Vol. 145, No. 5 — March 2, 2011
SOR/2011-31 February 10, 2011
FOOD AND DRUGS ACT
ARCHIVED — Regulations Amending the Food and Drug Regulations (Adverse Drug Reaction Reporting)
P.C. 2011-204 February 10, 2011
His Excellency the Governor General in Council, on the recommendation of the Minister of Health, pursuant to subsection 30(1) (see footnote a) of the Food and Drugs Act (see footnote b), hereby makes the annexed Regulations Amending the Food and Drug Regulations (Adverse Drug Reaction Reporting).
REGULATIONS AMENDING THE FOOD AND DRUG REGULATIONS (ADVERSE DRUG REACTION REPORTING)
1. The heading before section C.01.016 and sections C.01.016 and C.01.017 of the Food and Drug Regulations (see footnote 1) are replaced by the following:
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. 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:
(a) any serious adverse drug reaction that has occurred in Canada with respect to the drug; and
(b) any serious unexpected adverse drug reaction that has occurred outside Canada with respect to the drug.
Annual Summary Report and Case Reports
C.01.018. (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 submit to the Minister one or both of the following:
(a) the annual summary reports;
(b) the case reports relating to the adverse drug reactions and serious adverse drug reactions to the drug that are known to the manufacturer.
(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.
Issue-related Summary Report
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.
Maintenance of Records
C.01.020. (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.
COMING INTO FORCE
2. These Regulations come into force on the day on which they are registered.
(This statement is not part of the Regulations.)
Issue: The current Adverse Drug Reaction (ADR) Reporting section (C.01.016) of Part C of the Food and Drug Regulations (the Regulations) requires manufacturers to analyse adverse drug reaction data for safety concerns and prepare an annual summary report. However, the Minister of Health has a limited ability to require the results of this report to be provided to Health Canada (HC); this limitation does not support HC’s role in protecting and promoting the health and safety of Canadians.
Description: Health Canada has determined that the best approach to correct and strengthen the ADR Reporting provisions is to require the manufacturer to notify the Minister of a significant safety signal arising from their annual summary report; clarifying when the Minister can request case reports or summary reports; and enabling the Minister to request these reports when she considers it necessary to establish the safety of the drug under the conditions of use recommended. Additional revisions have been made for clarity.
Cost-benefit statement: The amendments will impose minimal costs to industry and to Health Canada, and some manufacturers are already in voluntary compliance with this amendment.
This regulatory amendment is intended to result in a positive impact on the health and safety of Canadians, as it will improve the Minister’s ability to effectively monitor the post-market safety of drug products.
Business and consumer impacts: The impact of the amendment will be minimal since manufacturers are already responsible for preparing these types of reports. However, providing the Minister with increased access to drug safety information will have a positive impact on the health and safety of Canadians. This regulatory amendment will not impact on employment or the labour force. Overall, there is support for this amendment by industry.
Domestic and international coordination and cooperation: This amendment does not conflict with international trade agreements; similar requirements already exist in other regulatory jurisdictions. It is not anticipated that this regulatory amendment will have an impact on international competitiveness.
Under the Adverse Drug Reaction (ADR) Reporting section of the Regulations [in particular subsections C.01.016(2) and (3)], manufacturers are required to analyse adverse drug reaction data and prepare annual summary reports. However, manufacturers cannot presently be compelled to provide these reports unless the Minister of Health (the Minister) first concludes the drug may not be safe — even if the manufacturer may have identified a safety issue. This limits the Minister’s ability to monitor post-market safety issues.
To request an annual summary report, the Minister must first have reviewed the adverse reaction reports submitted by the manufacturer and formed an opinion that the drug may not be safe when used under the recommended conditions of use. As the manufacturer is already analyzing the ADRs and drawing conclusions with respect to the risk-benefit profile of the drug, it would benefit Canadians to require the manufacturer to notify the Minister should the manufacturer detect a significant change in the risk-benefit profile of the drug.
