Vaccine safety and pharmacovigilance: Canadian Immunization Guide
Introduction
Since vaccines are usually given to healthy people, especially children, tolerance for adverse events following immunization (AEFI) is low. Perceived vaccine safety risks receive as much media attention as real safety risks and can be difficult to dispel despite credible scientific evidence. Loss of confidence in the safety of vaccines threatens the continued success of immunization programs.
Health care providers can develop competency in vaccine safety by:
- integrating knowledge about the main steps in vaccine development and evaluation into their practice.
- providing evidence-based information on the benefits and risks of vaccines.
- anticipating, identifying, reporting and managing AEFI as appropriate to their practice setting.
Vaccine safety applies not only to vaccine development but also to immunization practices for as long as a product is used. The term vaccine pharmacovigilance defines the science and activities related to the detection, assessment, understanding and communication of adverse events following immunization (AEFI) and other vaccine-related or immunization-related issues, and to the prevention of untoward effects of the vaccine or immunization. Health care providers have important roles to play in vaccine pharmacovigilance, including gaining and maintaining public confidence in the safety of vaccines.
This chapter and the Adverse Events Following Immunization chapter are intended to support health professionals learning the three immunization competencies listed above. To find out more about vaccine safety, you may refer to:
- The Canadian Immunization Guide's  in Part 4. These contain key condensed pre-authorization and post-marketing evidence-based safety data
- Health Canada's  which includes Canadian vaccine product monographs
Vaccine pharmacovigilance: overview

# Definitions of key vaccine pharmacovigilance terms
Pharmacovigilance in general, and as related to vaccines in particular, has many key concepts and terms that are important to understanding vaccine safety. The terms are used throughout this chapter and for ease of reference are defined below in alphabetical order.
Adverse events following immunization (AEFI): any untoward medical occurrence which follows immunization and which does not necessarily have a causal relationship with the usage of a vaccine. The adverse event may be any unfavourable or unintended sign, abnormal laboratory finding, symptom or disease.
This general definition is meant to guide timely AEFI reporting even before any certainty regarding causality can be established.

## Adverse reaction frequency terms
- Very common: occurring in 10% or more of subjects
- Common: occurring in 1% to less than 10% of subjects
- Uncommon: occurring in 0.1% to less than 1% of subjects
- Rare: occurring in 0.01% to less than 0.1% of subjects
- Very Rare: occurring in less than 0.01% of subjects
Good Clinical Practice (GCP): a standard for the design, conduct, performance, monitoring, auditing, recording, analyses, and reporting of clinical trials that provides assurance that the data and reported results are credible and accurate, and that the rights, integrity, and confidentiality of trial subjects are protected.
Good Laboratory Practice (GLP): the organizational process and the conditions under which laboratory studies are planned, performed, monitored, recorded, archived and reported. It is intended to promote the quality and validity of test data and improve the international acceptance of data generated in adherence to its principles.
Good Manufacturing Practices (GMP): the part of quality assurance that ensures that drugs are consistently produced and controlled in such a way to meet the quality standards appropriate to their intended use, as required by the marketing authorization.
Market Authorization Holders (MAH): the manufacturers or importers that have the legal authority to market their drug in Canada.
Notice of Compliance (NOC): A Notice of Compliance is issued pursuant to paragraph C.08.004(1)(a) of the Food and Drug Regulations when Health Canada has determined that the information submitted by the manufacturer has met Health Canada's standards for quality, efficacy and safety and complied with sections C.08.002 or C.08.003 of the Food and Drug Regulations.
Risk Management Plan (RMP): a document thatsummarizes known important safety information about a health product; identifies gaps in knowledge; outlines how known and potential safety concerns will be monitored by the market authorization holder; and provides a proposal to minimize any identified or potential risk.
Vaccine Attributable Risk: the difference between the frequency of an event in the vaccinated compared to unvaccinated population.
Vaccine Safety Signal: any information that arises from one or multiple sources and suggests a new potentially causal association, or a new aspect of a known adverse reaction (increased severity and/or increased frequency), between immunization and an event or set of related events, and is judged to be of sufficient concern to justify verification and remedial action if appropriate.

