# Presentation: 267646

## Developing Drugs for the Treatment of Infections due to Resistant Pathogens

**IDSA/PhRMA/FDA Workshop**
**November 19, 2002**
**Edward Cox, M.D., M.P.H.**
**Division of Special Pathogen and Immunologic Drug Products**
**Center for Drug Evaluation and Research**
**U.S. Food and Drug Administration**

## Identifying RP of PH Importance

**Which resistant pathogens (RPs) rise to the level of posing a significant public health (PH) problem in a specific indication(s)?**
**Antimicrobial resistance is a dynamic problem evolving over time**
**How do we identify these RPs?**

## Identifying RPs of PH Importance -       A Characteristic-based Approach

**Characteristics to identify resistant pathogens that pose a significant public health problem within an indication(s)**
**The RP should  meet some, but not necessarily all of the characteristics**

## Identifying RPs of PH Importance -       Characteristics

**Organism of sufficient prevalence**
**Organism of sufficient virulence**
**Data to show resistance affects outcomes**
**Is the drug commonly used to treat infections due to the organism?**
**Insufficient therapeutic alternatives**
**Is the organism resistant to multiple drug classes?**
**Resistance affects therapeutic decision making**
**Drug is an essential treatment to prevent spread of a disease in the population (e.g. TB, STDs)**

## Identifying RPs of PH Importance

**RPs for which we have previously awarded claims**
**Other RPs - Sponsors submit data addressing the characteristics of a RP of PH importance**
**Other proposals**

## Prior FDA Meetings on Resistance

***General***
**July, 1998**
**October, 1998**
**October, 1999**
**February, 2002**
***Product-specific***
**Synercid****	****	****February, 1998**
**Levaquin****	****	****October, 1999**
**Zyvox****	****	****	****April, 2000****	****	**
**AugmentinES****	****January, 2001**

## Types of Data - 1

## Types of Data - 2

**Quality of the agent in treating **
**the indication, e.g. CAP**
**the pathogen of interest including susceptibles**
**serious infections due to the pathogen of interest**
**the resistant pathogen of interest**

## Types of Data - 3

**To what degree can we rely on data other than clinical outcomes data (e.g. PK/PD, in vitro, animal model data) for the subject resistant pathogen in the target indication to provide support for a resistant pathogen claim?**
**What level of evidence should these data provide?**
**For out-of-class claims?**
**For in-class claims?**

## Data from Other Indications - 1 

**   ****What role can efficacy data from other indications for the same resistant organism play in supporting efficacy?**
**Can HAP support CAP?**
**Can meningitis data support CAP?**
**Can CAP support meningitis?**
**Can cSSSI data support HAP?**
**Can uUTI data support HAP?**
**Can OM data support ABS & vice versa?**

## Data from Other Indications - 2 

**   ****Factors to consider when weighing data from other indications?**
**Similarity of disease process across disease sites**
**Organs/tissues involved**
**Drug levels achieved**
**Spectrum of disease severity**
**Host differences**
**Certainty of diagnosis across sites**

## Points for Discussion

## Points for Discussion - 1

**    ****What are the characteristics that would deem a resistant organism to be “of public health importance”? Please include in your discussion such points as:**
**The prevalence of the organism in the disease under study**
**The virulence of the organism in question**
**How commonly is the drug used to treat infections caused by the organism**
**The availability of alternative therapies for the disease under study**
**Organisms resistant to multiple drug classes**
**Drug is an essential treatment to prevent spread of the disease in the population (e.g. sexually transmitted diseases) where vaccines are not available**
**Data demonstrating the correlation of *****in vitro***** resistance with clinical outcomes**

## Points for Discussion - 2a

-     **Please discuss the nature of the clinical data needed to demonstrate efficacy for a drug against resistant pathogens. Please include in your discussion such points as:**
**Demonstration of efficacy in the disease in which the resistant pathogen is most likely to be present (e.g. efficacy in hospital-acquired pneumonia when studying MRSA, complicated intra-abdominal infections for VRE).**
**The utility of demonstration of efficacy in susceptible isolates of the pathogen as it relates to efficacy against resistant pathogens. How does this equation differ for “in-class” resistance (e.g. a glycopeptide for VRE) as opposed to “out-of-class” resistance (e.g. a quinolone for PRSP)?**

## Points for Discussion - 2b

-     **Please discuss the nature of the clinical data needed to demonstrate efficacy for a drug against resistant pathogens. Please include in your discussion such points as:**
**Can one use efficacy in one disease to support efficacy in another disease? Please discuss such points as:**
**The severity of the disease in question (e.g. can microbiologically proven ABS support CAP?)**
**Relevance of the site of infection (e.g. can UTI studies support efficacy in pneumonia?)**
**Certainty of the diagnosis in question (can AECB support other respiratory tract infections?)**

## Points for Discussion - 2c

-     **Please discuss the nature of the clinical data needed to demonstrate efficacy for a drug against resistant pathogens. Please include in your discussion such points as:**
**In an effort to obtain quality data, what would help to define a “well-characterized” case of a given infection caused by a resistant pathogen? Please discuss such points as:**
**The certainty of diagnosis (e.g. bacteremia vs. other forms of disease)**
**The severity of disease (e.g. VRE UTI vs. intra-abdominal infections)**
**Certainty of poor outcome in absence of effective antimicrobial therapy (e.g. endocarditis or meningitis)**
**How comorbid conditions impact on assessment of outcome**

## Points for Discussion - 3

-     **Please discuss the strengths and limitations of data other than that obtained from Phase 3 clinical trials in supporting the demonstration of efficacy of drugs for resistant pathogens? Please include in your discussion such points as:**
**In vitro measurement of MICs/ MBCs**
**Animal models of infection**
**Pharmacokinetic and pharmacodynamic studies**