Clinical Trial Design in Clinical Trial Design in Acute Bacterial SinusitisAcute Bacterial SinusitisConsiderations for Future Considerations for Future

GuidanceGuidance

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

Re-addressing 1998 GuidanceRe-addressing 1998 Guidance

Defining the research question in ABS trialsDefining the research question in ABS trials

Considerations in clinical trials of ABSConsiderations in clinical trials of ABS Defining the disease and Patient populationDefining the disease and Patient population Types of studiesTypes of studies Endpoints and EvaluationEndpoints and Evaluation

Proposals for future guidanceProposals for future guidance

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Re-addressing previous Re-addressing previous GuidanceGuidance

Discussions at previous AIDAC and workshops Discussions at previous AIDAC and workshops and international meetings on selection of and international meetings on selection of non-inferiority (NI) margins in clinical trialsnon-inferiority (NI) margins in clinical trials February 2002February 2002 November 2002November 2002 ICH-E10 documentICH-E10 document

Lack of adequate selection of NI margin Lack of adequate selection of NI margin means cannot ensure adequacy of any drug means cannot ensure adequacy of any drug over placebo in setting of NI trialover placebo in setting of NI trial ICH-E10 suggests other study designs if NI margin ICH-E10 suggests other study designs if NI margin

unknownunknown

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Re-addressing previous Re-addressing previous GuidanceGuidance

Agreement to examine previous placebo-Agreement to examine previous placebo-controlled trials (PCTs) in each disease controlled trials (PCTs) in each disease state to select appropriate marginstate to select appropriate margin review all pertinent studies not just those which review all pertinent studies not just those which

show benefitshow benefit

Review of PCTs in acute bacterial sinusitisReview of PCTs in acute bacterial sinusitis Assessment of 14 PCTs in ABS in literature Assessment of 14 PCTs in ABS in literature

showed several issues with selection of marginshowed several issues with selection of margin

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Re-addressing previous Re-addressing previous GuidanceGuidance

Prior PCTs provide clues that antimicrobials Prior PCTs provide clues that antimicrobials may be effective in shortening duration of may be effective in shortening duration of symptoms in ABSsymptoms in ABS

Accurate assessment of magnitude of benefit Accurate assessment of magnitude of benefit of antimicrobials in ABS remains unknownof antimicrobials in ABS remains unknown

Need to discuss other study designsNeed to discuss other study designs

Other issues with ABS trials became Other issues with ABS trials became apparent as part of reviewapparent as part of review

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Research QuestionResearch Question

What are we trying to measure?What are we trying to measure? ““true” benefit of antimicrobials as sole therapy in true” benefit of antimicrobials as sole therapy in

bacterial diseasebacterial disease

OROR added benefitadded benefit of antimicrobials above and beyond of antimicrobials above and beyond

effect of standard non-antimicrobial therapies in effect of standard non-antimicrobial therapies in patients with bacterial diseasepatients with bacterial disease

no need for antimicrobials if decongestants, saline and no need for antimicrobials if decongestants, saline and anti-inflammatory agents are effective aloneanti-inflammatory agents are effective alone

other therapies do not result in antimicrobial resistanceother therapies do not result in antimicrobial resistance ABS fifth most common reason for prescribing ABS fifth most common reason for prescribing

antimicrobials in ambulatory settingantimicrobials in ambulatory setting McCaig L et al. JAMA 1995;273:214-9.McCaig L et al. JAMA 1995;273:214-9.

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Defining the DiseaseDefining the Disease Antibacterials would logically have greatest Antibacterials would logically have greatest

effect in patients with bacterial diseaseeffect in patients with bacterial disease recent FDA labeling rulerecent FDA labeling rule

Others have hypothesized “no proof” that Others have hypothesized “no proof” that antibacterials have no effect in viral diseaseantibacterials have no effect in viral disease previous PCTs would seem to contradict thisprevious PCTs would seem to contradict this use anti-inflammatory drugs if anti-inflammatory use anti-inflammatory drugs if anti-inflammatory

effects of antimicrobials predominate give issue of effects of antimicrobials predominate give issue of resistanceresistance

use in non-bacterial disease would seem to contradict use in non-bacterial disease would seem to contradict current appropriate use guidelinescurrent appropriate use guidelines

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Defining the DiseaseDefining the Disease

