Adverse Reaction Reporting Requirements and Blood Product Surveillance at Health Canada: A Review of the IGIVnex Issue November 6, 2014 Dr. Angela Tonary Senior Scientific Evaluator BTO Scientific Section, Marketed Biologicals, Biotechnology and Natural Health Products Bureau

Disclaimer The opinions expressed in this presentation are those of the presenter and do not necessarily reflect those of Health Canada. The presenter has no conflict of interest to declare.

Background: The NAC’s Request - 1 "At our recent NAC meeting, members discussed the quarantine notification issued on February 14, 2014 for IVIG lot 26NP0R. NAC expressed concern that there were multiple reactions communicated to the Vendor and felt Grifols had enough data to isolate the product much sooner to avoid patients having unnecessary potentially serious reactions. As neither CBS nor NAC owns this process, NAC would very much like to understand the process around reporting of adverse events for pharmaceutical drugs such as in the case of Grifols' IGIVnex."

Background: The NAC’s Request - 2 "NAC members would like similar information but of course related to reporting of adverse events for pharmaceutical drugs and the requirements of vendor's in such adverse events. As well, we would like to know more about alarms/thresholds that are in place to trigger an alert on adverse reporting and vigilant process."

Outline Health Canada’s Drug Regulatory Role and Mandate The Roles of Health Canada Groups Involved in Blood Product Surveillance in Canada A “Shared Responsibility” System for Drug Safety in Canada Regulatory Requirements for Reporting Adverse Drug Reactions and New Safety Information in Canada Blood Product Surveillance: Challenges and Limitations The Marketed Health Products Directorate – Blood Product Surveillance Program IVIGnex Chronology and Cases Summary

Health Canada’s Role in Blood Product Surveillance Health Products and Food Branch Mandate “The Health Products and Food Branch (HPFB)'s mandate is to take an integrated approach to managing the health-related risks and benefits of health products and food by: minimizing health risk factors to Canadians while maximizing the safety provided by the regulatory system for health products and food; and, promoting conditions that enable Canadians to make healthy choices and providing information so that they can make informed decisions about their health.” http://www.hc-sc.gc.ca/ahc-asc/branch-dirgen/hpfb-dgpsa/index-eng.php

Health Canada’s Drug Regulatory Role Health Products and Food Branch - Organization Directorates Offices Biologics and Genetic Therapies Directorate Food Directorate Health Products and Food Branch Inspectorate Marketed Health Products Directorate Natural and Non-prescription Health Products Directorate Policy, Planning and International Affairs Directorate Regional Operations Therapeutic Products Directorate Veterinary Drugs Directorate Office of Consumer and Public Involvement Office of Management and Program Services Office of Nutrition Policy and Promotion Office of Paediatric Initiatives Office of the Assistant Deputy Minister (Adapted from http://www.hc-sc.gc.ca/ahc-asc/branch-dirgen/hpfb-dgpsa/index-eng.php.) HPFB is comprised of nine Directorates and five Offices. The groups directly concerned with Blood Products are the BGTD, the MHPD and the HPFBI.

Health Canada’s Role in Blood Product Safety The Biologics and Genetic Therapies Directorate The BGTD’s key activities include: conducting pre-market review and approval of license applications reviewing and approving applications for clinical trials administering the Lot Release Program developing new regulations, policies and guidances conducting public and stakeholder consultations

Health Canada’s Role in Blood Product Surveillance The Marketed Health Products Directorate The MHPD’s key activities include: monitoring and collecting adverse reaction data reviewing and analysing marketed health product safety data conducting risk/benefit assessments of marketed health products communicating product-related risks to health care professionals and the public providing policies to effectively regulate marketed health products

Health Canada’s Role in Blood Product Surveillance The Health Products and Food Branch Inspectorate The HPFBI’s key activities include: promoting, monitoring and verifying compliance with the Food and Drug Regulations compliance enforcement inspection of establishments laboratory analyses

A “Shared Responsibility” System for Product Vigilance and Drug Safety in Canada Drug safety is a shared responsibility between the Federal Drug Regulator, drug manufacturers, health professionals, patients, consumers and stakeholder groups The market authorization holders (MAHs) have the primary responsibility for the safety and efficacy of their products and are expected to act in a timely and responsible manner to identify and minimise newly-identified risks associated with the products they market To reflect this shared responsibility, in recent years Health Canada has placed a greater focus on proactive surveillance of certain product lines and in monitoring industry's Good Product Vigilance Practices

A “Shared Responsibility” System for Product Vigilance and Drug Safety in Canada The Market Authorization Holder (MAH): The MAHs have the primary responsibility for the safety and efficacy of all products they manufacture, import, distribute or sell to the Canadian public and must comply with all Canadian legislative and regulatory requirements MAHs must report to Health Canada all serious adverse reactions they become aware of and any significant new safety information that impacts on the benefit-risk profile of the products they are authorized to sell or distribute in Canada

A “Shared Responsibility” System for Product Vigilance and Drug Safety in Canada Health Professionals, Patients, Consumers and Stakeholders: Health professionals play an important role in monitoring and voluntarily reporting on the real-world safety of health products to Health Canada. Physicians also share responsibility for the safe use of the products they prescribe to their patients Patients and consumers are responsible for making informed choices about the health products they use and for reporting adverse reactions to Health Canada on a voluntary basis Drug safety stakeholder groups work in collaboration with health professionals, patients, consumers and Health Canada to ensure that their constituents are aware of important drug safety issues and that important new safety information is acted upon in a timely manner

