ARCHIVED — Regulations Amending the Food and Drug Regulations (1319 — New Drugs for Extraordinary Use)

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Vol. 144, No. 14 — April 3, 2010

Statutory authority

Food and Drugs Act

Sponsoring department

Department of Health

REGULATORY IMPACT
ANALYSIS STATEMENT

(This statement is not part of the Regulations.)

Executive summary

Issue: The current regulations for the authorization for sale of a new drug in Canada include a requirement to provide substantial evidence demonstrating the safety and efficacy of the drug for the purpose of and under the recommended conditions of use. While this standard is appropriate for most new drugs, there are ethical and/or logistical challenges in designing appropriate clinical trials for a small number of emergency-use drugs, such as anthrax and pandemic influenza vaccines. These drugs are collectively referred to as Extraordinary Use New Drugs (EUNDs).

Description: The current practice of using the Special Access Programme (SAP) to authorize the sale of EUNDs for broad distribution has already been determined to be inappropriate by the Office of the Auditor General of Canada (OAG). The proposed regulatory amendment would create a new type of drug submission for an EUND within the Foodand Drug Regulations (the Regulations). The inclusion criteria for EUNDs are provided, and the regulations also outline the requirements for EUND submissions, labelling, plans for post-market safety and efficacy studies and annual reporting. Existing regulations that apply to other drugs including, but not limited to, those regarding adverse drug reaction reporting, establishment licensing, good manufacturing practices, and data and patent protection would also apply to EUNDs. Because of the nature and intended purpose of these drugs, manufacturers would only be able to sell EUNDs to different levels of Canadian governments (i.e. federal, provincial, territorial, and municipal).

Cost-benefit statement: The baseline for the cost-benefit analysis is the current situation in which the sale of an unmarketed EUND may be authorized through the SAP via the exemption of that one-time sale from the Food and Drugs Act and the Regulations. The cost to industry and government stakeholders is not expected to be significant, given their current roles and responsibilities within the existing drug development and authorization framework. The most significant benefit would be to Canadian patients who might use EUNDs, since there would be a pre-market review and enhanced post-market surveillance of these drugs, and to governments, who could then more easily prepare for extraordinary situations.

Business and consumer impacts: Drug manufacturers would be required to file EUND submissions and commit to post-market surveillance and data acquisition, none of which is required of manufacturers when drugs are authorized for sale through the SAP. Although the regulatory amendments would lead to additional costs for manufacturers, these costs are related to normal business activities in the development of any drug, not just EUNDs. Canadians, as potential consumers of EUNDs, would not experience any negative impact from the proposed amendments.

Domestic and international coordination and cooperation: The proposed regulatory framework would be aligned with requirements set by the United States Food and Drug Administration and the European Medicines Agency for drugs determined to be EUNDs.

Performance measurement and evaluation plan: The performance and evaluation of the EUND submission and review framework would fit into the current evaluation plan which is used for the Health Products and Food Branch’s (HPFB) Human Drug Activities. Many indicators can be drawn from HPFB’s existing Program Activity Architecture. Performance measurement and evaluation are ongoing at Health Canada, and a comprehensive review of the entire EUND regulatory framework is planned at the five-year mark.

Issue

Before a new drug can be sold in Canada, the manufacturer must submit to Health Canada a New Drug Submission (NDS), which includes information about the quality, safety and efficacy of the drug. A review is conducted, and if the submitted information is determined to meet the criteria set out in the Food and Drug Regulations (the Regulations), a Notice of Compliance (NOC) is issued. The manufacturer is then authorized to sell the drug in Canada.

The current regulatory framework for new drugs works well for most drugs, but there is a group of extraordinary use drugs for which traditional clinical trials cannot be conducted. According to C.08.002(2)(g) and (h) of the Regulations, the manufacturer must demonstrate clinical safety and provide substantial evidence of clinical effectiveness of the drug for the purpose and under the conditions of use recommended. For drugs such as those needed to prevent or treat pandemic influenza or to treat inhaled anthrax from a terrorist attack, there are ethical and/or logistical challenges in designing and conducting clinical trials. A researcher cannot intentionally expose clinical trial subjects to the causative agent in question, and the occurrence of the conditions of use recommended (i.e. pandemic influenza outbreak or anthrax exposure) is unpredictable, sporadic and infrequent, so the standards for clinical safety and effectiveness set out in the Regulations cannot be met.

Currently, access to quantities of military medical countermeasures and other emergency preparedness drugs may be requested by public health officials or senior medical staff from the Department of National Defence (DND) through the SAP. The SAP is a program through which practitioners can obtain non-marketed drugs for their patients via an exemption from the Food and Drugs Act and the Regulations. Drugs which are sold under the SAP provisions do not undergo a comprehensive pre-market review, nor are they subject to the same post-market safety provisions that apply to other new drugs. In a 2005 report, the OAG noted that the SAP, intended for a single practitioner-single patient relationship, is not an appropriate legal structure for the provision of large quantities of unauthorized drugs for emergency use. In response to the OAG’s report, Health Canada made a commitment to pursue an appropriate regulatory mechanism to allow authorization for sale of military medical countermeasures for emergency use.

In its 2005 document, Regulatory Preparedness for Pandemic Influenza Vaccines, Health Canada made a commitment to Canadians to provide an appropriate degree of regulatory oversight for any future pandemic influenza vaccine. The proposed regulatory amendments work towards meeting this commitment by providing a framework under which the safety, efficacy and quality of pandemic vaccines could be assessed and subsequently authorized for sale.