Effects of inclusion of patients likely to recover Effects of inclusion of patients likely to recover spontaneouslyspontaneously

in NI trial, biases conclusion toward non-inferiority in NI trial, biases conclusion toward non-inferiority when there may be true differences between drugswhen there may be true differences between drugs

in PCT, biases conclusion toward no difference from in PCT, biases conclusion toward no difference from placebo when there may be important differencesplacebo when there may be important differences inclusion of higher proportions of patients with inclusion of higher proportions of patients with

spontaneously resolving disease will result in less spontaneously resolving disease will result in less measured treatment effect of antimicrobialsmeasured treatment effect of antimicrobials

may explain results of many of previous PCTsmay explain results of many of previous PCTs

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Defining the DiseaseDefining the Disease Review of literature on correlation of clinical signs Review of literature on correlation of clinical signs

and symptoms or radiography and sinus punctureand symptoms or radiography and sinus puncture

more rigorous criteria seem to select for higher more rigorous criteria seem to select for higher proportion of patients with bacterial diseaseproportion of patients with bacterial disease

most rigorous criteria still would allow inclusion of 20% to most rigorous criteria still would allow inclusion of 20% to 40% of patients without bacterial disease40% of patients without bacterial disease

no adequately-sized prospective, reproduced studies to no adequately-sized prospective, reproduced studies to allow adequate selection criteriaallow adequate selection criteria

7 days of symptoms in clinical practice but evaluation in 7 days of symptoms in clinical practice but evaluation in clinical trial may be differentclinical trial may be different antibacterials may exert greatest effect early in diseaseantibacterials may exert greatest effect early in disease

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Defining the DiseaseDefining the Disease Sinus puncture remains gold standardSinus puncture remains gold standard

procedure considered unpalatable by manyprocedure considered unpalatable by many

newer procedures may obviate some of this newer procedures may obviate some of this discomfort and similar in performance to sinus discomfort and similar in performance to sinus endoscopy (through nose instead of oral approach)endoscopy (through nose instead of oral approach)

lack of accuracy with sinus endoscopy especially for lack of accuracy with sinus endoscopy especially for certain organisms e.g. certain organisms e.g. Staphylococcus aureusStaphylococcus aureus previous studies on nasopharyngeal and throat cultures previous studies on nasopharyngeal and throat cultures

show high level of discordanceshow high level of discordance Wald E et al. Pediatrics 1986; 77:795-800.Wald E et al. Pediatrics 1986; 77:795-800.

middle meatus not normally sterile sitemiddle meatus not normally sterile site Klossek JM et al. J Laryngol Otol 1996;110:847-9.Klossek JM et al. J Laryngol Otol 1996;110:847-9.

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Defining DiseaseDefining Disease Sinus puncture may be therapeutic by itselfSinus puncture may be therapeutic by itself

drainage of closed space infectiondrainage of closed space infection

Effect would be evenly distributed across arms of a Effect would be evenly distributed across arms of a trialtrial

Effect of puncture should be small relative to effect Effect of puncture should be small relative to effect of antimicrobialsof antimicrobials otherwise one could question benefit of antimicrobials in otherwise one could question benefit of antimicrobials in

this settingthis setting

Antimicrobials should address residual inflammation Antimicrobials should address residual inflammation caused by tissue invasion of pathogenscaused by tissue invasion of pathogens

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Defining DiseaseDefining Disease Sinus punctures are not done in clinical practiceSinus punctures are not done in clinical practice

Prior PCTs with clinical entry criteria show minimal if any Prior PCTs with clinical entry criteria show minimal if any benefit for antimicrobials in ABSbenefit for antimicrobials in ABS

Clinical trials versus clinical practiceClinical trials versus clinical practice many procedures done in setting of clinical trial that are not done many procedures done in setting of clinical trial that are not done

in clinical practicein clinical practice drug efficacy trial versus “strategy” trialdrug efficacy trial versus “strategy” trial

FDA mission is to approve FDA mission is to approve effectiveeffective drugs for disease under drugs for disease under studystudy

Two reasons why “strategy” trial may fail to show a Two reasons why “strategy” trial may fail to show a differencedifference drug is not effective in disease under studydrug is not effective in disease under study strategy for selecting patients is not specificstrategy for selecting patients is not specific

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Defining Disease and Sample Defining Disease and Sample SizeSize

Clinical enrollment criteria requires very large Clinical enrollment criteria requires very large sample size or very large treatment effect to show sample size or very large treatment effect to show a difference between drug and placeboa difference between drug and placebo

Example:Example: assume 35% of patients in trial have bacterial diseaseassume 35% of patients in trial have bacterial disease assume cure rate in viral disease is 80% in both arms and assume cure rate in viral disease is 80% in both arms and

cure rate with bacterial disease is 80% with antibacterial cure rate with bacterial disease is 80% with antibacterial agent and 65% in placeboagent and 65% in placebo

THENTHEN Cure rate with clinical enrollment criteria 80% vs. 75% Cure rate with clinical enrollment criteria 80% vs. 75%

with sample size of >2900 patientswith sample size of >2900 patients Cure rate with sinus puncture defined disease 80% vs. Cure rate with sinus puncture defined disease 80% vs.

