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Microbiologic Surrogate Endpoints in Clinical Trials-IDSA FDA/IDSA/ISAP Workshop April 15, 2004. Sheldon L. Kaplan, MD Baylor College of Medicine Texas Children’s Hospital Houston, TX. Sridhara et al http://www.fda.gov/www.fda.gov/cder/Offices/Biostatistics/presentations.htm.

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microbiologic surrogate endpoints in clinical trials idsa fda idsa isap workshop april 15 2004

Microbiologic Surrogate Endpoints in Clinical Trials-IDSAFDA/IDSA/ISAP WorkshopApril 15, 2004

Sheldon L. Kaplan, MD

Baylor College of Medicine

Texas Children’s Hospital

Houston, TX

slide2

Sridhara et al http://www.fda.gov/www.fda.gov/cder/Offices/Biostatistics/presentations.htm

slide3

Sridhara et al http://www.fda.gov/www.fda.gov/cder/Offices/Biostatistics/presentations.htm

infections for which microbiologic surrogate endpoints are useful for clinical trials
Infections For Which Microbiologic Surrogate EndpointsAre Useful for Clinical Trials
  • Group A streptococcus pharyngitis
  • Uncomplicated lower urinary tract infection
  • Shigella gastroenteritis
infections for which microbiologic surrogate endpoints are useful for clinical trials5
Infections For Which Microbiologic Surrogate EndpointsAre Useful for Clinical Trials
  • Group A Streptococcus Pharyngitis

-symptoms will resolve regardless of therapy; time to resolution can be compared

-suppurative and non-suppurative complications occur too infrequently to use as endpoints

slide6
Infections For Which Microbiologic Surrogate EndpointsAre Not Useful or Unproven for Clinical Trials
  • Skin and skin structure infections
  • Pneumonia
  • Acute hematogenous osteomyelitis or septic arthritis
  • Intra-abdominal infections
  • Viral meningitis or encephalitis
slide7
Infections For Which Microbiologic Surrogate EndpointsAre Not Useful or Unproven for Clinical Trials
  • Sites of infection are difficult to resample in order to document microbiologic eradication
  • Lack of eradication of the organism may not equal clinical failure-VAP and tracheal aspirates
  • Eradication of organism may not equal substantial clinical benefit-URI and pleconaril
infections for which microbiologic surrogate endpoints may be useful for clinical trials
Infections For Which Microbiologic Surrogate EndpointsMay be Useful for Clinical Trials
  • Bacterial meningitis
  • Acute otitis media and sinusitis
  • VP shunt infections
  • Coagulase-negative staphylococcus line-associated bacteremia
  • Pertussis
antimicrobial drug development for acute bacterial meningitis joint fda idsa phrma workshop

Antimicrobial Drug Development for Acute Bacterial MeningitisJoint FDA/IDSA/PhRMA Workshop

Imo Ibia, MD, MPH

Medical Officer

FDA/CDER/DSPIDP

November 20, 2002

Office of New Drugs IV

Center for Drug Evaluation and Research

www.fda.gov

outcomes
Outcomes
  • Are there data to show bacteriologic outcome is a good surrogate for clinical outcome?
  • Would bacterial endpoint alone miss the potential differential effect of drugs on inflammatory response?
  • How should clinical success/failure be defined and what should constitute the primary efficacy population?
    • ITT or evaluable?
  • How best can preclinical and early phase clinical trial data be used in meningitis trials to help address some of these issues?

Imo Ibia 2002 FDA/IDSA/PhRMA Workshop 2002

evaluations
Evaluations
  • Timing of repeat lumbar puncture
    • Is there data to establish the best time?
    • What factors could impact that time and how should they be factored in?
      • organism, baseline quantity, drug, host factors
  • How many organisms in repeat LP constitute delayed sterilization and what is its utility in trials?
      • Few and patient improving, optional (IDSA 1992)
  • Quantification of baseline CSF pathogens
    • How feasible and consistent across multinational sites?

Imo Ibia 2002 FDA/IDSA/PhRMA Workshop 2002

outcome of bacterial meningitis
Outcome of Bacterial meningitis
  • IDSA Guidelines 1992: Endpoints of

-cure

-survival with mild neurologic sequelae

-survival with severe neurologic sequelae (somewhat

dependent on the observer and some sequelae

improve with time)

-death

  • Mortality is low in US
  • Audiology testing is an objective and quantifiable measure
  • As with other sequelae, hearing loss may improve over time
ceftriaxone vs cefuroxime for bacterial meningitis in children
Ceftriaxone vs Cefuroxime for Bacterial Meningitis in Children
  • Prospective, randomized multicenter study
  • Ceftriaxone (n=53) or cefuroxime (n=53)
  • Repeat CSF culture at 18-36 hours
  • No significant differences in clinical characteristics between the groups at enrollment

Schaad et al N Engl J Med 1990;332:141-7

ceftriaxone vs cefuroxime for bacterial meningitis in children14
Ceftriaxone vs Cefuroxime for Bacterial Meningitis in Children

Schaad et al N Engl J Med 1990;332:141-7

ceftriaxone vs cefuroxime for bacterial meningitis in children15
Ceftriaxone vs Cefuroxime for Bacterial Meningitis in Children
  • Hearing loss for H. influenzae type b

Ceftriaxone-2/27 (7%); Cefuroxime-6/35 (17%)

  • 2 of 6 children who had hearing loss after cefuroxime therapy for Hib had delayed sterilization of the CSF i.e. 4 did not have delayed sterilization of CSF

Schaad et al N Engl J Med 1990;332:141-7

ceftriaxone vs cefuroxime for bacterial meningitis in children16
Ceftriaxone vs Cefuroxime for Bacterial Meningitis in Children
  • Hearing loss for S. pneumoniae

Ceftriaxone-0/7; Cefuroxime-2/6

None with hearing loss due to S. pneumoniae had delayed CSF sterilization

Schaad et al N Engl J Med 1990;332:141-7

ceftriaxone vs cefuroxime for bacterial meningitis in children17
Ceftriaxone vs Cefuroxime for Bacterial Meningitis in Children

Sensitivity-90/99=91% Specificity-2/7=29%

ceftriaxone vs cefuroxime for bacterial meningitis in children18
Ceftriaxone vs Cefuroxime for Bacterial Meningitis in Children
  • Four prospective studies conducted in Dallas-last 3 were dexamethasone trials. None of the studies were direct comparisons
  • Ceftriaxone-174; Cefuroxime-159
  • No significant differences between the groups at initiation of therapy

Lebel et al J Pediatr 1989;114:1049-54

ceftriaxone vs cefuroxime for bacterial meningitis in children19
Ceftriaxone vs Cefuroxime for Bacterial Meningitis in Children

Lebel et al J Pediatr 1989;114:1049-54

conclusions
Conclusions
  • Not clear how well repeat CSF culture at 24-36 hours after initiation of treatment predicts hearing impairment or

overall outcome (vast majority of patients with severe sequelae have sterile 2nd CSF)

● Not clear if findings for Hib meningitis are applicable to pneumococcal or meningococcal meningitis