# Presentation: 303110

##  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***

## Introduction

**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**

## 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**

## 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)**

## 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?**

## 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 **
**www.fda.gov/cder/drug/antimicrobial/FDA_IDSA_ISAP_Presentations.htm**

## 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 2004:38:864-70****.**
**Animal models**** of infection **
**Endocarditis? **
**Other potential metastatic sites of infection?**

## 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?**

## 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 314.126 (a)**

## Clinical Trials - Potential Biases

- 5

- Population
- with Disease

- Population
- in Study

- Treatment
- Arms

- Analysis
- and
- Conclusions

- 1

- 2

- 3

- 4

**Selection**
**of Study **
**Population**

**Randomization**
**and Blinding**

**Potential**
**Confounders**
**On Therapy**

**Endpoints**

**Analysis**

## 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**

## 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**

## 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**

## 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 1993:119:304-311.**

## 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**

## 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**

## 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**

## 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**

## 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**

## 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;851-75.**
**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**

## Clinical Trials ConsiderationsStatistical Considerations - Sample Size per Arm

**NI margin**

***Based upon 80% power**

*****

## 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?**

## 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?**

## 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?**