Microbiological Surrogate Endpoints in Clinical Trials of Infectious Diseases

1
Microbiological Surrogate Endpoints in Clinical
Trials of Infectious Diseases

• 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

• Differentiating clinical practice guidelines and
  clinical trials
• Definitions of endpoints, clinical endpoints,
  surrogate endpoints, and biomarkers
• Utility of surrogate and differentiating risk
  factors from surrogate endpoints
• Strengths and limitations of surrogate endpoints
• Surrogates in the setting of topical antiseptics
• Conclusions

3
Clinical Practice and Clinical Trials

• Clinical practice
• use of drug products already proven to be safe
  and effective
• not concerned with causality of outcomes
• treatment guidelines describe use of products
  based on best available evidence (optimally based
  on clinical trials)
• Clinical trials
• experiments in humans to determine if drugs
  products are safe and effective
• determine causality of outcomes related to
  interventions
• provide evidence for formulation of practice
  guidelines (not usually vice versa)
• need yardstick for determining if products are
  safe and effective

4
Definitions

• Endpoint - measure of the effect of an
  intervention on outcome (e.g. success or failure)
  in a clinical trial in treating or preventing a
  disease
• Several implications
• WHAT to measure - should be clinically relevant
  to the disease in question
• HOW to measure it - should be able to measure
  differences between therapies should they exist
  i.e. developing a yardstick to differentiate
  effective from ineffective drugs
• WHEN to measure it (timing) should be clinically
  relevant to the disease
• HOW MUCH to measure (magnitude) should correlate
  with clinical outcomes that are meaningful to
  patients
• HOW TO ANALYZE results as method may affect
  conclusions

5
GI symptoms bother me
Im worried and concerned
Heartburn disturbs my sleep
I cannot bend over or exercise
I cannot eat and drink whatever I like
My whole life is affected
6
Definitions

• Disease
• a constellation of signs and symptoms experienced
  by the patient
• infectious diseases caused by pathogenic
  organisms with resultant host response causing
  symptoms
• Kochs postulates relate to proving cause of
  disease, not effect of an intervention
• cause and effect are separate considerations
• Patients seek the care of clinicians because of
  symptoms, not because of presence of organism
• Verheij TJ et al. Fam Pract 19907175-80.
• In prevention trials, seek to prevent symptoms
  from occurring
• Powers JH Clin Infect Dis 200439S211-17.

7
Definitions

• Clinical endpoint direct measure of how a
  patient feels, functions or survives
• mortality
• resolution or prevention of symptoms of disease
• Surrogate endpoint laboratory measurement or
  physical sign used as a substitute for clinical
  endpoint
• culture results, radiological testing, histology
• other data like PK-PD predicts effect on organism
• Surrogate endpoint by itself does not confer
  direct clinical benefit to the patient
• NIH Biomarkers Definitions Working Group, Clin
  Pharmacol Ther.20016989-95.
• International Conference on Harmonization, ICH E9
  document

8
Definitions

• Biomarkers are analytical tools used to assess
  biological parameters
• Biomarkers are useful for purposes other than
  surrogate endpoints in trials
• 1) diagnostic tool - use of test as an inclusion
  criteria to define the disease based on presence
  of organism (increases specificity of diagnosis)
• 2) describe mechanism of action of drug - effect
  on organisms is mechanism, not goal of therapy
• 3) risk factor for acquisition of disease -
  colonization with particular organisms may be
  risk factor
• 4) risk factor for outcome - indicator of disease
  prognosis (HIV viral load and CD4 in HIV)
• Sande MA et al. NIH Consensus Conference on HIV,
  JAMA 19932702583-89.
• 5) surrogate endpoints

9
Definitions

• Surrogate - Etymology Latin surrogatus, past
  participle of surrogare to choose in place of
  another, substitute, from sub- rogare to ask
  to put in the place of another
• Merriam-Webster Dictionary
• Surrogate endpoint is substituting
  microbiological outcomes for clinical outcomes
  (both success AND failure) of disease in pivotal
  clinical trials to prove drug efficacy
• Surrogate endpoints very useful in early drug
  development as proof of principle of drug
  efficacy and selecting candidate drugs

10
Utility of Surrogates

• Useful in phase 3 trials when surrogate endpoint
  can be measured sooner than clinical endpoint
• When clinical endpoint events are more rare, can
  complete trial with smaller sample size
• Examples of successful surrogates
• lowering cholesterol to prevent CV disease
• lowering blood pressure to prevent CV disease
• suppression of HIV viral load as surrogate
  endpoint in treatment of HIV/AIDS

11
HIV Viral Load and CD4 as Risk Factors
12
Risk Factor and Endpoints Differ

• Level of HIV viral load and CD4 count both are
  risk factors for disease progression in HIV/AIDS
• HIV viral load functions well as surrogate
  endpoint but CD4 count not as useful as endpoint
  in clinical trials
• 7 of 8 trials in with positive effect on CD4
  showed positive effect on progression to
  AIDS/death
• BUT effect on CD4 positive in 6 of 8 trials with
  negative effect on AIDS progression/death
• CD4 count may not change fast enough over time
  course of trial
• Fleming TR. Stat Med 1994131423-35.

