1. Navigating HA websites - locating regulatory information DIA Patient Engagement Community March 9, 2015 Copyright Linda Bowen March 2015

2. The views expressed in this presentation are personal views of the author and do not necessarily represent the views of Sanofi, U.S. Inc. Disclaimer 2

3. Agenda Company websites United States Food & Drug Administration Health Canada European Medicines Agency Access to Information Comparison Open forum – your chance to ask questions

4. Publicly available information from company websites Press releases Annual Reports SEC Filings Pipeline Approved products Regions where products are marketed Regulatory actions

5. Publicly available regulatory and product information Health Authority Websites Reviews or Assessment Reports (SBoA/SBD/EPAR/JNDA/AusPAR)SBoASBDEPARJNDAAusPAR Labeling (current and historic) Advisory Committee briefing packages and transcripts (US) Compassionate Use

6. Publicly available regulatory and product information Patent and Exclusivity Orphan Drug Information Drug Shortages Pediatric Written Requests (FDA); EMEA decisions on paediatric investigation plans (PIPs) Clinical Trial Disclosure websites – WHO, IFPMA, EUDRACT, NIH-NLM

7. Health Authority Websites http://www.pmda.go.jp/english/index.html http://www.ema.europa.eu/ema/ http://www.hc-sc.gc.ca/dhp-mps/index-eng.php http://www.fda.gov/ http://www.tga.gov.au/index.htm And many others

8. Free Training provided by FDA FDA Basics CDER World CDRH Learn CBER OCTGT Learn Regulatory Education for Industry Conference Regulatory Education for Industry Conference Clinical Investigator Training Course

9. What is not publicly available? FDA generally does not disclose information about the existence, status, or contents of an application submitted to the Agency, until the product has been approved, licensed, or cleared. Statutes and FDA regulations generally prohibit the release of information from or about an unapproved application. This includes: – INDs or IDEs – INDs or IDEs on clinical hold – Marketing applications and supplements – Refusal to file information – Issuance of a complete response letter – Unapproved drug or uncleared 510k has been withdrawn

10. Drugs@FDA http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm Approval Letter Officer/Employee List Officer/Director Memo Cross Discipline Team Leader Review Printed Labeling Medical Review Microbiology Review Chemistry Review Pharmacology Review Clinical Pharmacology Biopharmaceutics Review Statistical Review Administrative Document & Correspondence Approval package aka Summary Basis of Approval (SBoA)

11. Drugs@FDA Approval Letter: – Timeline from submission to approval – Review cycles – Postmarketing requirements and commitments – Pediatric commitments – Risk Management Plans

12. Drugs@FDA Approved Labeling: – Archive of changes (also available from DailyMed)DailyMed – Approved Indications – Warnings – Summary of non-clinical and clinical

13. Administrative and Correspondence Section – Background information and regulatory history – Meeting minutes; discussion points/responses – Timeline and progression from Phase-to-Phase – Proprietary Name Review Issues (DMETS) – Scheduling – Reviewer profiles – Executive Summary – Expert Opinions – Previous Action Letters Summary Basis of Approval

14. Others Parts of the SBoA Chemistry Review Pharmacology Review Medical Review Statistical Review Microbiology Review Clinical Pharmacology & Biopharmaceutics Review Endpoints Pivotal Studies Target Population Demographics Adverse reactions Data sources Investigator names Review strategy Review names & opinions

15. Chemistry Review Pharmacology Review Medical Review Statistical Review Microbiology Review Clinical Pharmacology & Biopharmaceutics Review Study design Data analysis Reviewer names Others Parts of the SBoA

16. Medical Device Databases Premarket approvals database search Premarket approvals database search 510k PreMarket Notifications CDRH cleared (510k) devices CBER cleared (510k) devices CDRH approved PMAs Medical Device Approvals

17. An important source of information, especially for products NOT approved after an Advisory Committee meeting.Advisory Committee FDA’s briefing documents are the first public discussion about the safety and efficacy of the data in your filing. Advisory Committee Info

18. Expanded access, sometimes called "compassionate use," is the use outside of a clinical trial of an investigational medical product. Expanded access FDA;’s website includes – Statutory Background for All Expanded Access Uses – Investigational Medical Devices – Investigational Drugs (Including Biologics) – Expanded Access Requirements For Individual Patient Access to Investigational Drugs (Including Biologics) Compassionate Use (Expanded Access)

19. Orange Book – Includes products approved under FD&C Act Section 505 – Patent information – Exclusivity information – Reference Listed Drug (RLD) named – Therapeutic equivalence Codes Biologics in Purple BookPurple Book Patent and Exclusivity Information