As all drugs are associated with risks and benefits, the ADR reporting section of the Food and Drug Regulations (Regulations) was created to provide continuous monitoring of ADRs once a drug is authorized for sale on the Canadian market. Before a drug is marketed, safety and efficacy experience is limited to its use in clinical trials. However, these initial clinical trials mostly detect common and frequent ADRs. Some important reactions may take a long time to develop or occur infrequently. In addition, the controlled conditions under which patients use drugs in clinical trials (e.g. under direct medical supervision and without significant exposure to other products or underlying diseases) do not necessarily reflect the way in which the product will be used in “real life” conditions once it is marketed. For these reasons, the reporting and assessment of ADRs is essential to maintain a comprehensive safety and effectiveness profile of drugs made available to Canadians.
To address issues of enforceability, regulations of this nature must require a retention period for record keeping. Thus, this regulatory amendment will also include a provision requiring the manufacturer to maintain records of the reports and case reports for a period of 25 years from the date the record was created. The 25-year requirement aligns with the record retention requirement in Division 5 (Clinical Trials) of the Regulations. It is also consistent with the advice provided by the Veterinary Drugs Directorate for Veterinary Drug manufacturers, as well as the recommendation in the Guidance Document for Industry — Reporting Adverse Reactions to Marketed Health Products. The 25-year requirement should also provide sufficient time to develop a safety profile for the majority of products which fall under these Regulations.
The objective of this amendment is to strengthen the current ADR Reporting section of the Regulations in a way that benefits Canadians while also aligning with other regulatory jurisdictions. This amendment will require manufacturers to notify the Minister when there has been a significant change in a drug’s risk-benefit profile. It will also permit the Minister to obtain manufacturers’ analyses that led to these conclusions. This will permit the Minister to better monitor the safety of drug products in Canada.
These amendments pertain to drugs for human use, including biologics and pharmaceuticals, as well as veterinary drugs. They will require all drug manufacturers to notify the Minister if they conclude from their annual summary report that there has been a significant change in a drug’s risk-benefit profile. The amendments also permit the Minister to direct manufacturers to provide summary reports or case reports whenever the Minister decides to examine the safety and effectiveness of a drug. The Minister will be able to impose a deadline of less than 30 days for submitting these reports if a shorter deadline is necessary to respond to a serious and imminent risk to health. Manufacturers will also be required to maintain individual ADR reports, case reports, annual summary reports, and issue-related summary reports over a specified 25-year (as opposed to an indefinite) retention period, and to provide these records to the Minister upon request.
As described below, provisions similar to those in this submission either exist or are under development in other regulatory jurisdictions. In each case, the manufacturer notifies the regulator when it becomes aware of safety issues. This allows for the type of information found in summary reports and case reports to be requested at any point in time.
Volume 9A of the Rules Governing Medicinal Products in the European Union, finalized in March 2007, states that “It is the responsibility of the QPPV (Qualified Person Responsible for Pharmacovigilance) to provide the Competent Authority with any information relevant to the evaluation of benefits and risks afforded by a medicinal product, including appropriate information on post-authorisation safety studies.” As well, section 2.3.3 on Change in the Evaluation of the Risk-Benefit Balance of a Product states, “One of the key responsibilities of Marketing Authorisation Holders is to immediately notify the Competent Authorities of any change in the balance of risks and benefits of their products. Any failure to do so may pose a significant threat to public health. Any evidence of failure to notify such changes will result in consideration of enforcement action by the Competent Authorities.”
The Regulation (EC) No. 726/2004 requires that “The holder of the marketing authorisation for a medicinal product for human use shall maintain detailed records of all suspected adverse reactions within or outside the Community which are reported to him by a health-care professional. Unless other requirements have been laid down as a condition for the granting of the marketing authorisation by the Community, these records shall be submitted, in the form of a periodic safety update report, to the Agency and Member States immediately upon request or at least every six months after authorisation until the placing on the market. Periodic safety update reports shall be submitted immediately upon request or at least every six months during the first two years following the initial placing on the Community market and once a year for the following two years. Thereafter, the reports shall be submitted at three-yearly intervals, or immediately upon request. These reports shall be accompanied by a scientific evaluation particularly of the risk-benefit balance of the medicinal product.”
