Good Pharmacovigilance Practices (GVP) Guidelines (GUI-0102)

Notice

Contact Information

Our Mandate:
To manage and deliver a national compliance and enforcement program for blood and donor semen; cells, tissues and organs; drugs (human and veterinary); medical devices and natural health products, collaborating with and across, all regions.

Supersedes: Draft for comments

Date Issued: February 11, 2013

Date of Implementation: August 11, 2013

Disclaimer

This document does not constitute part of the Food and Drugs Act (Act) or its associated Regulations and in the event of any inconsistency or conflict between that Act or Regulations and this document, the Act or the Regulations take precedence. This document is an administrative document that is intended to facilitate compliance by the regulated party with the Act, the Regulations and the applicable administrative policies.

Table of contents

1.0 Introduction

The Food and Drug Regulations, more specifically sections C.01.016 to C.01.020, C.08.007 (h) and C.08.008 (c),set forth regulatory requirements for manufacturers, including but not limited to, the reporting of adverse drug reactions (ADR) and the reporting of unusual failures in efficacy of new drugs to Health Canada.  As part of Health Canada's mandate to maximize the safety, quality and efficacy of health products, Health Canada implemented on August 1, 2004, an inspection program for Good Pharmacovigilance Practices (GVP) (previously known as Post-Market Reporting Compliance). The GVP inspection program is intended to verify that the manufacturer meets the requirements of sections C.01.016 to C.01.020, C.08.007 (h) and C.08.008 (c) of the Food and Drug Regulations pertaining to ADR reporting.  Within the context of the GVP inspection program, Market Authorization Holders (MAH) and importers are subject to GVP inspections as their name appears on the label and as such may receive ADRs.

The content of this document should not be regarded as the only interpretation of the Food and Drug Regulations, nor does it intend to cover every conceivable case. Alternative means of complying with the Food and Drug Regulations can be considered with the appropriate justification.

2.0 Purpose

The purpose of this guidance document is to provide interpretive guidance to industry on the expectations of inspectors with respect to the adverse drug reaction and post-approval reporting requirements when conducting GVP inspections. These guidelines are designed to facilitate compliance by the regulated industry and to enhance consistency in the application of the regulatory requirements regarding Good Pharmacovigilance Practices.

3.0 Scope

The Food and Drug Regulations set forth regulatory requirements for manufacturers to report ADRs and to report unusual failure in efficacy of new drugs to Health Canada. Within the context of the GVP inspection program, MAH and importers are subject to GVP inspections as their name appears on the label and as such may receive ADRs.

This guide covers the following drugs marketed in Canada for human use which are subject to GVP inspections:

This guide does not currently apply to:

Requirements Applicable to the MAH and the Importer

The responsibilities of the MAH and the importer are outlined below. Based on contractual agreements, the responsibilities may differ as the MAH may contract out any of these responsibilities and the importer may have been delegated more responsibilities than the ones indicated below; however the MAH is required to ensure that all the requirements of the Food and Drug Regulations and any relevant Health Canada's guidance documents are met.

Requirements applicable to MAH:

Requirements applicable to Importer:

4.0 Regulation

Please note that an interpretation may apply to more than one regulation and in those instances, the interpretation is only stated once.

Prohibition - C.01.016

No manufacturer shall sell a drug unless the manufacturer complies with the conditions set out in sections C.01.017 to C.01.019.

Serious Adverse Drug Reaction Reporting - C.01.017

Regulation

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:

  1. any serious adverse drug reaction that has occurred in Canada with respect to the drug; and
  2. any serious unexpected adverse drug reaction that has occurred outside Canada with respect to the drug.

Rationale

MAHs and importers are required to collect comprehensive ADR information in a timely manner. This information must be submitted to Health Canada within the prescribed timelines in order for Health Canada to monitor the safety and effectiveness of drugs marketed in Canada. MAHs and importers must have a system in place that enhances the overall quality of the ADR report while ensuring that accurate and complete pharmacovigilance information is provided to Health Canada.

Interpretation

Note: Importers who have been delegated activities related to pharmacovigilance by the foreign MAH are required to meet all requirements outlined in the section below. Please note that all importers should have available evidence that the below requirements are met.

Adverse Drug Reaction Reporting

1. Procedures and Processes

2. Receipt of ADR Data

3. Evaluation of ADR data

4. Reporting of ADR data

5. Literature Search

Periodic Self-inspections

6. Market Authorization Holders and Importers

Personnel and Training

7. Market Authorization Holders and Importers

Contractual Agreements

8. Market Authorization Holders and Importer

Validation of Computerized Systems

9. Market Authorization Holders, Importer, and all parties involved in pharmacovigilance activities who use an electronic system

Annual Summary Report and Case Reports - C.01.018

Regulation

(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.

