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  • Obviously the choice of delta has a big impact on sample size required to provide robust evidence of efficacy. Let’s consider some examples. On the x-axis, we have assumed success rates FOR BOTH ARMS On the y-axis we have the sample size necessary to provide the burden of proof that a desired level of similarity is met with high confidence So when the underlying success rate if 80% for both AC and new -- we would need about 100 pts per arm with a delta of 15, 250 per arm for a delta of 10 and 1000 per arm for a delta of 10% Note that sample size requirements go down as the success rate approaches 100% and increase as the success rate approaches 50%.
  • Obviously the choice of delta has a big impact on sample size required to provide robust evidence of efficacy. Let’s consider some examples. On the x-axis, we have assumed success rates FOR BOTH ARMS On the y-axis we have the sample size necessary to provide the burden of proof that a desired level of similarity is met with high confidence So when the underlying success rate if 80% for both AC and new -- we would need about 100 pts per arm with a delta of 15, 250 per arm for a delta of 10 and 1000 per arm for a delta of 10% Note that sample size requirements go down as the success rate approaches 100% and increase as the success rate approaches 50%.
  • Transcript

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

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