Microbiologic surrogate endpoints in clinical trials idsa fda idsa isap workshop april 15 2004
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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 l.jpg

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


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


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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 l.jpg
Infections For Which Microbiologic Surrogate Endpoints http://www.fda.gov/www.fda.gov/cder/Offices/Biostatistics/presentations.htmAre 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 l.jpg
Infections For Which Microbiologic Surrogate Endpoints http://www.fda.gov/www.fda.gov/cder/Offices/Biostatistics/presentations.htmAre 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


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Infections For Which Microbiologic Surrogate Endpoints http://www.fda.gov/www.fda.gov/cder/Offices/Biostatistics/presentations.htmAre 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


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Infections For Which Microbiologic Surrogate Endpoints http://www.fda.gov/www.fda.gov/cder/Offices/Biostatistics/presentations.htmAre 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 l.jpg
Infections For Which Microbiologic Surrogate Endpoints http://www.fda.gov/www.fda.gov/cder/Offices/Biostatistics/presentations.htmMay 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 l.jpg

Antimicrobial Drug Development http://www.fda.gov/www.fda.gov/cder/Offices/Biostatistics/presentations.htmfor 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 l.jpg
Outcomes http://www.fda.gov/www.fda.gov/cder/Offices/Biostatistics/presentations.htm

  • 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


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Evaluations http://www.fda.gov/www.fda.gov/cder/Offices/Biostatistics/presentations.htm

  • 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 l.jpg
    Outcome of Bacterial meningitis http://www.fda.gov/www.fda.gov/cder/Offices/Biostatistics/presentations.htm

    • 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


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    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


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    Ceftriaxone vs Cefuroxime for Bacterial Meningitis in Children

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


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    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 l.jpg
    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 l.jpg
    Ceftriaxone vs Cefuroxime for Bacterial Meningitis in Children

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


    Ceftriaxone vs cefuroxime for bacterial meningitis in children18 l.jpg
    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 l.jpg
    Ceftriaxone vs Cefuroxime for Bacterial Meningitis in Children

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




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    Conclusions Children

    • 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


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