# Presentation: 155415

## Drug Development for Diabetic Foot Infections: Lessons Learned 

**Alfred F. Sorbello, DO, FACOI**
**Medical Officer, CDER/DAIDP**

**Anti-Infective Drug Advisory Committee Meeting**
**October 28, 2003**

## Introduction

**Defining Diabetic Foot Infections**
**Classifying Diabetic Foot Infections and Foot Ulcers**
**Characterization of Study Population**
**Adjunctive Treatment Measures**
**Microbiologic Considerations**

## Definition of a Diabetic Foot Infection

**No generally-accepted definition**
**Foot infections in diabetics can be ulcer- or non-ulcer related**
**~15% of diabetics develop chronic non-healing foot ulcers**
**Not all chronic foot ulcers are infected**
**Clinical trials**
**Broad studies of cSSSIs with supplemental studies involving diabetic foot infections**
**Eligibility criteria **
**Specific disease entities **
**Discrete clinical findings **
**Presence/absence of a foot ulcer**

## Common Lower Extremity Problems in Diabetics 

**Developmental foot deformities**
**hammer toes, valgus deformities**
**Soft tissue changes**
**chronic lower extremity edema**
**dependent rubor**
**stasis dermatitis**
**chronic ulcers colonized with bacteria**
**Decreased peripheral pulses**
**Sensory peripheral neuropathy**
**Charcot (neuropathic) joints**

## Comparative Prognostic Factors in Diabetics with Osteomyelitis of the Foot

**Bamberger et al. *****Am J Med***** 1987;83:653-660**

*** statistically significant**

## Clinical Trials: Framework for a Definition for a Diabetic Foot Infection

**Presence or absence of:**
**open wound, foot ulcer, break in skin**
**clinical findings**
**Anatomic location of primary site**
**Depth of infection**
**   ****(skin/soft tissue vs. bone/joint)**
**Isolation of pathogenic bacteria from an appropriate culture specimen**

## Classification Systems for Diabetic Foot Infections

**Classification systems**
**Severity of Infection**
**Foot Ulcer (Wound)**

**No generally-accepted classification**
**Differ in criteria & complexity**
**Require validation for clinical trials**

## Classification Systems for Severity of Diabetic Foot Infections

**Limb-threatening vs. non-limb threatening**
**Mild, moderate, severe**

## Classification Systems for Diabetic Foot Ulcers

- 			•**Wagner**
**	****	****	****•****Univ of ****Texas**
**	****	****	****•****S(AD) SAD**
**	****	****	****•****Simple staging**

## Clinical Trials: Framework to ClassifyDiabetic Foot Infections

**Standardize definitions **
**clinical disease entities**
**assessments of ischemia, neuropathy**
**Correlate with extent, natural history, and prognosis of the infection**
**Distinguish skin/soft tissue from bone/joint infections**
**Would need validation**

## Characterization of Study Population

**Demographics**
**Co-morbidities**
**Baseline Assessments**
**Clinical Diagnoses**

## Demographics and Co-morbidities

**Age**
**Gender**
**Race**
**Weight**
**Country of Origin**
**Study Center/Site**

**Type 1 vs type 2 DM**
**Peripheral neuropathy**
**Peripheral vascular disease**
**Renal insufficiency**
**History of osteomyelitis**
**History of lower extremity surgery**
**podiatric, orthopedic, vascular**

## Baseline Assessments

**Laboratory**
**hematology**
**chemistry**
**HgbA****1****C**
**C-Reactive Protein**
**Wound, tissue, and blood cultures**

**Radiologic imaging**
**Vascular evaluation**
**Neurologic exam**
**Pulse oxygenation measurement (toe)**
**Wound or ulcer dimensions**

## FDA

_**CRF Tabulation**_

_**FDA**_

**Heterogeneity of Baseline Clinical Diagnoses:**
**CRF Tabulation**

## Adjunctive Treatment Measures

**Adjunctive treatments permitted per protocol to *****augment wound healing***
**Are they utilized equally in all subjects in both treatment groups?**
**Could adjunctive treatments make two dissimilar drugs appear indistinguishable?**

## Adjunctive Treatments and Clinical Outcome

**EOT = end of therapy; N = number of subjects**

**Trend indicative of improved cure rate associated with increasing number of debridements.**

## Microbiologic Considerations

**Identify** **pathogens**
- among polymicrobial infections
**Standardize culture methodology**
- swabs, curettage, biopsy
**Microbiological outcome**
**Presumed** **pathogen eradications** predominate due to healing of pre-therapy wounds/ulcers
- outcome endpoints are **clinically-driven**
- follow-up cultures should be performed in treatment failures

## Guidance Development for DFIs 

**Define and classify diabetic foot infections and foot ulcers **
**Characterize study population**
**Primary focus is on clinical outcome  **
**Standardize microbiologic methodology**
**Effect of adjunctive treatment(s) on clinical outcome**
**Separate clinical trials to assess drug development for bone and joint infections**