• Share
  • Email
  • Embed
  • Like
  • Save
  • Private Content
nosocomial pneumonia
 

nosocomial pneumonia

on

  • 1,091 views

 

Statistics

Views

Total Views
1,091
Views on SlideShare
1,089
Embed Views
2

Actions

Likes
0
Downloads
14
Comments
0

1 Embed 2

http://www.slideshare.net 2

Accessibility

Upload Details

Uploaded via as Microsoft PowerPoint

Usage Rights

© All Rights Reserved

Report content

Flagged as inappropriate Flag as inappropriate
Flag as inappropriate

Select your reason for flagging this presentation as inappropriate.

Cancel
  • Full Name Full Name Comment goes here.
    Are you sure you want to
    Your message goes here
    Processing…
Post Comment
Edit your comment
  • 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%.

nosocomial pneumonia nosocomial pneumonia Presentation Transcript

  • Issues in Selection of Deltas in Non-Inferiority Trials : Acute Bacterial Meningitis and Hospital-Acquired Pneumonia dr shabeel pn www.hi-dentfinishingschool.blogspot.com
  • 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
  • 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
  • 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
  • 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%
  • 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
  • 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
  • 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
  • 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
  • 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?
  • 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
  • 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
  • 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.
  • 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
    • 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
  • 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
  • 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
  • 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
  • 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
  • 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?
  • 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
  • Clinical Trial Implications: Sample size per arm to achieve 80% power 
  • Epidemiology of Meningitis* *Based on 248 cases in 1995 from Schuchat et al. N Engl J Med. 1997;337:970-6.
  • 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.
  • 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.
  • 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
  • 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
  • Clinical Trial Implications: Sample size per arm to achieve 80% power 
  • 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
  • The Balance
    • Risk to patients of accepting larger deltas, especially in more severe disease
    • versus
    • Realities of performing clinical trials