65% with sample size of 370 patients65% with sample size of 370 patients

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Types of TrialsTypes of Trials

Current guidance (two studies)Current guidance (two studies)

Microbiological based non-comparative trial Microbiological based non-comparative trial with “presumed eradication” based on clinical with “presumed eradication” based on clinical outcome (“micro” study)outcome (“micro” study)

Clinical based NI study with clinical inclusion Clinical based NI study with clinical inclusion and outcome criteria (“clinical only” study)and outcome criteria (“clinical only” study)

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Types of TrialsTypes of Trials Issues with previous Guidance studiesIssues with previous Guidance studies

““Micro” study Micro” study presumes correlation of microbiological and clinical outcome that presumes correlation of microbiological and clinical outcome that

has never been shown in ABShas never been shown in ABS examples of other diseases with less than optimal correlation with examples of other diseases with less than optimal correlation with

micro and clinical outcomes (e.g AOM)micro and clinical outcomes (e.g AOM) Johann-Liang R et al. Pediatr Infect Dis J 2003;22:936-7.Johann-Liang R et al. Pediatr Infect Dis J 2003;22:936-7.

Pre and post therapy microbiological data very helpful in Pre and post therapy microbiological data very helpful in ascertaining contribution of drug to treatment effectascertaining contribution of drug to treatment effect

less helpful when used as less helpful when used as sole sole measure of efficacymeasure of efficacy

““Clinical only” NI studyClinical only” NI study may include significant proportion of patients with non-bacterial may include significant proportion of patients with non-bacterial

diseasedisease timing of measurement of endpoints may not be optimaltiming of measurement of endpoints may not be optimal selecting NI margin in NI trialsselecting NI margin in NI trials

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Prior Placebo Controlled TrialsPrior Placebo Controlled Trials Medline search for PCTs plus references of relevant Medline search for PCTs plus references of relevant

trialstrials

Evaluated 14 PCTs from medical literatureEvaluated 14 PCTs from medical literature

Varying quality of studiesVarying quality of studies blinding in blinding in randomization randomization sinus puncture sinus puncture with with culture in only two but analyzed culture in only two but analyzed

patients with and without positive culture together in patients with and without positive culture together in primary anaylsisprimary anaylsis numbers of patients with positive cultures smallnumbers of patients with positive cultures small

Wide variations in methods precludes meta-analysisWide variations in methods precludes meta-analysis

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Prior Placebo Controlled TrialsPrior Placebo Controlled Trials Widely varying methods of assessment of outcomes Widely varying methods of assessment of outcomes

(patients versus sinuses)(patients versus sinuses) clinician’s assessment of symptomatic cureclinician’s assessment of symptomatic cure non-validated scoring systems for symptomatic curenon-validated scoring systems for symptomatic cure radiological scoring systemsradiological scoring systems ““ostial patency” by pressure measurementsostial patency” by pressure measurements changes in nasal cytologychanges in nasal cytology

Timing of assessment of cure varies widelyTiming of assessment of cure varies widely various fixed time points from days to weeks after EOTvarious fixed time points from days to weeks after EOT time to resolution of symptomstime to resolution of symptoms

two used Kaplan-Meier curve but differing measures of outcome two used Kaplan-Meier curve but differing measures of outcome (one used pain only and other used non-validated symptom scale)(one used pain only and other used non-validated symptom scale)

several used “modified” time analysis of early fixed time pointsseveral used “modified” time analysis of early fixed time points

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Prior Placebo Controlled TrialsPrior Placebo Controlled Trials

Only two show benefit over placebo defined Only two show benefit over placebo defined as lower bound of 95% CI above zeroas lower bound of 95% CI above zero Two with sinus puncture data Two with sinus puncture data

one shows much better outcome in subgroup with one shows much better outcome in subgroup with bacterial disease (+25% vs. +3%)bacterial disease (+25% vs. +3%)

other trial shows worse outcome in subset with other trial shows worse outcome in subset with bacterial disease ( -12.0% vs. +2.3%)bacterial disease ( -12.0% vs. +2.3%)

both subsets with small numbers of patientsboth subsets with small numbers of patients