20. Searchable orphan drug databaseorphan drug database Searches may be run by entering the product name, orphan designation, and dates. Results can be displayed as a condensed list, detailed list, or an Excel spreadsheet. Can search by “all designations” or “approved products only”. Orphan Drug Database

21. Searchable database Drug Shortage FAQs Can sign up for email alerts Also available as a RSS feed Newly launched mobile app for both Apple devices and Androids Drug Shortages

22. Pediatric Therapeutics – Pediatric Information Labeling Database Pediatric Information Labeling Database – List of exclusivity determinations List of exclusivity determinations – Written requests and determinations FDASIA FDAAA – Medical, Statistical, and Clinical Pharmacology Reviews of Pediatric Studies FDASIA FDAAA 2002-2008 Information from PREA and BPCA

23. NIH-NLM Clinical Trials registry and results database (www.clinicaltrials.gov)www.clinicaltrials.gov Why important? IND information not released by FDA Clinical Trial Disclosure

24. Approval Information from Health Canada The Drug and Health Product Register Drug Products Database (Product Monographs) Notice of Compliance (NOC) list/database Summary Basis of Decision for drugs and devices Licensed Natural Health Products Database Special Access Programme (compassionate use)Special Access Programme Notice of Compliance with Conditions (NOC/c) list Register of Innovative Drugs (exclusivity)Register of Innovative Drugs Patent Register

25. The Drug and Health Product Register – Search for consumer information on drug product use, safety and common and reported side effects – Currently only provides the top 100 prescribed brand name and generic drug products – An additional 250 products are included that consist largely of generic drugs, but do include some brand name products. These have the same active ingredient(s) as the top 100.

26. Drug Product Database – Searchable database of approved drugs (Rx and non- Rx) and biologics – Brand Name, Drug Identification Number, Company, Active Ingredient, Route of Administration, Product Monograph (PM), Pharmaceutical Form, Package Sizes, Therapeutic Classification, Active Ingredient Group Number, and Pharmaceutical Standard.

27. Notice of Compliance Notice of Compliance Database – Searchable database of approved drugs (Rx and non-Rx) and biologics – A Notice of Compliance (NOC) is issued to a manufacturer following the satisfactory review of a submission for a new drug, and signifies compliance with the Food and Drug Regulations.

28. Summary Basis of Decision (SBD) Summary Basis of Decision – Document that outlines the scientific and benefit/risk based decisions that factor into Health Canada’s decision to grant market authorization for a drug or medical device. The document includes regulatory, safety, efficacy and quality considerations. – Implemented in a phased approach beginning with New Drug Submission (NDS), New Active Substances and a subset of Class IV medical device applications. Summary Basis of Decision

29. The Special Access Programme (SAP) provides access to nonmarketed drugs for practitioners treating patients with serious or life-threatening conditions when conventional therapies have failed, are unsuitable, or unavailable.Special Access Programme The SAP authorizes a manufacturer to sell a drug that cannot otherwise be sold or distributed in Canada. Special Access Programme

30. Available Product Information from the EU Centralized Procedure - applications for new human medicines under evaluation under evaluation Pending EC decisions European Public Assessment Reports (EPARs) European Public Assessment Reports Withdrawn applications Referrals Orphan designations Opinions and decisions on PIP applicationsPIP applications Marketing Authorization Withdrawals & Suspensions Refusal Assessment Report in case of negative CHMP opinion MRI-Product Index (products not approved via the centralized procedure) MRI-Product Index

31. Pending EC decisions When a pharmaceutical company applies for marketing authorisation through the Centralised authorisation procedure, the CHMP gives a positive or negative recommendation, in the form of a scientific opinion, on whether a medicine should be authorised. Immediately after the opinion is adopted, the EMA publishes a 'summary of opinion'. Pending EC decisionsPending EC decisions This summary is replaced by a full European Public Assessment Report once the European Commission has decided - taking the EMA opinion into consideration - whether to grant the marketing authorisation.

32. European Public Assessment Reports (EPAR) The EMA publishes an EPAR for every medicine granted a central marketing authorisation by the European Commission following an assessment by the EMA's Committee for Medicinal Products for Human Use (CHMP). EPARs are full scientific assessment reports of medicines authorised at a European Union level.EPAR Use this search to find information including a public- friendly summary in question-and-answer format and the package leaflet. You can also find information on medicines that have been refused a marketing authorisation or that have been suspended or withdrawn after being approved.

