Guidance on preparing and submitting summary reports for marketed drugs and natural health products: Preparing annual summary reports under the FDR

On this page

• About annual summary report preparation requirements
• Preparing annual summary reports
• Content of an annual summary report
• Acceptable document formats
• Canadian-specific information
• Notification of significant change
• Discontinued products

About annual summary report preparation requirements

In accordance with section C.01.018 of the Food and Drug Regulations (FDR), market authorization holders (MAHs) must prepare an annual summary report (ASR) of all information relating to adverse drug reactions and serious adverse drug reactions that they received or became aware of during the previous 12 months.

The annual summary report contains a concise, critical analysis of those reactions.

The requirement to prepare an ASR arises on the date that you first sell the product in Canada and continues throughout the product's life cycle.

In preparing the report, you must determine, based on the analysis, whether there has been a significant change in what is known about the drug's benefits and risks.

You must notify the Minister in writing without delay if you have not already done so, if in preparing the report you conclude that there has been a significant change.

Visit Definitions for an explanation of "sell" and of "significant change".

Preparing annual summary reports

You must meet all regulatory requirements of the FDR. Section C.01.018 includes a requirement to prepare and complete the report annually, and C.01.020 requires you to maintain the ASR for at least 25 years after the day on which it was created. You should also maintain documents used to prepare the ASR, to assist with compliance verification.

Preparing the report consists of collecting, analyzing and organizing the relevant data about adverse drug reactions and serious adverse drug reactions, including contextual information, that enables you to determine whether there has been a significant change in the risk-benefit profile. The preparation of the report is an ongoing activity throughout the reporting period linked to signal management processes and monitoring activities.

Continuous and periodic signal management processes and monitoring activities, such as environmental scanning, are important for the preparation of an ASR.

It's essential that manufacturers and regulatory authorities have the most up-to-date information on a drug. A concise, critical analysis must be rigorous enough to identify any significant changes in the risk-benefit profile. The timing, frequency and nature of monitoring activities for signal detection depend on a number of factors, such as:

• the product's risk profile
• known or specific emerging issues
• volume of adverse drug reaction reports received
• scheduled timing or preparation of the summary report

Identified and potential safety issues, as well as knowledge gaps (for example, toxicity in vulnerable sub-populations, interactions with other products, emergent use patterns) may require more active monitoring.

In addition to reviewing your internal databases and information, you are advised to review the Canada Vigilance Adverse Reaction online database for information relevant to the preparation of your ASR. For more information on scanning the database and your obligations concerning serious adverse drug reaction reporting, consult:

• Clarification of section 4.3 of the Reporting adverse reactions to marketed health products guidance: Notice

You are encouraged to use terminology from the Medical Dictionary for Regulatory Activities (MedDRA) to analyze and present data.

You may choose the 12-month period for which the ASR is prepared as long as there are no gaps between reporting periods. For example, you may choose to shift the 12-month period to align with your commitments in other jurisdictions, as long as there is no gap between the date on which you first sell your product and the ASR reporting periods. We prefer that ASRs be prepared with harmonized data lock points (DLPs) based on the international birth date (IBD) of the active substance. If you are unable to identify the IBD, refer to the EU reference dates (EURD) list.

The report must be prepared on an annual basis, regardless of timeline requirements in other jurisdictions. Common practice is to complete the report within 70 calendar days of the data lock point, as outlined by ICH E2C(R2) for an annual report, unless our request letter for the submission of an ASR specifies a different timeline.

ASRs are not expected to discuss problems related to quality or good manufacturing practices, unless they result in adverse clinical outcomes. Good manufacturing practices (GMP)-related safety issues should be distinguished from ingredient-related safety issues.

Visit Definitions for an explanation of "vulnerable sub-populations".

Although ASRs must be prepared annually, they are only to be submitted:

• upon our request
• to fulfill a term or condition imposed by the Minister under the Food and Drug Regulations

Visit Submitting annual reports for information on when to submit.

Content of an annual summary report

The information you include in the ASR will depend on the adverse reaction data received or known to you. If you cannot complete a section (for example because you have not become aware of any adverse reactions within a reporting period), note this and provide an explanation.

Adverse reaction reports as well as other sources of information that might be necessary for the analysis should be considered. Other data sources may include:

• foreign regulatory websites
• reports of medication errors (including incidents without clinical consequences such as near misses and reports of concern)
• public information, such as social media or media reports of side effects

You should include in your concise critical analysis, where available, information on emergent safety issues, whether domestic or foreign. Examples of such information include:

• findings from clinical studies
• actions on comparable products from foreign regulators or other MAHs
• new and significant safety findings published in peer-reviewed scientific and medical literature or made available as unpublished manuscripts, on the product or suspect ingredient(s)

Collecting this information is part of your ongoing routine pharmacovigilance and signal detection.

An ASR should add to what is known about the product's safety from real-world use. Available reference safety information, for example, product monographs, core company data sheets or core company safety information (referred to as "global reference safety information") should be part of your assessment. If your product has a Canadian risk management plan (RMP), the summary of safety concerns should also be part of your assessment.

