1. Overview of Drugs and Biologics Dr Léo Bouthillier, Therapeutic Products Directorate & Dr Omar Tounekti, Biologics and Genetic Therapies Directorate Health Products and Food Branch Health Canada

2. Health Products and Food Branch Mandate: Manage the health-related risks and benefits of health products 2 Therapeutic Products Biologics & Genetic Therapies Natural and Non- Prescription Veterinary Drugs Marketed Health Products Inspectorate Pharmaceuticals and Medical Devices Blood, vaccines, biological drugs, tissues, radiopharmaceuticals Non-prescription drugs, vitamins, herbal products, minerals, etc. Veterinary drugs administered to food- producing animals (e.g., milk, egg, meat, etc.) and companion animals Post-Market Surveillance Inspections, Investigations, Establishment and Site Licenses

3. Lifecycle of a Drug 3 Pre-Market Post-Market Drug Discovery Clinical Trials Drug Submission Review Market Authorization Decision Public Access Revisions To Product And Use Surveillance, Inspection and Investigation Post-Market Changes to Marketed Products The Food and Drugs Act and Regulations authorize the Therapeutic Products Directorate and the Biologics and Genetic Therapies Directorate to regulate the safety, efficacy and quality of pharmaceutical and biologic therapeutic products. Pre- clinical studies

4. Pre-clinical Studies 4 Objectives: - Identify the pharmacological properties: - PD (mode of action) - PK (metabolism) - Comparative physiology (extrapolation of animal data to humans) - Understand the toxicological profile: - Establish a safe initial dose level of the first human exposure - Identify parameters for clinical monitoring of potential adverse effects - Special toxicity (e.g. genotoxicity, carcinogenicity, reproduction toxicity)

5. Pre-clinical Studies 5 Toxicity studies are expected to be performed in compliance with Good Laboratory Practice (GLP). Good Laboratory Practice (GLP) embodies a set of principles that provides a framework within which laboratory studies are planned, performed, monitored, recorded, reported and archived. GLP helps assure regulatory authorities that the data submitted are a true reflection of the results obtained during the study and can therefore be relied upon when making risk/safety assessments.

6. Pre-clinical Studies 6 Toxicity studies are expected to be performed in compliance with Good Laboratory Practice (GLP). The GLP regulations are found in 21 CFR Part 58.1: Good Laboratory Practice for Nonclinical Laboratory Studies (USA). These regulations set the minimum basic requirements for: - study conduct - personnel - facilities - equipment - written protocols - operating procedures - study reports - and a system of quality assurance oversight for each study to help assure the safety of FDA-regulated product

7. CLINICAL TRIALS 7 Overarching principles Regulatory framework (pharmaceuticals) CTA statistics

8. Lifecycle of a Drug 8 Pre-Market Post-Market Drug Discovery Clinical Trials Drug Submission Review Market Authorization Decision Public Access Revisions To Product And Use Surveillance, Inspection and Investigation Post-Market Changes to Marketed Products The Food and Drugs Act and Regulations authorize the Therapeutic Products Directorate and the Biologics and Genetic Therapies Directorate to regulate the safety, efficacy and quality of pharmaceutical and biologic therapeutic products. Pre- clinical studies

9. 9 Disclosure of risks Data integrity Societal benefits Ethics review Guidelines (e.g., ICH) Regulations CMC is acceptable Trial has Scientific merit Protection of Clinical trial subjects

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11. 11 Division 5: Drugs for Clinical Trials Involving Human Subjects In effect since September 1 st, 2001 Two overarching objectives:  strengthen protections for human research subjects  increase R & D investment in clinical trials in Canada

12. 12 Division 5 (Cont’d) Post-authorization requirements Gives the Minister clear authority to reject, suspend or cancel the authorization of a clinical trial Good Clinical Practice (GCP) & inspection

13. 13 Authorization Requirements Clinical Trial Application (CTA):  Attestation  protocol  informed consent form  investigator’s brochure  chemistry & manufacturing information 2-day turnaround request for additional information 30-day review default period

14. 14 Statistics for CTs (pharmaceuticals)

15. 15 GOOD CLINICAL PRACTICES Health Canada has adopted the International Conference on Harmonization (ICH) Guideline on Good Clinical Practices (ICH E6) Clinical trials should be conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki, and that are consistent with GCP and the applicable regulatory requirement(s).

