Clinical Trial Design in Acute Bacterial Sinusitis Considerations for Future Guidance

1. Clinical Trial Design in Acute Bacterial SinusitisConsiderations for Future Guidance John H. Powers, MD Lead Medical Officer Antimicrobial Drug Development and Resistance Initiatives Office of Drug Evaluation IV Center for Drug Evaluation and Research U.S. Food and Drug Administration

2. Introduction • Re-addressing 1998 Guidance • Defining the research question in ABS trials • Considerations in clinical trials of ABS • Defining the disease and Patient population • Types of studies • Endpoints and Evaluation • Proposals for future guidance

3. Re-addressing previous Guidance • Discussions at previous AIDAC and workshops and international meetings on selection of non-inferiority (NI) margins in clinical trials • February 2002 • November 2002 • ICH-E10 document • Lack of adequate selection of NI margin means cannot ensure adequacy of any drug over placebo in setting of NI trial • ICH-E10 suggests other study designs if NI margin unknown

4. Re-addressing previous Guidance • Agreement to examine previous placebo-controlled trials (PCTs) in each disease state to select appropriate margin • review all pertinent studies not just those which show benefit • Review of PCTs in acute bacterial sinusitis • Assessment of 14 PCTs in ABS in literature showed several issues with selection of margin

5. Re-addressing previous Guidance • Prior PCTs provide clues that antimicrobials may be effective in shortening duration of symptoms in ABS • Accurate assessment of magnitude of benefit of antimicrobials in ABS remains unknown • Need to discuss other study designs • Other issues with ABS trials became apparent as part of review

6. Research Question • What are we trying to measure? • “true” benefit of antimicrobials as sole therapy in bacterial disease OR • added benefit of antimicrobials above and beyond effect of standard non-antimicrobial therapies in patients with bacterial disease • no need for antimicrobials if decongestants, saline and anti-inflammatory agents are effective alone • other therapies do not result in antimicrobial resistance • ABS fifth most common reason for prescribing antimicrobials in ambulatory setting • McCaig L et al. JAMA 1995;273:214-9.

7. Defining the Disease • Antibacterials would logically have greatest effect in patients with bacterial disease • recent FDA labeling rule • Others have hypothesized “no proof” that antibacterials have no effect in viral disease • previous PCTs would seem to contradict this • use anti-inflammatory drugs if anti-inflammatory effects of antimicrobials predominate give issue of resistance • use in non-bacterial disease would seem to contradict current appropriate use guidelines

8. Defining the Disease • Effects of inclusion of patients likely to recover spontaneously • in NI trial, biases conclusion toward non-inferiority when there may be true differences between drugs • in PCT, biases conclusion toward no difference from placebo when there may be important differences • inclusion of higher proportions of patients with spontaneously resolving disease will result in less measured treatment effect of antimicrobials • may explain results of many of previous PCTs

9. Defining the Disease • Review of literature on correlation of clinical signs and symptoms or radiography and sinus puncture • more rigorous criteria seem to select for higher proportion of patients with bacterial disease • most rigorous criteria still would allow inclusion of 20% to 40% of patients without bacterial disease • no adequately-sized prospective, reproduced studies to allow adequate selection criteria • 7 days of symptoms in clinical practice but evaluation in clinical trial may be different • antibacterials may exert greatest effect early in disease

10. Defining the Disease • Sinus puncture remains gold standard • procedure considered unpalatable by many • newer procedures may obviate some of this discomfort and similar in performance to sinus endoscopy (through nose instead of oral approach) • lack of accuracy with sinus endoscopy especially for certain organisms e.g. Staphylococcus aureus • previous studies on nasopharyngeal and throat cultures show high level of discordance • Wald E et al. Pediatrics 1986; 77:795-800. • middle meatus not normally sterile site • Klossek JM et al. J Laryngol Otol 1996;110:847-9.