# Vaccine product life cycle
Before the 1960s, it was erroneously thought that everything that could be known about a product could be learned prior to its authorization. The modern era of pharmacovigilance started with the understanding that while sufficient evidence of safety, efficacy and quality is an absolute requirement for regulators to grant authorization for marketing a product, sufficient evidence does not mean knowing everything that can be known about a product. It is impossible to learn everything about a product before its authorization and efforts to do so may delay proven product benefit from being realized in the population.
The concept of a life cycle for vaccines and other marketed products underscores the fact that knowledge regarding product safety and efficacy must be sought after as well as before marketing authorization.
- Good Laboratory Practice
1. Phase I
2. Phase II
3. Phase III
- Good Clinical Practice
1. very common
2. common
3. uncommon1 +/- rare
- Good Manufacturing Practice
- Other international quality guidance documents (ICH, WHO, other regulators)
- production processes and quality control
- production facilities
- Good Manufacturing Practice
- Other international quality guidance documents (ICH, WHO, other regulators)
Consistency testing
Sample analysis
- Good Manufacturing Practice
- Good Manufacturing Practice
- Public health legislation in some provinces and territories makes AEFI reporting mandatory
Randomized controlled trials
Vaccine attributable risk
Abbreviations:
AEFI: Adverse Events Following Immunization
Vaccine pharmacovigilance activities in Canada
As summarized in  and , vaccine safety assessment and monitoring is a continuum that spans all phases of the vaccine product 'life cycle' from discovery through market authorization and beyond. In Canada, many stakeholders and activities are involved. More detail on the specific processes and stakeholder activities in Canada that contribute to vaccine safety are provided below.

# Regulatory quality oversight and pharmacovigilance activities
The Health Products and Food Branch (HPFB) at Health Canada has the mandate to manage 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;
- providing information to Canadians so they can make healthy, informed decisions about their health

## Authorization for marketing a vaccine in Canada
Health Canada's Biologics and Genetic Therapies Directorate (BGTD) , including vaccines. Before manufacturers or sponsors are eligible to market a product in Canada, they must submit a "New Drug Submission". This submission contains extensive information and data about the vaccine's safety, efficacy and quality, including the results of the non-clinical and clinical studies, details regarding the production of the vaccine, packaging and labeling details, and information regarding therapeutic claims and side effects. The quality evaluation of the submission includes an onsite evaluation of the production facilities as well as laboratory testing of samples from three to five consecutive lots (or batches of vaccine production) to verify manufacturing consistency.
After BGTD determines that the vaccine is compliant with the , Health Canada will issue a  and a  for market authorization.
Compliance with Good Manufacturing Practices (GMP) is an additional Health Canada requirement for selling vaccines in Canada. The Health Canada Regulatory Operations and Enforcement Branch ensures this compliance through issuance of Establishment Licenses for manufacturing sites in Canada via its own GMP inspections or through Mutual Recognition Agreements with international regulatory bodies, such as the European Medicines Agency, for manufacturing sites outside of Canada.

## Quality monitoring activities
These strategies allow Health Canada to assess how well the manufacturing process is controlled and that the quality control tests remain suitable.

### Lot Release Program
Each vaccine lot is subject to the lot release program before sale in Canada. The results of key quality control tests performed throughout the manufacturing process of each individual vaccine lot must be submitted to Health Canada for review before a release letter is issued to allow the sale of the lot on the Canadian market. The purpose of the  is to ensure to the extent possible that each newly manufactured batch of vaccine matches the lots used to generate the safety and efficacy data for market authorization. As part of its lot release program, Health Canada performs testing of most vaccine lots as per its Lot Release Guidelines.
Vaccine manufacturers may be requested to submit a Yearly Biological Product Report. This report contains production information on both drug substance and drug product lots, including test methods and results, reasons for any recalls and corrective action taken, as well as other pertinent post-market information.
In addition, regular Good Manufacturing Practice inspections are conducted to ensure continued compliance and renewal of establishment licenses for vaccine manufacturing facilities.

## Safety monitoring activities

### Canada Vigilance Program
Market authorization holders (i.e., the sponsors or manufacturers that have the legal authority to market their drug in Canada) are required to report serious adverse reactions to the , as mandated by the Food and Drugs Act and Regulations. The Canada Vigilance Program also accepts reports from health professionals and consumers. This information is one of the tools that enable Health Canada to monitor the safety profile of vaccines to determine if their benefits continue to outweigh their risks.

### Safety reports
The Food and Drugs Act and Regulations require market authorization holders to analyze adverse drug reaction data for safety concerns and prepare an annual summary report which represents a comprehensive assessment of the worldwide safety data of the vaccine. Market authorization holders must also notify Health Canada if they become aware of a significant change in the product benefit-risk profile.
Safety reports are assessed by Health Canada and, if specific safety issues are identified, additional safety information may be requested.

### Risk management plans
Health Canada reviews the  when the market authorization holder is seeking authorization to market a new vaccine in Canada but can also request for one to be submitted at other times.

### Product risk/benefit assessments
Health Canada can ask the market authorization holder to submit a benefit-risk assessment of a therapeutic health product when the benefit-risk profile of a product has changed. Health Canada evaluators reviewing benefit-risk assessments use science-based procedures to determine whether the benefits outweigh the risks or whether the product needs regulatory intervention.

