Clinical Trials Considerations Clinical Trials Considerations in Primary Bacteremia due toin Primary Bacteremia due to

Staphylococcus aureusStaphylococcus aureus

John H. Powers, MDJohn H. Powers, MDLead Medical OfficerLead Medical Officer

Antimicrobial Drug Development and Resistance InitiativesAntimicrobial Drug Development and Resistance Initiatives

Office of Drug Evaluation IVOffice of Drug Evaluation IV

Center for Drug Evaluation and ResearchCenter for Drug Evaluation and Research

U.S. Food and Drug AdministrationU.S. Food and Drug Administration

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IntroductionIntroduction Defining the indicationDefining the indication

Place of this potential indication in clinical development Place of this potential indication in clinical development programprogram pre-clinical developmentpre-clinical development prior clinical trials dataprior clinical trials data

Issues in clinical trials of study of this indicationIssues in clinical trials of study of this indication selecting appropriate patient populationselecting appropriate patient population endpoints with focus on metastatic diseaseendpoints with focus on metastatic disease selection of duration of therapyselection of duration of therapy selection of control drugsselection of control drugs statistical considerationsstatistical considerations

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Defining the IndicationDefining the Indication Should Primary Bacteremia due to Should Primary Bacteremia due to S. aureusS. aureus (PBSA) (PBSA)

constitute a separate indication?constitute a separate indication?

Indication and patients studied should be Indication and patients studied should be clearly defined disease entityclearly defined disease entity clinicians should be able to appropriately select clinicians should be able to appropriately select

patients for treatmentpatients for treatment allow for adequate description in product labelingallow for adequate description in product labeling

Primary bacteremia due to Primary bacteremia due to S. aureusS. aureus (PBSA) (PBSA) evidence of systemic signs and symptoms with positive blood evidence of systemic signs and symptoms with positive blood

cultures for cultures for S. aureusS. aureus and no identified source of infection at and no identified source of infection at time of enrollmenttime of enrollment

signs and symptoms part of definition given previous AIDAC signs and symptoms part of definition given previous AIDAC discussions that bacteremia alone is not a diseasediscussions that bacteremia alone is not a disease

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Defining the IndicationDefining the Indication Should one differentiate from secondary bacteremia with a Should one differentiate from secondary bacteremia with a

known source of infection?known source of infection? differential efficacy of drugs based on site of infectiondifferential efficacy of drugs based on site of infection previous discussions of AIDAC regarding importance of primary previous discussions of AIDAC regarding importance of primary

site of infectionsite of infection bacteremia related to intravascular catheter often diagnosis of bacteremia related to intravascular catheter often diagnosis of

exclusion so may be logical to include in categoryexclusion so may be logical to include in category

Would this indication provide useful information Would this indication provide useful information to clinicians?to clinicians? Would data from this indication add to data from clinical Would data from this indication add to data from clinical

trials of patients with a known source of infection?trials of patients with a known source of infection? Does this indication provide opportunity to study Does this indication provide opportunity to study

patients not included in clinical trials of patients with a patients not included in clinical trials of patients with a known source of infection (e.g. endocarditis)known source of infection (e.g. endocarditis)

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Defining the IndicationDefining the Indication Does efficacy in PBSA imply efficacy in endocarditis?Does efficacy in PBSA imply efficacy in endocarditis?

Clinical concern in patients with PBSA is occurrence of Clinical concern in patients with PBSA is occurrence of endocarditis or other metastatic site of infection that may be endocarditis or other metastatic site of infection that may be occult at time of initial diagnosisoccult at time of initial diagnosis Implies different outcomes and Implies different outcomes and different duration of therapydifferent duration of therapy

Can drugs be studied without examining efficacy in Can drugs be studied without examining efficacy in endocarditis? endocarditis? Are there differences between right and left sided disease?Are there differences between right and left sided disease? Can drugs be studied in “staged” approach of first studying Can drugs be studied in “staged” approach of first studying

uncomplicated disease, then right sided, then left sided disease? uncomplicated disease, then right sided, then left sided disease? Can this be reflected in labeling?Can this be reflected in labeling?

