Overview of the Canadian Federal Drug Review Process University of Toronto – Faculty of Pharmacy

1. Overview of the Canadian Federal Drug Review ProcessUniversity of Toronto – Faculty of Pharmacy Marilyn Schwartz A/Director, Bureau of Operational Services Therapeutic Products Directorate September 27, 2004

2. Responsibilities for Drugs • Federal • Regulates the safety, efficacy and quality of drugs • Ensures patent linkage (Health Products & Foods Branch) • Controls the price of patented medicines (Patented Medicines Prices Review Board) • Coordination and leadership on FPT pharmaceutical issues • Provincial • Delivery of healthcare • Practice of Medicine/Pharmacy • Reimbursement issues • Drug Formularies

3. Federal Legislation and Guidance for Drugs • Food and Drugs Act and Regulations • Governs the safety, effectiveness and quality of drugs and medical devices available to Canadians. • Patented Medicines (NOC) linkage Regulation • Financial Administration Act (fees for review-cost recovery) • Access to Information and Privacy Act • Controlled Drugs and Substances Act (governs narcotic & controlled drugs) • Policies and Guidelines (including International Guidelines - ICH) in support of the Acts and Regulations

4. Health Canada

5. Health Products and Food Branch

6. Therapeutic Products Directorate Therapeutic Products Directorate Effective April 1, 2002

7. Health Products and Food Branch (HPFB) Responsibilities for Drugs • Therapeutic Products Directorate (TPD) Responsible for evaluating the safety, effectiveness and quality of pharmaceutical drugs and medical devices available to Canadians. • Similar to CDER in U.S. – F.D.A. • Biologics and Genetic Therapies Directorate (BGTD) Responsible for evaluating the safety, effectiveness and quality of biological and radiopharmaceutical drugs, as well as blood and blood products, viral and bacterial vaccines, genetic therapeutic products, tissues, organs and xenografts. • Similar to CBER in U.S. – F.D.A.

8. Health Products and Food Branch (HPFB) Responsibilities for Drugs - cont’d • HPFB Inspectorate – Compliance & Enforcement • Responsible for delivery of inspections and investigations, and for most establishment licensing and related laboratory analysis functions. • Marketed Health Products Directorate (MHPD) • Responsible for post-market assessment and surveillance of pharmaceutical and biological drugs, medical devices, natural health products, radio-pharmaceuticals.

9. Health Products and Food Branch Natural Health Products Directorate (NHPD) Ensures that Canadians have ready access to health products that are safe, effective, and high quality by maintaining proper labelling and implementing regulatory framework which supports freedom of choice and cultural diversity New regulations came in Jan 2004 Veterinary Drugs Directorate (VDD) Ensures the safety of foods such as milk, meat, eggs, fish and honey from animals treated with veterinary drugs, and that veterinary drugs sold in Canada are safe and effective for animals

10. Product Types Regulated as “Drugs” • Pharmaceuticals (prescription, non-prescription, brand name, generic) • Biological drugs (vaccines, recombinant drugs, blood products) • Radiopharmaceuticals • Natural Health Products (Transition to NHPD, January 1st, 2004) • Homeopathic products • Traditional herbal medicines • Other Herbals • Disinfectants for use on medical instruments, hospital and food preparation surfaces • Veterinary Drugs

11. Life of a New Drug Research Create/Isolate Chemicals Tissue/Culture More Specific animal (14,000 tested to get one as marketable) small animals testing and in vitro tests (e.g. carcinogenicity, reproductive studies) Human Testing Special Access Program (SAP) (Clinical Trial) (emergency release) HC approval required (Food & Drug Act & Regulations 30 day default) Post Market Surveillance Provincial Formulary Decisions All testing is done, drug company completes analysis of data, prepares New Drug PMPRB Submission (NDS) (price controls) HC Review Decision

12. Life of a New “Drug” – cont’d Industry Government Create/Isolate Chemicals Tissue/Culture More Specific Animal Tests Human Testing (Clinical Trials)HC Approval required Special Access Complete Analysis of data HC Review / Decision Prepare New Drug Submission PMPRB Federal Price Control Negotiate with Provinces P/T Formulary Decisions Marketing and Promotion to Physicians Post-Market Surveillance Updates to Product Monographs Dear Health Care Provider Letters Post-Market Regulatory Actions Product on Market or Removal

13. Drugs Sold in Canada • All drugs sold in Canada must be approved by Health Canada. These include but are not limited to the following: • drugs imported from other countries; • drugs manufactured in Canada; • drugs for export where the exporting company needs a Canadian approval in order to enter into another country.