13
Strengths and Limitations

• The logic string for topical antiseptic
  products
• colonization with organisms precede infection
  (risk factor)
• organisms can cause infection and resulting host
  response
• since organisms cause infection, eliminating or
  decreasing organisms should results in positive
  clinical outcomes for patients
• So logical, so objective..but is it correct?
• DeGruttola V et al. Ann Intern Med
  1997175237-46.
• Deductive, not inductive reasoning
• Need to test this logic to see if it is true
• Prentice RL Stat Med 19898431-440.

14
Strengths and Limitations

• Reasons why surrogate may not accurately predict
  clinical outcomes
• unmeasured harms caused by intervention
• unmeasured benefits caused by intervention
• other mechanisms of disease other than those
  affected by intervention
• issues with measuring surrogate
• issues with measuring clinical outcomes

15
Strengths and Limitations

• Surrogate may not take into account unmeasured
• benefits and harms of treatment (not just
  correlate)
• Knowledge about how a drug achieves clinical
  results may be incomplete
• Conservation of processes in human body

16
Strengths and Limitations

• Unmeasured benefits
• effects of drug other than eradication of
  organisms
• sub-inhibitory effects of antimicrobials on
  organisms
• bactericidal therapy not necessary in many
  infections
• direct effects of antimicrobials on host immune
  system
• Labro MT et al. Curr Opin Investig Drugs
  2002361-8.
• Nau R et al. Clin Micro Rev 20021595-110.
• Unmeasured harms
• deleterious effects on host that may promote
  infection
• replacement of one organism with another that may
  cause infection
• other sources of infection other than those
  affected by drug

17
Strengths and Limitations

• Unmeasured benefits
• rifaximin approved for treatment of travelers
  diarrhea
• drug have similar rate of positive cultures for
  pathogens in stool compared to placebo
• drug still decreased time to resolution of
  diarrhea compared to placebo (for some, not all
  organisms)
• Steffen R et al. Am J Gastroenterol
  2003981073-8.
• Unmeasured harms
• dose escalation trial of clarithromycin for
  disease due to Mycobacterium avium-intracellulare
  in patients with AIDS
• higher doses had higher rates of negative blood
  cultures (microbiological outcomes) but also
  higher mortality (clinical outcomes)
• Chaisson et al. Ann Intern Med 1994121905-911

18
Strengths and Limitations
Intervention may affect one pathway of disease
and not other pathways that are as important or
more important in resulting clinical outcomes
19
Strengths and Limitations

• Other mechanisms of disease not affected by
  intervention
• several trials show decreased rates of
  colonization with S. aureus (microbiological
  outcome) with intranasal mupirocin
• prevention of infections (clinical outcome) in
  patients not lower than placebo
• Kalmiejer MD et al. Clin Infect Dis
  200235353-8.
• Perl TM et al. N Engl J Med 20023461871-7.
• Wertheimer HF et al. Ann Intern Med
  2004140419-25.
• May be due to infection caused by sources of S.
  aureus other than the nose

20
Strengths and Limitations

• Issues with accuracy of how surrogate is
  measured
• it may be reproducible (precision) but is it
  telling
• us the correct inference (accuracy)?
• what, when, how and magnitude of what is measured

21
Strengths and Limitations

• Culture techniques based on methodology from late
  1800s with inherent error (same organisms can
  give MIC one to tube dilutions different on
  serial testing)
• Issues with microbiological outcomes
• patient population sampled
• sampling technique
• culture methodology
• when culture is performed (on therapy) and
  follow-up period
• frequency of sampling
• criteria applied for classification (all or
  nothing vs. quantitative)

22
Strengths and Limitations
Suppression vs. Eradication
Patient 1
Microbial load
level of detection
Patient 2
baseline
end of study
on therapy
Time
23
Strengths and Limitations

• Measurement of clinical endpoint may not
• be relevant based on natural history of disease
• inaccurate measurement of clinical endpoint does
  not
• justify use of unvalidated surrogate

