# Presentation: 416477

## Regulatory and Other Incentives for Antibiotic Development

- David M. Cocchetto, Ph.D.
- PhRMA Antibiotics Working Group & GlaxoSmithKline
- November 19, 2002

## Two Factors Affecting Discovery and Development of New Antibiotics

- Medical need exists for new antibiotics to treat patients with resistant pathogens of public health importance
- Discovery and development of new antibiotics are at a competitive disadvantage in an R&D portfolio

## Why Are New Antibiotics at a Disadvantagein R&D Portfolios?

- Most antibiotics are used for limited durations of treatment
- Prescribers increasingly try to avoid non-essential use of antibiotics  (to  selection pressure for resistance and  cost of care)
- Growth of antibiotics’ market value is considerably below the average growth for other classes of prescription drugs
- Declining prescription volumes for antibiotics

## Prescriptions for Antibacterial Drugs

**Prescriptions for Antibacterial Drugs**

- Source:  GSK database, MAT to June 2002  (indexed to 1997)

**Prescription volumes  for antibiotics  are declining**

## What Can Be Done To Position Antibiotics More Favorably in R&D Portfolios?

**Incentives:**   current & new incentives
- Cost side:  increase efficiency (and **** cost) of development of an antibiotic for resistant pathogens
- Return side:  reduce uncertainty & solidify the return on R&D investment in such drugs
**Receptive environment:  the medical community & health regulatory authorities recognize the need for new product development**
**Application of current incentives (Subpart E, Subpart H, Fast Track Designation, Priority review)**
**Clarify achievable labeling via Guidance**

##  Possible Incentives for R&D on Antibiotics:  Market Exclusivity

- Extend market exclusivity for the antibiotic
**Not a substantial incentive for a niche product focused solely on resistant pathogens (due to limited use of the drug)**
- Extend market exclusivity for another prescription drug owned by the sponsor
**“****wild card” exclusivity - *****high potential impact***
- An exclusivity incentive would require a change in law

## Possible Additional Incentive:   A Guidance on Development & Labeling of Antibacterial Drugsfor Treatment of Resistant Pathogens

**Reduces uncertainty !**
**On regulatory expectations**
**On the investment needed to work in  this area of R&D**
**By identifying points of medical/scientific debate (so that such points can be addressed in the development program)**
**By providing transparency regarding labeling expectations and likely Phase IV activities**

##  Guidance Can Be An Incentive . . .

- Proceedings of this workshop and other clear statements of interest (by regulatory authorities and ID experts) in new antibiotics
- FDA / IDSA Guidance that encourages timely development of new antibiotics (particularly products for drug-resistant pathogens)
- FDA Guidance that describes the labeling that can reasonably be expected based on a sponsor’s successful completion of *in vitro*, animal, pk/pd, and clinical studies

## Guidance Could Address Inclusion of  More Information on Activity/Efficacy in Labeling

- PhRMA suggests that a hierarchy of  labeling outcomes should be attainable from an NDA providing a hierarchy of activity/efficacy evidence for the drug against drug-resistant bacteria:
*    **In vitro* data  ****  pk/pd data  ****** **  evidence of
-                                                         clinical efficacy

## Question for Consideration

- Do the workshop participants support inclusion in FDA Guidance of a hierarchy of  labeling outcomes based on increasing evidence of activity/efficacy against resistant pathogens, as outlined in the following examples?
*Let’s look at 3 scenarios . . . *

## Scenario # 1:  In Vitro Data

- Sponsor presents data showing the *in vitro* susceptibility of clinical isolates to an antibiotic, and also documents *in vitro* resistance of these clinical isolates to one or more other antibiotics

## Scenario # 1:  PhRMA Proposal

- The results of *in vitro* testing should continue to be included in the **MICROBIOLOGY** section of labeling under the following statement:
-    "The following *in vitro* data are available, but their clinical significance is unknown.  The effectiveness of Drug X in treating clinical infections due to these microorganisms has not been established in adequate and well-controlled clinical trials."

## Scenario # 2:  In Vitro + PK/PD  Data

- Sponsor presents data demonstrating a pk/pd relationship in humans that is applicable to the resistant pathogen of interest, thereby showing a reasonable likelihood of clinical benefit in patients with an infection due to this resistant pathogen **(**e.g., mean serum drug concentrations associated with benefit in an appropriate animal model of infection are reached or exceeded in humans)

## Scenario # 2:  PhRMA Proposal

**A statement would be included in the INDICATIONS AND**
**USAGE section of labeling.  A model statement is**
**suggested as follows:**
-     **"Drug X is indicated for treatment of patients with infection Y due to pathogen Z.  ****Drug X has been shown to be active against Pathogen Z both *****in vitro***** and by use of serum drug concentrations as a surrogate marker****.  The pharmacokinetic properties of Drug X have been evaluated in humans and compared to concentrations needed for bacterial killing of Pathogen Z.  ****Serum concentrations of Drug X over time in humans serve as a surrogate endpoint that is reasonably likely to predict clinical benefit and provide the basis for this indication.  Direct evidence of clinical efficacy is not yet available****."**
- Example:  Cipro (ciprofloxacin) for post-exposure treatment of inhalational anthrax

## Scenario # 3:  Clinical Efficacy

- Sponsor presents evidence of clinical efficacy of the drug in a small number of well documented cases with an infection due to the resistant pathogen of interest, recruited into a "catch all" protocol (with isolation of the resistant pathogen from any relevant body site)

## Scenario # 3:  PhRMA Proposal

- A conventional statement would be included in the **INDICATIONS AND USAGE** section of labeling.  A model statement is suggested as follows:
-     **"Drug X is indicated for treatment of patients with infection Y due to pathogen Z."**
- In addition, the **CLINICAL STUDIES** section will summarize the clinical data on efficacy of the drug for this specific pathogen

## Summary

- Antibiotics are disadvantaged in an R&D portfolio
- Incentives are needed to stimulate investment in antibiotics for drug-resistant pathogens
- Viable incentives can be achieved via “wild card” market exclusivity and a new Guidance
- Durable medical interest in new antibiotics and provision of clear regulatory guidance (including guidance on achievable labeling) are important incentives within the scope of this workshop