14. New Drug Approval Process

15. New Drug Approval Process – More Details

16. Submission Processing – more details

17. Submission Type (examples) • Submission Type Examples: NDS – New Drug Submission SNDS – Supplement to New Drug Submission ANDS – Abbreviated New Drug Submission (generics)

18. Classifying Submissions • The submission package determines the class of the submission. Listed below are examples of submission classes. • NAS: New Active Substance (pharmaceuticals & biologicals) • Clin Only: clinical data only (e.g. new indication) • Clin/C&M: clinical and chemistry & manufacturing data but is not a NAS (e.g. new dosage form, new use)

19. Classifying Submissions – cont’d • Comp/C&M: comparative (clinical, bioavailability, etc.) data and C&M (e.g. generics; new dosage forms for innovator products) • C&M/Labelling: no clinical data(e.g. ANDS where no clinical data is required - injectable, ophthalmic, nasal sol’n) • The submission class determines the performance target.

20. Data Requirements Summary • New Drugs typically require preclinical, clinical, chemistry & manufacturing data • Generics typically require bioequivalence and/or pharmaceutical equivalence data • Other Drugs (not new) - information ranging from chemistry & manufacturing data and/or only formulation and labelling

21. Priority Review • ... for a drug submission for a serious, life threatening or severely debilitating disease or condition for which there is substantial clinical evidence that the drug provides: • effective treatment/prevention/diagnosis of a disease or condition for which no drug is presently marketed in Canada… http://www.hc-sc.gc.ca/hpb-dgps/therapeut/zfiles/english/policy/issued/prirevw_e. pdf

22. Performance Targets • The type of data package (safety, efficacy, quality) submitted and whether or not it is accepted for priority review determines the performance target Examples: • Processing - 10 days* • Screening priority - 25 days* • Screening - 45 days* • NDS – Review : priority - 180 days* non-priority - 300 days* • ANDS - Review : - 180 days* * Calendar days

23. Performance Reporting • Drug submission performance is reported quarterly and annually • Reports are posted on our website: http://www.hc-sc.gc.ca/hpb-dgps/therapeut/htmleng/drug_submission_reports

24. Cost Recovery • Involves the processing of fees for: • Annual authority to market a drug in Canada ($8-10 million) • 1300 companies • 22,000 marketed products • Submission evaluation fees (determined by data package submitted i.e. number of indications, number of dosage forms, etc.) $20 million • Fees for Establishment Licences for drugs (1000 licences) and medical devices (900 licences) $6 million • As outlined in the Financial Administration Act

25. Submission Evaluation Fees • The type of data package submitted determines the submission evaluation fee • Examples: New Drugs • Preclinical & Clinical - $117,000 • Clinical (no preclinical) - $ 52,900 • Comparative data - $ 17,200 • C& M for active ingred. - $ 11,500 • C&M for 1 dosage form - $ 15,300

26. Drug Identification Numbers (DINs)and Notices of Compliance (NOC) • DINS are issued to all drugs approved for marketing in Canada. (8 digit number generated by DPD) • Must appear on the label • Notification of first sale • NOC are issued to all new drugs that are approved.

27. Tracking Drugs in Canada • Health Canada keeps records of drugs marketed in Canada – it does not keep records of drugs approved in the US or any other country. • DPD web query – a database on our website http://www.hc-sc.gc.ca/hpb/drugs-dpd/ listing all products marketed in Canada.

28. Tracking Drugs in Canada – cont’d • Continued monitoring, enhancement, synchronization for: • Drug Submission Tracking System (DSTS) • Drug Establishment Licensing System (DEL) • Drug Product Database System (DPD) • SAP Financial System • 6000 Licence / DIN holders / importers / agents / sites • Mergers, buyouts, bankruptcies, licence agreements • Account access, training, management of pick lists and linkages between systems

29. Why are Some Drugs not Approved? • All drugs must be reviewed to ensure that they meet the requirements of the Food and Drugs Act and Regulations • Drug must have sufficient evidence to support the safety, efficacy or quality claims, to be approved • Drug companies may submit further info. to ensure that the safety, efficacy, and quality standards are met (e.g. may require further research in animals and/or humans) • HPFB decision not to approve a drug may be appealed by applicant

30. Biologics and Genetic Therapies Directorate

31. Key Differences with Biologicals • Biological drug review also includes: • On-site evaluations • Assessment of the production process and facility for a specific product which ensures that the manufacturing process conforms to information described in the submission. • Additional GMP (Good Manufacturing Practices) • Special considerations and issues pertinent to manufacturing and control of biological drugs, blood and blood components. • Lot-release • Laboratory work on samples received from drug companies to confirm potency, purity and safety. • Only high risk products are tested (new products and vaccines).