(2) The annual summary report shall contain a concise, critical analysis of the adverse drug reactions and serious adverse drug reactions to the drug.

(3) In preparing the annual summary report, the manufacturer shall determine, on the basis of the analysis referred to in subsection (2), 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 and shall include its conclusions in this regard in the summary report.

(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.

(5) The Minister may, for the purposes of assessing the safety and effectiveness of the drug, request in writing that the manufacturer submits to the Minister one or both of the following:

(6) The Minister shall, after giving the manufacturer an opportunity to be heard, specify a period for the submission of the annual summary reports or case reports, or both, that is reasonable in the circumstances, and the manufacturer shall submit the reports within that period.

Rationale

The annual summary report is an achievable mechanism for summarizing interval safety data, and for conducting an overall safety evaluation. MAHs are to conduct systematic analyses of safety data on a regular basis. The annual summary report can be used to identify safety signals or changes to what is known about the risks and benefits of the drug.

Interpretation

Note: The MAH is responsible for this section of the Food and Drug Regulations. Importers who have been delegated the activities related to pharmacovigilance by the foreign MAH are required to meet all requirements outlines in the section below. Please note that all importers should have available evidence that the below requirements are met.

1. Written procedure for the preparation of the annual summary report (ASR) which should be in place and should include, but is not limited to the following:

Note: When Health Canada requests the annual summary report, it is preferred that it be submitted in the Periodic Safety Update Report (PSUR) format in accordance with the standards defined in the ICH E2C(R1)8 guideline.

2. The MAH should consult the Canada Vigilance Adverse Reaction Online Database or request line-listing summaries to obtain reports that were sent directly to the Canada Vigilance Regional or National Offices on an annual basis.

3. The MAH shall prepare an ASR of all information relating to ADRs and serious ADRs to the drug that it received or became aware of during the previous 12 months.

4. The ASR must contain a concise, critical analysis of the ADR and serious ADRs.

5. In preparing the ASR, the MAH shall assess any changes since the last annual summary report, and shall include its conclusions in this regard in the summary report. Any recommendation to take action (or not) must be included.

6. The MAH shall notify the Minister without delay, in writing, if in preparing the ASR the MAH concludes that there has been a significant change in what is known about the risks and benefits of the drug.

7. If the MAH has advised Health Canada that there is a significant change relating to its safe use, then records of the significant changes identified and records of the notification to the Health Canada must be available on file.

8. Requests for information from Health Canada should be maintained.

9. If the MAH chooses to use a third party to prepare the ASR, contractual agreements should be in place defining their respective responsibilities.

10. Annual summary report reviewed by Health Canada and for which comments were received by the MAH should be documented and changes should be implemented in subsequent summary report.

11. Signal detection

12. Product Safety Information

Issue-related Summary Report - C.01.019

Regulations

C.01.019

(1) The Minister may, for the purposes of assessing the safety and effectiveness of the drug, request in writing that the manufacturer submit to the Minister an issue-related summary report.

(2) The report shall contain a concise, critical analysis of the adverse drug reactions and serious adverse drug reactions to the drug, as well as case reports of all or specified adverse drug reactions and serious adverse drug reactions to the drug that are known to the manufacturer in respect of the issue that the Minister directs the manufacturer to analyze in the report.

(3) The Minister shall, after giving the manufacturer an opportunity to be heard, specify a period for the submission of the report that is reasonable in the circumstances. The Minister may specify a period that is shorter than 30 days if the Minister needs the information in the report to determine whether the drug poses a serious and imminent risk to human health.

(4) The manufacturer shall submit the report within the specified period.

Rationale

The issue-related summary report is a practical and achievable mechanism for summarizing a specific issue with a drug. That summary report contains information such as adverse drug reactions and serious ADRs to the drug and case reports of all or specified ADRs and serious ADRs to the drug that are known to the MAH.

Interpretation

Note: The MAH is responsible for this section of the Food and Drug Regulations. Importers who have been delegated the activities related to pharmacovigilance by the foreign MAH are required to meet all requirements outlines in the section below. Please note that all importers should have available evidence that the below requirements are met.

1. Written procedure should be in place for the preparation of an issue-related summary report upon request from the Minister which includes but is not limited to:

Maintenance of Records - C.01.020

Regulation

(1) The manufacturer shall maintain records of the reports and case reports referred to in sections C.01.017 to C.01.019.

(2) The manufacturer shall retain the records for 25 years after the day on which they were created.

Rationale

Good documentation is an essential part of the quality assurance system and should therefore be related to all aspects of pharmacovigilance. Its aims are to ensure that the pharmacovigilance department has all the information necessary regarding the safety of a drug.

