1. Introduction to EPARs and FDA Approval Packages: Finding and Analyzing Unpublished Information about Pivotal Studies 23 June 2008 Session Chair: Amy N. Grant, MS Director, Regulatory Strategy & Science ViroPharma Incorporated

2. 2 Learning Objectives Identify the basic structure of EPARs and FDA approval packages; Take away techniques for finding and analyzing key parts of assessment reports and approval packages that can be used to support decision making in drug development; and Discuss examples of analyses of EPARS and FDA approval packages from health authorities, academia, and industry

3. 3 Speakers Marlene Bobka - A Pragmatic Journey through FDA Approval Packages and Other Key Materials: Researching Drug Studies Amy Grant - Introduction to European Public Assessment Reports (EPARs) and Researching Drug Studies Linda Bowen - Researching Drug Studies across European Public Assessment Reports (EPARs) and FDA Approval Packages Question & Answer Session

4. Milestones US 42 Years Freedom of Information Act of 1966 First FDA Summary Basis of Approvals (SBAs) 1970’s Privacy Act of 1974 FDA Title 21 CFR 20 regulations - Public information, 22 March 1977 FDA stopped providing Summary Basis of Approval Equivalents (SBA) in 1994 and started providing hundreds of pages of review information instead. FOI Electronic Records Amendment of 1996 The Open Government Act of 2007 FDAAA of 2007, Section 916: Action Package for Approval posted to website EU 7 Years Primary Legislation - Various Treaties, e.g., Treaty of Maastricht, of Amsterdam, and of Nice (Co- decision procedure applicable to pharmaceutical law - 2001). Regulation (EC) No 1049/2001 regarding public access to European Parliament, Council and Commission documents, 30 May 2001 Article 13(3) of Regulation (EC) No 726/2004, 31 Mar 2004 Decision EMEA/MB/203359/2006 - Rules for the implementation of Regulation (EC) No 1049/2001 on access to EMEA documents, 19 Dec 2006 EMEA SOPs and Procedures for EPARs 2006 - 2007

5. Timing US FDAAA of 2007, Section 916: Action Package for Approval posted to website –Summary Review Not later than 48 hours after the date of approval of the drug, except where such materials require redaction by the Secretary Summary includes: conclusions about the drug from all review disciplines –Action Package Not later than 30 days after the date of approval for a drug no active ingredient of which has been approved in any other application and not later than 30 days from the third request for any other drug approval Action Package includes: (1) documents generated by FDA related to review of the application; (2) labeling submitted by the applicant; and (3) the Division Director and Office Director’s decision document EU EPAR publication can only take place once the Commission Decision (CD) has been issued, and should be within 15 days of the issue of the CD. EMEA SOPs and Procedures for EPARs –Preparation of a European Public Assessment Report (EPAR) for a medicinal product following positive or negative opinion, 19 Nov 2007 –Non-removal of the EPAR following withdrawal/expiry of the Marketing Authorisation, 14 Sep 2007 –Procedure for review of information on product by patients’/consumers’ organisations, 25 Jan 2007 –Preparation and updates of EPAR summaries by the Medical Information Sector, 6 Dec 2006

6. 6 Definitions FDA Summary Basis of Approval (SBA) vs. Approval Packages Published vs. Unpublished information Pivotal Studies –Adequate and well-controlled clinical investigations providing the crucial data each health authority will base its decision on for approval or rejection of a product application. –FDA and EMEA Differences

7. Pivotal Studies US Adequate and well controlled clinical investigations providing substantial evidence that the drug will have the effect it claims under conditions of use prescribed in the proposed labeling. (21 CFR 314.125(b)(5) – 126) Study design permitting valid comparison with a control to provide a quantitative assessment of drug effect and benefit/risk. EU Pivotal studies confirm the effectiveness of a product in the intended population by using clinical meaningful endpoint(s) in adequate and well-controlled clinical trials. (Section 3.3.1, Guidance on Elements Required to Support the Significant Clinical Benefit) The fundamental requirement on the phase III documentation is that it consists of adequate and well-controlled data of good quality from: –a sufficient number of patients, –with a sufficient variety of symptoms and disease conditions, –collected by a sufficient number of investigators, –demonstrating a positive benefit/risk in intended population at the intended dose and manner of use. (Points to Consider on Validity and Interpretation of Meta-Analyses, and one Pivotal Study - CPMP/EWP/2330/99, p. 6)

8. 8 Pivotal Studies - continued ICH E5, E6, E8 E9 (GCP) –Adequate and well controlled studies to establish efficacy and provide an adequate basis for assessing the benefit/risk relationship to support licensing. (Table 1 – An Approach to Classifying Clinical Studies According to Objective, ICH Topic E8, General Considerations for Clinical Trials, p. 5) –An adequate and well-controlled trial has the following characteristics: A design that permits a valid comparison with a control to provide a quantitative assessment of treatment effect; The use of methods to minimise bias in the allocation of patients to treatment groups and in the measurement and assessment of response to treatment; and An analysis of the study results appropriate to the design to assess the effects of the treatment (Glossary in ICH Topic E5, Ethnic Factors in the Acceptability of Foreign Clinical Data, p. 10)

9. 9 Examples of Pivotal Study Research Using EPARs and/or FDA Approval Packages Health Authorities –Review of 1996-2007 EMEA-approved CNS products - pivotal trials (Saint-Raymond, A., Global Clinical Trial Session, US DIA Annual Meeting, 2007) –Analysis of reasons for rejection at EMEA for applications with reviews starting between September 1997 and April 2000 (Aronsson, B., European Journal of Clinical Pharmacology, 2002 Dec; 58 (9):573- 80 ) –CPMP opinions September 1997 to July 2002 (Aronsson, B., Competing Risks Analysis, EU DIA Annual Meeting, 2003) –FDA preservation project for research access to historically significant NDAs to capture changes in drug evaluation methodology over time http://www.fda.gov/oc/history/resourceguide/unpub.html, 2002http://www.fda.gov/oc/history/resourceguide/unpub.html

10. 10 Examples of Pivotal Study Research Using EPARs and/or FDA Approval Packages Academic –Pilot study to verify publication status of pivotal trail studies identified in FDA Approval Packages in 1997 (Division of Drug Information Service, University of Iowa, 1998) –Analysis of SBAs for Duloxetine and Escitalopram Clinical Trials (Kahn and Schwartz, Northwest Clin Research and Duke Univ Med Center, 2007) Industry –Case studies to be presented at this session