Point estimates in majority of studies show Point estimates in majority of studies show small benefit, on the order of small benefit, on the order of approximately 4%approximately 4%

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Types of TrialsTypes of Trials

ICH-E10 suggests choosing trial design other ICH-E10 suggests choosing trial design other than NI trial if NI margin unknownthan NI trial if NI margin unknown cannot ensure benefit of any drug over placebocannot ensure benefit of any drug over placebo cannot scientifically justify picking margin without cannot scientifically justify picking margin without

datadata

Other types of trial designsOther types of trial designs dose-response trialdose-response trial ““placebo” controlled trialplacebo” controlled trial

more accurate to refer to as superiority trial vs. “other more accurate to refer to as superiority trial vs. “other symptomatic therapies”symptomatic therapies”

give other appropriate medications other than give other appropriate medications other than antimicrobials for symptom reliefantimicrobials for symptom relief

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Types of TrialsTypes of Trials Antimicrobials plus other symptomatic therapies Antimicrobials plus other symptomatic therapies

vs. other symptomatic therapiesvs. other symptomatic therapies

no issue of selection of appropriate NI margin in no issue of selection of appropriate NI margin in superiority trialsuperiority trial

trial has own internal validity since direct comparison trial has own internal validity since direct comparison rather than indirect comparison with no antimicrobial rather than indirect comparison with no antimicrobial therapytherapy

PCTs suggested by independent reviewsPCTs suggested by independent reviews ““Given the small number of trials with heterogeneous results, Given the small number of trials with heterogeneous results,

additional placebo-controlled trials are needed to evaluate the additional placebo-controlled trials are needed to evaluate the efficacy of antibiotics.”efficacy of antibiotics.”

Williams JW Jr et al. Williams JW Jr et al. Cochrane Database Syst Rev. 2003;(2):CD000243

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Types of TrialsTypes of Trials Ethical consideration given rare but serious Ethical consideration given rare but serious

adverse events associated with ABSadverse events associated with ABS

Balances risk of adverse outcomes of ABS with Balances risk of adverse outcomes of ABS with risks of adverse outcome with antimicrobialsrisks of adverse outcome with antimicrobials serious adverse events e.g. anaphylaxisserious adverse events e.g. anaphylaxis spread of antimicrobial resistancespread of antimicrobial resistance

No data on antimicrobials decreasing risk of No data on antimicrobials decreasing risk of complicationscomplications would require very large sample size given rare eventswould require very large sample size given rare events complications may be due to altered anatomy or host complications may be due to altered anatomy or host

factors factors

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Types of TrialsTypes of Trials

Other infectious diseases with higher Other infectious diseases with higher mortality and complications studied as PCTsmortality and complications studied as PCTs

new influenza drugs studied as PCTs despite new influenza drugs studied as PCTs despite availability of older drugsavailability of older drugs

mortality of influenza in outbreak setting ranges mortality of influenza in outbreak setting ranges from 10 to 600 per 100,000 persons in healthy from 10 to 600 per 100,000 persons in healthy and chronically ill respectively and chronically ill respectively

Barker WH et al Arch Intern Med 1982;142:85.Barker WH et al Arch Intern Med 1982;142:85.

Selection of exclusion criteria to minimize riskSelection of exclusion criteria to minimize risk

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Types of TrialsTypes of Trials Exclusion criteria to minimize riskExclusion criteria to minimize risk

exclude frontal and sphenoidal diseaseexclude frontal and sphenoidal disease

? exclude patients with certain organisms? exclude patients with certain organisms brain abscess associated with microaerophilic streptococci brain abscess associated with microaerophilic streptococci

((S. anginosusS. anginosus group) in 70% group) in 70% S. pneumoniaeS. pneumoniae and and H. influenzaeH. influenzae in <1% in <1%

Chun CH et al Medicine 1986;65:415-31Chun CH et al Medicine 1986;65:415-31 Kao PT et al. J Microbiol Immunol Infect 2003;36:129-36.Kao PT et al. J Microbiol Immunol Infect 2003;36:129-36.

excluding “severe” diseaseexcluding “severe” disease but has several associated issuesbut has several associated issues