Interpretation

Note: Importers who have been delegated the activities related to pharmacovigilance by the foreign MAH are required to meet all requirements outlines in the section below. Please note that all importers should have available evidence that the below requirements are met.

All relevant pharmacovigilance documents (such as associated records of actions taken or conclusions reached) and procedures are prepared by the relevant department. No changes are made without the approval of the qualified person in charge of the pharmacovigilance. Any alteration made to a document is signed and dated; the alteration permits the reading of the original information. Where appropriate, the reason for the change is recorded.

Any documentation requested for evaluation by Health Canada is provided in one of the official languages.

1. Market Authorization Holders and Importers

2. The MAH retains all ADR records and ASRs

3. The importer retains at the minimum the following documents (depending on their responsibilities):

4. A process should be established by the importer and the MAH for the accurate and timely retrieval of stored data or records from the pharmacovigilance system.

New Drugs - C.08.007 (h) and C.08.008 (c)

Regulation

C.08.007 (h)

Where a manufacturer has received a notice of compliance issued in respect of a new drug submission, an extraordinary use new drug submission, an abbreviated new drug submission, an abbreviated extraordinary use new drug submission or a supplement to any of those submissions, the manufacturer shall establish and maintain records, in a manner that enables an audit to be made, respecting...
(h) any unusual failure in efficacy of that new drug.

C.08.008 (c)

No manufacturer shall sell a new drug unless the manufacturer has, with respect to all the manufacturer's previous sales of that new drug, furnished to the Minister...
(c) within 15 days after the receipt by the manufacturer of information referred to in paragraphs C.08.007 (g) and (h), a report on the information received.

Rationale

The safety and effectiveness of a new drug have not been established; therefore, MAH and importers should have a system in place that would allow them to provide to Health Canada, within prescribed time lines, the information related to any unusual failure in efficacy of a new drug product. The underlying principle is that if a product fails to produce the expected intended effect, there may be an adverse outcome for the patient including an exacerbation of the condition for which the health product is being used.

Interpretation

Note: The MAH is responsible for this section of the Food and Drug Regulations. Importers who have been delegated the activities related to pharmacovigilance by the foreign MAH are required to meet all requirements outlines in the section below. Please note that all importers should have available evidence that the below requirements are met.

1. The MAH should have systems and procedures in place to receive, evaluate and report to Health Canada within 15 days of the receipt of the information, any unusual failure in efficacy report of new drugs marketed in Canada.

2. The MAH should identify products with new drug status. Generally, a new drug is a drug which received a Notice of Compliance (NOC).

3. Every ADR report that meets the established criteria for reporting unusual failure in efficacy shall be submitted to Health Canada within the appropriate timeframe (within 15 days).

4. A qualified health care professional should evaluate potential cases of unusual failure in efficacy to determine if the case qualifies for expedited (15-day) reporting. These evaluations and assessments should be adequately documented.

5. The complete documentation of ADR reports of unusual failure in efficacy should be available for auditing purposes.

6. The complete documentation of ADR report of unusual failure in efficacy is retained for a minimum of 25 years after the day on which they were created.

Appendix A

Glossary of Terms

The following definitions are provided to complement those already available under the glossary of terms in the current edition of the Canada Vigilance (MHPD) Guidance Document for Industry - Reporting Adverse Reactions to Marketed Health Products, the Inspection Strategy for Good Pharmacovigilance Practices (GVP) for Drugs (POL-0041), the Risk Classification for Good Pharmacovigilance Practices (GVP) Observations (GUI-0063) and other related documents referenced in these documents.

Adverse Drug Reaction (ADR ) - "A noxious and unintended response to a drug, which occurs at doses normally used or tested for the diagnosis, treatment or prevention of a disease or the modification of an organic function." (C.01.001. (1))

Note: For new drugs marketed in Canada, reports of unusual failure in efficacy are considered to be a type of adverse drug reactions (ADR) report.

Annual Summary Report - In accordance with the Food and Drug Regulations, the market authorization holder (MAH) must, on an annual basis and whenever requested by Health Canada, conduct a concise, critical analysis of the adverse drug reactions and serious adverse drug reactions to a drug and prepare a summary report in respect of the reports received during the previous twelve months or received during such period of time as Health Canada may specify. Annual summary reports may be submitted in the form of a Periodic Safety Update Report (PSUR) as defined by ICH E2C(R1) guideline.

