1. KEY CURRENT ISSUES IN EUROPEAN REGULATON Michael A. Swit, Esq. Vice President, Life Sciences Pharmaceutical Education Associates From Pipeline to Product: Navigating the FDA Approval Process Alexandria, VA November 30, 2007

2. 2 Disclaimer This outline is intended to support an oral briefing and should not be relied upon solely to support any conclusion of fact or law. The views reflected in this presentation are solely those of the presenter and do not necessarily reflect the position of my firm, any of its clients, or any of my friends and colleagues that contributed their thoughts to this presentation.

3. 3 WHAT WE WILL COVER SCIENTIFIC ADVICE SMALL-TO-MEDIUM ENTERPRISES (SME’s) TIPS & PITFALLS

4. 4 SCIENTIFIC ADVICE

5. 5 LEGISLATION Article 57(1) (n) of Regulation (EC) No 726/2004: “the Agency, acting particularly through its committees, shall undertake the following tasks: Advising undertakings on the conduct of the various tests and trials necessary to demonstrate the quality, safety and efficacy of medicinal products” Purpose To ensure CHMP support, through SAWP, to companies developing medicinal products To reduce the uncertainty of the Marketing Authorisation outcome

6. 6 SCIENTIFIC ADVICE WORKING PARTY Scientific Advice Working Party (SAWP) –Internal processes within CHMP to allow for advice to be given to all companies, in particular, small and medium sized enterprises –Provides both general and in-depth Scientific Advice through experts within national Regulatory Agencies and from consultants –Others involved -- patient organizations and health-care professionals associations

7. 7 SCIENTIFIC ADVICE WORKING PARTY Areas of particular interest –Products intended for the new mandatory centralized procedure –Emerging therapies and New therapies –Safety aspects –Conditional marketing authorizations –Authorizations under Exceptional Circumstances –Significant clinical benefit for orphan drugs

8. 8 SCIENTIFIC ADVICE AREAS Frequency of requests for Scientific Advice - - by CTD areas: –Quality (i.e., CMC) – 20% –Nonclinical – 30% –Clinical – 50% Most issues at Marketing Authorisation stage -- relate to clinical efficacy

9. 9 SCIENTIFIC ADVICE PROCESS Timing of request –At any sage of development process –Not specific phase – unlike FDA (eg pre-IND, end of Phase II) Process for obtaining advice –Request –Presubmission meeting (not essential but valuable for fine tuning questions) –Formal submission of data –Potential face to face meeting

10. 10 QUALITY (CMC) Quality requests (20%) Comparability (38%) Change in manufacturing process Biotechnology ‘similarity’ issues Change of formulation Stability (15%) TSE, viral safety issues (7%)

11. 11 NONCLINICAL Nonclinical requests (30%) Bridging toxicology programmes (eg new indication for existing molecule) 16% Carcinogenicity (waivers, timing, models) 38% Reproduction toxicology (waivers, timing) 21% Studies in juvenile animals (eg linked to paediatric development issues) 3% Pharmacological models for biological/biotech products

12. 12 CLINICAL Clinical (50%) Clinical efficacy endpoints –Primary (75% requests) Choice, acceptability, relevance Surrogate endpoints as opposed to hard clinical endpoints Composite endpoints –Secondary (30%)

13. 13 USEFULNESS OF S.A. Does Scientific Advice have an impact? –SA seems to correlate with positive outcome on Marketing Authorisation Not a guarantee for a positive outcome –SA is not a means of changing data –SA is useful if advice is followed (do not ignore recommendations) –SA cannot have an impact if relevant issue was not part of the SA request

14. 14 FEES Fees payable for Scientific Advice Cost dependent on extent of enquiry –Clinical development (CD) –Quality (Q) –Safety (S) Fees reduced for companies with SME status (10%) No charge for advice on Orphan Products (SA termed Protocol Assistance)

15. 15 COSTS Fee level Area of AdviceInitial advice Follow –up advice IIIQ, S and CD Q and CD S and CD € 69,600 $ 101,600 € 34,800 $ 50,808 IICD Q and S € 52,200 $ 76,212 € 26,100 $ 38,106 IQSQS € 34,800 $ 50,808 € 17,400 $ 25,404

16. 16 TIMELINES Formal request submitted –On day -30, or day -60 if pre-submission meeting requested Pre-submission meeting (still optional but advisable) –Systematic involvement of coordinators and experts –Receive early feedback on content –Fine tune questions –Increase quality of request before start of procedure Day 0 – start of procedure By Day 70 – adoption of final letter (maximum time) –Following 3 SAWP meetings (expert appointment, discussion of report, final meeting) Possibility of finalization by Day 40 –Following 3 SAWP meetings (expert appointment, discussion of report)

17. 17 FOLLOW-UP REQUEST Follow-up advice –Any subsequent request falling within the same therapeutic indication and areas as the initial request –Not restricted to the questions raised in the initial request –Initial request may be only on the dose-finding study, subsequent request on Phase III will attract only a reduced follow-up fee –Areas includes quality or nonclinical or clinical including pharmacovigilance / risk management aspects

18. 18 FOLLOW-UP REQUESTS Ensure continuity of support from the CHMP during development of medicinal products Should reduce the uncertainty of the Marketing Authorization outcome Permit more interactions between development companies and SAWP

19. 19 SMALL-TO-MEDIUM ENTERPRISES (SME’s)

