# Presentation: 855899

## 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**

## Surrogate Endpoints:

**Substitute for clinical endpoints**
**Measurable with minimal error**
**Predictive of clinical outcome**

## 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”**

## 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**

## 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**

## 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**

## 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

## 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)**

## 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**
- Berbari et al.; CID 1998; 27:1247-54** **
- Darouiche; NEJM 2004; 350:1422-9

## 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**

## 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 | THA | TKA | TKA |
| --- | --- | --- | --- | --- |
| Sensitivity | S | R | S | R |
| %success | 81% | 48% | 89% | 18% |

- Hope et al.; J Bone Joint Surg Br. 1989; 71:851-5
- Kilgus et al.; Clin Orthop 2002; 404:116-24

## 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** **

## 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**