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

2

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

3

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.

4

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

5

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

6

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

10

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)

11

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

12

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

14

15

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

16

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

17

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