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Clinical Development ProgramClinical Development Program April 2004 FDA/IDSA/ISAP workshop began preliminary April 2004 FDA/IDSA/ISAP workshop began preliminary

discussions on this indication discussions on this indication

Participants expressed view that this is serious disease Participants expressed view that this is serious disease with potential for development of endocarditiswith potential for development of endocarditis

Given serious nature of disease, unlikely that data from Given serious nature of disease, unlikely that data from trials in this indication would be sole basis for approvaltrials in this indication would be sole basis for approval

Expressed view that there should be body of Expressed view that there should be body of information on potential drug efficacy in such a serious information on potential drug efficacy in such a serious disease disease

www.fda.gov/cder/drug/antimicrobial/FDA_IDSA_ISAP_Presentations.htmwww.fda.gov/cder/drug/antimicrobial/FDA_IDSA_ISAP_Presentations.htm

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Clinical Development ProgramClinical Development Program What kinds of What kinds of pre-clinicalpre-clinical studies would be helpful in forming studies would be helpful in forming

hypotheses about potential efficacy and safety in this hypotheses about potential efficacy and safety in this indication ?indication ?

In vitroIn vitro data data on biological activity against isolates of on biological activity against isolates of SS. . aureusaureus (e.g. (e.g. bacteriostatic vs. bactericidal?)bacteriostatic vs. bactericidal?) traditionally believed that bactericidal activity necessary in treatment of traditionally believed that bactericidal activity necessary in treatment of

endocarditisendocarditis Inconsistencies across organisms and methodsInconsistencies across organisms and methods Clinical significance? Should drugs bacteriostatic against S. aureus Clinical significance? Should drugs bacteriostatic against S. aureus

exclude patients with endocarditis from studies? At least initially (staged exclude patients with endocarditis from studies? At least initially (staged approach)?approach)? Pankey GA et al. Clin Infect Dis 2004:38:864-70Pankey GA et al. Clin Infect Dis 2004:38:864-70..

Animal modelsAnimal models of infection of infection Endocarditis? Endocarditis? Other potential metastatic sites of infection?Other potential metastatic sites of infection?

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Clinical Development ProgramClinical Development Program What clinical experience would be helpful in evaluating a new What clinical experience would be helpful in evaluating a new

drug for this indication?drug for this indication?

patients with no primary site found still have some occult source of patients with no primary site found still have some occult source of infectioninfection

serious nature of illness and potential differences in efficacy of drugs serious nature of illness and potential differences in efficacy of drugs based on primary site of infection would weigh against this indication based on primary site of infection would weigh against this indication as sole basis for approval of a new drugas sole basis for approval of a new drug

data from clinical trials of infections of sufficient severity where data from clinical trials of infections of sufficient severity where S. S. aureusaureus is a potential pathogen is a potential pathogen hospital-acquired pneumoniahospital-acquired pneumonia community-acquired pneumoniacommunity-acquired pneumonia complicated skin and skin structure infectionscomplicated skin and skin structure infections others?others?

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Clinical Trials ConsiderationsClinical Trials Considerations Clinical trials should provide information that is useful in Clinical trials should provide information that is useful in

clinical practiceclinical practice

However, clinical trials are not clinical practiceHowever, clinical trials are not clinical practice

Clinical trials are scientific experiments performed in human Clinical trials are scientific experiments performed in human beingsbeings scientific method = hold as many factors constant as possible other scientific method = hold as many factors constant as possible other

than drugs administered so as to ascribe causality of results to the than drugs administered so as to ascribe causality of results to the drugsdrugs

““The purpose of performing clinical investigations is to distinguish the The purpose of performing clinical investigations is to distinguish the effects of a drug from other influences, such as spontaneous change effects of a drug from other influences, such as spontaneous change in the course of the disease, placebo effect, or biased observation.”in the course of the disease, placebo effect, or biased observation.”

