nosocomial pneumonia

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nosocomial pneumonia

  1. 1. Issues in Selection of Deltas in Non-Inferiority Trials : Acute Bacterial Meningitis and Hospital-Acquired Pneumonia dr shabeel pn www.hi-dentfinishingschool.blogspot.com
  2. 2. Introduction <ul><li>Clinical perspective on delta </li></ul><ul><ul><li>definition of delta and components </li></ul></ul><ul><ul><li>impact of deltas in clinical setting </li></ul></ul><ul><li>Delta 1 issues in acute bacterial meningitis and HAP </li></ul><ul><ul><li>data from pre-antibiotic and antibiotic eras </li></ul></ul><ul><ul><li>confounders in determining efficacy of control regimens </li></ul></ul><ul><li>Delta 2 issues with acute bacterial meningitis and HAP </li></ul><ul><ul><li>consequences of less effective therapy </li></ul></ul><ul><ul><li>practical issues in selecting delta </li></ul></ul>
  3. 3. Clinical Trials <ul><li>Purpose of clinical trials </li></ul><ul><ul><li>Distinguish effects of drug from other influences </li></ul></ul><ul><ul><ul><li>spontaneous change in course of disease </li></ul></ul></ul><ul><ul><ul><li>placebo effect </li></ul></ul></ul><ul><ul><ul><li>biased observations </li></ul></ul></ul><ul><ul><li>difficult for clinicians to make judgments on drug efficacy/safety outside of setting of clinical trial </li></ul></ul><ul><ul><ul><li>high spontaneous resolution rate in less serious diseases </li></ul></ul></ul><ul><ul><ul><li>confounding factors for lack of patient improvement in serious diseases </li></ul></ul></ul><ul><ul><ul><li>lack of direct comparison of safety of two drugs in similar patient population </li></ul></ul></ul>
  4. 4. Non-Inferiority Trials <ul><li>Non-inferiority trials attempt to prove test drug is not inferior to control drug by some margin </li></ul><ul><ul><ul><li>cannot statistically prove two drugs are identical in efficacy </li></ul></ul></ul><ul><ul><ul><li>need some way to estimate the variability around the difference between two treatments </li></ul></ul></ul><ul><li>Non-inferiority margin (delta) = maximum degree of inferiority of test drug compared to control drug that trial will attempt to exclude statistically </li></ul><ul><ul><ul><li>specified prior to initiation of trial </li></ul></ul></ul>
  5. 5. Non-Inferiority Margins <ul><li>After completion of trial: </li></ul><ul><li>1) calculate difference in point estimates of efficacy </li></ul><ul><li>of test agent minus control agent </li></ul><ul><ul><li>2) calculate 95% confidence interval around difference in point estimates </li></ul></ul><ul><ul><ul><li>gives some idea of variability around the estimate in the differences </li></ul></ul></ul><ul><ul><li>3) compare lower bound of 95% CI to pre-specified non-inferiority margin </li></ul></ul>-20% +20% -8% -15%
  6. 6. Components of Delta <ul><li>Delta 1 </li></ul><ul><ul><li>conservative estimate of advantage of active control over placebo </li></ul></ul><ul><ul><ul><li>data-based </li></ul></ul></ul><ul><li>Delta 2 </li></ul><ul><ul><li>largest clinically acceptable difference between active control and experimental drug </li></ul></ul><ul><ul><ul><li>judgement based on consequences to patients of treatment failure </li></ul></ul></ul><ul><li>overall delta for clinical trial smaller of the two values </li></ul><ul><ul><li>if delta 1 is large, overall delta set by delta 2 </li></ul></ul>
  7. 7. Components of Delta - Delta 1 <ul><li>Historically-based data </li></ul><ul><ul><li>Do we really know what we think we know? </li></ul></ul><ul><ul><ul><li>lack of data from pre-antibiotic era </li></ul></ul></ul><ul><ul><ul><li>change in resistance patterns and epidemiology of organisms </li></ul></ul></ul><ul><ul><ul><li>differing response rates in sub- populations </li></ul></ul></ul><ul><ul><ul><li>changes in practice of medicine </li></ul></ul></ul><ul><ul><ul><li>problems with defining patients with bacterial infection vs. non-bacterial/non-infectious causes </li></ul></ul></ul><ul><ul><ul><li>different definitions of success and failure in current trials compared to previous mortality-based trials </li></ul></ul></ul>