24
Strengths and Limitations

• Example
• Catheter tip decolonization claimed to be
  validated as surrogate endpoint for clinical
  trials in prevention of catheter-related
  bloodstream infections (BSI) based on
  correlation of two endpoints
• Rijnders BJA et al. Clin Infect Dis
  2002351053-8.
• Definition of bloodstream infection in some of
  these studies is positive blood culture AND a
  positive culture of a catheter tip
• residual antimicrobial activity in the removed
  catheter sufficient to prevent growth from the
  cultured catheter segments would substantially
  reduce the apparent rate of catheter-related
  bloodstream infections. could it be that use of
  minocyclinerifampin impregnation prevents growth
  from catheters in the microbiology laboratory but
  does not eliminate the clinical syndrome of
  catheter-related bloodstream infection?
• Paterson DL N Engl J Med 19993401761.
• Studies submitted to FDA show no effect on BSI
  relative to placebo despite effect on
  decolonization

25
Correlating Surrogates
clinical success
success with surrogate

• Surrogate must measure effects similarly for
• all drugs studied

26
Correlating Surrogates
clinical success
success with surrogate

• Surrogate must measure effects similarly for all
  drugs studied
• adapted from Baker SG et al. BMC Medical Research
  Methodology 2003316.

27
Regulatory Issues

• Traditional approval based on surrogate endpoints
  only in cases where endpoint already validated to
  predict clinical endpoint
• Accelerated approval based on surrogate endpoints
  (Subpart H, 21 CFR 314.510)
• serious and life threatening disease
• surrogate endpoint reasonably likely to predict
  clinical outcome
• requires confirmatory post-approval trial based
  on clinical endpoint (usually from a trial that
  is already ongoing)
• TFM predates these regulations

28
Surrogates and Topical Antiseptics

• Unmeasured harms
• unintended effects on microscopic breakage in
  skin may result in greater infection rate
  (example of shaving and peri-operative
  infections)
• Seropian R et al. Am J Surg 1971121251-4.
• effects on common pathogens may be less than that
  on marker organisms in skin
• selection of resistance to systemic
  antimicrobials?
• Unintended benefits
• some products may have positive effects other
  than those on organisms
• effects on common pathogens may be greater than
  that on marker organisms used to contaminate skin

29
Surrogates and Topical Antiseptics

• Other mechanisms not affected by intervention
• data obtained on surrogate endpoint is from most
  superficial layer of skin (stratum corneum of
  epidermis)
• source of organisms causing infection may not be
  the same as site measured by surrogate
• skin stripping experiments using cellophane
  tape
• 12 different sites on body had variable colony
  counts of coagulase negative staphylococci
• top 5 layers of stratum corneum had higher colony
  counts and next 20 layers with stable counts
• return of same organisms 18 hours
  post-sterilization with alcohol indicates
  reservoir of normal skin flora may be below
  stratum corneum in hair follicles/glands in
  dermis
• Brown E et al. J Infect Dis 1989160644-50.

30
Skin Anatomy
31
Skin Anatomy
32
Surrogates and Topical Antiseptics

• Issues with measurement of surrogate
• Population in whom surrogate is measured may be
  different from actual use population in
  unmeasured ways
• Organisms measured not necessarily those that
  cause infection
• Is timing of measurements relevant to disease
  process?
• Are conditions of testing same as those that
  would be encountered in real life situations?
• Does variations in methodology (vigor of
  scrubbing, use of neutralizers) affect
  consistency of results?
• What log reduction is clinically significant? How
  to analyze numbers obtained on log reductions?
  Changing method of analysis may change clinical
  conclusions

33
Surrogates and Topical Antiseptics

• Clinical endpoints
• What is data showing correlation of reduction in
  bacteria with decrease in infection rates?
• What does dose response curve look like for
  infection rates and numbers of bacteria? Is this
  a threshold effect (lower infection rates below
  some amount of bacteria) or a continuous
  variable?
• Are correlations the same for all types of
  products?

34
Surrogates and Topical Antiseptics
Dose Response of Numbers of Skin Bacteria and
Infection Rates
Rate of infection
Change in numbers of bacteria on skin
35
Surrogates and Topical Antiseptics
Dose Response of Numbers of Skin Bacteria and
Infection Rates
Rate of infection
Change in numbers of bacteria on skin
36
Surrogates and Topical Antiseptics
37
Conclusions

• Surrogate endpoints must not only correlate
  with clinical outcomes but must also take into
  account
• unmeasured harms and benefits
• methodology and uncertainties in measuring
  surrogate
• appropriate measurement of clinical endpoint
• Clinical endpoint for efficacy of topical
  antiseptic products would be prevention of
  infections
• condition of testing today are not those of
  Semmelweis
• Further discussion today on what is known about
  surrogates in setting of topical antiseptics

38

• Far better an approximate answer to the right
  question, which is often vague, than an exact
  answer to the wrong question, which can always be
  made precise.
• John W. Tukey (1962)
• Annals of Mathematical Statistics
• 1962331-67.