Regulatory Requirement for Reporting Adverse Drug Reactions in Canada Food and Drug Regulations: C.01.017. The manufacturer shall submit to the Minister a report of all information relating to the following serious adverse drug reactions within 15 days after receiving or becoming aware of the information, whichever occurs first: (a) any serious adverse drug reaction that has occurred in Canada with respect to the drug; and (b) any serious unexpected adverse drug reaction that has occurred outside Canada with respect to the drug

Regulatory Requirement for Reporting on New Drug Safety Information Food and Drug Regulations:  C.01.018. (1) The manufacturer shall prepare an annual summary report of all information relating to adverse drug reactions and serious adverse drug reactions to the drug that it received or became aware of during the previous 12 months C.01.018. (4) If, in preparing the annual summary report, the manufacturer concludes that there has been a significant change, it shall notify the Minister without delay, in writing, unless this has already been done

Reporting: Where to Report Adverse Reactions Health Care Professionals and Consumers Serious Adverse Events or Reactions to Blood Components and/or Plasma Derivatives Spontaneous Reports Adverse Event Reporting from Hospitals via TTISS Manufacturers Plasma Derivatives and Blood Components (CBS / H-Q) Mandatory: Serious ADRs 15 day reporting and 24 hour reporting of fatalities associated with blood and blood components Provincial Blood Office (TTISS provincial site) Health Canada HPFB - BGTD CBS / H-Q PHAC Health Canada HPFB - MHPD Health Canada

Blood Product Surveillance: Challenges and Limitations under-reporting of adverse reactions lack of reliable denominator data (e.g., number of patients exposed to the drug) receipt of poor quality AR reports Potential for emerging infectious diseases issues with awareness of “new” infectious diseases transmissible through fractionated or biotechnology-derived blood products

The Marketed Health Products Directorate Blood Product Surveillance Program Adverse reaction reports are received, processed and assessed by the Canada Vigilance Program staff There is regular (biweekly) review of all AR reports for all blood products by lot numbers by the MBBNHPB medical and scientific evaluators, with consensus decisions on needed follow-up actions, if any There is ongoing communication with internal (BGTD, HPFBI) and external (CBS / H-Q, PHAC and TTISS) partners

IGIVnex Chronology Date Action Nov. 19, 2013 Lot 26NPOR1 was released by Health Canada Nov. 20, 2013 Lot 26NPOR1 was released by Grifols Canada Nov. 26, 2013 First shipment of lot was to CBS Jan. 24, 2014 First shipment from CBS to hospitals Feb. 18, 2014 Dr. Alan Tinmouth in Ottawa advised members of the NAC via email of 4 severe allergic reactions that occurred with lot 26NP0R1 of IGIVnex /10% / 20 g; “….CBS was notified and was in contact with the fractionator” Grifols placed units in their inventory on hold CBS placed units in their distribution centres on hold; confirmed there were other AE reports

IGIVnex Chronology Date Action Feb. 19, 2014 CBS requested hospitals to quarantine the units MHPD notified Inspectorate of issue via email Feb. 20, 2014 First two reports sent to Inspectorate; further reports followed Inspectorate sent questions to Grifols and received response same day Grifols’ medical assessment and investigation expected to be completed Feb. 25, 2014 Feb. 21, 2014 CBS requested hospitals to also quarantine lot 26NP2W1 due to shared plasma pool(s) Feb. 25, 2014 Grifols issued a Type II recall for lot 26NP0R1 Feb. 28, 2014 CBS issued quarantine notification to hospitals for third lot 26NP691 due to mild allergic reactions

IVIGnex Chronology and Current Status Date Action Mar. 6, 2014 Health Canada groups met to discuss status and next steps Oct. 31, 2014 Health Canada expects to receive Grifols’ updated report and decision for the two quarantined lots 26NP0R1 and 26NP691

The Canadian IGIVnex cases AR Report No. Date Rec’d by HC Serious? Lot No. AR terms 588899 Feb. 19 yes 26NPCRT pruritus; urticaria 588901 26NPOR1 589109* Feb. 20 anaphylactic reaction; angioedema; flushing; urticaria 589110* no angioedema; flushing; respiration abnormal; urticaria 589111* angioedema; chest discomfort; dizziness; dysphagia; throat tightness; urticaria 589112* chest discomfort; dyspnoea; hypoxia; urticaria 589264 pruritus; throat tightness; urticaria 589265 chest discomfort; cough; urticaria 589266 drug hypersensitivity; pruritus; urticaria 589421 Feb. 21

Thresholds Health Canada has well established signal detection and signal prioritization processes The decision to take action depends on the context and requires consideration of many factors, including: the seriousness of the reaction; whether the reaction is a known/labeled adverse reaction; the population being treated; the exposure of the drug in the population; and possible other factors specific to a given drug

Summary The MAH has the primary responsibility for the safety and efficacy of the health products they market in Canada Health Canada conducts regular monitoring of all blood product ARs but, with the potential lag time in reporting, are not likely to be the first to identify a cluster of reactions or trending safety issue The NAC, as a blood safety stakeholder group, can act on safety information by contacting the Blood Operator (CBS or H-Q), blood product MAH and Health Canada as soon as they become aware of an issue Health Canada will intervene if the MAH is not taking appropriate action(s) to address the issue and minimize the risk in a timely manner

Thank you! Comments … Questions?