United States (U.S.) Food and Drug Administration (FDA)
Section 314.81 under Title 21 of the Code of Federal Regulators (current regulation) requires that the manufacturer submit an annual report which includes “A brief summary of significant new information from the previous year that might affect the safety, effectiveness, or labelling of the drug product.” The U.S. therefore has the means to obtain safety information from the manufacturer. Currently it is submitted with the manufacturer’s annual report. In the U.S. FDA Proposed Rule on Safety Reporting Requirements for Human Drugs and Biological Products (U.S. Federal Register; Friday, 2003-03-14, Docket OON-1484), the U.S. is proposing to have it submitted more frequently, as the manufacturer becomes aware of a safety finding.
Australia New Zealand Therapeutic Products Authority (ANZTPA)
The Consultation paper, Product Vigilance in the Australia New Zealand Therapeutic Products Authority (ANZTPA), written in September 2006, states that, “Included as part of a Product Vigilance System, all Product Licence Holders would be obligated to: Ensure all information that ANZTPA considers relevant to the risk-benefit balance of a therapeutic product is reported to the Agency fully and promptly.” The manner in which this information is reported is not indicated. The Therapeutic Goods Administration (TGA), in the “Australian regulatory guidelines for OTC medicines,” requires that manufacturers: “Notify the TGA of any changes in information that may have been relevant to a decision to register the goods” (July 2003). (see footnote 2)
International best practices
To the greatest extent possible, Health Canada aims to adopt international best practices. With respect to requiring notification from manufacturers when manufacturers receive information on or conclude that there is a significant change to the risk-benefit profile of a product, the European Union has a broader authority than what is being brought forward by Health Canada, and the U.S. FDA is also moving towards establishing broader authorities. Health Canada’s current amendment is limited to information related to case reports, summary reports or ADRs, whereas in other jurisdictions, manufacturers are required to report all information related to the risk-benefit profile of a product to the regulator. Requiring the reporting of all information is outside the scope of the current amendment. This regulatory amendment is meant to provide the Minister with timely access to the results of the critical analysis conducted by the manufacturer on an annual basis, should the critical analysis reveal a change to the benefit-risk profile of the product.
Regulatory and non-regulatory options considered
Option 1: Status quo
This option would have required manufacturers to submit case reports and summary reports only upon the Minister’s request after becoming aware of a safety occurrence. This option was rejected because it failed to recognize that the Minister is not always the first to be aware of safety issues. Adverse drug reaction information is available from a variety of sources and it is primarily the manufacturer’s responsibility to initially compile and analyze it. This places the manufacturer in the best position to first identify new safety concerns. This option was also less consistent with the overall scheme of the Regulations, in which manufacturers are primarily responsible for demonstrating to the regulator that the anticipated benefits of a drug outweigh its risks under the conditions of use for which it is recommended, and providing the regulator with the data and analysis needed to independently assess this benefit-risk profile. While this option did not provide any additional benefit or cost to the manufacturer, there would have been a potential cost for the Minister in terms of missing opportunities for international alignment and collaboration, and for improved post-market monitoring activities, which would have led to improved patient safety.
Option 2: Amend C.01.016 to put the onus on the manufacturer to submit all case reports and a summary report upon identification of a significant change to a product’s risk-benefit profile.
In this option, C.01.016 would have been amended to require manufacturers to always submit summary reports or case reports when a significant safety issue triggers a shift in the benefits and risks of a drug product.
