Issues with Effectiveness, Issues with Effectiveness, Resistance and Ethics in Resistance and Ethics in
Antimicrobial Clinical TrialsAntimicrobial Clinical Trials
How We Can Do BetterHow We Can Do BetterJohn H. Powers, MD FACP FIDSAJohn H. Powers, MD FACP FIDSA
Former Lead Medical Officer for Antimicrobial Drug Former Lead Medical Officer for Antimicrobial Drug Development and Resistance Initiatives, FDADevelopment and Resistance Initiatives, FDA
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Substantial Evidence of EffectivenessSubstantial Evidence of Effectiveness
FDA’s own regulations call for substantial FDA’s own regulations call for substantial evidence of effectiveness based on adequate evidence of effectiveness based on adequate and well-controlled trialsand well-controlled trials
Substantial evidence not based on opinions of Substantial evidence not based on opinions of clinicians, use in clinical practice, or marketing clinicians, use in clinical practice, or marketing successsuccess
Standards Standards not meant to be applied prospectively not meant to be applied prospectively onlyonly
““Totality of the evidence” has unclear meaning Totality of the evidence” has unclear meaning and is not the standard of substantial evidenceand is not the standard of substantial evidence
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Noninferiority trials do not show that two drugs are Noninferiority trials do not show that two drugs are “equivalent” or “as effective as” each other“equivalent” or “as effective as” each other
Noninferiority trials designed to rule out how much less Noninferiority trials designed to rule out how much less effective a new drug might be compared to an old drugeffective a new drug might be compared to an old drug
Need to first know whether the old drug is better than Need to first know whether the old drug is better than placebo and by how muchplacebo and by how much
These principles outlined in FDA guidance that applies to These principles outlined in FDA guidance that applies to all therapeutic areas since 2000 ICH E-10 guidance all therapeutic areas since 2000 ICH E-10 guidance publicationpublication
Resp Med 2002;96(11):862-71.
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Not Just About the MarginNot Just About the Margin
Enrolling patients who do not have the diseaseEnrolling patients who do not have the disease Telithromycin vs cefuroxime axetil in ABS had 38.7% of total enrolled Telithromycin vs cefuroxime axetil in ABS had 38.7% of total enrolled
subjects in bacteriological per protocol analysissubjects in bacteriological per protocol analysis Buchanan PP et al. Am J Rhinology 2003;17:369-77.Buchanan PP et al. Am J Rhinology 2003;17:369-77.
Applying margin from severe form of disease to less severe form Applying margin from severe form of disease to less severe form of diseaseof disease Tunisian trial in intubated AECB patients does not apply to subjects Tunisian trial in intubated AECB patients does not apply to subjects
enrolled in current NI trialsenrolled in current NI trials Nouira S et al. Lancet 2001;358:2020-25.Nouira S et al. Lancet 2001;358:2020-25.
