# Presentation: 229273

##  Issues in Antimicrobial Resistance and Antimicrobial Development

**John H. Powers, MD**
***Assistant Professor of Medicine***
***George Washington University School of Medicine***
***University of Maryland School of Medicine***

## Basic Principles

**Antimicrobial resistance is a reason to develop new antimicrobials, but same principles apply to antimicrobial development in general****	**
**Few drug sponsors develop drugs only for diseases due to resistant pathogens**
**Need for new drugs is always there but is not a reason to lower scientific/regulatory standards**
**Clinical trials in infectious diseases have not met FDA’s own standards for “adequate and well-controlled” trials**
**Antimicrobials are developed to treat “recognized disease or condition” not organisms (21CFR201.57)**
**Colonization is not a disease**
**Goal of prescribing antimicrobials is to improve health of people in terms of how they feel, function or survive**

## Basic Principles

**Principles of experimentation, drug development and regulatory issues apply to antimicrobials as they do to other therapeutic areas**
***In vitro***** testing and animal models are not “Bayesian” evidence but help form a hypothesis that requires confirmation in clinical trials**
**“****Bayesian” evidence would be prior clinical trials with a given drug – already incorporated in FDA regulations which allow one trial with confirmatory evidence**
**Highest success rates (28.1%) of any therapeutic class but not 100% (contrast with oncology (15.8% and respiratory 12.0%)**
**DiMasi J Clin Pharm Therapeutics 2001;**
**Addressed by courts in Upjohn v Finch in 1970 that in vitro data and animal models are not sufficient for approval of antimicrobials**

## Issues

**1) Defining “resistance” and clinical impact for patients**
**2) *****Better***** and more efficient clinical trial designs**
**3) Appropriate information in labeling to describe conditions of use of antimicrobials based upon current science**
**4) Data on antimicrobial usage in animals and humans**
**5) Updating of FDA guidances for animal and human drug development**
**6) Incentives**

## 1) Defining Resistance

**Changes in amount of drug needed to inhibit growth of an organism is a test tube may or may not reflect changes in clinical outcomes in patients**
**Antimicrobials one of only classes in which changes in EFFECTIVENESS over time is the rule**
**FDAAA requires FDA to update definitions of “resistance” at least every 5 years**

## 1) Defining Resistance

**FDA cannot and should not delegate regulatory authority to those outside the agency to accomplish this task**
**FDA already has methods to get outside advice through advisory committee process**
**New methods to formalize process?**
**FDA efforts to acquire safety data from other public agencies and private partners should include data on effectiveness of antimicrobials are well**
**Need clinical data to assess impact of in vitro changes**
**Final authority to make changes to labeling should rest with FDA**
**Weinberger v Hynson, Westcott and Dunning 1973 **

## 2) Better Clinical Trials

**Has become evident that inappropriate use of non-inferiority trials actually contributes to problem of antimicrobial resistance and excess adverse events in patients**
**FDA guidance on non-inferiority trials is huge step forward in addressing this issue**
**FDA can and should change “previous agreements” when science changes (already specified in FD&C Act)**

## 2) Better Clinical Trials

**Better enrollment criteria – need defined disease  **
**Enrollment of patients without disease exposes them to unnecessary harm**
**Dilutes out treatment effect**
**Need point of care rapid diagnostics**
**Better outcome measurements – **
**no need for biomarkers in acute infectious diseases**
**More precise measures of outcomes important to patients**
**Lack of evidence of validity of “clinician reported outcomes”**

## 3) Appropriate Conditions of Use

**Use of antimicrobials is greatest in self-resolving infectious diseases**
**Acute otitis media**
**Acute bacterial sinusitis**
**Acute execerbations of chronic bronchitis**
**Current evidence shows basis for approval of these drugs (non-inferiority trials) not sufficient to differentiate ineffective drugs from placebo**
**Labeling still remains unchanged for these drugs**
**This is a patient safety issue since relates to appropriate conditions of use of drugs**
**Misleading to physicians and patients**
**Unfair to drug sponsors who now will do placebo controlled trials**

## 4) Data on Usage

**Need accurate data on antimicrobial drug usage in animals and humans**
**FDA currently receives data on animal drug usage but not in usable form**
**Change reporting to be on yearly basis so data in usable and comparable across drugs**

## 5) Update FDA Guidances

**Update Guidance 152 based on WHO meeting ranking of drugs according to importance in human medicine**
**Updating of 1992 “Points to Consider” document and 1998 FDA guidances  based on current appropriate scientific principles**
**All guidances need updating on regular basis based on new information**

## 6) Incentives

**How will incentives promote the public health? What will patients get in return for incentives to industry?**
**Need data showing superiority of newer drugs to older agents in disease due to resistant pathogens**
**Non-inferiority illogical when showing that new drug might be less effective than older drug that one claims is no longer effective**
**Better safety profile would justify slightly less effectiveness**
**A “new class” is a pharmacological distinction, not evidence of improved outcomes for patients**
**Incentives to develop rapid point of care diagnostics and studies that show clinical impact of such diagnostics**

## Conclusions

**The risks of inappropriate clinical trials is to patients, not just to drug sponsors**
**We can and must do better in developing antimicrobials that provide added benefit to patients, not something that’s a little worse than what we already have**
**FDA can and should provide leadership to help advance public health**