This would have provided additional benefit to the public by providing the Minister with additional information that could be used to improve post-marketing monitoring activities. The option also would have facilitated international alignment and collaboration. It would not result in significant additional costs to manufacturers, as they already have the processes in place to prepare the reports, and it would only require submitting them to the Minister. The number of submissions (case reports and summary reports) or relevant safety information this change could initiate is difficult to estimate. It may have required supplemental resourcing for manufacturers to provide, and for the Minister to review additional documents. The benefits of imposing this additional regulatory burden, compared to a regulation that permits these documents to be compelled, as needed by the Minister, are unclear. Option 2 also could have resulted in the less focussed use of Health Canada’s limited post-market surveillance capacities.
This option was not recommended, due to the lack of clearly identifiable benefits, given the potential costs of implementation.
Option 3: Amend C.01.016 to require the manufacturer to notify the Minister of a significant change in a product’s risk-benefit profile, and provide the Minister with the authority to request case reports or a summary report where the Minister determines that an examination of the safety and effectiveness of a drug is warranted (selected option).
This option differs from Option 2 in several ways. First, the trigger for notifying the Minister will be the manufacturer’s own conclusion in preparing the summary report, which is required under the current Regulations. A change in the risk-benefit profile which is deemed significant by industry is triggered, for example, by concerns arising from the nature, severity or frequency of the ADRs being analysed (including the identification of a previously unknown risk). Second, manufacturers will not automatically be required to submit case reports and a summary report upon identification of a significant change in the risk-benefit profile. They would instead submit only the overall safety evaluation of their summary report in which the issue is identified. The Minister would then determine if further documentation would be needed to permit the Minister to evaluate the risks and benefits of the drug. This option will also give the Minister, if she decides to examine the safety and effectiveness of a drug, access to case reports of all adverse drug reactions and serious adverse drug reactions to that drug that are known to the manufacturer, and a summary report. This will allow the Minister to engage the manufacturer in the examination of the risks and benefits of the drug in a way that benefits Canadians and is consistent with other parts of the Regulations.
Option 4: Produce a guidance document recommending that the manufacturer notify the Minister of significant safety issues.
This option would have made the manufacturers aware of the recommendation to notify the Minister if the manufacturer concluded (from the annual summary report) that there was a significant change in the risk-benefit profile of a drug relating to its safe use. This would have provided a means for the Minister to be notified of important safety considerations of which the manufacturer became aware. However, this option would not have had the force of a regulation. It is uncertain if all manufacturers would have voluntarily provided the notification to the Minister. Finally, this option would have left Canada out of step with international regulators.
Benefits and costs
The ADR Reporting section of the Regulations applies to a substantial number of products. There are over 22 000 drug products for human use, 1 450 veterinary drug products, and 400 biologics currently being regulated and approved for sale in the Canadian marketplace. Animal health products, including veterinary drugs, had sales of about $500 million in 2005. According to the Canadian Institute for Health Information (CIHI), Canadians spent $22.5 billion on prescription and $4.4 billion on non-prescription drugs outside of hospitals in 2007. Pharmaceuticals, including biologics, represent the second largest component of overall health spending at 16.8%. The public sector funded 38.7% of the expenditure in Canada, with the rest covered by patients and private insurance plans.
The requirement in Option 3, for manufacturers to notify the Minister if they conclude from their summary report that there is a significant change in risk-benefit profile of a drug, is anticipated to be low cost to the manufacturer since
1. these conclusions are not expected to occur with great frequency (it is estimated that 10 to 15 reports to the Minister would occur per year);
2. the requirement requires notification of a significant change in a product’s risk-benefit profile by way of submission of the Overall Safety Evaluation section of the annual summary report, not a new report for the manufacture to produce;
3. the majority of respondents during the consultation indicated that they are already proactively informing the Minister of significant safety issues that come to light when the manufacturer is preparing the summary report; and
4. the requirements for keeping these records would drop from an indefinite interval to 25 years.
The potential benefit would be that the Minister would be promptly informed once a manufacturer had concluded that there was a significant change in the risk-benefit profile of the drug and could therefore take appropriate actions to mitigate risks. These actions could range from discussions with manufacturers to issuing risk communications to health professionals or consumers or to stopping the sale of the drug.