Evaluating patients at time point beyond spontaneous resolution Evaluating patients at time point beyond spontaneous resolution of diseaseof disease Acute otitis media resolves in 3-4 days without treatment but Acute otitis media resolves in 3-4 days without treatment but
endpoint placed at day 17-21 after initiation of therapyendpoint placed at day 17-21 after initiation of therapy
Noninferiority trials limit ability to evaluate novel trial designs Noninferiority trials limit ability to evaluate novel trial designs since they must keep constant the study design of the placebo since they must keep constant the study design of the placebo controlled trials upon which they are basedcontrolled trials upon which they are based
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Noninferiority TrialsNoninferiority Trials
Noninferiority trials Noninferiority trials areare appropriate in serious and life- appropriate in serious and life-threatening diseases where benefit of antimicrobials on threatening diseases where benefit of antimicrobials on decreasing mortality is reliable, reproducible and largedecreasing mortality is reliable, reproducible and large
Noninferiority trials do not provide evidence of Noninferiority trials do not provide evidence of effectiveness in self-resolving respiratory tract diseaseseffectiveness in self-resolving respiratory tract diseases 12 of 17 placebo controlled trials in ABS fail to show benefit 12 of 17 placebo controlled trials in ABS fail to show benefit
of antimicrobialsof antimicrobials 9 of 14 placebo controlled trials in AECB fail to show benefit 9 of 14 placebo controlled trials in AECB fail to show benefit
of antimicrobialsof antimicrobials
Published meta-analyses have methodological issues and Published meta-analyses have methodological issues and are not appropriate basis for noninferiority trialsare not appropriate basis for noninferiority trials Do not evaluate all the available trials (Saint meta-analysis in Do not evaluate all the available trials (Saint meta-analysis in
AECB does not include 5 of 14 (36%) of PCTs)AECB does not include 5 of 14 (36%) of PCTs) Pool data across trials with very different designsPool data across trials with very different designs Evaluate subgroups of patients from placebo controlled trialsEvaluate subgroups of patients from placebo controlled trials
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7
8504030201001020304050
Ganaca et al. 1973 n=50
Lindbaek et al. 1996 n=127
Haye et al. 1998 n=168
Hansen et al. 2000 n=127
Wald et al. 1986 n=93
Varonen et al. 2003 n=146
van Buchem et al. 1997 n=206
deSutter et al. 2003 n=135Axelsson et al. 1970 n=142
Norrelund et al. 1978 1978 n=135
Kaiser et al. 2001 n=265a (77)b
Bucher et al. 2003 n=251
Garbutt et al. 2001 n=161
Stalman et al. 1997 n=186
Analysis of Efficacy in Placebo Controlled Trials in Acute Bacterial Sinusitis
Kristo et al. 2005 n=82
Lindbaek et al. 1998 n=70 Merenstein et al. 2005 n=135
aabb
Study 3011Study 3011Study 3005Study 3005Study 3002Study 3002
cefuroxime d14cefuroxime d14
amox or amoxicillin-clav d14amox or amoxicillin-clav d14
azithromycin d8azithromycin d8
pivampicillin d8pivampicillin d8
pencillin or lincomycin d10pencillin or lincomycin d10
amoxicillin d14amoxicillin d14
amoxicillin d14amoxicillin d14
amox or doxy or penicillin d 14amox or doxy or penicillin d 14
amoxicillin or amox-clav d10amoxicillin or amox-clav d10
penicillin d7penicillin d7
azithromycin d14azithromycin d14
amoxicillin or penicillin d10amoxicillin or penicillin d10
amoxicillin or penicillin d10amoxicillin or penicillin d10
amoxicillin d10amoxicillin d10
doxycycline d10doxycycline d10
amoxicillin-clavulanate d14amoxicillin-clavulanate d14
9504030201001020304050
Analysis of Placebo Controlled Trials in Acute Exacerbations of Chronic Bronchitis
Elmes et al. 1957 n=88 no significant difference in time to resolution of symptoms p = 0.20no significant difference in time to resolution of symptoms p = 0.20 oxytetracyclineoxytetracycline
Fear et al. 1962 n=62 no significant difference in time to resolution of symptoms p = 0.30no significant difference in time to resolution of symptoms p = 0.30 oxytetracycline d12oxytetracycline d12
Elmes et al. 1965 n= 56 no significant difference in investigator clinical assessment of matched pairsno significant difference in investigator clinical assessment of matched pairs ampicillin d7ampicillin d7
Petersen et al 1967 n=19 chloramphenicol d 10chloramphenicol d 10
