Microbiologic Surrogate Endpoints in Clinical Trials-IDSA FDA/IDSA/ISAP Workshop April 15, 2004 Sheldon L. Kaplan, MD Baylor College of Medicine Texas.

Microbiologic Surrogate Endpoints in Clinical Trials-IDSA

FDA/IDSA/ISAP WorkshopApril 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

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

• Group A streptococcus pharyngitis

• Uncomplicated lower urinary tract infection

• Shigella gastroenteritis

Infections For Which Microbiologic Surrogate Endpoints

Are 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

Infections For Which Microbiologic Surrogate Endpoints

Are 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

Infections For Which Microbiologic Surrogate Endpoints

Are 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

• 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

Imo Ibia, MD, MPH

Medical Officer

FDA/CDER/DSPIDP

November 20, 2002

Office of New Drugs IVOffice of New Drugs IV

Center for Drug Evaluation and ResearchCenter for Drug Evaluation and Research www.fda.gov

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• 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

• 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

• 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 Children

Variable Ceftriaxone Cefuroxime P value

+ CSF culture at

f/up (all Hib)

1/52 6/52 0.112

Hearing loss 2 (4%) 9 (17%) 0.052

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

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 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 ChildrenHearing Repeat

CSF sterile

Repeat CSF

positive

Total

Normal 90 5 95

Impaired 9 2 11

Total 99 7 106

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

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 Children

Variable Ceftriaxone Cefuroxime P value

+ CSF culture at

f/up

“Uniformly sterile”

14/157

(8.9%)

< 0.001

Hearing loss 16/148

(11%)

25/139

(18%)

NS

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

Meropenem vs Cefotaxime for Bacterial Meningitis in Children

End of Treatment

Evaluable

Meropenem

N=79

Cefotaxime

N=75

Cure 36 (46%) 42 (58%)

Mild sequelae 21 20

Severe sequelae 20 10

2nd CSF sterile 75 (95%) 72 (96%)

2nd CSF delayed sterilization

2

Hib

1

Hib

Odio et al Pediatr Infect Dis J 1999;18:581-90

Trovafloxacin vs Ceftriaxone for Bacterial Meningitis in Children

End of Treatment

Evaluable

Trovafloxacin

N=108

Ceftriaxone

N=95

Cure 53 (49%) 57 (60%)

Mild sequelae 28 21

Severe sequelae 20 13

Failure 5 1

2nd CSF delayed sterilization

5 3

Sáez-Llorens et al Pediatr Infect Dis J 2002;21:14-22

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