  8. 8. Components of Delta - Delta 2 <ul><li>Judgement based “acceptable loss” relative to current therapy </li></ul><ul><ul><li>ideal situation </li></ul></ul><ul><ul><ul><li>smaller delta for more severe disease </li></ul></ul></ul><ul><ul><ul><ul><li>less loss relative to current therapy given potential for greater overall morbidity/mortality </li></ul></ul></ul></ul><ul><ul><ul><li>larger delta for less severe disease </li></ul></ul></ul><ul><ul><ul><ul><li>greater loss relative to current therapy may not translate into as great a consequence for patients </li></ul></ul></ul></ul><ul><ul><li>BUT we don’t live in an ideal world </li></ul></ul><ul><ul><ul><li>practicalities of performing clinical trials </li></ul></ul></ul>
  9. 9. Components of Delta - various diseases <ul><li>Acute bacterial meningitis </li></ul><ul><ul><li> 1 = magnitude of advantage over placebo well-known AND large </li></ul></ul><ul><ul><li> 2 = decision on “acceptable loss” </li></ul></ul><ul><li>Hospital-acquired pneumonia </li></ul><ul><ul><li> 1 = magnitude of advantage over placebo not as clear </li></ul></ul><ul><ul><li> 2 = decision on “acceptable loss” </li></ul></ul><ul><li>Acute exacerbations of chronic bronchitis </li></ul><ul><ul><li> 1 = advantage over placebo unclear (and small?) </li></ul></ul><ul><ul><li> 2 = decision on acceptable loss not as critical </li></ul></ul>
  10. 10. Components of Delta Meningitis and HAP <ul><li>Delta 1 - important questions </li></ul><ul><ul><li>Q1: What is the magnitude of benefit of any antibiotic therapy over placebo? </li></ul></ul><ul><ul><li>Q2: Is the benefit of antimicrobial therapy in current trials measured in the same way as in the original trials showing benefit? </li></ul></ul><ul><ul><li>Q3: Is the magnitude of benefit of therapy over placebo large enough that it should not affect the selection of the overall delta for a trial? </li></ul></ul>
  11. 11. Components of Delta Meningitis and HAP <ul><li>Delta 2 </li></ul><ul><ul><li>Q: What is an “acceptable loss” of efficacy compared to accepted therapy in a serious disease ? </li></ul></ul><ul><ul><li>Scientific considerations </li></ul></ul><ul><ul><ul><li>consequences of treatment failure in various patient subsets with meningitis or HAP </li></ul></ul></ul><ul><ul><li>Practical considerations </li></ul></ul><ul><ul><ul><li>effect of changes in delta on sample size as efficacy rate changes </li></ul></ul></ul>
  12. 12. Historical Data - Meningitis <ul><li>Acute bacterial meningitis highly lethal in pre-antibiotic era </li></ul><ul><ul><li>meningococcal disease most common and occurred in previously healthy young people </li></ul></ul><ul><ul><li>overall mortality 70-90% without specific therapy </li></ul></ul><ul><ul><li>mortality decreased to 30% with introduction of antimeningococcal serum </li></ul></ul><ul><ul><ul><ul><li>Flexner S. J Exp Med 1913;17:553-76 </li></ul></ul></ul></ul><ul><ul><li>sulfanilamide treatment reduced mortality to 10% (9/11 patients survived in original series) </li></ul></ul><ul><ul><ul><ul><li>Schwenker F et al. JAMA 1937;108:1407-8 </li></ul></ul></ul></ul>
  13. 13. Historical Data - Meningitis <ul><li>Problems with historical data </li></ul><ul><ul><li>different endpoints in current trials </li></ul></ul><ul><ul><ul><li>developmental, neurologic, audiologic sequelae as well as mortality </li></ul></ul></ul><ul><ul><li>different epidemiology </li></ul></ul><ul><ul><ul><li>pneumococcal meningitis most common now in U.S. </li></ul></ul></ul><ul><ul><li>different populations </li></ul></ul><ul><ul><ul><li>proportionately more older adults with meningitis since introduction of HIB vaccine </li></ul></ul></ul><ul><ul><ul><ul><li>Schuchat A et al. N Engl J Med 1997;337:970-6. </li></ul></ul></ul></ul>
  14. 14. Historical Data - HAP <ul><li>Clinical entity of HAP not described in pre-antibiotic era </li></ul><ul><ul><li>only 2 spontaneous cures out of 151 cases in military recruits in S. aureus outbreaks in 1918 </li></ul></ul><ul><ul><li>few reports of gram-negative pneumonias </li></ul></ul><ul><ul><ul><li>How certain is diagnosis in these case reports? </li></ul></ul></ul><ul><li>No way to compare antibiotic therapy to placebo </li></ul>
  15. 15. <ul><li>Celis R. Chest 93;318-24.1988 </li></ul><ul><ul><li>30.5% (33/108) all-cause mortality with “appropriate” antibiotics </li></ul></ul><ul><ul><li>91.6% (11/12) all-cause mortality with“inappropriate” antibiotics </li></ul></ul><ul><li>Alvarez-Lerma et al. Intensive Care Med 1996;22:387-94. </li></ul><ul><ul><li>16.2% (36 /146)attributable mortality with “appropriate” antibiotics </li></ul></ul><ul><ul><ul><li>all-cause mortality 34.9% (51/146) </li></ul></ul></ul><ul><ul><li>24.7% ( 46/284) attributable mortality with “inappropriate” antibiotics </li></ul></ul><ul><ul><ul><li>all-cause mortality 32.4% (92/284) </li></ul></ul></ul>Historical Data - HAP
