1. 1 FDA Trial Design Requirements for CABP David M. Shlaes MD, PhD Anti-infectives Consulting, LLC Stonington, CT

2. Disclosures I consult for the pharmaceutical industry. –See my website – www.antiinfectivesconsulting.com for a list of recent clients. www.antiinfectivesconsulting.com I am an IDSA member – participated in drafting Bad Bugs, No Drugs. The opinions expressed here are my own. 2

3. About Me 16 year career as an academic physician scientist at the Cleveland VAMC and CWRU School of Medicine. 15 year career in industry 31 years working on antimicrobial resistance and antimicrobial product discovery and development. 3

4. FDA and Antibiotics We need a strong, vibrant, scientifically- based, interventionist FDA to assure that we have efficacious and safe drugs. To help combat infections caused by resistant pathogens, we need a robust pipeline of new antibiotics. These two concepts are still mutually exclusive. 4

5. Feasibility The FDA is to be commended for their approach to making trial design for CABP feasible at least as far as required trial size is concerned. An NI margin of 15% plus the possibility of pooling microbiologically documented patients across two studies or simply allowing the conduct of a single study (given additional supporting data) makes the trial size feasible. An NI margin of 10% would take us back to infeasible numbers. The proscription against prior antibiotics remains a roadblock to trial feasibility. 5

6. Recent Experience – Phase II, IV- Oral Antibiotic US, Canada, Hungary, Poland. Difficulty recruiting investigators in the US - most sites contacted don’t want to participate due to restrictions on prior antibiotic use. High percentage of long-acting antibiotic use (quinolones, azithromycin) both for US and EX-US sites. Overall they screened over 860 patients to recruit approximately 32 patients. 220 of the ~860 were disqualified due to prior antibiotic use, largely occurring in days prior to ER –hospital admission. 6

7. Recent Experience – Phase II, IV-Oral antibiotic Not able to change behaviors of ER staff in the US. – due to ingrained rules from hospital quality procedures, despite training and reinforcement to not give long acting antibiotics in ER – contributed to sizeable number of screen fails. They enrolled a total of 32 patients of > 860 screened. 7

8. Endpoints I have not addressed the issue of endpoints. There are many MDs who believe that the early endpoints are less relevant than the traditional TOC endpoint and that they should therefore be secondary, not primary. In this regard, why does the FDA not want to use newer methods for establishing treatment effects to establish M1 and M2 (pharmacometrics)? 8

9. 9 Striking the Right Balance Reduce cost of development and maintaining license Protect Intellectual Property Level playing field Reduce barriers to entry More effective and timely responses to emerging public health needs e.g. resistance FDA CDC Public Companies Acceptable risk for reasonable overall return Prudent use of novel agents supported by surveillance for emerging pathogens or resistance Better postmarketing surveillance for safety Presented by PhRMA to FDA 2002

10. Today and Tomorrow Number of ongoing Phase III trials for new antibiotics for CABP today = 0! Just because resistance is not an issue for CABP (or other RTIs) today, does not mean it will not be a problem in 10 years (e.g. VRE). 10

11. Conclusions In its briefing materials for this meeting, the FDA has made clear progress. We are still not quite there. –We need to change our approach to enrolling patients who have had prior antibiotics (stratification?). –We need to keep the NI margin reasonable for oral antibiotics if we ever want any to be developed for pneumonia. –Endpoints should be reconsidered using pharmacometrics to define M1 and M2 for clinical outcome at TOC. 11