The Role of Research and Clinical Trials Defining and Studying Disease Due to Resistant Pathogens

1
The Role of Research and Clinical Trials
Defining and Studying Disease Due to Resistant
Pathogens

• John H. Powers, MD FACP FIDSA
• Senior Medical Scientist
• SAIC in support of Collaborative Clinical
  Research Branch
• Division of Clinical Research
• National Institute of Allergy and Infectious
  Diseases
• National Institutes of Health

2
Introduction

• Defining resistance linking in vitro
  observations with outcomes in patients
• Issues with clinical trials
• Clarify goals of administering medical
  interventions
• Use of superiority trials
• Blinding of microbiological information
• Rapid diagnostics
• Appropriate endpoints
• Appropriate analysis

3
Defining Resistance

• Minimum inhibitory concentration (MIC)
  observation of concentration of drug needed to
  inhibit growth of organisms in vitro
• Methods developed over 100 years ago
• Inherent imprecision in measurement
• Never meant for the purpose for which it is now
  used
• Kerr JK J Clin Path 200558786-7.
• Need to link in vitro observation to important
  clinical outcomes in patients
• Mortality
• Functional status
• Patient symptoms

4
Defining Resistance

• In vitro conditions of testing differ from those
  in vivo especially lack of immune response so
  cannot expect perfect correlation
• MICs are continuous variables
• Current definition of resistance assigns
  categories of breakpoints susceptible,
  intermediate, and resistant
• Categorization assumes all data within category
  are similar
• Loss of information of within category variation
• Unclear meaning of intermediate category
• Is an MIC the best (or only) way to describe
  appropriate conditions of use of a drug?

5
Defining Resistance
Dose response of clinical outcomes and MIC
I
R
S
Rate of clinical success
In vitro MIC of infecting organism
6
Defining Resistance

• One size fits all definition of resistance for
  all infections may not be appropriate
• Bases resistance definition on organism instead
  of disease
• Differential effectiveness of drugs at various
  sites of infection
• Different magnitude of treatment effect
• Different consequences of treatment failure
• Does not take into account safety issues

7
Defining Resistance
Impact of In Vitro Resistance on Clinical Outcomes
95
acute otitis media ??
90
60
Rate of clinical success
acute bacterial meningitis
30
In vitro MIC of infecting organism
8
Defining Resistance

• Definition of resistance categorization of
  organisms that predicts proportion of patients
  with fewer successful clinical outcomes when
  treated with a given drug compared to proportion
  of patients with disease due to susceptible
  pathogens
• Comparing groups of patients, not individuals
• Many patients with susceptible pathogens can
  fail treatment making case reports of failure
  less useful
• Need comparison of subjects with similar baseline
  characteristics i.e. disease due to organisms
  with higher MICs may merely select a patient
  group who will do less well
• Attempting to discern effect of a given drug on
  outcome not just effect of organisms on outcome

9
Defining Resistance

• Patients with disease due to organisms with
  higher MICs may be
• Older
• More concomitant illnesses
• More prior antimicrobial therapy
• More days in hospital
• Severity of illness
• Association is not necessarily evidence of
  causality
• Association of higher MIC with worse outcome may
  be due to above confounders
• Need to take into account these factors when
  evaluating resistance

10
Defining Resistance

• Need clinical data to evaluate definitions of
  resistance
• When drug first approved for clinical use
  resistance may be rare
• Need to continue to acquire data over time with
  drug use
• Databases to link to clinical outcomes
• Need to link surveillance of organisms to people
• Antimicrobial resistance IS a safety issue
• Lack of effectiveness is a safety issue
• Even more of an issue with antimicrobials as
  impacts other patients, not just the person who
  takes the drug

11
Staphylococcus aureus Multi-drug Resistance
Patterns by Patient Location
Inpatient Total n 10,951
Outpatient Total n 8,269
Antimicrobials Ciprofloxacin, Clindamycin,
Erythromycin, Linezolid, Oxacillin, Tetracycline,
Trimeth/sulfa
Each data point plotted represents 4 results
Each data point plotted represents 4 results
12
Outpatient Staphylococcus aureus Multi-drug
Resistance Patterns 2003 - 2004
Outpatient Total n 8,269
12
13
Defining Resistance

• Examples of instances in which definitions of
  resistance unclear
• Penicillin and macrolides in pneumococcal
  pneumonia
• Peterson L Clin Infect Dis 200642224-33.
• Nuermberger and Bishai Clin Infect Dis
  20043899-103
• Any resistance in diseases such as otitis,
  sinusitis and bronchitis where benefit over
  placebo unclear
• Powers JH Lancet Infect Dis 2007775-8.
• Methicillin resistance in S. aureus skin
  infections with recent study showing gt90
  effectiveness with ID alone
• Young D et al (in press)
• Consequences
• Limits available therapies
• May shift usage to drugs with more toxicity or
  lack of evidence of effectiveness
• Cost

14
Clinical Trials

• Clarify goals of administering drug
• Goal of therapy is to have positive therapeutic
  benefit for patients in terms of improved
  mortality, increased functional status and cure
  of symptoms
• Goal is not merely to exert an effect on
  organisms
• Treatment of disease under study versus
  prevention of rare complications
• Use of superiority trials
• Problem is that older drug may have decreasing
  effectiveness in various diseases
• Seems illogical to evaluate similarity of new
  drug to older drug that one hypothesizes is no
  longer effective

15
Clinical Trials

• Blinding of microbiological information
• Allows evaluation of correlation of clinical
  outcomes with microbiological outcomes
• Knowledge of microbiological outcomes may bias
  clinician assessments
• Rapid diagnostics
• Allow enrollment of patients most likely to
  benefit
• Allow appropriate study of patients with disease
  due to resistant pathogens
• Appropriate use to limit adverse events and
  resistance in clinical practice
• Inclusion of subjects with range of MICs (only
  exception would be serious and life threatening
  diseases where organisms with MICs where drug
  would not have any effect at all)

16
Clinical Trials

• Appropriate endpoints
• Time to resolution of symptoms in short term
  self-resolving diseases
• Microbiological outcomes are surrogates for
  clinical outcomes but less need for surrogate in
  short term diseases
• Poor correlation of microbiological and clinical
  outcomes in some self-resolving diseases
• Presumed eradication of organisms presumes what
  one is trying to measure need to actually
  measure the correlation
• Development of valid patient reported outcomes
  instruments for diseases whose primary
  manifestations are symptoms
• Death is not a successful outcome or
  indeterminate
• Appropriate analysis
• Intent to treat analysis preserves protection
  from selection bias (randomization) while per
  protocol analysis is a subgroup analysis
• Issue of appropriate measurement of multiple
  endpoints
• Issue of large amounts of missing data and
  unevaluable

17
Adequate and Well-Controlled

• Clear statement of objectives
• Study design permits valid quantitative
  comparison with a control
• Select patients with disease (treatment) or at
  risk of disease (prevention)
• Baseline comparability (randomization)
• Minimize bias (blinding, etc.)
• Appropriate methods of assessment of outcomes
• Appropriate methods of analysis
• 21 CFR 314.126