1. Regulatory Intelligence for the Emerging Markets Lisa Rysso-DeMaggio President, RAQUELIAN Consulting DIA Regulatory Intelligence Working Group, 10 Sep 2013

2. Agenda Challenges of working in the emerging markets Purpose of regulatory intelligence How to obtain and track Questions to ask 2

3. Challenges Massive amounts of information Difficult to find guidances in English Guidelines can be extremely vague or lacking altogether Big difference between stated metrics and regulatory reality Difficult to rely on precedence or agency advice – Lack of formal meetings – Advice can be reviewer dependent 3

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6. Purpose of Regulatory Intelligence Influencing development plan – Clinical, CMC Creating the regulatory strategy – Drives the content of the submission (e.g. label, clinical data, CPP, stability data) Creating the regulatory submission plan – Details the list of activities and timings (e.g. inspections, meetings, dependencies, rate-limiting factors) Choosing a business model – Affiliates vs. partners Choosing target markets 6

7. 7 Choosing Target Markets 7 Target Markets Regulatory Assessment Commercial Assessment Sourcing Development work MAH/local agents Registration costs Inspection fees Method transfers Labor costs Sales potential Price Prevalence Competition Business costs Taxes Partnerships IP concerns Cost of goods

8. How to Obtain & Track (1 of 2) Push vs. pull model Tools – Document bases – Databases Methods – Regulatory questionnaire for planning – Gap analysis for completed programs Distributed vs. centralized approach 8

9. How to Obtain & Track (2 of 2) Must have highly experienced staff physically located in all target markets (e.g. employee, consultant, local partner) Regulatory intelligence should include general guidances and also product specific advice Informal discussions with some agencies may be required 9

10. Questions to Ask 10

11. Overview A regulatory survey should introduce the product as specifically as possible. – Avoid long answers with multiple scenarios! Talk through questions and answers with affiliates if possible. Organize the survey by timeline. – What activities must take place first? 11

12. Organization Product classification Development requirements (clinical, stability) CPP requirements Requirements for local partners (agent, MAH, facilities) Pre-submission activities (agency meetings, inspections, applications for patent/brandname) Registration procedure and requirements 12

13. Clinical Development What type of data package is required? Are local clinical trials required? Are bridging waivers accepted? Can protocol be part of a global or regional study? Is a comparator trial required? – Does the comparator need to be approved or sourced locally? 13

14. Stability What zone? – Is controlled room temperature acceptable? How much stability data? From commercial site? Bracketing/matrixing accepted? Needed for in-use? Local stability required? 14

15. CPP Requirements CPP needed? When? (Submission, during review, approval) From which country(ies)? – How is “source” country defined? – What is required and what is preferred? Is a marketing statement required? What attachments are required? – Is local label dependent on reference label? What kinds of comments are needed? What kind of legalization is needed? What language? 15

16. Local Partners Can a foreign company be the MAH? – If so, what are the requirements for a local agent? – If not, what are the requirements for a local MAH? Personnel, facilities, licenses What is the process to switch an MAH? What local facilities can be contracted? Does submission need to contain contracts or a list of local partners? 16

17. Pre-Submission Activities Are agency meetings required or recommended? How far in advance of submission must meetings be requested? What inspections are required before submission? Does the company or manufacturing site need to be registered in advance? Do brandname applications need to be submitted in advance? What else needs to be done before submission? – E.g. Local CoA for Mexico 17

18. Registration Procedure How is application submitted? – Eg. Electronically, in person How is application fee paid? When are registration samples submitted and how many are required? Is there a validation procedure? When can queries be expected and what are the timelines to respond? How long does the review take? Can information be submitted during review? 18

19. Submission Requirements What is the required format and content of the dossier? What language? What documents with wet signature? Tip: Provide a list of all documents included in a CTD and have the affiliate indicate which ones are required. Have affiliate specify if redactions are acceptable. 19

20. Submission Planning Need to know for each country: – All pre-submission activies and lead time required – Rate limiting factors – When to submit – Review timelines Depending on the rate limiting factor, filing waves can be created. 20

21. Thank you! Lisa Rysso-DeMaggio President, RAQUELIAN Consulting Email: LRD@raquelian.comLRD@raquelian.com Phone: 843.405.1134 Web: www.raquelian.comwww.raquelian.com 21

22. Backup Slides 22

23. Choosing Countries Regulatory assessment Sourcing issues Need for further development work Requirements to be a Marketing Authorization holder (MAH) or local agent Costs of registration fees and analytical methods transfers Labor costs (e.g. employees, consultants, contract facilities) 23

24. Choosing Countries Commercial assessment Sales potential – Price – Prevalence – Competition (e.g. other drugs, procedures) Cost of doing business – Tax implications – Partnerships – IP concerns Cost of goods 24

25. Price Who is your customer? Payor driven (e.g. Established national health care system, insurance agencies): Health economics assessment will determine price. Consumer driven: Increased convenience or quality of life In some countries, price is not open to negotiation. Drugs should be developed with reimbursement in mind.* *See “Collaboration and Convergence: Bringing New Medicines to Global Markets in the 21 st Century”; Alberto Grignolo; Therapeutic Innovation & Regulatory Science; Volume 47, Number 1, January 2013; http://dij.sagepub.com/content/47/1/8.short?rss=1&amp%3bssource=mfr&related- urls=yes&legid=spdij;47/1/8 http://dij.sagepub.com/content/47/1/8.short?rss=1&amp%3bssource=mfr&related- urls=yes&legid=spdij;47/1/8 25

26. Cost of Submissions Registration fees – US: $1,958,800 (for applications containing clinical data) – EU: €267,400 (centralized procedure) Fees for inspections, site registrations, etc. Costs to transfer methods Labor costs Payments to third party vendors 26

27. Gap Analysis Two methods – Distributed: Dossier can be sent to in-country staff for individual evaluations – Centralized: Above country staff can gather and compile requirements using a survey and analysis approach Choose a method based on the number of products/countries filing and the expertise of above country staff Must know what questions to ask! 27

28. Gap Analysis Two phases 1.Pre-submission activities Regulatory environment Development requirements (e.g. clinical, stability) Requirements for CPP, GMP inspections, registration samples Local lab requirements Policies on agency meetings Requirements for MAH, local agents and 3 rd party vendors Activities and timelines 2.Submission requirements Submission procedures Dossier requirements 28