11. Defining Disease • Sinus puncture may be therapeutic by itself • drainage of closed space infection • Effect would be evenly distributed across arms of a trial • Effect of puncture should be small relative to effect of antimicrobials • otherwise one could question benefit of antimicrobials in this setting • Antimicrobials should address residual inflammation caused by tissue invasion of pathogens

12. Defining Disease • Sinus punctures are not done in clinical practice • Prior PCTs with clinical entry criteria show minimal if any benefit for antimicrobials in ABS • Clinical trials versus clinical practice • many procedures done in setting of clinical trial that are not done in clinical practice • drug efficacy trial versus “strategy” trial • FDA mission is to approve effective drugs for disease under study • Two reasons why “strategy” trial may fail to show a difference • drug is not effective in disease under study • strategy for selecting patients is not specific

13. Defining Disease and Sample Size • Clinical enrollment criteria requires very large sample size or very large treatment effect to show a difference between drug and placebo • Example: • assume 35% of patients in trial have bacterial disease • assume cure rate in viral disease is 80% in both arms and cure rate with bacterial disease is 80% with antibacterial agent and 65% in placebo THEN • Cure rate with clinical enrollment criteria 80% vs. 75% with sample size of >2900 patients • Cure rate with sinus puncture defined disease 80% vs. 65% with sample size of 370 patients

14. Types of Trials • Current guidance (two studies) • Microbiological based non-comparative trial with “presumed eradication” based on clinical outcome (“micro” study) • Clinical based NI study with clinical inclusion and outcome criteria (“clinical only” study)

15. Types of Trials • Issues with previous Guidance studies • “Micro” study • presumes correlation of microbiological and clinical outcome that has never been shown in ABS • examples of other diseases with less than optimal correlation with micro and clinical outcomes (e.g AOM) • Johann-Liang R et al. Pediatr Infect Dis J 2003;22:936-7. • Pre and post therapy microbiological data very helpful in ascertaining contribution of drug to treatment effect • less helpful when used as sole measure of efficacy • “Clinical only” NI study • may include significant proportion of patients with non-bacterial disease • timing of measurement of endpoints may not be optimal • selecting NI margin in NI trials

16. Prior Placebo Controlled Trials • Medline search for PCTs plus references of relevant trials • Evaluated 14 PCTs from medical literature • Varying quality of studies • blinding in • randomization • sinus puncture with culture in only two but analyzed patients with and without positive culture together in primary anaylsis • numbers of patients with positive cultures small • Wide variations in methods precludes meta-analysis

17. Prior Placebo Controlled Trials • Widely varying methods of assessment of outcomes (patients versus sinuses) • clinician’s assessment of symptomatic cure • non-validated scoring systems for symptomatic cure • radiological scoring systems • “ostial patency” by pressure measurements • changes in nasal cytology • Timing of assessment of cure varies widely • various fixed time points from days to weeks after EOT • time to resolution of symptoms • two used Kaplan-Meier curve but differing measures of outcome (one used pain only and other used non-validated symptom scale) • several used “modified” time analysis of early fixed time points

18. 70 50 30 10 -10 -30 -50 -70 1 14 2 11 3 4 10 7 5 12 6 8 9 16 13 15 Antimicrobial Efficacy ( 95% CI) Study

19. Prior Placebo Controlled Trials • Only two show benefit over placebo defined as lower bound of 95% CI above zero • Two with sinus puncture data • one shows much better outcome in subgroup with bacterial disease (+25% vs. +3%) • other trial shows worse outcome in subset with bacterial disease ( -12.0% vs. +2.3%) • both subsets with small numbers of patients • Point estimates in majority of studies show small benefit, on the order of approximately 4%

20. Types of Trials • ICH-E10 suggests choosing trial design other than NI trial if NI margin unknown • cannot ensure benefit of any drug over placebo • cannot scientifically justify picking margin without data • Other types of trial designs • dose-response trial • “placebo” controlled trial • more accurate to refer to as superiority trial vs. “other symptomatic therapies” • give other appropriate medications other than antimicrobials for symptom relief