Drug - "Any substance or mixture of substances manufactured, sold, or represented for use in (a) the diagnosis, treatment, mitigation, or prevention of a disease, a disorder, an abnormal physical state, or the symptoms thereof, in humans or animals, (b) restoring, correcting, or modifying organic functions in humans or animals, or (c) ' disinfection ' in premises in which food is manufactured, prepared, or kept." (Section 2 of the Food and Drugs Act)

Import - "To import into Canada a drug for the purpose of sale" (C.01A.001)

Manufacturer - "Manufacturer" or "distributor" means a person, including an association or partnership, who under their own name, or under a trade-, design or word mark, trade name or other name, word or mark controlled by them, sells a food or drug. (A.01.010)  Within the context of the GVP inspection program, MAH and importers are subject to GVP inspections as their name appears on the label and as such may receive ADRs.

Market Authorization Holder - For the purpose of this guidance document means the entity that holds the Notice of Compliance or the Drug Identification Number (DIN).

New Drug - "(a) a drug that contains or consists of a substance, whether as an active or inactive ingredient, carrier, coating, excipient, menstruum or other component, that has not been sold as a drug in Canada for sufficient time and in sufficient quantity to establish in Canada the safety and effectiveness of that substance for use as a drug;
(b) a drug that is a combination of two or more drugs, with or without other ingredients, and that has not been sold in that combination or in the proportion in which those drugs are combined in that drug, for sufficient time and in sufficient quantity to establish in Canada the safety and effectiveness of that combination and proportion for use as a drug; or
(c) a drug, with respect to which the manufacturer prescribes, recommends, proposes or claims a use as a drug, or a condition of use as a drug, including dosage, route of administration, or duration of action and that has not been sold for that use or condition of use in Canada, for sufficient time and in sufficient quantity to establish in Canada the safety and effectiveness of that use or condition of use of that drug." (C.08.001)
Generally, if a NOC was issued for a drug, then that drug is considered to be a "new drug", regardless of how long it has been on the market.

Notice of Compliance - A notification, issued pursuant to paragraph C.08.004 (1) (a), indicating that a manufacturer has complied with sections C.08.002 or C.08.003 and C.08.005.1 of the Food and Drug Regulations. Notices of Compliance are issued to a manufacturer following the satisfactory review of a submission.

Qualified Health Care Professional - A person who is a member in good standing of a professional medical, nursing, pharmacists' or other health care practitioner association and entitled to provide health care under the laws of the jurisdiction in which the person is located, and other individuals retained by the MAH who have the appropriate health care education and therapeutic expertise.

Serious Adverse Drug Reaction - "A noxious and unintended response to a drug that occurs at any dose and that requires in-patient hospitalization or prolongation of existing hospitalization, causes congenital malformation, results in persistent or significant disability or incapacity, is life-threatening or results in death." (C.01.001. (1))

Serious Unexpected Adverse Drug Reaction - "A serious adverse drug reaction that is not identified in nature, severity or frequency in the risk information set out on the label of the drug." (C.01.001. (1))

Signal Detection - Many information sources may be combined to identify a signal or a preliminary indication of a product-related safety issue. Assessment consists of the scientific/medical review of multiple data sources to analyze risks and benefits, while determining the likelihood of the association between the reaction and the health product.

Unusual Failure in Efficacy - This has been considered an adverse drug reaction for many years under the Food and Drug Regulations. It applies to new drugs only. The underlying principle is that if a health product fails to produce the
expected intended effect, there may be an adverse outcome for the patient, including an exacerbation of the condition
for which the health product is being used.  Clinical judgment should be exercised by a qualified health care professional from the market authorization holder (MAH) to determine if the problem reported is related to the product itself, rather than one of treatment selection or disease progression since health products cannot be expected to be effective in 100% of the patients. One example of unusual failure in efficacy is a previously well-stabilized condition that deteriorates when the patient changes to a different brand or receives a new prescription. Another example of a case that should be reported on an expedited basis is a life-threatening infection where the failure in efficacy seems to be due to the development of a newly resistant strain of bacterium previously regarded as susceptible.

Appendix B

Associated Documents

  1. Food and Drugs Act
  2. Food and Drug Regulations
  3. Compliance and Enforcement Policy (POL-0001)
  4. Guidance Document for Industry - Reporting Adverse Reactions to Marketed Health Products (2011)
  5. ICH Harmonised Tripartite Guideline, Clinical Safety Data Management: Periodic Safety Update Reports for Marketed Drugs E2C (R1) (2005).
  6. Inspection Strategy for Good Pharmacovigilance Practices (GVP) for Drugs (POL-0041)
  7. International Conference on Harmonisation, Post-approval Safety Data Management: Definitions and Standards for Expedited Reporting (ICH E2D) (2003)
  8. Risk Classification for Good Pharmacovigilance Practices (GVP) Observations (GUI-0063)

Page details

2017-05-04