[Table of Contents]

Volume: 26S1 - February 2000

Guidelines for Reporting Adverse Events Associated with Vaccine Products
Supplementary guidelines for the Canadian Pharmaceutical Industry

I. Introduction

These Guidelines are a Supplement to the "Guidelines for Reporting Adverse Reactions to Marketed Drugs" (Cat. H49-106/1996E) distributed by Canada Communications Group - Publishing and should be used with them. Where the two documents differ in requirements or definitions, in the case of vaccine products these guidelines should be followed.

A. Background - Drugs and Vaccines

As announced in the Canada Gazette Part II, Vol. 129, No. 24, in accordance with Schedule No. 844, the Food and Drug Regulations were amended to require manufacturers of all drugs marketed in Canada to submit adverse drug reaction (ADR) reports according to defined criteria, effective January 1, 1996. The amendment harmonizes definitions of ADRs with those of the World Health Organization (WHO), the Council for International Organizations of Medical Sciences (CIOMS), the International Conference on Harmonization (ICH) and the U.S. Food and Drug Administration (FDA).

In order to facilitate the ADR reporting process for manufacturers, the Therapeutic Products Programme (TPP) (previously known as the Drugs Directorate) prepared official guidelines for the Canadian pharmaceutical industry entitled "Guidelines for Reporting Adverse Reactions to Marketed Drugs" (TPP Guidelines). The TPP Guidelines (but not the Regulations) specifically exclude vaccine products, as the postmarketing surveillance of vaccines is the responsibility of the Division of Immunization, Bureau of Infectious Diseases, at the Laboratory Centre for Disease Control (LCDC). This separation of drug and vaccine adverse event reporting has been in place since 1987. The Division of Immunization collaborates with the Vaccines Division of the TTP's Bureau of Biologics and Radiopharmaceuticals in this activity. The Division of Immunization retains the responsibility for conducting postmarketing surveillance activities and maintaining the Vaccine Associated Adverse Event Surveillance System (VAAESS). Both TPP and LCDC fall under the umbrella of the Health Protection Branch (HPB) of Health Canada, however, and where the Regulations refer to "the Director", this is defined in the Food and Drugs Act as the Assistant Deputy Minister, HPB.

The purpose of this document is to provide additional information for companies that manufacture or distribute vaccine products regarding special considerations for the reporting of adverse events associated with vaccines.

B. Principles of Adverse Reaction Reporting for Vaccines

At Health Canada, vaccine ADRs are referred to as "vaccine associated adverse events" or VAAEs. As with the activities of the Bureau of Drug Surveillance described in the TPP Guidelines, voluntary reporting of suspected events by health care providers is a key element in the monitoring of vaccine safety. Although there are similarities with the reporting of adverse reactions to drugs, as described in the TPP Guidelines, reporting of events associated with vaccines is distinguished by several unique characteristics:

1. Reporting of cases of VAAEs to LCDC is through public health authorities in each province, in contrast to reporting of ADR cases, which are reported directly to the TPP through regional centres or through industry. For vaccines, more than 95% of cases are reported directly to a local health unit rather than through a manufacturer; in contrast, approximately 40%-50% of ADR reports are submitted to TPP by manufacturers.

2. There will be cases of VAAEs reported to the manufacturer directly by the consumer rather than by a health care professional.

3. In contrast to ADRs, a greater proportion of VAAEs are reported to LCDC by public health practitioners than by physicians or pharmacists. Public health nurses constitute about 90% of VAAE reporters, a proportion similar to that of the pharmacists who report the majority of ADRs. This is expected for vaccines for several reasons. Public health clinics deliver a high proportion of vaccinations across Canada, and in many provinces the routine childhood immunization programs are provided exclusively by public health authorities. Even in jurisdictions where private physicians deliver vaccines, nurses at local public health units receive telephone calls from practitioners who wish to report a reaction.  

4. There is often large-scale use of vaccines shortly after marketing in comparison with the slower distribution of drug products to the Canadian consumer.

5. Lot release numbers are important in VAAE surveillance.

As for other drug products, it should be emphasized that reports of adverse events from manufacturers or practitioners are for the most part only suspected associations. Reporters are not required to have made any formal causality assessment in their reports.

C. The Vaccine Associated Adverse Events Surveillance System (VAAESS)

Although vaccine manufacturers are required by law to submit reports on VAAEs received, the cornerstone of vaccine surveillance activities is a voluntary system in which health care providers (mainly public health nurses and physicians) report to local, provincial/territorial public health authorities events they feel are temporally associated with an immunization. These authorities forward all such reports for compilation at a national level to the Division of Immunization at LCDC. Although the form has many check boxes indicating serious VAAEs of interest, other severe or unusual events are also solicited and reported if the health care provider feels that they may have been due to the administration of a vaccine. The current edition of the Canadian Immunization Guide⁽¹⁾ provides more information on the nature of adverse events occurring with specific immunizing agents. The data from the reports received are entered into the VAAESS, a computerized database. To calculate adverse event rates, the Division of Immunization obtains lot specific data from vaccine manufacturers on the number of doses of their products distributed across the country. These vaccine distribution data are used as an approximation of the actual number of doses of vaccine administered. Because of varying reporting practices, differences in lot-specific adverse event rates require cautious interpretation; however, they are useful in generating signals that should be further investigated.