33. European Public Assessment Reports Summary for the Public (multilingual) List of authorized presentations Product information – SPC – Labeling and package leaflet Scientific discussion Background Material/Procedural steps

34. Scientific Discussion Introduction Quality Aspects Nonclinical reports – Pharmacokinetics – Toxicology Clinical aspects Pharmacovigilance Overall Conclusions Similar to SBoA medical review

35. Withdrawn Applications This page allows you to find information on the decision by a pharmaceutical company to withdraw an application made to the EMA for a human medicine.withdraw an application It includes withdrawals of new marketing authorisation applications or for changes to existing marketing authorisations, which are evaluated by the Committee for Medicinal Products for Human Use (CHMP). When an application is withdrawn after the first stage of evaluation by the CHMP, a withdrawal assessment report is published.

36. Referrals A referral is a procedure used to resolve issues such as concerns over the safety or the benefit- risk balance of a medicine or a class of medicines. The matter is ‘referred’ to the European Medicines Agency, so that it can make a recommendation for a harmonized position across the European Union.referral

37. Rare Disease Designations Allows you to find information on rare disease (orphan) designations based on applications that have been assessed by the European Medicines Agency's (EMA) Committee for Orphan Medicinal Products.orphan Applications for orphan designation are examined by the COMP, which adopts an opinion that is forwarded to the European Commission. The European Commission then decides whether to grant an orphan designation for the medicine in question.

38. MRI-Product Index – Contains approx. 11,000 medicinal products which have been granted a marketing authorization through the Mutual Recognition or Decentralised procedures – Product Locator contains multiple search capabilities; can search for products with SPC, PIL, NPAR (Public Assessment Report) – Links updated by Reference Member State

39. 39 COMPARISONS EMA-FDA-HEALTH CANADA

40. Approval Packages All three regulatory authorities provide summary information on drug/biologic approvals: – EMA: Summary of Opinion, European Public Assessment Reports (EPAR) and CMD(h) MRI- Product Index – FDA: Summary Basis of Approval (SBoA); can include FDA meeting minutes not previously released for public viewing (Drugs@FDA) – Health Canada: For New Active Substances, subsequent entry biologics and selected Class III & IV medical devices - the Summary Basis of DecisionSummary Basis of Decision 40

41. Negative Decisions & Withdrawals EMA: Positive and negative opinions with reasons; Information on withdrawn applications; Public Assessment Reports for positive and negative opinions, and for withdrawn applications FDA: Negative decisions such as Refusal to File and Complete Response Letters – are not made public. Sponsor withdrawn applications are published in the Federal Register. Health Canada: Negative decisions such as the content of Notices of Deficiency/Notices of Non- compliance, and clarifaxes – are not made public. 41

42. Access to Information - approvals EMA: In 2010 publishes policy on Access to Documents based on Regulation 1049/2001. Allows for reactive disclosure of approved marketing applications with appropriate redaction, as well as proactive disclosure. FDA and Health Canada do NOT disclose marketing applications, only the summaries FDA: Access to information via the Freedom of Information Act of 1966. FDA FOIA logbook available.FOIA Health Canada: Legislated by the Access to Information Act of 1985 and regulated by the Access to Information Regulations. List of completed requests available.completed requests 42

43. Labeling (Drugs) EMA: The EPAR contains both the package leaflet (patient) and summary of product characteristics (SmPC).EPAR FDA: Most recent FDA labels (package inserts) are available on DailyMed website. Labeling also posted at Drugs@FDA.DailyMed website Health Canada: The Product Monographs are disclosed by Health Canada via the Drug Product Database.Drug Product Database 43

44. Linda Bowen, M.S, RAC, FRAPS Linda is Head of U.S. Regulatory Policy and Intelligence at Sanofi. She has held regulatory and quality positions at Bayer Healthcare and GSK (Block Drug), with global regulatory responsibilities for submissions, life cycle management, business development and due diligence activities. She has been working in the Pharmaceutical industry for 30+ years. Linda holds bachelor's degrees in Microbiology and English from Rutgers University and an M.S. in Drug Regulatory Affairs from the Arnold and Marie Schwartz College of Pharmacy, where she was inducted into the Rho Chi Society. She attained regulatory affairs certification for the US, Canada and Europe, and was an inductee to the 2011 Class of RAPS Fellows. Linda was honored with the Drug Information Association's 2012 Excellence in Volunteer Leadership Award. She is a past two-term member of the RAPS Board of Directors and past chair of the NJ/NY RAPS Chapter. Linda is Chair of the DIA Regulatory Affairs Community and past chair and founder of the Regulatory Intelligence Working Group. She has sat on the planning committee for the 2012-2014 DIA Regulatory Information Management Conferences, the 2013-2015 DIA Annual Conferences, and the 2011-2014 RAPS Annual Conferences. She is a frequent speaker and author on various regulatory policy and intelligence topics. She is most proud of her accomplishments as an educator, mentor and patient advocate.

45. Questions? Linda.Bowen@sanofi.com