDA/IDSA/ISAP workshop began preliminary discussions on this indication  Participants expressed view that this is serious disease with potential for development of endocarditis  Given serious nature of disease, unlikely that data from trials in this indication would be sole basis for approval  Expressed view that there should be body of information on potential drug efficacy in such a serious disease 

7 Clinical Development Program  What kinds of pre-clinical studies would be helpful in forming hypotheses about potential efficacy and safety in this indication ?  In vitro data on biological activity against isolates of S. aureus (e.g. bacteriostatic vs. bactericidal?)  traditionally believed that bactericidal activity necessary in treatment of endocarditis  Inconsistencies across organisms and methods  Clinical significance? Should drugs bacteriostatic against S. aureus exclude patients with endocarditis from studies? At least initially (staged approach)?  Pankey GA et al. Clin Infect Dis 2004:38:  Animal models of infection  Endocarditis?  Other potential metastatic sites of infection?

8 Clinical Development Program  What clinical experience would be helpful in evaluating a new drug for this indication?  patients with no primary site found still have some occult source of infection  serious nature of illness and potential differences in efficacy of drugs based on primary site of infection would weigh against this indication as sole basis for approval of a new drug  data from clinical trials of infections of sufficient severity where S. aureus is a potential pathogen  hospital-acquired pneumonia  community-acquired pneumonia  complicated skin and skin structure infections  others?

9 Clinical Trials Considerations  Clinical trials should provide information that is useful in clinical practice  However, clinical trials are not clinical practice  Clinical trials are scientific experiments performed in human beings  scientific method = hold as many factors constant as possible other than drugs administered so as to ascribe causality of results to the drugs  “The purpose of performing clinical investigations is to distinguish the effects of a drug from other influences, such as spontaneous change in the course of the disease, placebo effect, or biased observation.”  21 CFR (a)

10 Clinical Trials - Potential Biases 5 Population with Disease Population in Study Treatment Arms Analysis and Conclusions Selection of Study Population Randomization and Blinding PotentialConfounders On Therapy Endpoints Analysis

11 Clinical Trials Considerations Defining Patient Populations  Inclusion/ Exclusion Criteria used to define population under study  Balance between homogenous population so outcomes are not related to host rather than drug, yet heterogeneous enough to extrapolate to clinically relevant population  Need to differentiate among patients with “Gram-positive cocci” in blood  S. epidermidis more common than S. aureus  newer diagnostic tests may allow differentiation prior to enrollment

12 Clinical Trials Considerations Defining Patient Populations  Considerations in studying this indication  different natural histories for various populations of patients in whom subsequent testing after randomization shows a source/metastatic site of infection (e.g. endocarditis)  different success rates  different duration of therapy  even patients with “uncomplicated” disease such as catheter-related disease may have subsequent metastatic disease

13 Clinical Trials Considerations Defining Patient Populations  Complicated vs. uncomplicated disease  complicated = patients who develop further clinical manifestations not present at the time of diagnosis that portend a worse prognosis and/or need for prolonged therapy  severe sepsis, acute respiratory distress syndrome, DIC  metastatic sites of infection  Community acquired vs. nosocomial  may refer to differing hosts (underlying diseases) as much as different geography of acquisition  may refer to differences in bacterial load, delay in diagnosis and initiation of therapy  may not be as useful a distinction in clinical trials or for labeling given significant overlap in populations

14 Clinical Trials Considerations Defining Patient Populations  Difficult to stratify at time of enrollment since metastatic infections may become clinically apparent at some time after enrollment  How well do risk factors select patients with “complicated” disease and those who may receive “short-course” therapy?  many of studies differentiating complicated from uncomplicated infection are retrospective or  other methodological issues such as treatment allocation bias  Jernigan JA et al. Ann Intern Med 1993:119:

15 Clinical Trials Considerations Defining Patient Populations  How useful are these risk factors in clinical trials?  some risk factors (duration of fever and duration of bacteremia) occur randomization  these risk factors based upon outcomes with known effective therapies but how would they perform with an experimental drug?  duration of bacteremia and duration of fever may differ between drugs i.e. patients treated with new drug may have longer duration of bacteremia/ fever yet still have similar clinical efficacy relative to the control drug

16 Clinical Trials Considerations Defining Patient Populations  How should patients who develop a site of infection after randomization be handled?  Could patients with no signs and symptoms of primary site of infection at time of enrollment be left in trial when they develop a site of infection on therapy?  example of candidemia trials  Patients would need standardized evaluation at time of enrollment so that there are no potential differences between arms of study  what tests would be appropriate? e.g. echocardiography to evaluate for endocarditis

17 Clinical Trials Considerations Endpoints  Should patients who develop a site of infection on study be considered clinical failures of therapy?  Should one differentiate “baseline” from “breakthrough” infections?  Some data indicate that metastatic disease decreases with institution of effective therapy  Less effective drug could result in more metastatic disease  Clinical endpoints important in this disease  given risk of metastatic disease, clinical outcomes would be most relevant primary endpoint  negative cultures alone/time to negative cultures did correlate with clinical outcomes in previous trials

18 Clinical Trials Considerations Duration of Therapy  How should the duration of therapy in studies of this indication be determined?  Important to define duration of therapy for patients based on upon characteristics of disease  duration based upon “investigator discretion” could introduce potential bias  significant variation in clinical practice in duration of therapy even for uncomplicated disease  most straightforward design and analysis would be to define one duration of therapy for all or could be based upon risk factors at time of enrollment

19 Clinical Trials Considerations Selection of Control Drug  What would be appropriate control regimens for this indication?  Most straightforward analysis would be to specify one control regimen prior to initiation of trial  Selection of control regimen based upon investigator discretion may introduce potential bias  benefit of addition of aminoglycosides in cases of endocarditis remains unclear but may increase adverse event profile in control arm  could have protocol defined switch from vancomycin to other regimen (anti-staphylococcal penicillin) after determination of susceptibilities of organisms

20 Clinical Trials Considerations Statistical Considerations  What would be an acceptable loss of efficacy relative to control drugs for this indication?  Trials in this indication would most likely be non- inferiority trials  Selection of non-inferiority margin  magnitude of benefit of antibacterials compared to no treatment in pre-antibiotic era appears to be large  Skinner D, Keefer C. Arch Intern Med 1941:68;  what would clinically acceptable loss of efficacy relative to control?  larger non-inferiority margin translates into smaller sample size but potential for more uncertainty regarding results

21 Clinical Trials Considerations Statistical Considerations - Sample Size per Arm NI margin *Based upon 80% power *

22 Issues for Discussion  Should patients with primary bacteremia due to S. aureus constitute a separate indication? Do these patients constitute a clinically relevant group of patients that can be described in product labeling?  Does efficacy in PBSA imply efficacy in endocarditis? Can drugs be studied without examining efficacy in endocarditis, or in a “staged” with appropriate labeling?

23 Issues for Discussion  What pre-clinical information and information from other clinical trials would be helpful in evaluating drugs that may be appropriate for study in this indication?  What evaluation should patients have prior to enrollment or shortly thereafter to rule out a known focus of infection?  How should patients who develop a site of infection after randomization be handled? Should they be left on study drug? Should they be considered failures of study medication?

24 Issues for Discussion  How should the duration of therapy in studies of this indication be designated?  What would be appropriate control regimens for this indication?  What would be an acceptable loss of efficacy relative to control drugs, balancing the certainty of results with the practicality of sample size?