John H. Powers, MD FACP FIDSA

1. Issues with Effectiveness, Resistance and Ethics in Antimicrobial Clinical TrialsHow We Can Do Better John H. Powers, MD FACP FIDSA Former Lead Medical Officer for Antimicrobial Drug Development and Resistance Initiatives, FDA

2. Substantial Evidence of Effectiveness • FDA’s own regulations call for substantial evidence of effectiveness based on adequate and well-controlled trials • Substantial evidence not based on opinions of clinicians, use in clinical practice, or marketing success • Standards not meant to be applied prospectively only • “Totality of the evidence” has unclear meaning and is not the standard of substantial evidence

3. Resp Med 2002;96(11):862-71. • Noninferiority trials do not show that two drugs are “equivalent” or “as effective as” each other • Noninferiority trials designed to rule out how much less effective a new drug might be compared to an old drug • Need to first know whether the old drug is better than placebo and by how much • These principles outlined in FDA guidance that applies to all therapeutic areas since 2000 ICH E-10 guidance publication

4. Not Just About the Margin • Enrolling patients who do not have the disease • Telithromycin vs cefuroxime axetil in ABS had 38.7% of total enrolled subjects in bacteriological per protocol analysis • Buchanan PP et al. Am J Rhinology 2003;17:369-77. • Applying margin from severe form of disease to less severe form of disease • Tunisian trial in intubated AECB patients does not apply to subjects enrolled in current NI trials • Nouira S et al. Lancet 2001;358:2020-25. • Evaluating patients at time point beyond spontaneous resolution of disease • Acute otitis media resolves in 3-4 days without treatment but endpoint placed at day 17-21 after initiation of therapy • Noninferiority trials limit ability to evaluate novel trial designs since they must keep constant the study design of the placebo controlled trials upon which they are based

5. Noninferiority Trials • Noninferiority trials are appropriate in serious and life-threatening diseases where benefit of antimicrobials on decreasing mortality is reliable, reproducible and large • Noninferiority trials do not provide evidence of effectiveness in self-resolving respiratory tract diseases • 12 of 17 placebo controlled trials in ABS fail to show benefit of antimicrobials • 9 of 14 placebo controlled trials in AECB fail to show benefit of antimicrobials • Published meta-analyses have methodological issues and are not appropriate basis for noninferiority trials • Do not evaluate all the available trials (Saint meta-analysis in AECB does not include 5 of 14 (36%) of PCTs) • Pool data across trials with very different designs • Evaluate subgroups of patients from placebo controlled trials

8. Analysis of Efficacy in Placebo Controlled Trials in Acute Bacterial Sinusitis Study 3002 Study 3005 Study 3011 Kristo et al. 2005 n=82 cefuroxime d14 Norrelund et al. 1978 1978 n=135 pivampicillin d8 doxycycline d10 Stalman et al. 1997 n=186 amox or amoxicillin-clav d14 Garbutt et al. 2001 n=161 Lindbaek et al. 1998 n=70 amoxicillin or penicillin d10 Bucher et al. 2003 n=251 amoxicillin-clavulanate d14 Merenstein et al. 2005 n=135 amoxicillin d14 van Buchem et al. 1997 n=206 amoxicillin d14 deSutter et al. 2003 n=135 amoxicillin d10 Axelsson et al. 1970 n=142 pencillin or lincomycin d10 Varonen et al.2003 n=146 amox or doxy or penicillin d 14 Wald et al. 1986 n=93 b amoxicillin or amox-clav d10 a Kaiser et al. 2001 n=265a (77)b azithromycin d8 Hansen et al. 2000 n=127 penicillin d7 Haye et al. 1998 n=168 azithromycin d14 Lindbaek et al. 1996 n=127 amoxicillin or penicillin d10 Ganaca et al. 1973 n=50 0 50 40 30 20 10 30 40 50 10 20

9. Analysis of Placebo Controlled Trials in Acute Exacerbations of Chronic Bronchitis oxytetracycline no significant difference in time to resolution of symptoms p = 0.20 Elmes et al. 1957 n=88 no significant difference in time to resolution of symptoms p = 0.30 oxytetracycline d12 Fear et al. 1962 n=62 no significant difference in investigator clinical assessment of matched pairs ampicillin d7 Elmes et al. 1965 n= 56 tetracycline d7 no significant difference in mean change in Pa O2 between groups Nicotra et al. 1982 n=40 Study 3003 Study 3007 Study 3013 chloramphenicol d 10 Petersen et al 1967 n=19 Jorgensen et al. 1992 n=278 amoxicillin d8 Sachs et al. 1995 n=71 amoxicillin or TMP-SMX d14 oxytetracycline d14 Berry et al 1960 n=53 Manresa et al. 1987 n=19 (not randomized) cefaclor d8 Anthonisen et al. 1987a n = 116 (crossover) TMP-SMX or doxycycline d21 (first exacerbation only) Nouira et al. 2001 n=93 ofloxacin d30 penicillin +streptomycin d14 Pines et al. 1968 n=30 tetracycline or chloramphenicol d7 Pines et al.1972 n=259 amoxicillin-clavulanate d5 Allegra et al 1991 n=335 0 50 40 30 20 10 30 40 50 10 20

10. Labeling • INDICATIONS AND USAGE SECTION“If there is a common belief that the drug may be effective for a certain use or if there is a common use of the drug for a condition, but the preponderance of evidence related to the use or condition shows that the drug is ineffective or that the therapeutic benefits of the product do not generally outweigh its risks, FDA may require that this section state that there is a lack of evidence that the drug is effective or safe for that use or condition. • 21 CFR201.57 (c)(2)(ii)

11. Ethics • “Equipoise” is basic principle in clinical trials – patients should be enrolled in trials only if there is substantial uncertainty about which of the interventions would benefit the patients more • Declaration of Helsinki notes placebo controlled trials are ethical when: • Scientifically sound methodological issues to determine safety and efficacy of drug • Subjects not exposed to additional risks of serious harm • Patients in placebo groups may receive benefit of fewer drug related adverse events • Placebo controlled trials do not mean no treatment

12. Scientific Validity as Ethical Requirement • “It is well established that for research in human beings to be ethical it must be scientifically worthy…. An improperly designed study involving human subjects – one that could not possibly yield scientific facts relevant to the question under study is by definition unethical. A worthless study cannot possibly benefit anyone, least of all the subject himself. Any risk to the patient, no matter how small, cannot be justified. A study cannot become ethical by trading some deficiency in scientific worth for a superfluity of some other element.” Friedman B. IRB 1987;9(6):7-10. FIRST DO NO HARM

13. JAMA 2001;285(9):1206-8

15. Time to Move On • Need to improve on clinical trial design: • Placebo controlled trials to answer important basic questions about drug effectiveness in self-resolving • Pharmacodynamic analyses to choose most appropriate dose • Ensuring subjects in clinical trial have disease under study • Standardized, more accurate, more frequent measures using validated Patient Reported Outcomes instruments • Time to response as primary endpoint

16. Time to Resolution and Sample Size Sample Size Estimation

17. 68 NDA approvals 19 approvals for acute otitis media 20 approvals for acute bacterial sinusitis 29 approvals for acute exacerbations of chronic bronchitis (*5 withdrawn due to adverse effects)