### Canadian Adverse Events Following Immunization Surveillance System (CAEFISS)
The  is a collaborative post-marketing federal/provincial/territorial (F/P/T) passive surveillance system with the following objectives:
- to continuously monitor the safety of marketed vaccines in Canada;
- to identify increases in the frequency or severity of previously identified vaccine-related reactions;
- to identify previously unknown AEFI that could possibly be related to a vaccine (unexpected AEFI);
- to identify areas that require further investigation and/or research; and
- to provide timely information on AEFI reporting profiles for vaccines marketed in Canada that can help inform immunization-related decisions.
CAEFISS includes spontaneous, enhanced and active AEFI reporting processes. Each province and territory has their own reporting system that includes activities at the local/regional as well as the provincial/territorial levels. All provincial and territorial systems are part of CAEFISS.
Spontaneous AEFI reports may come from health care professionals and the public. F/P/T immunization program authorities encourage vaccine providers and others to report AEFI of particular public health importance and sometimes conduct enhanced AEFI surveillance as part of new publicly-funded immunization programs or as a response to possible emerging vaccine safety signals. In most jurisdictions (Ontario, Quebec, Nova Scotia, Manitoba, New Brunswick, Saskatchewan, Prince Edward Island and Northwest Territories, British Columbia, Alberta and Nunavut) AEFI reporting is a legislated requirement.

### Immunization Monitoring Program ACTive (IMPACT)
There is also an active syndromic surveillance component to CAEFISS. This is provided by Canada's . IMPACT is a pediatric hospital-based network funded by the Public Health Agency of Canada (PHAC) and administered by the Canadian Paediatric Society (CPS). IMPACT conducts national surveillance for selected AEFIs, vaccine failures and vaccine preventable diseases in children. The 12 IMPACT hospitals encompass approximately 90% of tertiary care pediatric beds in Canada. Nurse monitors actively search for children admitted to IMPACT hospitals with neurologic and other AEFIs of public health importance. The nurse monitors determine whether these events meet a standard case definition and have occurred within a specific interval following immunization that could implicate the vaccine as a possible cause. All such AEFI are reported to PHAC as well as to local public health officials and are included in CAEFISS.

### AEFI report flow and associated activities
Local public health officials are usually the first to receive an AEFI report. A public health professional reviews the report to determine the safety of administering further doses of the implicated vaccine(s). Efforts may also be made to gather additional information, validate a report diagnosis, and follow up investigation results and/or final outcome of the AEFI. Vaccine safety signals such as unexpected events or increases in severity or frequency of expected AEFI, especially vaccination site reactions or allergic events, may first be recognized at the local level. Such concerns are communicated to appropriate regional and/or provincial/territorial personnel for further assessment and investigation, if needed. Refer to  for a diagram illustrating the AEFI report flow. 
Provincial/territorial immunization programs receive and review all AEFI reports to carry out jurisdictional level analysis including estimation of rates of occurrence of specific AEFI and, in some cases, preparation of periodic jurisdictional summaries. With a larger volume of reports than is seen at local levels, this is another opportunity to identify possible vaccine safety signals and take action as appropriate. Actions may include: undertaking additional epidemiological investigation; consulting with experts, advising federal public health or regulatory authorities; or creating an AEFI alert to notify and seek input from all F/P/T vaccine safety leads. In addition to being the lead on jurisdictional pharmacovigilance activities, P/T vaccine safety coordinators remove personal identifiers in AEFI reports and send the reports to PHAC. 
Vaccine Safety Section at PHAC receives AEFI reports from multiple sources (provinces, federal jurisdictions and IMPACT), identifies duplicates and collates them into a national database. The key activities at the national level include coding of AEFI using the international Medical Dictionary for Regulatory Activities (MedDRA) and medical case review to detect vaccine safety signals, including any unexpected or unusual AEFI. Analyses are done regularly to search for vaccine safety signals, and information is shared with Health Canada. Reports are produced for F/P/T review as well as review by the National Advisory Committee on Immunization (NACI).