20. 20 LEGAL SOURCE Commission Recommendation 2003/361 –Defines SME: Micro, Small and Medium –Provides Framework for Incentives Commission Regulation 2049/2005 -- Applies Recommendation 2003/361 to Human and Veterinary Medicinal Products when Submitted via the Centralised Procedure –Does Not Apply to Authorisation Applications via National Procedures. –Some EU Member States have Limited SME Initiatives (Denmark, Germany, Portugal, Sweden and UK)

21. 21 SME DEFINITIONS 1 LimitsMicroSmallMedium Employees AND 1050250 Annual Turnover AND / OR €2 million $3 million €10 million $15 million €50 million $73 million Annual Balance Sheet €2 million $3 million €10 million $15 million €43 million $63 million

22. 22 SME DEFINITIONS 2 Autonomous< 25% Partner25 – 50% Linked> 50%

23. 23 SME STATUS Restricted to companies “established” in the EEA –defined as having a legal presence in an EEA Member State “… permanent legal structure which is formed in accordance with the laws of the EU or EEA member state …” In practice, SME Status is not Limited to Companies with Local Offices in the EEA -- Consultants Established in the EEA can act on behalf of Companies from any Country if the company otherwise qualifies

24. 24 SME APPLICATION PROCESS Self-Certification re Number of Employees and Provision of Appropriate Financial Information, normally in the form of the Latest Audited Annual Report No fixed time limit for approval, but normally within three to four weeks

25. 25 KEY SME BENEFITS Fee Reductions for Scientific Advice Deferral of MAA Fee and related Inspections Conditional Fee Exemption Assistance with Translations

26. 26 SME BENEFITS Fee Reduction for Scientific Advice -- 90% Reduction for Initial and Repeat Advice in all areas – CMC, Nonclincal, Clinical €3,500 - €7,000 $5,000 - $10,000 Deferral of MAA Fee and related Inspection Fees -- can be deferred until 45 Days after Approval

27. 27 SME BENEFITS Conditional Fee Exemption -- where Scientific Advice is followed and a Marketing Authorisation Application is not successful Assistance with Translations -- SmPC, Package Labels, Package Inserts –EEA = 30 Countries and 23 Languages

28. 28 BENEFIT PARAMETERS Equal Benefits for all SMEs (Micro, Small, Medium) Most Favourable Benefit Applies (SME versus Orphan) Benefits not Cumulative (Not SME and Orphan)

29. 29 SME STATUS SUMMARY SME Status available to any company, within the Headcount and Financial Limits Companies in the EEA Apply Directly Companies outside the EEA apply via an Agent Significant Fee Reductions and Deferrals

30. 30 EUROPEAN TIPS & PITFALLS Plan Out Timelines For Each Country –CTA needed in all member states –May be additional committees for gene therapy, GMOs, etc. Set Your Regulatory Submission Plan Carefully –Identify coordinating centers 'strategically' –Prepare documents for EC and Competent Authority submissions – evaluate requirements for translation and any additional documents. number of copies required.

31. 31 TIPS & PITFALLS … Product Release -- If Company Has No 'Presence' In The EU, Qualified Person (“QP”) Release Of Your Product Will Be Required. Product Distribution Requirements, Including Labeling -- considered and planned for in advance.

32. 32 TIPS & PITFALLS … Seek Advice In Parallel With U.S. If Possible – EMEA Or Individual State. –EU May Approve Where U.S. Does Not –EU advice also can help “inform” FDA strategy –Key Opinion Leaders: are especially important in Europe

33. 33 Call, e-mail, fax or write: Michael A. Swit, Esq. Vice President, Life Sciences THE WEINBERG GROUP INC. 336 North Coast Hwy. 101 Suite C Encinitas, CA 92024 Phone 760.633.3343 Fax 760.633.3501 Cell 760.815.4762 D.C. Office 202.730.4123 michael.swit@weinberggroup.com www.weinberggroup.com Questions?

34. 34 About your speaker… Michael A. Swit, Esq., is Vice President, Life Sciences at THE WEINBERG GROUP, where he develops and ensures the execution of a broad array of regulatory and other services to clients, both directly and through outside counsel. His expertise includes FDA and CMS development strategies, compliance and enforcement initiatives, recalls and crisis management, submissions and related traditional FDA regulatory activities, labeling and advertising, and clinical research efforts for drug, biologic, device, IVD, and other life sciences companies, as well as those in the food and dietary supplement industries. Mr. Swit has been addressing critical FDA legal and regulatory issues since 1984. His vast and multi-faceted experience includes serving for three and a half years as corporate vice president, general counsel and secretary of Par Pharmaceutical, a prominent, publicly-traded, generic drug company and, thus, he brings an industry and commercial perspective to his work with FDA-regulated companies. Mr. Swit then served for over four years as CEO of FDANews.com, a premier publisher of FDA regulatory newsletters and other specialty information products for the FDA-regulated community. His private FDA regulatory law practice has included service as Special Counsel in the FDA Law Practice Group in the San Diego office of Heller Ehrman White & McAuliffe and with the Food & Drug Law practice at McKenna & Cuneo, both in the firm’s Washington office and later in San Diego. He first practiced FDA regulatory law with the D.C. office of Burditt & Radzius. Mr. Swit has taught and written on a wide variety of subjects relating to FDA law, regulation and related commercial activities, including, since 1989, co-directing a three-day intensive course on the generic drug approval process and editing a guide to the generic drug approval process, Getting Your Generic Drug Approved. A former member of the Food & Drug Law Journal Editorial Board, he also has been a prominent speaker at numerous conferences sponsored by such organizations as RAPS, FDLI, and DIA.

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