As well, Health Canada would more closely align with international partners, including Australia, Europe and the U.S., who have published regulations or guidance with similar objectives. In recognition of the principles of the paperwork burden reduction initiative, which aims to reduce the regulatory burden on Canadian industries, efforts were made to develop a reporting system that provides the Minister with essential information while minimizing the burden on industry.
Further, it is anticipated that Option 3 will have minimal impacts on the government as it is not expected that a large number of submissions will result from this requirement. The majority of safety concerns are identified by other means, including ADR reports submitted, international collaboration, and environmental scanning.
The second requirement in Option 3 provides the Minister with the authority to require case reports or a summary report after deciding to examine the safety and effectiveness of a drug. This would provide additional information to the Minister to monitor drugs once marketed, setting reasonable parameters for when these reports could be required, i.e., when the Minister feels it is necessary to evaluate the drug’s risks and benefits.
Option 3, the selected option, is expected to benefit the health and safety of the public with a limited burden to industry. It will improve Health Canada’s capability to monitor manufacturer compliance and will provide Health Canada with another mechanism to obtain important safety information.
The principle that the manufacturer should notify the Minister should the manufacturer become aware of a safety concern was consulted on in the Guidance Document for Industry — Reporting Adverse Reactions to Marketed Health Products, which was posted on the HC Web site for comment from January 16, 2008, to March 16, 2008. The section on Summary Reports has the following voluntary provision:
In addition to complying with regulatory requirements to report safety and efficacy information, Health Canada expects that manufacturers inform MHPD if the manufacturer concludes from the annual summary report that there is a significant change in the risk-benefit profile of a product relating to its safe use. Examples may include a significant change in the frequency or severity of a known risk or the identification of a previously unknown risk.
Significant input and comments were received on the Guidance for Industry - Reporting Adverse Reactions to Marketed Health Products, from a variety of industry associations, sectors and companies of various sizes. However, there were no comments concerning this section, which suggests that stakeholders may not have serious concerns about this topic.
As well, a letter to stakeholders was posted on the Health Canada Web site on July 7, 2008, advising of the “Proposal to Amend the Food and Drug Regulations with respect to Annual Pharmacovigilance Reports.” The letter invited input from organizations on the impact of this regulatory amendment on industry, and to bring any specific considerations to the Minister’s awareness. The response showed unanimous support for the proposal to require the manufacturer to notify the Minister if the manufacturer concluded from the annual summary report that there was a significant change in the risk-benefit profile of a product relating to its safe use. This was viewed as an international best practice and the majority of respondents indicated that this was consistent with their current practices. Stakeholders requested further clarification around expectations for the proposal to clearly permit the Minister to request that manufacturers provide a summary report or case reports, whenever the Minister decides to examine the safety and effectiveness of a drug; and the Minister’s imposing a deadline shorter than 30 days for the submission of these reports, if the Minister considered that a shorter deadline was necessary to respond to a serious and imminent risk to health.
Stakeholders supported the need for the Minister to be able to request information in a timely manner in order to respond to a serious and imminent risk to health, but suggested that in the situation where a new summary report needed to be created to address a serious and imminent risk to health that timelines be negotiated between the manufacturer and the Minister, or that there be flexibility in the format of the information to be submitted. To address this, Health Canada has amended the wording of the Regulations to provide flexibility regarding the time allowed for the submission of the report and intends that the following wording be included in guidance, “The adequacy of the content of an issue-related summary report would normally be determined by taking account of what the manufacturer can reasonably provide in the time frame set by the Minister. This would, as a minimum, typically include an analysis of the risk of the product based on available data and conclusions regarding the safety of the product as marketed in Canada.”
On June 13, 2009, the proposed Regulations were pre-published in the Canada Gazette, Part I, followed by a 75-day comment period. Thirty-five specific comments were received from 13 stakeholders, on subjects including alignment between domestic and international regulations, clarification of terminology, time lines for reporting, flexibility, and enforcement issues. In principle, stakeholders supported the proposed measures.