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Types of TrialsTypes of Trials ““Severe” diseaseSevere” disease

severity defined as clinical characteristics predicting worse severity defined as clinical characteristics predicting worse outcome (regardless of therapy) e.g PORT criteria for outcome (regardless of therapy) e.g PORT criteria for community- acquired pneumoniacommunity- acquired pneumonia

Fine MJ et al N Engl J Med 1997;336:243-50.Fine MJ et al N Engl J Med 1997;336:243-50. no criteria exist for ABSno criteria exist for ABS

criteria used in previous trials (fever) may select for criteria used in previous trials (fever) may select for bacterial diseasebacterial disease

patients with facial swelling may have periorbital cellulitis patients with facial swelling may have periorbital cellulitis which may be considered a separate diseasewhich may be considered a separate disease

patients with “severe” disease may be most likely to patients with “severe” disease may be most likely to benefit from antimicrobialsbenefit from antimicrobials

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Trial Design and Sample SizeTrial Design and Sample Size MoreMore conservativeconservative assumptions:assumptions:

Non-inferiority (Non-inferiority (=.05): =.05): 27002700 Placebo w/ 10 Day Endpoint (.80 v. .70): Placebo w/ 10 Day Endpoint (.80 v. .70): 780780 Placebo with time-to-resolution: Placebo with time-to-resolution: 520520

More More aggressiveaggressive assumptions: assumptions: Non-inferiority (Non-inferiority (=.10): =.10): 670670 Placebo w/ 10 Day Endpoint (.80 v. .65): Placebo w/ 10 Day Endpoint (.80 v. .65): 370370 Placebo with time-to-resolution: Placebo with time-to-resolution: 250250

Current sample sizes of ABS databases from NDAsCurrent sample sizes of ABS databases from NDAs 680 patients/drug in “clinical only” trials (range 142 to 680 patients/drug in “clinical only” trials (range 142 to

1965)1965) 580 patients/drug in “micro” trials (range 192 to 1103)580 patients/drug in “micro” trials (range 192 to 1103)

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Types of TrialsTypes of Trials Implications for pharmaceutical industryImplications for pharmaceutical industry

current trial design affords low risk of failure as current trial design affords low risk of failure as difficult to distinguish any drug from placebodifficult to distinguish any drug from placebo

ABS is large market and proof that ABS does not need ABS is large market and proof that ABS does not need treatment in some portion of patients would decrease treatment in some portion of patients would decrease market sizemarket size

opportunity for smaller trials and more streamlined opportunity for smaller trials and more streamlined development programdevelopment program use of supportive data from CAP trials allows opportunity use of supportive data from CAP trials allows opportunity

for one rigorous ABS trialfor one rigorous ABS trial less data but higher quality dataless data but higher quality data

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Endpoints and TimingEndpoints and Timing Most appropriate measurement would examine Most appropriate measurement would examine

resolution of signs and symptoms of diseaseresolution of signs and symptoms of disease

several PCTs evaluated time to return to normal daily several PCTs evaluated time to return to normal daily activities which may be patient dependentactivities which may be patient dependent

radiographic scores not validated and not correlated with radiographic scores not validated and not correlated with clinical signs and symptomsclinical signs and symptoms

correlation with microbiolgical endpoints and clinical correlation with microbiolgical endpoints and clinical outcomes not demonstrated to dateoutcomes not demonstrated to date

Time to resolution of disease may be most Time to resolution of disease may be most appropriate in self-resolving diseasesappropriate in self-resolving diseases influenza and traveler’s diarrhea trialsinfluenza and traveler’s diarrhea trials

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Endpoints and TimingEndpoints and Timing

Nicholson KG et al. Lancet 2000;355:1845-1850.Nicholson KG et al. Lancet 2000;355:1845-1850.

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Proposal for Future GuidanceProposal for Future Guidance

1) Define population with bacterial disease by sinus 1) Define population with bacterial disease by sinus puncturepuncture would not necessarily require 7 days of symptomswould not necessarily require 7 days of symptoms perhaps improve selection criteria for clinical practiceperhaps improve selection criteria for clinical practice

2) Superiority trial design of symptomatic therapy vs. 2) Superiority trial design of symptomatic therapy vs. symptomatic therapy plus antimicrobialsymptomatic therapy plus antimicrobial discussion of appropriate exclusion criteriadiscussion of appropriate exclusion criteria role of antimicrobial resistancerole of antimicrobial resistance

3) Endpoint of time to resolution of symptoms3) Endpoint of time to resolution of symptoms similar to previous trials of influenzasimilar to previous trials of influenza requires validation of patient diariesrequires validation of patient diaries

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