1. Microbiologic Surrogates: An Industry Perspective Barry Eisenstein, MD Senior Vice President, Research and Development Cubist Pharmaceuticals Clinical Professor of Medicine, Harvard Medical School FDA/IDSA/ISAP Workshop April 15, 2004

2. Surrogate Endpoints: Substitute for clinical endpoints Measurable with minimal error Predictive of clinical outcome

3. The Use of Surrogate Endpoints for Accelerated Approval: Subpart H 1.“… reasonably likely… to predict clinical benefit…” 2.Requirement: “… verify and describe clinical benefit…” 3.Limited to conditions described as “serious or life threatening”

4. Accelerated Approval Under Subpart H: Incentive to Industry Positive incentive in indications with large patient populations and delayed clinical endpoints (e.g., HTN, LDL, HIV) –Earlier patient evaluation –Earlier submission of registration package –Possible earlier approval –No reduction in overall development cost because of requirement for clinical confirmation –Cost can be offset by early approval No incentive in indications with smaller populations –Difficult accrual leads to high development cost –Cost of demonstrating clinical benefit remains –Cost not offset by earlier approval in small treatment population

5. The Use of Surrogate Endpoints in Traditional Approval: Incentive? Allowed only when surrogate is fully validated –ID Examples: Urinary tract infection, Gonorrhea, Pharyngitis Full validation often impossible or not feasible –Can a superimposed infection be separated from an ultimately fatal disease? (e.g., VRE bacteremia in CA) –Followup often measured in years (e.g., osteomyelitis) More limited validation could provide enabling incentive –Reduced error in endpoint measurement increases power –Increased power permits smaller study populations –Smaller studies are more feasible –Major impact in serious indications that affect smaller numbers of patients

6. Potential Applications of Surrogate Endpoints: Anti-infective Examples Accelerated approval under Subpart H –Chronic viral infections: HIV, Hepatitis C? –Tuberculosis Surrogate endpoint with limited validation used in traditional approvals –Bacteremia –Osteomyelitis –Prosthetic joint infections –Sensitive isolates as surrogates for resistant isolates »VSE/VRE »MSSA/MRSA

7. Surrogate Microbiologic Endpoints: Considerations Causation vs. Correlation: 1 –Best surrogates are both necessary and sufficient in the causation of disease –Microbiologic surrogates: Satisfy Koch’s postulates Culture sample acquisition is critical –Ensure sterile access to otherwise sterile samples (avoid false positives) –Avoid sampling error (avoid false negatives) 1. Fleming and DeMets; Ann. Int. Med., 1996;125:605-13

8. Traditional Approval for Osteomyelitis: Currently Impossible? Hematogenous Osteomyelitis –Initial culture is clean (false positives unlikely) –False negatives possible (e.g., biopsy for vertebral osteomyelitis) –Post treatment culture not clinically feasible –Potential late recurrence Contiguous Osteomyelitis –Culture diagnosis fraught with error (false positives/negatives) –Potential late recurrence Prosthetic joint infection with adjacent osteomyelitis –Initial culture is clean (open surgery) –Post treatment culture is clean and standard of care –Infrequent late recurrence if (and only if) cultures are negative –Antibiotics needed in addition to surgery (no/weak placebo)

9. Staph. aureus Prosthetic Joint Infection (PJI) Serious Disease 1,2 –600,000 total arthroplasty procedures per year –12,000 PJIs per year –PJI associated mortality rate of 2.7-18% –Cost per episode of PJI: $30,000 to >$50,000 Clinical evaluation of cure requires prolonged follow-up Difficult and costly to enroll large numbers of patients 1.Berbari et al.; CID 1998; 27:1247-54 2.Darouiche; NEJM 2004; 350:1422-9

10. Management of PJI: Two stage, Delayed Reimplantation Arthroplasty Removal and debridement Optional local antibiotic (beads, cement) Systemic antibiotics: 4-6 weeks Interval off of antibiotics –Total knee arthroplasty (TKA) ~6-8 weeks –Total hip arthroplasty (THA) ~3 months Replace artificial joint and obtain intraoperative cultures during surgery: High specificity and sensitivity. Results of culture at reimplantation currently used as major indicator of therapeutic success

11. Impact of Antibiotic Therapy on PJI Two-stage vs. one-stage reimplantation arthroplasty 1 –91 cases of coagulase-negative Staphylococcus-infected THA –72 one-stage: 13% failure –12 two-stage: 0% failure Outcome with methicillin-sensitive vs. -resistant staph 2 –Failure defined as permanent excision or amputation –35 THAs and 35 TKAs reviewed THA TKA Sensitivity SRSR %success 81%48%89%18% 1.Hope et al.; J Bone Joint Surg Br. 1989; 71:851-5 2.Kilgus et al.; Clin Orthop 2002; 404:116-24

12. Surrogate in PJI: Negative Culture at Reimplantation is Predictive of Outcome 927 THA/TKA (Retrospective; 1980-1991) 200 Staph aureus 42 in staph group had delayed reimplantation 38 of 42 uninfected at reimplantation (22 THA and 16 TKA) Median follow-up of 7.4 years (0.9-16.4). Definite treatment failure occurred in 1/38 (2.6%) 1.4 years following reimplantation Two possible additional failures at 5.2 and 8.9 years (poorly documented). Negative predictive value: 97% at 5 yrs, 92-97% at 9 yrs. Brandt et al.; Mayo Clin Proc. 1999; 74:553-558

13. Concluding remarks Microbiologic surrogates for accelerated approval useful for large patient populations Microbiologic surrogates with limited validation used for traditional approval would enable development of drugs for treatment of smaller patient populations Promising example: PJI –Serious disease –Difficult to enroll many patients –Clinical test of cure not a feasible endpoint –Clean, predictive microbiologic surrogate endpoint –Negligible placebo effect