Even for products with well-established safety profiles, safety issues may emerge. The depth of analysis needed for the ASR depends on the nature and amount of the information collected. ASRs summarize and integrate new cumulative safety knowledge gained from experience during the reporting period.

At minimum, your concise critical analysis should address the following, where relevant:

• whether there is a need to take action or if action has been taken (for example, for safety reasons) during the reporting interval by MAH or foreign competent authorities
• changes to reference safety information during the reporting interval
• separate global and Canadian exposure (interval/cumulative) in
  • related clinical trials
  • post-marketing
• summary of significant safety findings from clinical (interventional and non-interventional) studies during the reporting interval
• summary of medication errors during the reporting interval, including incidents without clinical consequences
• summary of significant safety findings from non-clinical studies during the reporting interval, if applicable
• summary of significant findings from a literature search covering the reporting interval
• summary of reports of unusual failure in efficacy or lack of effectiveness during the reporting interval
• opened, ongoing and closed safety signals during the reporting interval
• summary of new safety information identified during the reporting interval, including new information for each safety concern in the Canadian RMP for:
  • important identified risks
  • important potential risks
  • missing information
• summary of new information arising from each additional pharmacovigilance activity in the Canadian RMP during the reporting interval
• evaluation of effectiveness of the risk minimization measures in the Canadian RMP during the reporting interval
• changes to the Canadian RMP implemented during the reporting interval or changes in-progress
• a discussion on misuse, off-label use, and deliberate or inadvertent exposures or intentional overdose
• conclusions on whether there has been a significant change in what is known about the risks and benefits during the reporting interval
• new safety information about the class of drugs in which the current drug is included, where evidence also exists that the safety concern also involves the current drug

Conclusions about a significant change

In preparing your ASR, you must include your conclusions on whether there has been a significant change in what is known about the risks and benefits of the drug during the period covered by the report. We expect you to determine whether there has been a change in the balance of the benefits and risks that would warrant urgent action. These conclusions are based on your concise critical analysis of the evidence, including an evaluation of the safety findings.

Not all safety findings or changes to the known risks and benefits of a drug are considered significant. You should note safety findings and changes and assess whether they meet the threshold of significant change.

Conclusions about a significant change could arise from information involving authorized or off-label use and may identify urgent action needed to:

• modify labelling or Canadian product monograph to include serious, boxed warnings and precautions or contraindications
• change in packaging to modify the dosing device
• communicate risks to public or health professionals
• update or add additional risk minimization measures, such as educational materials, pregnancy prevention program or controlled distribution or access

The focus of the assessment should be on the clinical significance of such a change, for example:

• the potential for significant morbidity or mortality
• the impact on patient quality of life or public health
• whether the change may alter clinical practice

The discovery of a significant change could have an impact on other vigilance activities and requirements. For example, a need to update your risk management plan (RMP), including measures that you intend to take.

For new drugs, you should also consider if the significant change represents a significant difference from material contained in the new drug submission (as described in s. C.08.003 (1) of the FDR) for which you are considering a supplement to a submission.

For more information on risk management plans and supplements to a submission, consult:

• Submitting risk management plans guidance document
• Guidance on management of drug submissions and applications

If, in preparing the ASR, you have concluded that there was a significant change and have already notified Health Canada without delay, you should document within the report the date and the means of notification.

Visit Definitions for an explanation of "significant change".

Acceptable document formats

You may prepare an ASR using one of the following standardized document formats:

• Periodic benefit-risk evaluation report (PBRER) format
  • preferred international format for drug summary safety reporting
  • follow the standards defined in the ICH E2C (R2) guidance (PDF)
• Periodic safety update report (PSUR) format
  • EU format and comparable to the PBRER format

You may also prepare an ASR using a non-standardized format, as long as it respects the expected content outlined in this guidance.

The format you choose will depend on the nature of the product and your preference. However, you are encouraged to use the PBRER format. The PBRER format helps manufacturers:

• prepare a comprehensive, cumulative, concise and critical analysis of new or emerging information on the risks and benefits of their products throughout their life cycle
• evaluate a product's overall benefit-risk profile

If our request letter specifies a preferred format, such as PBRER or PSUR, you should prepare the ASR in the format requested, where possible.

You may use two consecutive 6-month summary reports prepared for another regulatory authority to meet the regulatory requirements.

Canadian-specific information

Although standardized periodic summary reports such as PBRERs and PSURs are used globally, regional differences may exist. You should consider the need for a Canadian-specific section or addendum when preparing an ASR.

A concise critical analysis of Canadian-specific data should include, where relevant:

• adverse drug reactions occurring in Canada
• when there is no existing RMP in Canada, information such as the epidemiology of the medical condition or risk factors that reflect the authorized indication in Canada in cases where it varies from the authorized indication in other jurisdictions
• date of first marketing and current marketing status in Canada
• information on Canadian patient exposure
• interval post-marketing experience in Canada
  • updated information on safety concerns outlined in the Canadian RMP
  • updated information on pharmacovigilance activities in Canada, including summary of new information
  • information on risk minimization strategies, implementation of risk minimization measures outlined in the RMP, and evaluation of effectiveness of risk minimization activities in Canada
• specific analyses requested by Health Canada
• conclusions about significant changes

Note that the concise critical analysis should include both global and Canadian-specific information and should address the impact of any conclusions on the safety of the product in Canada, including:

• actions that have been taken in Canada for safety reasons during the reporting interval, for example, changes to reference safety information, such as the Canadian Product Monograph or Canadian labelling
• actions intended to be taken in Canada for safety reasons

If actions taken or intended to be taken in Canada differ from those taken in the foreign jurisdiction, a rationale should be provided.

