ARCHIVED - Summary Report of the Post-Market Reporting Compliance Inspections Conducted from September 1, 2005 to March 31, 2008

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Supersedes: April 2006

Date issued: August 7, 2009

Date of implementation: December 1, 2009

Disclaimer

This document does not constitute part of the Food and Drugs Act (Act) or the Food and Drugs Regulations (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. This document is not intended to provide legal advice regarding the interpretation of the Act or Regulations. If a regulated party has questions about their legal obligations or responsibilities under the Act or Regulations, they should seek the advice of legal counsel.

Table of Contents

Executive Summary

This document provides the results and analysis of the findings of Post-Market Reporting Compliance (PMRC) inspections conducted by the Health Products and Food Branch Inspectorate (Inspectorate) from September 1, 2005 to March 31, 2008. This is the second report for PMRC inspections, and is intended to assess compliance of manufacturers with the Food and Drug Regulations1 pertaining to the reporting of adverse drug reactions, as set forth in sections C.01.016 and C.01.017 of the Regulations, and to the reporting of unusual failure in efficacy of new drugs, as set forth in sections C.08.007 and C.08.008 of the Regulations.

A total of 309 PMRC inspections were conducted from September 1,  2005 to March 31, 2008.  Although all PMRC inspections resulted in a compliant rating assigned, Inspectors made a total of 354 observations that were noted in 215 out of 309 inspection reports.  Two risk 1 observations were noted during inspections.  A compliant rating was assigned in both cases because the risk 1 observations were corrected in a satisfactory manner prior to the exit meeting. Every observation represents a deviation from a regulatory requirement pertaining to reporting of adverse drug reactions and/or unusual failure in efficacy of new drugs. The Inspectorate required every observation included in individual inspection reports to manufacturers to be addressed through corrective actions, within a set time frame, in order to ensure that all observations noted during inspections were rectified.  All 215 manufacturers addressed the observations by initiating corrective measures in the set time frame.

The five main deficiencies that were noted, in decreasing frequency, were deficiencies related to:

  • the reporting of domestic and foreign adverse drug reactions within 15 days to Health Canada,
  • the maintenance of records related to adverse drug reactions,
  • the preparation of annual summary reports,
  • the maintenance of records related to unusual failure in efficacy of new drugs, and
  • the reporting of domestic and foreign unusual failure in efficacy of new drug within 15 days to Health Canada.

The second year of PMRC inspections was successful and provided an opportunity to assess regulatory compliance of manufacturers with the Regulations pertaining to the reporting of adverse drug reactions and the reporting of failure in efficacy of new drugs. Overall, Health Canada found that manufacturers are in compliance with the Food and Drugs Act and Regulations.  In sharing excerpts of observations made during these inspections in a manner that respect the confidentiality and privacy of those involved, Health Canada seeks to raise the awareness of the requirements for regulatory compliance, with a view to ensuring greater compliance.

1.0 Background

The mandate of the Health Products and Food Branch (HPFB) of Health Canada is to take an integrated approach to the management of the risks and benefits to health related to 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.

The HPFB Inspectorate (Inspectorate) has the role of delivering a national compliance and enforcement program for all products under the mandate of the HPFB, with the exception of food products. The authority to deliver this compliance and enforcement program for these products is derived from the Food and Drugs Act and its Regulations. The Inspectorate's "Compliance and Enforcement Policy (POL-0001)"2 provides the guiding principles for the fair, consistent and uniform application and enforcement of the Food and Drugs Act and Regulations.

The Marketed Health Products Directorate (MHPD) of HPFB works to assure that HPFB programs take a consistent approach to post-approval safety surveillance, assessment of signals and safety trends and risk communications concerning all regulated marketed health products.

The Food and Drug Regulations set forth requirements for manufacturers regarding reporting of adverse drug reactions and the reporting of unusual failure in efficacy of new drugs to Health Canada. As part of its mandate to maximize the safety and efficacy of drugs, Health Canada implemented an inspection programme for Post-Market Reporting Compliance (PMRC).

An "Inspection Strategy for Post-Market Reporting Compliance"3 was published in June 2004 and implemented in August 2004. The Inspectorate, in collaboration with the MHPD, assesses the compliance of manufacturers with the Regulations pertaining to adverse drug reaction reporting, specifically, sections C.01.016 and C.01.017 of the Regulations. The compliance of establishments with regards to requirements for reporting failure in efficacy of new drugs, as set forth in sections C.08.007 and C.08.008 of the Regulations are also assessed.