In response to stakeholder concerns that the timelines proposed for providing the Issue-related summary report were not sufficiently flexible, the wording has been amended to allow the Minister to set a shorter or longer time frame, further to discussion with manufacturers. Stakeholders who raised this issue were invited to comment on the new text and all those who responded supported the intent and substance of the revisions. Two stakeholders supported the intent and offered variations in wording, but since these variations were not substantively different from the text proposed by Health Canada or from each other, the revised Health Canada proposal will stand since it represents current drafting conventions. In response to other suggestions, some confusing language has been removed from the original Regulatory Impact Analysis Statement and additional clarifications have been added to the Guideline. The net result is that manufacturers will be given an opportunity to be heard regarding the establishment of time frames for providing the required reports, and that these time frames will be reasonable, given the circumstances and the information required.
Manufacturers suggested that Health Canada amend the periodicity of summary reporting to align with those of other regulatory authorities (e.g. in the European Union, Periodic Safety Update Reports (PSURs) are required to be submitted every six months for the first two years of commercialization, every year for the next two years and then every three years). The suggestion to align with the EU’s reporting schedule is outside the scope of this project, which aims to align Health Canada with other regulatory authorities’ capability to obtain all information related to the benefit-risk of a product. However, it is timely to have obtained this feedback from manufacturers as it will be useful in Health Canada’s full implementation of ICH E2C and E2E (Pharmacovigilance Planning) Guidelines which together require periodic review of a product’s risk-benefit profile.
Manufacturers also suggested that further explanation of “significant change” be provided. The Guidance Document for Industry - Reporting Adverse Reactions to Marketed Health Products provides examples of significant change (e.g. a significant change in the frequency or severity of a known risk or the identification of a previously unknown risk).
Following pre-publication in the Canada Gazette, Part I, some stakeholders found the term “risk-benefit profile” to be unclear, and this wording has now been dropped in favour of plainer language, i.e. “what the manufacturer knows about the risks and benefits of the drug.”
Also as a result of stakeholder comments following pre-publication, it came to light that a requirement already exists in Division 8 of Part C of the Regulations for manufacturers to notify the Minister of benefit-risk concerns for “new drugs” for which a Notice of Compliance has been issued, and that the proposal as worded could have been duplicative for these products. In response to this concern, the regulatory language has been amended to the effect that manufacturers will not have to notify the Minister twice regarding the same issue.
The Guidance Document for Industry - Reporting Adverse Reactions to Marketed Health Products now includes the following wording to further interpret the Regulations: “In addition to complying with regulatory requirements to report safety and efficacy information, Health Canada expects that manufacturers inform MHPD if the manufacturer concludes from the annual summary report that there is a significant change in the risk-benefit profile of a product relating to its safe use. Examples may include a significant change in the frequency or severity of a known risk or the identification of a previously unknown risk.”
Following prepublication, one stakeholder raised the issue of alignment between the Regulations and the Natural Health Product Regulations (NHPR). The Natural Health Products Regulatory Review, conducted in March 2007 as part of Health Canada’s commitment to review the NHPR, gave stakeholders an opportunity to provide feedback on their experiences with the NHPR. This feedback is helping Health Canada to further refine and improve its regulatory framework for natural health products, while ensuring that Canadians have continued access to natural health products that are safe, effective and of high quality. As part of these refinements to the NHPR, Health Canada will consider the need for revisions to the adverse reaction reporting provisions. In the interim, differences between adverse reaction reporting requirements in the Food and Drug Regulations and the NHPR are mitigated in the 2009 Guidance Document for Industry - Reporting Adverse Reactions to Marketed Health Products, which includes analogous provisions for natural health products within its scope.
Adverse reaction reporting requirements for blood and blood components are addressed in the terms and conditions of their respective establishment licences, and will not be substantively affected by this amendment.
