1. 1 FDA Trial Design Requirements for HABP/VABP 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 at least in HABP/VABP. 4

5. HABP/VABP Endpoint 28 d mortality in the context of a HABP/VABP trial is a confounded variable that depends as much on comorbidities as it does on pneumonia. A more appropriate endpoint based on clinical outcomes could easily be justified using pharmacometrics – why don’t we take advantage of this for M1 and M2 calculations? 5

6. Margin and Trial Size The 20% or higher mortality rates required and the approach using an 80% power to keep sample size down increases the sponsor risk. The 10% NI margin is MUCH too conservative and the OR method makes things worse as you decrease mortality rates. –M1 based on the 95/95 discounting –But uses “inappropriate” therapy as opposed to NO therapy – therefore the setpoints for treatment effect are already conservative. The possibility to carry out a single trial in VABP and obtain an indication for HABP and VABP is attractive but why are we doing this to ourselves? 6

7. Prior Antibiotic Use Virtually all patients in the ICU and 60-80% of patients in hospitals for any length of time receive antibiotics. Why should we try and limit our trials to outliers? We actually want to enroll patients with prior treatment into our trials to enroll patients more likely to have resistant pathogens so that we can test whether new products work as expected against such infections. Are there data that suggest that HABP/VABP patient outcomes are affected by prior antibiotic use? Data cited in the docket indicates that outcomes are affected in a negative way – therefore prior use is a conservative approach. 7

8. HABP/VABP is an Area of High Medical Need Given the urgent medical need for new antibiotics to treat patients with antibiotic- resistant infections in this indication, why are we making it impossible to get drugs approved for Americans? Number of ongoing phase III trials for new antibiotics in HABP/VABP– 0!!! But several new drugs are on the cusp of starting such trials. 8

9. Going Forward Declare an immediate moratorium on implementation of the 2009 Draft Guidance. –Go back to previous guidance while awaiting new guidance. –This will eliminate the proscription against prior antibiotics as well. Use pharmacometrics to define an M1 for HABP/VABP and derive an appropriate M2 and NI margin for clinical outcome at TOC. EMA has allowed 15-20% NI trials with a primary endpoint of clinical outcome at TOC and they are willing to discuss use of pharmacometrics. 9

10. Antibiotic Market Dynamics 10

11. Alternative If we do not provide a regulatory pathway for new antibiotics in the US – –Americans will be deprived of new antibiotics for key indications other than off label (paid for by Medicare and other payors). –The US market for antibiotics will be further marginalized putting Americans in a take it or leave it position for new antibiotics. –Companies will shift their focus overseas leading to a US innovation drain – this is already occurring. DON’T LET THIS HAPPEN! 11