It is the responsibility of the Inspectorate and the MHPD to collaborate and act in partnership in the application of the PMRC inspection programme. It is the Inspectorate's responsibility to perform inspections and the responsibility of MHPD to analyze the data provided by the Inspectorate in conjunction with their objectives.

From September 1, 2005 to March 31, 2008, a total of 309 PMRC inspections were conducted. The geographic distribution of the sites inspected is outlined in Table 1 on the next page.

Table 1: Geographic distribution of sites inspected
Operational Centre Number of sites inspected
Atlantic 7
Quebec 108
Ontario 117
Manitoba and Saskatchewan 14
Western 63
Total 309

The inspections were conducted in accordance with procedures and guidance documents developed by the Inspectorate for PMRC inspections. During these PMRC inspections, deviations from the Food and Drug Regulations are noted by the inspector and are then recorded as observations in the Inspection Exit Notice. With the aid of the document entitled “Risk Classification of Post-Market Reporting Compliance Observations"4, a judgement is made of the observations and each observation is risk rated. Subsequently, an overall compliance rating is attributed to the inspected site. The possible compliance ratings are defined below:

  • "C" means no objectionable conditions or practices were observed with regards to regulatory requirements pertaining to reporting of adverse drug reactions and/or reporting of unusual failure in efficacy of new drugs
  • "NC" means objectionable conditions or practices were observed with regards to regulatory requirements pertaining to reporting of adverse drug reactions and/or reporting of unusual failure in efficacy of new drugs

It is recognized that the evaluation of the conformity of manufacturers with their regulatory responsibilities should commensurate with the risk involved taking into account the nature and extent of the deviation. Nonetheless, situations involving fraud, misrepresentation or falsification of drug safety data will generate a NC rating.

The assignment of a NC rating may have serious consequences for an establishment. These consequences may include the implementation of immediate corrective measures. Therefore, these situations of non-conformity have to be well defined, unambiguous and directly supported by the applicable Regulations.

Where in the opinion of the inspector the resulting products present a significant health hazard, the company is expected to address the issue immediately. Appropriate compliance and enforcement actions may be initiated according to the Inspectorate's "Compliance and Enforcement Policy (POL-0001)".

2.0 Definitions

Adverse Drug Reaction: 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)) The term ADR includes unusual failure in efficacy as defined below.

GMP: Good Manufacturing Practices - Part C, Division 2 of the Food and Drug Regulations and the interpretive guidelines.

Importer: A person who imports into Canada a drug for the purpose of sale.

Inspection: On-site monitoring and assessment against the applicable requirements of the FDA and its associated Regulations. Inspections are routinely conducted on a predetermined cycle or as required to assess compliance.

Inspector: Any person designated as an inspector for the purpose of the enforcement of the Food and Drugs Act under subsection 22(1).

Manufacturer: "Amanufacturer" 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) This definition would also include contract fabricators that do not own the DIN but whose name appears on the label.

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..." (C.08.001)

Observation: A deviation or deficiency to the Food and Drug Regulations pertaining to reporting of adverse drug reactions and unusual failure in efficacy of new drugs noted by an inspector during the inspection of a drug establishment that is confirmed in writing to the company in the Exit Notice.

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 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))

Unusual Failure in Efficacy: Lack of efficacy has been considered an adverse reaction for many years in the Canadian Food and Drug Regulations. The underlying principle is that if a drug fails to produce the expected pharmacological or therapeutic benefit, there may be an adverse outcome for the patient, including a worsening of the condition for which the medication is being taken. One example of unusual failure is a previously well-stabilized condition that deteriorates when the patient changes to a different brand or received a new prescription.

For additional definitions, consult the documents listed at the end of this summary report.

3.0 Inspection Program

The inspections were conducted in accordance with procedures and guidance documents developed by the Inspectorate for PMRC inspections. The "Inspection Strategy for Post-Market Reporting Compliance (POL-0041)" provides further guidance for the effective and uniform conduct of these inspections. The "Risk Classification of Post-Market Reporting Compliance Observations" is a guide to classify the observations noted during PMRC inspections to their risk. Furthermore, the Marketed Health Products Directorate "Guidance Document for Industry - Reporting Adverse Drug Reactions to Marketed Health Products"5 provides guidance to industry on reporting adverse reactions to marketed drugs.