32. Review of Generic New Drugs Federal Level • Food & Drugs Act and Regulations amended 1995 • Allows for a generic manufacturer to file an ANDS • Establishment of bioequivalence by requiring a Canadian Reference Product (CRP) • Same route of administration as CRP • Same conditions of use as the CRP • Ensured safety, efficacy and high quality

33. Review of Generic New Drugs – cont’d ANDS Patent check Pharmaceutically equivalent and/or Bioequivalence data (Canadian Reference Product required) Review Bioequivalence info PM/ label Chemistry & Manufacturing Pharmaceutical equivalent Approval recommended NOC issued (approval & declaration of Bioequivalence) NOC on HOLD (until patent issued get resolved Patent Check Provincial Assessment

34. Patented Medicines (NOC) Regulations • Protect intellectual property while allowing generics to come on the market immediately after patent expiry. • Brand name companies can file a patent to protect a drug which is added to the Patent Register. • Generic companies have to clear all patent issues before being allowed to market.

35. Regulatory Scheme

36. Patented Medicines (NOC) Regulations

37. Post Market Roles and Activities • Role • Legislated responsibilities, ‘Duty of Care’ regarding safety of new drugs • Activities • Monitor and collect adverse drug reaction and medication incident data and communicate these to health professionals and public (e.g. Advisories for therapeutic products, Canadian Adverse Drug Reaction Newsletter, Health_Prod_Info) • Review and analyze safety data • Conduct risk/benefit assessments of marketed products • Overview of regulatory advertising activities

38. Strengthening Post-Market Safety of New Drugs Measures will include: • Moving from reactive to proactive and preventative measures • Expanding network of Regional Adverse Reaction Centers • Launching investigations and requiring manufacturers to conduct post-approval clinical trials • More timely and accurate advice to health care professionals and the public Outcomes: • Will reduce risks to Canadians from preventable adverse drug events

39. International Harmonization • HPFB has been very active in helping develop and implement international standards for the registration of new drugs. • HPFB has contributed significantly to the development of over 45 harmonized technical guidelines. • Canada is the only observer country to the International Conference on Harmonization (ICH) and is committed to implementing finalized ICH guidelines and standards including the Common Technical Document (CTD).

40. Drug Submissions Received Annually (approx.) (TPD & BGTD) Total: 4,400 per year • 80 – NDS (New Drug Submission) • 35 for new active substances • 170 – SNDS (Supplement to NDS) • 80 – ANDS(Abbreviated New Drug Submission) • 10 – SANDS(Supplement to ANDS) • 800 – NC (Notifiable Change)

41. Drug Submissions Received Annually (approx.) (TPD & BGTD) – cont’d • 1700 – DINA(Drug Identification Number Application) • 360 – Administrative Change Submissions • Change in manufacturer’s name and/or product name; cross-reference submissions • 1400 – Clinical Trial Applications(previously INDs – Investigational New Drug Submissions)

42. Drugs Marketed in Canada • 22,000 (approx.) Human Drug Products • 6,000 Prescription • 9,000 Non-Prescription (includes natural health products with DINs) • 6,000 Homeopathics • 1,000 Controlled Drugs, Narcotics & Biologics • 1,450 (approx.) Veterinary Drug Products

43. The expectations of stakeholders are clear….. A review process that is more: • Timely • Predictable • Consistent • Sustainable • Transparent

44. The TPD Journey from where we are….to where we need to be Some of the time Meet Performance Target Not always Predictable Not necessarily Consistent Resource poor Sustainable Not very Transparent Desired State Current State

45. Business Transformation Strategy – Plan for Change • Project Management Tools • Enhance Capacity – internal & external eg: Expert Advise, Academic Instructions • Good Guidance Practices • Communication/Consultation eg: Public Advisory Committee (PAC), ACM, PPF • International Regulatory Cooperation • E-Review – eCTD • Transparency eg: PM project, Summary Basis of Decision

46. Strategic investments in key areas will drive our Business Transformation Strategy InvestmentsObjectivesAttributesResults Project Management Quality Submission Predictable Good Review Practices Good Guidances Quality Review Consistent A timely Enhanced Capacity drug International Cooper- Quality Decision Sustainable approval ation process Transparency Performance Transparent E-Review Measurement

47. Backlog Reduction – Milestones and interim commitments

48. Workload Management

49. Continuous Balancing Act • Drug submission review performanceis impacted by the many other issues and challenges which we strive to keep in balance: • advancements in science and technology • timeliness vs. ensuring safety / efficacy • adhering to strict regulations/policies and being flexible and reasonable • participating in an international community while respecting our domestic environment

50. Lexicon ADR Adverse Drug Reaction ANDSAbbreviated New Drug Submission API Active Pharmaceutical Ingredient C&MChemistry and Manufacturing CBERCenter for Biologics Evaluation & Research CDERCenter for Drug Evaluation & Research CRP Canadian Reference Product DIN Drug Identification Number (an 8-digit number that all drugs in Canada must have) DMFDrug Master File DPDDrug Product Database FPT Federal / Provincial / Territorial