21 CFR 314.126 (a)21 CFR 314.126 (a)

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Clinical Trials - Potential BiasesClinical Trials - Potential Biases

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Populationwith Disease

Population in Study

Treatment Arms

Analysisand

Conclusions

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SelectionSelectionof Study of Study PopulationPopulation

RandomizationRandomizationand Blindingand Blinding

PotentialPotentialConfoundersConfoundersOn TherapyOn Therapy

EndpointsEndpointsAnalysisAnalysis

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Clinical Trials ConsiderationsClinical Trials ConsiderationsDefining Patient PopulationsDefining Patient Populations

Inclusion/ Exclusion Criteria used to define population Inclusion/ Exclusion Criteria used to define population under studyunder study

Balance between homogenous population so outcomes Balance between homogenous population so outcomes are not related to host rather than drug, yet heterogeneous are not related to host rather than drug, yet heterogeneous enough to extrapolate to clinically relevant populationenough to extrapolate to clinically relevant population

Need to differentiate among patients with “Gram-positive Need to differentiate among patients with “Gram-positive cocci” in blood cocci” in blood S. epidermidisS. epidermidis more common than more common than S. aureusS. aureus newer diagnostic tests may allow differentiation prior to enrollmentnewer diagnostic tests may allow differentiation prior to enrollment

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Clinical Trials ConsiderationsClinical Trials ConsiderationsDefining Patient PopulationsDefining Patient Populations

Considerations in studying this indicationConsiderations in studying this indication

different natural histories for various populations of different natural histories for various populations of patients in whom subsequent testing patients in whom subsequent testing after after randomizationrandomization shows a source/metastatic site of shows a source/metastatic site of infection (e.g. endocarditis)infection (e.g. endocarditis) different success ratesdifferent success rates different duration of therapydifferent duration of therapy

even patients with “uncomplicated” disease such as even patients with “uncomplicated” disease such as catheter-related disease may have subsequent catheter-related disease may have subsequent metastatic diseasemetastatic disease

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Clinical Trials ConsiderationsClinical Trials ConsiderationsDefining Patient PopulationsDefining Patient Populations

Complicated vs. uncomplicated diseaseComplicated vs. uncomplicated disease complicated = patients who develop further clinical complicated = patients who develop further clinical

manifestations not present at the time of diagnosis that portend a manifestations not present at the time of diagnosis that portend a worse prognosis and/or need for prolonged therapyworse prognosis and/or need for prolonged therapy severe sepsis, acute respiratory distress syndrome, DICsevere sepsis, acute respiratory distress syndrome, DIC metastatic sites of infection metastatic sites of infection

Community acquired vs. nosocomialCommunity acquired vs. nosocomial may refer to differing hosts (underlying diseases) as much as may refer to differing hosts (underlying diseases) as much as

different geography of acquisitiondifferent geography of acquisition may refer to differences in bacterial load, delay in diagnosis and may refer to differences in bacterial load, delay in diagnosis and

initiation of therapyinitiation of therapy may not be as useful a distinction in clinical trials or for labeling may not be as useful a distinction in clinical trials or for labeling

given significant overlap in populationsgiven significant overlap in populations

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Clinical Trials ConsiderationsClinical Trials ConsiderationsDefining Patient PopulationsDefining Patient Populations

Difficult to stratify at time of enrollment since Difficult to stratify at time of enrollment since metastatic infections may become clinically apparent metastatic infections may become clinically apparent at some time after enrollmentat some time after enrollment

How well do risk factors select patients with How well do risk factors select patients with “complicated” disease and those who may receive “complicated” disease and those who may receive “short-course” therapy? “short-course” therapy?

many of studies differentiating complicated from many of studies differentiating complicated from uncomplicated infection are retrospective or uncomplicated infection are retrospective or

other methodological issues such as treatment allocation biasother methodological issues such as treatment allocation bias Jernigan JA et al. Ann Intern Med 1993:119:304-311.Jernigan JA et al. Ann Intern Med 1993:119:304-311.