  16. 16. Historical Data - HAP <ul><li>Problems with historical data </li></ul><ul><ul><li>Difficulty in clinical diagnosis of HAP </li></ul></ul><ul><ul><ul><li>patients in study who do not have disease </li></ul></ul></ul><ul><ul><li>Change in nosocomial organisms over time </li></ul></ul><ul><ul><ul><li>changes in resistance patterns </li></ul></ul></ul><ul><ul><li>Different outcomes in various patient populations </li></ul></ul><ul><ul><ul><li>mechanically ventilated pts. Vs. others </li></ul></ul></ul><ul><ul><li>Death attributable to pneumonia vs. all-cause mortality </li></ul></ul><ul><ul><li>Clinical endpoints other than mortality in current trials </li></ul></ul>
  17. 17. Components of Delta Meningitis <ul><li>Delta 1 - important questions </li></ul><ul><ul><li>Q1: What is the magnitude of benefit of any antibiotic therapy over placebo? </li></ul></ul><ul><ul><li>Appears as large as 60%-80% mortality benefit but magnitude of benefit on clinical parameters not as clear </li></ul></ul><ul><ul><li>Q2: Is the benefit of antimicrobial therapy in current trials measured in the same way as in the original trials showing benefit? </li></ul></ul><ul><ul><li>Yes and No </li></ul></ul><ul><ul><li>Q3: Is the magnitude of benefit of therapy over placebo large enough that it should not affect the selection of the overall delta for a trial? </li></ul></ul><ul><ul><li>Yes </li></ul></ul>
  18. 18. Components of Delta HAP <ul><li>Delta 1 - important questions </li></ul><ul><ul><li>Q1: What is the magnitude of benefit of any antibiotic therapy over placebo? </li></ul></ul><ul><ul><li>May be anywhere from 8.5%-60% depending on how and in whom it is measured. Unclear benefit on clinical parameters </li></ul></ul><ul><ul><li>Q2: Is the benefit of antimicrobial therapy in current trials measured in the same way as in the original trials showing benefit? </li></ul></ul><ul><ul><li>Yes and No </li></ul></ul><ul><ul><li>Q3: Is the magnitude of benefit of therapy over placebo large enough that it should not affect the selection of the overall delta for a trial? </li></ul></ul><ul><ul><li>Point for committee discussion </li></ul></ul>
  19. 19. Components of Delta Meningitis and HAP <ul><li>Delta 2 </li></ul><ul><ul><li>Q: What is an “acceptable loss” of efficacy compared to accepted therapy in a serious disease ? </li></ul></ul><ul><ul><li>Scientific considerations </li></ul></ul><ul><ul><ul><li>consequences of treatment failure in various patient subsets with HAP </li></ul></ul></ul><ul><ul><li>Practical considerations </li></ul></ul><ul><ul><ul><li>effect of changes in delta on sample size as efficacy rate changes </li></ul></ul></ul>
  20. 20. Consequences of Failure <ul><li>Meningitis </li></ul><ul><ul><li>clear mortality benefit of antibiotic therapy </li></ul></ul><ul><ul><li>morbidity is developmental, neurological and audiological sequelae </li></ul></ul><ul><ul><ul><li>what is magnitude of benefit of antibiotics? </li></ul></ul></ul><ul><li>HAP </li></ul><ul><ul><li>mortality </li></ul></ul><ul><ul><ul><li>magnitude of benefit varies depending on how and in whom it is measured </li></ul></ul></ul><ul><ul><li>morbidity </li></ul></ul><ul><ul><ul><li>increased costs and hospital stay </li></ul></ul></ul><ul><ul><ul><li>effect on rate of clinical resolution? </li></ul></ul></ul>
  21. 21. Practical Issues <ul><li>Effect of success rate and delta selection on sample size </li></ul><ul><ul><li>Selection of a smaller delta in more severe diseases with relatively lower success rates would increase sample size </li></ul></ul><ul><ul><li>Is larger sample size practical given: </li></ul></ul><ul><ul><ul><li>1) epidemiology of the disease </li></ul></ul></ul><ul><ul><ul><li>2) limitations of inclusion and exclusion criteria </li></ul></ul></ul><ul><ul><ul><li>3) inability to continue on randomized therapy in studies of severe disease </li></ul></ul></ul>
  22. 22. Clinical Trial Implications: Sample size per arm to achieve 80% power 
  23. 23. Epidemiology of Meningitis* *Based on 248 cases in 1995 from Schuchat et al. N Engl J Med. 1997;337:970-6.