Pines et al. 1968 n=30 penicillin +streptomycin d14penicillin +streptomycin d14
Pines et al.1972 n=259tetracycline or chloramphenicol d7tetracycline or chloramphenicol d7
Nicotra et al. 1982 n=40 no significant difference in mean change in Pa O2 between groupsno significant difference in mean change in Pa O2 between groups tetracycline d7tetracycline d7
(first exacerbation only)
Anthonisen et al. 1987a n = 116 (crossover)TMP-SMX or doxycycline d21TMP-SMX or doxycycline d21
Manresa et al. 1987 n=19 (not randomized) cefaclor d8cefaclor d8
Berry et al 1960 n=53 oxytetracycline d14oxytetracycline d14
Allegra et al 1991 n=335amoxicillin-clavulanate d5amoxicillin-clavulanate d5
Jorgensen et al. 1992 n=278 amoxicillin d8amoxicillin d8
Sachs et al. 1995 n=71 amoxicillin or TMP-SMX d14amoxicillin or TMP-SMX d14
Nouira et al. 2001 n=93 ofloxacin d30ofloxacin d30
Study 3003Study 3003Study 3007Study 3007Study 3013Study 3013
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LabelingLabeling
INDICATIONS AND USAGE SECTIONINDICATIONS AND USAGE SECTION“If there is a common belief that the drug may be “If there is a common belief that the drug may be effective for a certain use or if there is a effective for a certain use or if there is a common use of the drug for a condition, but the common use of the drug for a condition, but the preponderance of evidence related to the use or preponderance of evidence related to the use or condition shows that the drug is ineffective or condition shows that the drug is ineffective or that the therapeutic benefits of the product do that the therapeutic benefits of the product do not generally outweigh its risks, FDA may not generally outweigh its risks, FDA may require that this section require that this section state that there is a lack state that there is a lack of evidence that the drug is effective or safeof evidence that the drug is effective or safe for for that use or condition.that use or condition.
21 CFR21 CFR 201.57 (c)(2)(ii)201.57 (c)(2)(ii)
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EthicsEthics ““Equipoise” is basic principle in clinical trials – patients Equipoise” is basic principle in clinical trials – patients
should be enrolled in trials only if there is substantial should be enrolled in trials only if there is substantial uncertainty about which of the interventions would uncertainty about which of the interventions would benefit the patients morebenefit the patients more
Declaration of Helsinki notes placebo controlled trials are Declaration of Helsinki notes placebo controlled trials are ethical when:ethical when: Scientifically sound methodological issues to determine Scientifically sound methodological issues to determine
safety and efficacy of drugsafety and efficacy of drug Subjects not exposed to additional risks of serious harmSubjects not exposed to additional risks of serious harm
Patients in placebo groups may receive benefit of fewer Patients in placebo groups may receive benefit of fewer drug related adverse eventsdrug related adverse events
Placebo controlled trials do not mean no treatmentPlacebo controlled trials do not mean no treatment
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Scientific Validity as Ethical RequirementScientific Validity as Ethical Requirement ““It is well established that for research in human It is well established that for research in human
beings to be ethical it beings to be ethical it must be scientifically must be scientifically worthyworthy…. An improperly designed study …. An improperly designed study involving human subjects – one that could not involving human subjects – one that could not possibly yield scientific facts relevant to the possibly yield scientific facts relevant to the question under study is by definition unethical. question under study is by definition unethical. A worthless study cannot possibly benefit A worthless study cannot possibly benefit anyone, least of all the subject himself. anyone, least of all the subject himself. Any risk Any risk to the patient, no matter how small, cannot be to the patient, no matter how small, cannot be justified.justified. A study cannot become ethical by A study cannot become ethical by trading some deficiency in scientific worth for a trading some deficiency in scientific worth for a superfluity of some other element.”superfluity of some other element.”
Friedman B. IRB 1987;9(6):7-10.Friedman B. IRB 1987;9(6):7-10.