3.1 Objectives of an Inspection

Health Canada developed the Therapeutics Access Strategy (TAS), with partners and stakeholders, to help Canadians maintain and improve their health. TAS supports Health Canada's efforts to ensure that human drugs and other therapeutic products are as safe as possible, accessible, of high quality, therapeutically effective, and used properly. TAS also supports the Inspectorate's inspection programme for PMRC because it aims to improve drug safety information reporting.

Specifically, the main objectives of a PMRC inspection are:

  1. To assess the level of compliance of manufacturers with the Food and Drugs Act and the Food and Drug Regulations with regards to reporting of adverse drug reactions and reporting of unusual failure in efficacy of new drugs to Health Canada,
  2. To request corrective actions from a manufacturer whenever observations are made,
  3. To take action regarding compliance and enforcement when deemed necessary, and,
  4. To increase awareness of regulatory requirements for the reporting of adverse drug reactions and unusual failure in efficacy of new drugs to Health Canada.

4.0 Regulations

All observations made during the inspections relate to specific requirements under the Food and Drugs Regulations (Annex A - sections C.01.016, C.01.017, C.08.007 and C.08.008).

5.0 Analysis of Observations

Observations were noted regarding the level of compliance to the legislative and regulatory requirements of the Food and Drugs Act and Regulations. The following table (table 2) lists the number of observations against each of these sections / sub-sections of the Regulations.

Table 2 : Number and types of observations made during PMRC inspections of manufacturers conducted from September 1, 2005 to March 31, 2008.
Regulation Brief description of Section Number of Observations
C.01.016 (1) Reporting domestic and foreign adverse drug reactions (ADR) within 15 days 227
C.01.016 (2) Preparing annual summary reports 79
C.01.017 Maintaining records related to reports and case reports 33
C.08.007(h) Maintaining records related to unusual failure in efficacy 6
C.08.008 Reporting of unusual failure in efficacy 9
Total number of observations 354

All 309 PMRC inspections conducted resulted in a compliant rating ("C"). A total of 354 observations were noted in 215 out of 309 inspection reports.

The following sections of this summary report will give examples of observations made by Inspectors during PMRC inspections.

5.1 Adverse Drug Reaction Reporting - C.01.016

5.1.1 Reporting domestic and foreign adverse drug reactions within 15 days - C.01.016 (1)

The highest numbers of observations made were deficiencies in the reporting of domestic and foreign adverse drug reactions within 15 days to Health Canada. Of a total of 354 deficiencies noted during PMRC inspections, 227 observations (2 Risk 1 observation, 68 Risk 2 observations and 157 Risk 3 observations) were related to reporting adverse drug reactions.

The Food and Drug Regulations set forth requirements for manufacturers regarding reporting of adverse drug reactions, which allows Health Canada to monitor the safety and effectiveness of these products once they are in use. Specifically, manufacturers are required to report all information in respect of any serious adverse drug reaction that has occurred in Canada and in respect of any serious unexpected adverse drug reaction that has occurred outside Canada with respect to the drug, within 15 days after receiving the information.

Four examples of these deficiencies are:

Example #1 (Risk 1 observation): None of the foreign serious unexpected adverse drug reactions received were reported to Health Canada.

Example #2 (Risk 2 observation): Less than the total number of reports received by the manufacturer of domestic serious expected and unexpected and foreign serious unexpected adverse drug reactions were reported to Health Canada.

Example #3 (Risk 3 observation): There was no procedure for reporting any serious adverse drug reactions that occurred in Canada or any unexpected adverse drug reaction that occurred outside Canada within 15 days of receiving the information to the Director in accordance with the requirements of section C.01.016 of the Food and Drugs Regulations.

Example #4 (Risk 3 observation): The ADR system was inadequate as there was no formal written system or procedure for the receipt, evaluation, and/or reporting to sustain ADR reporting.

5.1.2 Preparing annual summary reports - C.01.016 (2)

The second highest numbers of observations made were deficiencies in the preparation of annual summary reports. Of a total of 354 deficiencies noted during PMRC inspections, 79 observations (32 Risk 2 observations and 47 Risk 3 observations) were related to preparing annual summary reports.

Pursuant to C.01.016 (2) of the Food and Drug Regulations, manufacturers are required to conduct a concise, critical analysis of the adverse drug reactions and serious adverse drug reactions to a drug referred to in subsection C.01.016 (1) of the Food and Drug Regulations and to prepare a summary report. The summary report is to be prepared annually and is to be maintained on site (or be easily accessible). Health Canada may request that the manufacturer submit a summary report within 30 days for the purposes of a safety assessment.