  24. 24. Epidemiology of Meningitis <ul><li>Case fatality rates and incidence vary by organism </li></ul><ul><ul><li>H. influenzae lower case fatality rates than S. disease caused by S. pneumoniae </li></ul></ul><ul><ul><li>S. pneumoniae now more common overall </li></ul></ul><ul><ul><li>mortality rates in future trials may be higher than those in past given shift in epidemiology </li></ul></ul><ul><li>Number of cases in U.S. declining since introduction of HIB vaccine </li></ul><ul><ul><li>estimated 12,920 cases in 1986 </li></ul></ul><ul><ul><li>estimated 5,755 cases in 1995 </li></ul></ul><ul><ul><ul><li>Schuchat et al. N Engl J Med 1997;337:970-76. </li></ul></ul></ul>
  25. 25. Epidemiology of HAP <ul><li>Actual incidence of HAP unclear (not a reportable illness) </li></ul><ul><ul><li>NNIS data estimates 250,000 cases/year in U.S. </li></ul></ul><ul><ul><ul><li>uses clinical definition of HAP </li></ul></ul></ul><ul><ul><li>estimated 1% of all patients entering hospital develop pneumonia </li></ul></ul><ul><ul><li>15-18% of all hospital acquired infections </li></ul></ul><ul><ul><ul><li>2nd most common after UTI </li></ul></ul></ul><ul><ul><ul><li>most common infection in ICU setting </li></ul></ul></ul><ul><ul><ul><ul><li>ICARE report. Am J Infect Control 1999;27:279-84. </li></ul></ul></ul></ul>
  26. 26. Epidemiology <ul><li>Estimated U.S. cases per year (1994) </li></ul><ul><ul><li>acute otitis media 26,000,000 </li></ul></ul><ul><ul><li>acute sinusitis 23,000,000 </li></ul></ul><ul><ul><li>tonsillitis/pharyngitis 21,000,00 </li></ul></ul><ul><ul><li>pneumonia (community) 4,000,000 </li></ul></ul><ul><ul><li>hospital-acquired pneumonia 250,000 </li></ul></ul><ul><ul><li>acute bacterial meningitis <10,000 </li></ul></ul><ul><ul><li>acute bacterial endocarditis 10,000 </li></ul></ul>
  27. 27. Recent Trials <ul><li>Practical Points </li></ul><ul><ul><li>success rates in HAP trials in 50% - 70% range </li></ul></ul><ul><ul><ul><li>much larger sample size with smaller delta </li></ul></ul></ul><ul><ul><li>recent approvals with 20% delta based on 1992 guidance in all recent HAP trials </li></ul></ul><ul><ul><ul><li>theoretically a new drug could be as much as 20% less effective than comparator </li></ul></ul></ul><ul><ul><li>almost half of patients do not complete trial </li></ul></ul><ul><ul><ul><li>must take into account when planning sample size </li></ul></ul></ul>
  28. 28. Clinical Trial Implications: Sample size per arm to achieve 80% power 
  29. 29. Components of Delta Meningitis and HAP <ul><li>Delta 2 </li></ul><ul><ul><li>Q: What is an “acceptable loss” of efficacy compared to accepted therapy in a serious disease ? </li></ul></ul><ul><ul><ul><li>serious nature of meningitis and HAP would seem to call for selection of smaller deltas </li></ul></ul></ul><ul><ul><ul><li>smaller deltas would result in larger sample size of clinical trials - is this practical? </li></ul></ul></ul><ul><ul><ul><li>balance with risk of accepting drugs which may be 20% less effective than currently approved therapy </li></ul></ul></ul><ul><ul><ul><ul><li>could be success rate of 40% for new drug for HAP </li></ul></ul></ul></ul>
  30. 30. The Balance <ul><li>Risk to patients of accepting larger deltas, especially in more severe disease </li></ul><ul><li>versus </li></ul><ul><li>Realities of performing clinical trials </li></ul>

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