1. Predictors of orphan drug approval Harald E. Heemstra, PhD hheemstra@pharmerit.com European Conference on Rare Diseases Krakow, 15 May 2010 15 May 2010 Xxx Company X Xxx Company X Xxx Company X Harald Heemstra, PhD hheemstra@pharmerit.com

2. Introduction Utrecht InstituteforPharmaceutical Sciences Dutch Steering CommitteeonOrphan Drugs

3. Aim of the presentation To discuss predictors of successfully obtaining marketing authorization for orphan drugs in the European Union or the United States Based on the results of two studies

4. Regulation (EC) No. 141/2000 of the European Parliament and of the Council The Orphan Drug Act. United States Public Law No 97-414. 1983 Incentivemeasuresfororphan drugs in the EU and the US

5. The three stage process to patientaccess Marketingauthorization Orphandesignation National authorities decide Differences in access and reimbursement throughout the EU Market Access Centralised procedure mandatory for designated orphan drugs Authorisation valid throughout the EU Onlydesignationas potentialOD No marketing authorization

6. Orphan drug development in the EU #ODs=8.8*y + 13.3 (R2=0.87) #authorizedODs=1.0*y + 0.6 (R2=0.76) www.ema.europa.eu

7. #authorizedODs=1.2*y + 4.6 (R2=0.83) Orphan drug development in the US #ODs=11.8*y + 44.5 (R2=0.86) www.fda.gov/orphan

8. Is orphan drug development in the EU laggingbehind the US? 1Designations active at April 2010 only 2Corrected forindicationextensions

10. High costsII. Increasing number of orphan designations I. Increasing awareness 2000 2005 Adapted from: Leufkens, Epposi 2007

11. Slow developmentof anorphandesignated product intoanapproved product Low quality of the clinicaldevelopment program Poordocumentation Manyuncontroled trials / small sample sizes Criticismon the speed of orphan drug development in the EU Joppi et al. Br J ClinPharmacol2009

12. Design of the study A1 A2 … A36 2000 D1a/D1b/D1c D2a/D2b/D2c … Dxa/Dxb/Dxc 2006 Comparison of authorized EU orphan drugs (cases) with designated products (controls) Study period: Jan 2000-Oct 2006 Case control design Controls are matched 1:3 on date of designation Controls are sampled from total cohort (n=386) Public domain data Comparison of the products on three groups of characteristics: Characteristics of the indication Characteristics of the product Characteristics of the sponsor

13. Predictors of orphan drug development in the EU 17.3 (5.6-53.1) 3.9 (0.9-16.6)

14. Follow-up studies including FDA and EMA data

15. Predictors of orphan drug failure in the US Interaction and dialogue with regulatory authorities Scientific advice / guidance meetings Discuss and agree on the design issues of the clinical trials Comply to outcomes of these discussions Informal at meetings/conferences Design of the pivotal trial: Endpoint selection Choice of target population

16. Experience Sponsor Drug substance/formulation Interaction with regulatory authorities Consensus and compliance to agreements on trial design Careful design of the clinical trial Endpoint selection Target population Take home message: predictorsforsuccessfulorphan drug development

17. Thankyou! Harald E. Heemstra, PhD hheemstra@pharmerit.com