The reporting of a VAAE by a health care provider is voluntary, with the exception of Ontario, which has specific mandatory reporting requirements. However, there is no evidence of a higher rate of reporting with this approach.

In addition to this passive reporting system, Canada also has an active surveillance system for serious VAAEs, vaccination failures and selected infectious diseases, known as IMPACT (Immunization Monitoring Program ACTive)⁽²⁾. The system is operated through a contract with the Canadian Paediatric Society and involves a network of 12 pediatric centres across Canada, where more than 90,000 children are admitted annually. The 12 centres account for more than 88% of all pediatric tertiary care admissions in the country. At each centre a nurse monitor and clinical investigator perform active case-finding based on a daily search of admission records for diagnoses of conditions potentially linked to immunization.

In order to enhance signal generating capabilities, an external and multidisciplinary advisory group, the Advisory Committee on Causality Assessment (ACCA), was set up in 1994 to assist with the evaluation of all cases involving serious events and to help identify signals for in-depth investigation⁽³⁾. The specific mandate of this group is to review, in a systematic fashion, all serious VAAE reports (see Appendix 2 for definition of ACCA criteria) temporally associated with immunization that are reported to LCDC and entered into the VAAESS database.

D. Guidelines for Industry to Report Vaccine Associated Adverse Events

Where to Report?

Because routine vaccination program delivery and the purchase of vaccines for public use are almost exclusively the responsibility of each province/territory, the monitoring of adverse events at the local level is vital. This allows the local medical officer of health to properly counsel vaccine recipients and providers when an adverse event is reported. It also permits him or her to maintain an awareness of the status of vaccination programs in the jurisdiction.

For these reasons, practitioners' reporting of adverse events directly to manufacturers, and indeed even directly to the LCDC, without reporting through a local medical officer of health is discouraged. There will always be instances in which practitioners, the public and provincial public health authorities report the same case to a manufacturer. In the case of the provincial authority, this is usually done as a duplicate of the report sent to the VAAESS program. In the case of members of the public or providers, it may be the only report made. It is vital in such circumstances that LCDC be made aware of such cases. The philosophy behind the case reporting network in place in Canada is to ensure that (1) the flow and exchange of vaccine safety information benefits the vaccine recipient first, through appropriate case management at the local level; (2) vaccine safety information is streamlined to avoid duplication during aggregation at the national level; and (3) it can be shared, to ensure that all key players are kept informed.

What to Report?

The reporting rules are those of the TPP Guidelines. The definitions of "serious" and "non-serious, unexpected", although similar to those described in the TPP Guidelines, differ somewhat for VAAEs. Furthermore, because of requirements to monitor the safety of each lot of vaccines, the VAAESS program needs all reports related to vaccines, including "non-serious, expected".

Serious The definition of "serious" is listed in Appendix 2. In addition to the accepted international definition, there also is an LCDC-defined definition of "serious" listed in Appendix 2.

Non-serious, unexpected This implies that product information available to the health care provider, such as the package insert and product monograph, did not describe the reaction and therefore vaccine recipients could not have been adequately warned. This situation occurs either because the reaction had not been reported before or was of such low frequency or of uncertain relation with the vaccine that it was not listed in, for example, the package insert or product monograph. Reporting these events is crucial in order to affect changes in the product information, if warranted, or to be able to counsel others who report similar events.

Non-serious, expected Many reactions are expected by the nature of the response to vaccination (such as the rash that frequently occurs 7-10 days after measles vaccination, representing a mild measles-like illness in response to the live vaccine at the appropriate incubation period).

E. Confidentiality of Case Reports - Industry Access to Data

Under federal access to information (ATI) legislation, all case reports (with personal identifiers removed) are theoretically available on request to the public. However, VAAE data are considered medical records and, as such, photocopies of actual cases will not be provided even with identifiers removed, as it is theoretically possible for a link to a known case to be made. There are several exceptions to this LCDC policy regarding the provision of "detailed" (but with identifiers removed) case reports:

1. such case reports are provided to ACCA for evaluation;
2. such case reports will be provided on request to the company whose product is implicated, or when they are required for a periodic safety update to be completed;
3. such case reports are passed on (in this case with identifiers) to the appropriate provincial public health authorities so that they may be followed up as needed with a health care provider; and
4. anonymous case reports may be available for specific research purposes after ethical review of the study protocol.

Routine requests under ATI will be answered using aggregate data or, if necessary, line listings that include only basic information and exclude personal, provincial and manufacturer identities. All releases of information are accompanied by a "caveat document" (Appendix 3), adapted from that used by the World Health Organization's International Drug Monitoring Program, to explain the nature of spontaneous case reporting, the difficulty in making causal inferences from such data, and a requirement that the requester be responsible in the use that is made of the data according to the provision of the caveat document.

Any requirements for follow-up can be made through the Division. However, requests to follow up those cases reported through a provincial public health authority (the majority) must first be cleared with the appropriate reporting province. In those cases the Division of Immunization does not have the authority to disclose personal identifiers.

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