21. Types of Trials • Antimicrobials plus other symptomatic therapies vs. other symptomatic therapies • no issue of selection of appropriate NI margin in superiority trial • trial has own internal validity since direct comparison rather than indirect comparison with no antimicrobial therapy • PCTs suggested by independent reviews • “Given the small number of trials with heterogeneous results, additional placebo-controlled trials are needed to evaluate the efficacy of antibiotics.” • Williams JW Jr et al. Cochrane Database Syst Rev. 2003;(2):CD000243

22. Types of Trials • Ethical consideration given rare but serious adverse events associated with ABS • Balances risk of adverse outcomes of ABS with risks of adverse outcome with antimicrobials • serious adverse events e.g. anaphylaxis • spread of antimicrobial resistance • No data on antimicrobials decreasing risk of complications • would require very large sample size given rare events • complications may be due to altered anatomy or host factors

23. Types of Trials • Other infectious diseases with higher mortality and complications studied as PCTs • new influenza drugs studied as PCTs despite availability of older drugs • mortality of influenza in outbreak setting ranges from 10 to 600 per 100,000 persons in healthy and chronically ill respectively • Barker WH et al Arch Intern Med 1982;142:85. • Selection of exclusion criteria to minimize risk

24. Types of Trials • Exclusion criteria to minimize risk • exclude frontal and sphenoidal disease • ? exclude patients with certain organisms • brain abscess associated with microaerophilic streptococci (S. anginosus group) in 70% • S. pneumoniae and H. influenzae in <1% • Chun CH et al Medicine 1986;65:415-31 • Kao PT et al. J Microbiol Immunol Infect 2003;36:129-36. • excluding “severe” disease • but has several associated issues

25. Types of Trials • “Severe” disease • severity defined as clinical characteristics predicting worse outcome (regardless of therapy) e.g PORT criteria for community- acquired pneumonia • Fine MJ et al N Engl J Med 1997;336:243-50. • no criteria exist for ABS • criteria used in previous trials (fever) may select for bacterial disease • patients with facial swelling may have periorbital cellulitis which may be considered a separate disease • patients with “severe” disease may be most likely to benefit from antimicrobials

26. Trial Design and Sample Size • Moreconservativeassumptions: • Non-inferiority (D=.05): 2700 • Placebo w/ 10 Day Endpoint (.80 v. .70): 780 • Placebo with time-to-resolution: 520 • More aggressive assumptions: • Non-inferiority (D=.10): 670 • Placebo w/ 10 Day Endpoint (.80 v. .65): 370 • Placebo with time-to-resolution: 250 • Current sample sizes of ABS databases from NDAs • 680 patients/drug in “clinical only” trials (range 142 to 1965) • 580 patients/drug in “micro” trials (range 192 to 1103)

27. Types of Trials • Implications for pharmaceutical industry • current trial design affords low risk of failure as difficult to distinguish any drug from placebo • ABS is large market and proof that ABS does not need treatment in some portion of patients would decrease market size • opportunity for smaller trials and more streamlined development program • use of supportive data from CAP trials allows opportunity for one rigorous ABS trial • less data but higher quality data

28. Endpoints and Timing • Most appropriate measurement would examine resolution of signs and symptoms of disease • several PCTs evaluated time to return to normal daily activities which may be patient dependent • radiographic scores not validated and not correlated with clinical signs and symptoms • correlation with microbiolgical endpoints and clinical outcomes not demonstrated to date • Time to resolution of disease may be most appropriate in self-resolving diseases • influenza and traveler’s diarrhea trials

29. Endpoints and Timing Nicholson KG et al. Lancet 2000;355:1845-1850.

30. Proposal for Future Guidance 1) Define population with bacterial disease by sinus puncture • would not necessarily require 7 days of symptoms • perhaps improve selection criteria for clinical practice 2) Superiority trial design of symptomatic therapy vs. symptomatic therapy plus antimicrobial • discussion of appropriate exclusion criteria • role of antimicrobial resistance 3) Endpoint of time to resolution of symptoms • similar to previous trials of influenza • requires validation of patient diaries