Microbiologic Surrogates: An Industry Perspective

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 • “… reasonably likely… to predict clinical benefit…” • Requirement: “… verify and describe clinical benefit…” • 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 Disease1,2 • 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 • Berbari et al.; CID 1998; 27:1247-54 • 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 arthroplasty1 • 91 cases of coagulase-negative Staphylococcus-infected THA • 72 one-stage: 13% failure • 12 two-stage: 0% failure • Outcome with methicillin-sensitive vs. -resistant staph2 • Failure defined as permanent excision or amputation • 35 THAs and 35 TKAs reviewed • Hope et al.; J Bone Joint Surg Br. 1989; 71:851-5 • 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