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Clinical Trials ConsiderationsClinical Trials ConsiderationsDefining Patient PopulationsDefining Patient Populations

How useful are these risk factors in clinical trials?How useful are these risk factors in clinical trials?

some risk factors (duration of fever and duration of some risk factors (duration of fever and duration of bacteremia) occur randomizationbacteremia) occur randomization

these risk factors based upon outcomes with known these risk factors based upon outcomes with known effective therapies but how would they perform with an effective therapies but how would they perform with an experimental drug?experimental drug?

duration of bacteremia and duration of fever may differ duration of bacteremia and duration of fever may differ between drugs i.e. patients treated with new drug may have between drugs i.e. patients treated with new drug may have longer duration of bacteremia/ fever yet still have similar longer duration of bacteremia/ fever yet still have similar clinicalclinical efficacy relative to the control drug efficacy relative to the control drug

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Clinical Trials ConsiderationsClinical Trials ConsiderationsDefining Patient PopulationsDefining Patient Populations

How should patients who develop a site of How should patients who develop a site of infection after randomization be handled?infection after randomization be handled?

Could patients with no signs and symptoms of primary Could patients with no signs and symptoms of primary site of infection at time of enrollment be left in trial site of infection at time of enrollment be left in trial when they develop a site of infection on therapy?when they develop a site of infection on therapy? example of candidemia trialsexample of candidemia trials

Patients would need standardized evaluation at time of Patients would need standardized evaluation at time of enrollment so that there are no potential differences enrollment so that there are no potential differences between arms of study between arms of study what tests would be appropriate? e.g. echocardiography what tests would be appropriate? e.g. echocardiography

to evaluate for endocarditisto evaluate for endocarditis

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Clinical Trials ConsiderationsClinical Trials ConsiderationsEndpointsEndpoints

Should patients who develop a site of infection on study Should patients who develop a site of infection on study be considered clinical failures of therapy?be considered clinical failures of therapy?

Should one differentiate “baseline” from “breakthrough” Should one differentiate “baseline” from “breakthrough” infections?infections? Some data indicate that metastatic disease decreases with institution Some data indicate that metastatic disease decreases with institution

of effective therapyof effective therapy Less effective drug could result in more metastatic diseaseLess effective drug could result in more metastatic disease

Clinical endpoints important in this diseaseClinical endpoints important in this disease given risk of metastatic disease, clinical outcomes would be most given risk of metastatic disease, clinical outcomes would be most

relevant primary endpointrelevant primary endpoint negative cultures alone/time to negative cultures did correlate with negative cultures alone/time to negative cultures did correlate with

clinical outcomes in previous trialsclinical outcomes in previous trials

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Clinical Trials ConsiderationsClinical Trials ConsiderationsDuration of TherapyDuration of Therapy

How should the duration of therapy in studies of this How should the duration of therapy in studies of this indication be determined?indication be determined?

Important to define duration of therapy for patients based on upon Important to define duration of therapy for patients based on upon characteristics of diseasecharacteristics of disease

duration based upon “investigator discretion” could introduce duration based upon “investigator discretion” could introduce potential biaspotential bias

significant variation in clinical practice in duration of therapy even significant variation in clinical practice in duration of therapy even for uncomplicated diseasefor uncomplicated disease

most straightforward design and analysis would be to define one most straightforward design and analysis would be to define one duration of therapy for all or could be based upon risk factors at duration of therapy for all or could be based upon risk factors at time of enrollmenttime of enrollment

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Clinical Trials ConsiderationsClinical Trials ConsiderationsSelection of Control DrugSelection of Control Drug

What would be appropriate control regimens for this What would be appropriate control regimens for this indication?indication?