Four examples of these deficiencies are:

Example #1 (Risk 2 observation): Written Summary reports of adverse drug reactions as required by this regulation had not been prepared for most pharmaceutical DIN products.

Example #2 (Risk 2 observation): The manufacturer did not, on an annual basis, conduct a concise, critical analysis of the adverse drug reactions and prepare a summary report in respect of the reports received during the previous twelve months.

Example #3 (Risk 3 observation): The manufacturer had not included in the annual summary reports all foreign serious expected and unexpected adverse drug reactions, and non-serious unexpected adverse drug reactions received.

Example #4 (Risk 3 observation): A comprehensive procedure and system for the receipt, evaluation and reporting of adverse drug reactions, the preparation of annual summary reports and the retention of all related data had not been formally defined and established.

5.2 Adverse Drug Reaction Reporting - C.01.017

5.2.1 Maintaining records related to reports and case reports - C.01.017

The third highest numbers of observations made were deficiencies in the maintenance of records. Of a total of 354 deficiencies noted during PMRC inspections, 33 observations (7 Risk 2 observations, and 26 Risk 3 observations) were related to the maintenance of records.

The Food and Drug Regulations set forth requirements for manufacturers to maintain records of the reports and case reports of adverse drug reactions for auditing purposes. Furthermore, every manufacturer should put into place written procedures for the receipt, evaluation, and reporting of adverse drug reactions.

Three examples of these deficiencies are:

Example # 1 (Risk 2 observation): The adverse events procedure was deficient in that it did not include criteria used to determine whether or not a reported event is serious or not.

Example #2 (Risk 3 observation): There were no records of annual summary reports pertaining to adverse drug reactions (ADRs) as described in MHPD's guideline entitled "Guidance Document for Industry - Reporting Adverse Reactions to Marketed Health Products".

Example #3 (Risk 3 observation): The annual summary report was deficient in that it did not include a critical analysis of the ADR reports, and recommended actions.

5.3 New Drugs - C.08.007

5.3.1 Maintaining records related to unusual failure in efficacy - C.08.007 (h)

The fifth highest numbers of observations made were deficiencies in the maintenance of records related to unusual failure in efficacy of new drugs. Of a total of 354 deficiencies noted during PMRC inspections, 6 observations (2 Risk 2 observations and 4 Risk 3 observations) were related to the maintenance of records.

Lack of efficacy has been considered an adverse reaction for many years in the Food and Drug Regulations. The underlying principle is that if a drug fails to produce the expected pharmacological or therapeutic benefit, there may be an adverse outcome for the patient, including a worsening of the condition for which the medication is being taken. Thus, according to C.08.007(h) of the Food and Drug Regulations, where a manufacturer has received a notice of compliance issued in respect of a new drug, the manufacturer shall establish and maintain records respecting any unusual failure in efficacy of that new drug.

Two examples of these deficiencies are:

Example #1 (Risk 2 observation): The program of adverse drug reaction reports for marketed drugs did not include or address specifically the unusual failure in efficacy.

Example #2 (Risk 3 observation): The procedure for Post-Market Surveillance did not specify that any unusual failure in efficacy of new drugs were to be submitted to Health Canada. Reports were being submitted.

5.4 New Drugs - C.08.008

5.4.1 Reporting domestic and foreign lack of unusual failure in efficacy within 15 days - C.08.008

The fourth highest numbers of observations made were deficiencies in the reporting of unusual failure in efficacy of new drugs. Of a total of 354 deficiencies noted during PMRC inspections, 9 observations (4 Risk 2 observations and 5 Risk 3 observations) were related to the reporting.

According to C.08.008(c) of the Food and Drug Regulations, where a manufacturer has received a notice of compliance issued in respect of a new drug, the manufacturer shall report to Health Canada any unusual failure in efficacy of that new drug.

Two examples of these deficiencies are:

Example 1 (Risk 2 observation): At least one case received by the manufacturer of domestic unusual failure in efficacy of new drugs had not been reported to Health Canada. The list used by pharmacovigilance personnel had not been updated to reflect the status of certain drugs.

Example 2 (Risk 3 observation): One case received by the manufacturer of domestic unusual failure in efficacy of new drugs, had not been reported to Health Canada within 15 calendar days.

6.0 Conclusion

Overall, Health Canada found that manufacturers are in compliance with the regulatory requirements for the reporting of adverse drug reactions and unusual failure in efficacy of new drugs.