### Vaccine Vigilance Working Group
The  includes members representing all federal (First Nations and Inuit Health Branch, National Defence and the Canadian Armed Forces, Royal Canadian Mounted Police, Correctional Services of Canada) and P/T immunization programs as well as Health Canada regulators and IMPACT. The working group reports to the Canadian Immunization Committee and its activities include:
- preparation of national guidelines and procedures for monitoring AEFIs in Canada;
- providing a national forum to identify, share and promote best practices regarding vaccine pharmacovigilance; and
- providing a national vaccine safety surveillance network that can rapidly share and disseminate information to appropriate stakeholders regarding vaccine safety signals or other relevant issues.
Key Stakeholder Roles and Responsibilities
Timely, comprehensive and multidirectional communication between key stakeholders is essential to the effectiveness of the pharmacovigilance process. For example:
- Scientists and regulators give information to health care providers and public health authorities;
- Health care providers need to give information to public health authorities;
- Public Health authorities collate and analyze information for regulators, healthcare providers, scientists and consumers.
- Vaccine lot release program
- Reviews/approves post-marketing product changes that could impact quality, safety or efficacy
- Reviews safety data submitted by market authorization holders (adverse reaction reports, safety reports, issue-specific safety reports, risk management plans, etc.)
- Conducts risk-benefit assessments
- Issues risk communications
- During inspections, monitors and enforces vaccine industry compliance with the Food and Drugs Act and Regulations, including Good Manufacturing Practice
- Comply with the Food and Drugs Act and Regulations, including Good Laboratory Practice, Good Clinical Practice, and Good Manufacturing Practice
- Prepare Annual Summary Reports
- NACI Secretariat coordinates and supports the activities of NACI such as evidence reviews and publications, including the Canadian Immunization Guide and position statements.
- Provinces and territories
- First Nations & Inuit Health Branch
- Department of National Defense
- Royal Canadian Mounted Police
- Correctional Services of Canada
- Collates, codes, reviews, analyzes and communicates jurisdictional level AEFI report data from multiple sources
- Jurisdictional vaccine safety signal detection/investigation
- Share de-identified jurisdictional AEFI report data with PHAC
- Conduct individual public health action after an AEFI (e.g., AEFI validation and/or investigation; decisions on future re-immunization)
- Provide evidence-based information on the benefits and risks of vaccines
- Anticipate, identify, report and manage AEFI as part of their clinical and/or public health professional practice
- Notify their healthcare provider about AEFIs to enable prompt assessment, appropriate management, and timely reporting.
Global pharmacovigilance partners
Vaccine pharmacovigilance is a global effort with many participants conducting similar activities to those outlined in ,  and  and sharing vaccine safety information. In addition to individual country pharmacovigilance systems, Canada's other global partners in vaccine pharmacovigilance are briefly described below with a link to more detailed information.

# World Health Organization (WHO)
The WHO has a mandate from member states to develop, establish and promote international standards with respect to a wide variety of products including biologics such as vaccines. Since 1965, the WHO has had a global program for International Drug Monitoring based at the  in Sweden. The Centre receives a subset of AEFI report data gathered by member states which enable the main objective of the program: safety signal detection at a global level.
In 1999, the WHO established the  (GACVS) to provide independent evidence-based responses to safety issues of global concern. The expert committee meets twice yearly (usually June and December) and publishes their conclusions and recommendations shortly thereafter in the WHO Weekly Epidemiological Record. The GACVS also maintains a subject-specific topic index at their website. As part of their work, GACVS established the  which identifies and promotes websites on vaccine safety that adhere to good information practices.

# Council for International Organizations of Medical Sciences (CIOMS)
The Council for International Organizations of Medical Sciences is an international, non-governmental, non-profit organization established jointly by the WHO and the United Nations Educational, Scientific and Cultural Organization (UNESCO) in 1949 to facilitate and promote international activities in the field of biomedical sciences, including making recommendations on the assessment and monitoring of adverse reactions. The WHO and CIOMS jointly formed a Working Group to develop definitions relevant to vaccine pharmacovigilance which were published in 2012.

# Brighton Collaboration
The , so named because it was initiated in 1999 at a Vaccine conference in Brighton, England, is a global expert network which seeks to create methodological standards for vaccine pharmacovigilance, including standardized case definitions of AEFI. These case definitions have been adopted by the Vaccine Vigilance Working Group (VVWG) and are captured to some extent in the National .

# Health and Medicine Division of the National Academies of Sciences, Engineering and Medicine
The United States National Academy of Sciences formed the Institute of Medicine in 1970 to function as an independent, expert professional body that examines issues of relevance to the health of the public. In March 2016, the Institute of Medicine was renamed the Health and Medicine Division (HMD). Since 1991 several vaccine safety issues have been rigorously assessed by Immunization Safety Review Committees. These committees contain a broad range of expertise in clinical medicine (pediatrics, internal medicine, infectious disease, nursing), public health (epidemiology, biostatistics, health communication), medical research (immunology, genetics, neurology) as well as risk perception, decision analysis and ethics. Since 2001, an absolute criterion for committee membership has been lack of any association with vaccine manufacturers or their parent organizations and no prior function as a legal expert witness.
For each issue studied, the HMD's Immunization Safety Committee reviews all pertinent theoretical, experimental, clinical and epidemiologic evidence and hears presentations from the public and health professionals. There is no prior assumption regarding a positive or negative connection between the vaccine and the issue at hand. The scientific evidence is then reviewed, and biologic mechanisms for a possible causal association carefully considered. Prior to publication, each report is reviewed by a separate expert panel, chosen by the National Academies of Sciences but anonymous to the Committee. Reviewer's comments are given due consideration, but ultimately the final published report represents the consensus of the safety Committee alone. All  can be viewed online.