Most straightforward analysis would be to specify one control Most straightforward analysis would be to specify one control regimen prior to initiation of trialregimen prior to initiation of trial

Selection of control regimen based upon investigator discretion may Selection of control regimen based upon investigator discretion may introduce potential biasintroduce potential bias

benefit of addition of aminoglycosides in cases of endocarditis benefit of addition of aminoglycosides in cases of endocarditis remains unclear but may increase adverse event profile in control armremains unclear but may increase adverse event profile in control arm

could have protocol defined switch from vancomycin to other could have protocol defined switch from vancomycin to other regimen (anti-staphylococcal penicillin) after determination of regimen (anti-staphylococcal penicillin) after determination of susceptibilities of organismssusceptibilities of organisms

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Clinical Trials ConsiderationsClinical Trials ConsiderationsStatistical ConsiderationsStatistical Considerations

What would be an acceptable loss of efficacy relative to What would be an acceptable loss of efficacy relative to control drugs for this indication?control drugs for this indication?

Trials in this indication would most likely be non-inferiority Trials in this indication would most likely be non-inferiority trialstrials

Selection of non-inferiority marginSelection of non-inferiority margin magnitude of benefit of antibacterials compared to no treatment in magnitude of benefit of antibacterials compared to no treatment in

pre-antibiotic era appears to be largepre-antibiotic era appears to be large Skinner D, Keefer C. Arch Intern Med 1941:68;851-75.Skinner D, Keefer C. Arch Intern Med 1941:68;851-75.

what would clinically acceptable loss of efficacy relative to control?what would clinically acceptable loss of efficacy relative to control?

larger non-inferiority margin translates into smaller sample size but larger non-inferiority margin translates into smaller sample size but potential for more uncertainty regarding resultspotential for more uncertainty regarding results

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Clinical Trials ConsiderationsClinical Trials ConsiderationsStatistical Considerations - Sample Size per Statistical Considerations - Sample Size per

ArmArm

1570

393

175

1507

377

168

1319

330

147

1005

252

112

566

142

63

0

200

400

600

800

1000

1200

1400

1600

Sa

mp

le S

ize

oe

r A

rm

50 60 70 80 90

Success Rate

5%10%15%

NI margin

*Based upon 80% power*Based upon 80% power

**

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Issues for DiscussionIssues for Discussion

Should patients with primary bacteremia due to Should patients with primary bacteremia due to S. aureusS. aureus constitute a separate indication? Do constitute a separate indication? Do these patients constitute a clinically relevant these patients constitute a clinically relevant group of patients that can be described in product group of patients that can be described in product labeling?labeling?

Does efficacy in PBSA imply efficacy in Does efficacy in PBSA imply efficacy in endocarditis? Can drugs be studied endocarditis? Can drugs be studied without examining efficacy in without examining efficacy in endocarditis, or in a “staged” with endocarditis, or in a “staged” with appropriate labeling?appropriate labeling?

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Issues for DiscussionIssues for Discussion What pre-clinical information and information from other What pre-clinical information and information from other

clinical trials would be helpful in evaluating drugs that clinical trials would be helpful in evaluating drugs that may be appropriate for study in this indication?may be appropriate for study in this indication?

What evaluation should patients have prior to What evaluation should patients have prior to enrollment or shortly thereafter to rule out a enrollment or shortly thereafter to rule out a known focus of infection?known focus of infection?

How should patients who develop a site of How should patients who develop a site of infection after randomization be handled? infection after randomization be handled? Should they be left on study drug? Should they Should they be left on study drug? Should they be considered failures of study medication?be considered failures of study medication?

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Issues for DiscussionIssues for Discussion

How should the duration of therapy in How should the duration of therapy in studies of this indication be designated?studies of this indication be designated?

What would be appropriate control What would be appropriate control regimens for this indication?regimens for this indication?

What would be an acceptable loss of What would be an acceptable loss of efficacy relative to control drugs, efficacy relative to control drugs, balancing the certainty of results with balancing the certainty of results with the practicality of sample size?the practicality of sample size?