A total of 309 manufacturers were inspected for PMRC from September 1, 2005 to March 31, 2008. Although all PMRC inspections resulted in a compliant rating assigned, a total of 354 observations were noted in 215 out of 309 inspection reports. The 215 manufacturers addressed the observations by initiating corrective measures in a set time frame.

These inspections and this document, a second summary report, provide Health Canada with the opportunity to increase awareness of regulatory requirements for the reporting of adverse drug reactions and unusual failure in efficacy of new drugs. Furthermore, it is hoped that providing examples, made anonymous, of a range of deficiencies noted during inspections will also help promote greater compliance.

Therefore, all the main objectives of these PMRC inspections (listed in section 3.1 of this summary report) have been met.

7.0 References

  1. Food and Drugs Act and Food and Drug Regulations, Department of Justice Canada
  2. Inspection Strategy for Post-Market Reporting Compliance (POL-0041), Health Canada, June 2004
  3. Risk Classification for Post-Market Reporting Compliance Observations (GUI-0063), Health Canada
  4. Compliance and Enforcement Policy (POL-0001) Health Canada, May 2005
  5. Guidance Document for Industry - Reporting Adverse Reactions to Marketed Health Products 2009 Edition.

Annex A

Food and Drug Regulations, Part C, Division 1, sections C.01.016, C.01.017:

Adverse Drug Reaction Reporting

C.01.016.

  1. No manufacturer shall sell a drug unless the manufacturer, with respect to any adverse drug reaction or any serious adverse drug reaction known to the manufacturer that occurs after this section comes into force, furnishes to the Director
    • (a) a report of all information in respect of any serious adverse drug reaction that has occurred in Canada with respect to the drug, within 15 days after receiving the information; and
    • (b) a report of all information in respect of any serious unexpected adverse drug reaction that has occurred outside Canada with respect to the drug, within 15 days after receiving the information.
  2. The manufacturer shall, on an annual basis and whenever requested to do so by the Director, conduct a concise, critical analysis of the adverse drug reactions and serious adverse drug reactions to a drug referred to in subsection (1) and prepare a summary report in respect of the reports received during the previous twelve months or received during such period of time as the Director may specify.
  3. Where, after reviewing any report furnished pursuant to subsection (1) and any available safety data relating to the drug, the Director considers that the drug may not be safe when used under the recommended conditions of use, the Director may, for the purpose of assessing the safety of the drug, request in writing, that the manufacturer submit
    • (a) case reports of all adverse drug reactions and serious adverse drug reactions to that drug that are known to the manufacturer; and
    • (b) a summary report prepared pursuant to subsection (2).
  4. The manufacturer shall submit the case reports and summary report referred to in subsection (3) within 30 days after receiving the request from the Director. SOR/95-521, s. 2.

C.01.017. The manufacturer shall maintain records of the reports and case reports referred to in section

C.01.016. for auditing purposes. SOR/95-521, s. 2.

Food and Drug Regulations, Part C, Division 8, sections C.08.007, C.08.008:

C.08.007. Where a manufacturer has received a notice of compliance issued in respect of a new drug submission or abbreviated new drug submission or a supplement to either submission, the manufacturer shall establish and maintain records, in a manner that enables an audit to be made, respecting

  • (a) animal or clinical experience, studies, investigations and tests conducted by the manufacturer or reported to him by any person concerning that new drug;
  • (b) reports from the scientific literature or the bibliography therefrom that are available to him concerning that new drug;
  • (c) experience, investigations, studies and tests involving the chemical or physical properties or any other properties of that new drug;
  • (d) any substitution of another substance for that new drug or any mixing of another substance with that new drug;
  • (e) any error in the labelling of that new drug or in the use of the labels designed for that new drug;
  • (f) any bacteriological or any significant chemical or physical or other change or deterioration in any lot of that new drug;
  • (g) any failure of one or more distributed lots of the new drug to meet the specifications established for that new drug in the submission or supplement; and
  • (h) any unusual failure in efficacy of that new drug. SOR/95-411, s. 10; SOR/95-521, s. 3.
  • (i) [Repealed, SOR/95-521, s. 3]

C.08.008. 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

  • (a) on request, reports of all records respecting the information described in paragraphs C.08.007(a) to (c);
  • (b) immediately on receipt by the manufacturer, reports of all records respecting the information described in paragraphs C.08.007(d) to (f); and
  • (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. SOR/95-411, s. 11; SOR/95-521, s. 4.

Source: Food and Drug Regulations, Division 1, "General", and Division 8, "New Drugs"

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