FIRST DO NO HARMFIRST DO NO HARM
13JAMA 2001;285(9):1206-8JAMA 2001;285(9):1206-8
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Time to Move OnTime to Move On
Need to improve on clinical trial design:Need to improve on clinical trial design:
Placebo controlled trials to answer important basic questions about Placebo controlled trials to answer important basic questions about drug effectiveness in self-resolvingdrug effectiveness in self-resolving
Pharmacodynamic analyses to choose most appropriate dose Pharmacodynamic analyses to choose most appropriate dose
Ensuring subjects in clinical trial have disease under studyEnsuring subjects in clinical trial have disease under study
Standardized, more accurate, more frequent measures using Standardized, more accurate, more frequent measures using validated Patient Reported Outcomes instrumentsvalidated Patient Reported Outcomes instruments
Time to response as primary endpointTime to response as primary endpoint
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Time to Resolution and Sample SizeTime to Resolution and Sample SizeSample Size Estimation
Median Time to Resolution for Active agent
4 5 6 7 8 9
Median Time to Resolution forPlacebo
5 407
6 131 662
7 74 207 1029
8 51 112 307 1458
9 40 75 161 426 1984
10 33 57 106 222 583 2742
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19 approvals 19 approvals for acute otitis mediafor acute otitis media
20 approvals 20 approvals for acute bacterial sinusitisfor acute bacterial sinusitis
29 approvals 29 approvals for acute exacerbationsfor acute exacerbationsof chronic bronchitisof chronic bronchitis
(*5 withdrawn due to (*5 withdrawn due to adverse effects)adverse effects)
Acute Otitis Media Acute Bacterial Sinusitis Acute Exacerbations of Chronic Bronchitis
cephalexin (Keflex) cefuroxime axetil (Ceftin) cefuroxime axetil (Ceftin) cefuroxime axetil (Ceftin) cefprozil (Cefzil) cefprozil (Cefzil) cefaclor (Ceclor) cefpodoxime (Vantin) cefpodoxime (Vantin) cefprozil (Cefzil) loracarbef (Lorabid) loracarbef (Lorabid) cefpodoxime (Vantin) cefdinir (Omnicef) cefditoren (Spectracef) loracarbef (Lorabid) moxifloxacin (Avelox) cefdinir (Omnicef) ceftriaxone (Rocephin) clarithromycin (Biaxin) cefixime (Suprax) cefixime (Suprax) clarithromycin (Biaxin XL) ceftibuten (Cedax) ceftibutin (Cedax) telithromycin (Ketek) moxifloxacin (Avelox) penicillin G Benzathine/ PenG Procaine (Bicillin)
levofloxacin (Levaquin) 500 mg q day for 10 days
clarithromycin (Biaxin)
Augmentin (amoxicillin-clavulanate)
levofloxacin (Levaquin) 750 mg mg q day for 5 days
clarithromycin (Biaxin XL)
Augmentin ES (amoxicillin-clavulanate
gatifloxacin (Tequin) gemifloxacin (Factive)
erythromycin ethylsuccinate/ sulfisoxazole acetyl (Pediazole)
Augmentin (amoxicillin-clavulanate) ofloxacin (Floxin)
trimethoprim -sulfamethoxazole (Septra and Bactrim)
Augmentin XR (amoxicillin-clavulanate) telithromycin (Ketek)
amoxicillin (Amoxil)* ciprofloxacin (Cipro) levofloxacin (Levaquin) clarithromycin (Biaxin) trovafloxacin (Trovan)* gatifloxacin (Tequin)* cefdinir (Omnicef) azithomycin extended release (Zmax) azithromycin (Zithromax) azithromycin (Zithromax) amoxicillin (Amoxil)* grepafloxacin (Raxar)* cephradine (Velosef) doxycycline (Vibra-Tabs)! sparfloxacin (Zagam)* tetracycline (Achromycin) cefaclor (Ceclor) trovafloxacin (Trovan)* dirithromycin (Dynabac) lomefloxacin (Maxaquin) ciprofloxacin (Cipro) trimethoprim -sulfamethoxazole
(Septra and Bactrim) tetracycline (Achromycin)** doxycycline (Vibra-Tabs)! amoxicillin (Amoxil)* temafloxacin (Omniflox)*
68 NDA approvals68 NDA approvals