16. 16 GOOD CLINICAL PRACTICES (Cont’d) Research Ethics Board Compliance with protocol Informed consent form Documentation and record keeping ADR reporting (REB, sponsor)

17. 17 Inspection Program Conducted by the HPFBI, with authority under section 23 of the Food and Drugs Act Inspections conducted against requirements of Division 5 and generally accepted principles of GCP Sites chosen at discretion of HC or if complaints arise Sites may or may not be forewarned of the planned inspection

18. 18 Pre-CTA Meetings Present relevant data, clarify requirements, discuss concerns, and resolve potential issues

19. 19 References Division 5 Regulations http://laws.justice.gc.ca/en/F-27/C.R.C.- c.870/ Guidance for Clinical Trial Sponsors http://www.hc-sc.gc.ca/dhp- mps/prodpharma/applic-demande/guide- ld/clini/ctdcta_ctddec-eng.php Quality (Chemistry and Manufacturing) Guidance: Clinical Trial Applications (CTAs) for Pharmaceuticals http://www.hc-sc.gc.ca/dhp- mps/prodpharma/applic-demande/guide- ld/clini/qual_cta_dec-eng.php Quality requirements for biologics and radiopharmaceuticals http://www.hc-sc.gc.ca/dhp- mps/brgtherap/applic- demande/guides/qualit/index-eng.php

20. Lifecycle of a Drug 20 Pre-MarketPost-Market Drug Discovery Clinical Trials Drug Submission Review Market Authorization Decision Public Access Revisions To Product And Use Surveillance, Inspection and Investigation Post-Market Changes to Marketed Products Pre- clinical studies

21. Pre-submission Meetings Sponsors can deliver a brief presentation to the appropriate Directorate within Health Canada prior to filing an NDS, SNDS, ANDS, SANDS, CTA or request for Priority Review or Notice of Compliance with Conditions status. Purpose: Discuss data in support of the submission. Familiarize review staff with the submission prior to its filing. Obtain feedback regarding areas of concern based on current experience and regulatory requirements. Identify potential problems and manage disputes early in the submission process. Provide the Directorate the opportunity to re-align resources, if necessary, to accommodate the filing of the submission. 21

22. Health Santé Canada Health Products and Food Branch Direction générale des produits de santé et des aliments Submission Process – Major Steps Receipt & Processing Data entry File preparation Screening for acceptability Chem. & Man. evaluation Clinical evaluation Label review Notice of Deficiency (gross deficiencies) Screening Deficiency Notice or Notice of Noncompliance Response to SDN, NOD, NON Management of Drug Submission Policy Market Authorization Notice of Compliance and/or DIN

23. Screening (all submission types):- 45 days NDS - Review Clinical/C&M:- 300 days p riority - 180 days 23

24. Purpose: Assess the safety, quality and effectiveness of a pharmaceutical. Review is organised by stream: Clinical Non-clinical Chemistry and Manufacturing Labelling (Review of Product Monograph, Inner/Outer Labels) Brand Name Analysis Other (Biopharmaceutic Evaluation, Biostatistics, Risk Management Plan, etc.) 24 Review

25. Lot Release Program: Legislative Authority  The Lot Release Program derives its legislative authority from section C.04.015 of the Food and Drug Regulations C.04.015 On written request from the Director, every fabricator, packager/ labeller, tester, distributor referred to in paragraph C.01A.003(b) and importer of a drug shall submit protocols of tests together with samples of any lot of the drug before it is sold, and no person shall sell any lot of that drug if the protocol or sample fails to meet the requirements of these regulations  Each lot of a Schedule D (biologic) drug is subject to the Lot Release Program before sale in Canada. 25

26. Lot Release: Life Cycle Approach Canada’s lot release program spans the product lifecycle :  Clinical Trials  Consistency Testing  Routine Lot Release  Response to Emerging issues Routine Lot Release Support for investigations and response to emerging issues Pre-Market Review Lot Release Program Clinical Trials 26

27. Evaluation Groups  Pre-approval  Group 1: a) clinical trial lots & b) consistency lots  Post-approval  Group 2: Protocol review & test each lot (vaccines)  Group 3: Protocol review & periodic testing  Group 4: No testing: results reported through fax-back 27

28. Lot Release: Risk-Based Oversight While all biologics on the Canadian market are within the scope of the lot release program, activities carried out range from:  Receiving notifications only  Document review only  Document review and targeted testing 28

29. Lifecycle of a Drug 29 Pre-MarketPost-Market Drug Discovery Clinical Trials Drug Submission Review Market Authorization Decision Public Access Revisions To Product And Use Surveillance, Inspection and Investigation Post-Market Changes to Marketed Products Pre- clinical studies

30. QUESTIONS???