Hepatitis C: Perspective on Drug Development Issues Debra Birnkrant, M.D. Director, Division of Antiviral Products FDA Antiviral Drugs Advisory Committee October 19 and 20, 2006

2 Hepatitis C Infection United States New infections (cases)/year ,000 Persons ever infected ~ 4 million Persons with chronic infection~ 3 million Most common indication for liver transplantation Deaths /year ~ 10,000 ~ 170 million chronically infected worldwide

3 Hepatitis C Infection: Therapy Five interferon alpha products approved alone or in combination with ribavirin Pegylated interferon with ribavirin = SOC –Limited efficacy in certain subgroups –Tolerability issues –Cost

4 Polymerase Inhibitors Protease Inhibitors Interferons TLR agonists Antisense oligonucleotides Cyclosporine A analogs Other

5 Meeting Scope Solicited information from HCV IND sponsors on clinical trial design issues: –Patient populations –Controls for phase 3 studies –Clinical trial designs –Endpoint(s) to evaluate efficacy –Long-term follow-up of patients

6 Patient Population(s) at the Time of Initial Approval Naïve or experienced Compensated or decompensated Genotype Co-infection Liver transplantation Pediatrics Racial or ethnic subgroups

7 Control Groups Placebo controls SOC control Deferred therapy vs immediate therapy –Need to consider patient population

8 Clinical Trial Designs Adding investigational agent to SOC Lower dose +/- shorter duration of PEG-IFN plus investigational agent Ribavirin substitution Use of 2 or more investigational agents Monotherapy

9 Endpoints Histologic, virologic and biochemical Timing –SVR 12 –SVR 24 Patient population dependent

10 Agenda Epidemiology, natural history and viral kinetics Trial design difficulties Community perspective FDA summary of industry responses Questions and discussion