1. 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

2. 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.

3. 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."

4. 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."

5. 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

6. 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.”

7. 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
HPFB is comprised of nine Directorates and five Offices. The groups directly concerned with Blood Products are the BGTD, the MHPD and the HPFBI.

8. 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

9. 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

10. 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

11. 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

12. 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

13. 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

14. Regulatory Requirement for Reporting Adverse Drug Reactions in Canada
Food and Drug Regulations:
C  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

15. Regulatory Requirement for Reporting on New Drug Safety Information
Food and Drug Regulations:
 C (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 (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

16. 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

17. 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

18. 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

19. 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 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

20. IGIVnex Chronology Date Action Feb. 19, 2014
CBS requested hospitals to quarantine the units
MHPD notified Inspectorate of issue via
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

21. 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

22. 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

23. 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

24. 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

25. Thank you! Comments … Questions?