Implementation, enforcement and service standards
At the time of publication of the regulatory amendment in the Canada Gazette, Part II, a Notice will be posted on the Health Canada Web site advising stakeholders of the regulatory change. The process for manufacturers to notify the Minister will be clarified in guidance documents.
HC Standard Operating Procedures (SOPs) currently exist for receiving and reviewing case reports and summary reports. These SOPs will require altering to allow the receipt of notifications of significant changes in the benefit-risk profile of a drug relating to its safe use, and to include the changes to requests for these reports.
Compliance and enforcement will be conducted by Health Canada’s Health Products and Food Branch Inspectorate (the Inspectorate). Compliance monitoring for the notification of significant safety concerns will be part of the Post-Market Reporting Compliance (PMRC) inspection programme. This programme, implemented as a pilot in 2004 and fully implemented in 2005, verifies manufacturer compliance with regulatory requirements regarding handling of drug safety information and reporting on adverse drug reactions, specifically sections C.01.016, C.01.017, C.08.007, and C.08.008 of the Food and Drug Regulations. This inspection programme is carried out by the Inspectorate in collaboration with the Marketed Health Products Directorate. Observations of deviations from the Food and Drug Regulations are noted during PMRC inspections and are evaluated relative to their risk together with the extent and nature of the deviations noted.
Methods of compliance verification and enforcement will not change to a great extent as a result of this regulatory amendment. Current C.01.016 report requirements, such as for serious adverse drug reactions, serious unexpected adverse drug reactions, annual summary reports, and case reports, are already part of the inspection programme. The regulatory amendment will require that this same activity be continued, except that the Inspectorate will also verify if the manufacturer has notified the Minister when they conclude from the annual summary report that there is a significant change in what the manufacturer knows about the risks and benefits of a drug relating to its safe use, as the manufacturer will be required to record in their conclusion if such a change exists. This section of the Regulations has been re-organized to clarify the responsibilities for the manufacturer and facilitate the PMRC inspection programme. As well, the amendment will clarify when annual summary reports, case reports, adverse drug reactions, and serious adverse drug reactions can be required by the Minister. For this reason, the verification of a manufacturer’s compliance with the amended C.01.016 regulatory requirements is a feasible addition to the PMRC inspection programme.
Training for inspectors expected to monitor compliance of this regulatory change will be required. However, as the regulatory change would not greatly alter the current inspection programme it is not anticipated that training would be onerous, and would therefore not require the allocation of additional resources. Inspectors will be expected to monitor for compliance; to do so, they will be provided with guidance on the expectations for this requirement.
A similar regulatory requirement to the current C.01.016 exists in the Natural Health Products Regulations. The Natural Health Products Directorate will develop a suitable solution to promote consistency between the regulations. As the Guidance Document for Industry - Reporting Adverse Reactions to Marketed Health Products includes natural health products within its scope, the continuation of voluntary provisions found in the guidance can serve as an interim measure.
Currently, the Guidance Document for Industry - Reporting Adverse Reactions to Marketed Health Products states that “The preferred format for annual summary reports prepared by manufacturers is the PSUR format ... manufacturers may also use an annual summary report format.” Canada has not yet fully implemented a PSUR requirement but is doing so in a stepwise fashion, starting with the harmonization of the Annual Summary Report with the ICH E2C Guideline in the Guidance Document for Industry - Reporting Adverse Reactions to Marketed Health Products. While PSURs were developed for newly marketed products, the C.01.016 regulatory requirement is for all drugs. The C.01.016 regulatory requirement will be compatible with future work on PSUR.
Head, Unit 2
Policy and Regulatory Affairs
Therapeutic Effectiveness and Policy Bureau
Marketed Health Products Directorate
Address Locator: 0701C
S.C. 2005, c. 42, s. 2
R.S., c. F-27
C.R.C., c. 870
www.tga.gov.au/docs/pdf/argom.pdf, accessed on August 28, 2007.