Where applicable, the analysis should refer to:

• RMPs
• terms and conditions
• approved product labelling
• Canadian product monograph (CPM)

This section can be prepared as a Canadian-specific summary report or as an addendum to an already prepared summary report. This section can be prepared as a Canadian-specific summary report or as an addendum to an already prepared summary report, ensuring that the Canadian-specific information is annualized to meet the regulatory requirements, if the report is for a period greater than one year.

Notification of significant change

The regulations require that you notify the Minister in writing without delay, if, in preparing the ASR, you conclude that there has been a significant change in what is known about the risks and benefits of the drug during the period covered by the report.

The conclusion of a significant change depends on the available evidence and can occur at any time while the report is being prepared. The ASR does not need to be finalized for you to conclude that there has been a significant change and the requirement to notify without delay to be triggered. This can occur at any time during the annual cycle. However, the significant change must also be noted in the completed report.

To avoid overburdening the system, do not submit a notification of significant change unless it meets the threshold outlined in the definition of significant change.

Visit Definitions for an explanation of "significant change".

Issues related to the quality of the product or GMP are not in scope of this requirement and should not be notified in this manner.

Contact us if you have questions about notification of a significant change.

How to notify

The notification of a significant change must be made without delay, be clear and explicit, and must contain a description of:

• the significant change, including the emerging safety issue
• the basis on which the conclusion was made

You are also encouraged to include in your notification the following:

• clinical impacts of the issue on patient or public health, or impact on the product's benefit-risk profile
• what further assessments may be needed in the Canadian context
• follow-up actions needed in Canada with proposed timelines, if applicable, including:
  • enhanced or novel pharmacovigilance measures or risk minimization measures
  • changes to packaging, labelling, product design or product accessibility
  • risk communication

Note: You are expected to proceed with any intended actions outlined in your notification.

To notify us of a significant change, complete the form:

• Notifying Health Canada of a significant change in what is known about the risks and benefits of a product

The form is available upon request by emailing no-reply.MHPD.publications.DPSC.non-reponse@hc-sc.gc.ca. To receive the form automatically, the subject line must be exactly "Notifying Health Canada of a significant change form". Do not modify the subject line, as this may prevent the form from being delivered automatically.

Once complete, submit the form without delay in an electronic common technical document (eCTD) or non-eCTD format via the electronic submissions gateway (ESG) using the regulatory enrolment process (REP). A cover letter or note to reviewer is not required with your notification.

For information on how to prepare transactions in eCTD or non-eCTD format, consult:

• Filing submissions electronically

Contact us if you have questions about your submission.

It is not sufficient to provide an ASR instead of a notification of a significant change. You should not submit the ASR with your notification of significant change. If we need to assess the safety and effectiveness of the drug further to the significant change, we will request the ASR in writing.

If you have already notified us of a significant change, you do not need to notify us again, unless there is new information that represents another significant change.

If the significant change is identified as a consequence of receiving or becoming aware of information regarding a foreign action subject to the reporting requirements under C.01.050 of the Food and Drug Regulations, you may satisfy both requirements by notifying us without delay using the form:

• Notifying Health Canada of foreign actions in respect of a serious risk of injury to human health (safety signal or toxicity, adverse reactions, unsafe use)

The form is available upon request by emailing no-reply.MHPD.publications.DPSC.non-reponse@hc-sc.gc.ca. Ensure that only the exact text “Notifying Health Canada of foreign actions form” is in the subject line of the email.

Consult:

• Guidance on notifying Health Canada of foreign actions
• Submitting risk management plans guidance document
• Guidance to market authorization holders on issuing health product risk communications
• Guidance document: Post-notice of compliance (NOC) changes: Safety and efficacy document (for pharmaceutical, biologic and radiopharmaceutical drugs for human use only)

Discontinued products

After a product is discontinued in Canada, you should still prepare an ASR and report significant changes until the expiry date of the last lot sold.

Some adverse reactions and associated safety signals may appear soon after treatment starts, while others may take longer to appear. For example:

• Late reactions that occur rarely or not at all at the beginning of treatment, but whose incidence increases with continued or repeated exposure.
• Delayed reactions become apparent some time after a drug is used, even if the drug is withdrawn before the reaction appears.

Late and delayed adverse reactions can be due to carcinogenesis, development of drug tolerance and physical dependence or chronic organ damage caused by, for example, pulmonary fibrosis.

Well-known historical examples are:

• corticosteroids and osteoporotic fractures
• pergolide and cardiac valve fibrosis
• females exposed to diethylstilbestrol (DES) in utero developing lower genital tract cancers

Visit Definitions for an explanation of "discontinued".