Objectives

The purpose of the proposed regulatory amendments is to create a regulatory mechanism by which Health Canada would be able to review and authorize extraordinary use drugs such as military medical countermeasures and pandemic influenza vaccines. The EUND regulations take into account the exceptional circumstances under which this group of drugs would be used and the challenges manufacturers face when designing clinical studies for these drugs, allowing the manufacturer to use results of animal studies in conjunction with results from limited human safety studies, in support of their drug submission. The goal is to provide Canadians with access to extraordinary use drugs which have undergone a pre-market review for safety and quality and would be followed in the post-market period for safety and efficacy. In bringing about the proposed regulatory changes, Health Canada would also be meeting its commitments to the OAG to have a route of regulatory authorization for sale of military medical countermeasures.

Description

The proposed regulatory amendments would create a new type of drug submission in Division 8, Part C of the Regulations. Divisions 1, 4 and 5 of Part C of the Regulations would be amended to support the changes proposed in Division 8, and some consequential amendments to the Patented Medicines (Notice of Compliance) Regulations [PM(NOC) Regulations] under the Patent Act would also be required.

Overview of new regulatory framework

The proposed Regulations set out to define the term “extraordinary use new drug” (EUND) by detailing the criteria which a new drug would have to meet before the manufacturer could file an EUND submission. The regulatory framework also outlines requirements for EUND submissions, labelling, plans for post-market safety and efficacy data acquisition and annual reporting. Existing regulations that apply to other drugs including, but not limited to, those regarding adverse drug reaction reporting, establishment licensing, good manufacturing practices and data and patent protection would apply to EUNDs as well. Because of the nature and intended purpose of these drugs, manufacturers would only be permitted to sell EUNDs to federal, provincial, territorial or municipal governments.

What is an EUND?

In order for a manufacturer to file an EUND submission, the drug would have to meet the following inclusion criteria:

(1) The drug must be intended for use in emergency situations where immediate action is required to treat, mitigate or prevent a life-threatening health condition that result from exposure to a chemical, biological, radiological or nuclear (CBRN) substance; and

(2) Due to logistical and ethical considerations, specified below, traditional clinical trials cannot be conducted, so the drug cannot meet the safety and efficacy standards set out in C.08.002(2)(g) and (h):

(a) exposing human subjects to the causative CBRN substance might be lethal or permanently disabling, and

(b) the circumstances under which the CBRN exposure might occur are unpredictable, sporadic and infrequent.

Submission requirements

If a drug were to meet the inclusion criteria, then the manufacturer could file an EUND submission with Health Canada. The submission would contain the following:

  • a signed attestation from the manufacturer, certifying that the drug meets the inclusion criteria;
  • all the information required in an NDS, except for that outlined in C.08.002(2)(g) and (h);
  • information about how the drug works against the CBRN substance;
  • results of in vitro and animal studies which support the use of the drug in humans; information about the pharmacokinetics and pharmacodynamics of the drug in animals and in humans;
  • results of clinical trials to demonstrate safety of the drug in humans, if any;
  • draft labels;
  • a plan to monitor and establish safety and effectiveness of the drug in the post-market period; and
  • if the drug has been reviewed by foreign regulators, copies of those evaluation reports.

The term “EUND” includes a wide range of drugs, so the proposed submission requirements aim to provide sufficient detail to set scientific criteria, yet be flexible enough to cover drugs with vastly different chemical and physiological characteristics. Health Canada intends to provide further information on submission requirements in a guidance document, which is currently under development.

Under the proposed amendments, an abbreviated EUND submission could be filed for a subsequent-entry (generic) product if the inclusion criteria, set out in C.08.002.01(1), were met. The current provisions regarding data protection in C.08.004.1 would apply to EUNDs, as would the PM(NOC) Regulations. The abbreviated EUND submission would contain information that is required for a regular Abbreviated New Drug Submission, along with draft labels for the generic EUND, a plan to monitor and establish the safety and effectiveness of the drug in the post-market period and, if the drug has been reviewed by foreign regulators, copies of those evaluation reports.

Post-market requirements

The manufacturer would be required to submit a post-market plan describing how they plan to monitor the safety and effectiveness of the EUND. The plan should include details of how the data would be gathered and analyzed. Sample reporting templates might also be required to facilitate the collection of data during an anticipated emergency. The manufacturer would provide updated information on the safety and effectiveness of the drug on an annual basis, or whenever requested by Health Canada.

Other requirements

All other regulations that set requirements and provisions for new drugs, including those respecting adverse drug reaction reporting, establishment licensing, good manufacturing practices, patent and data protection, record keeping and cost recovery fees would also apply to EUNDs.

Authorization and restriction of sales

Under the proposed regulatory scheme, if the information in the EUND submission is acceptable, Health Canada would issue an NOC and drug identification number (DIN) to the manufacturer. The NOC for an EUND would be different than those issued for other new drugs in that it would only authorize the manufacturer to sell to federal, provincial, territorial and municipal governments.

Consequential amendments to the Patented Medicines (Notice of Compliance) Regulations

Minor changes are proposed to the definitions under the PM(NOC) Regulations in order to ensure that those Regulations apply to EUND submissions. The amendments would enable an innovative manufacturer, referred to as a first person, to list patents in accordance with the provisions currently outlined in the PM(NOC) Regulations. In addition, the PM(NOC) Regulations would be applicable to second persons, including the manufacturer of a subsequent entry EUND or an abbreviated EUND, pursuant to section 5 of the PM(NOC) Regulations.

Consequential amendments to C.08.004.1 of the Food and Drug Regulations

Minor amendments to the data protection section of these Regulations are proposed to expand the definition of new drug submission to include an EUND submission and likewise to expand the definition of abbreviated new drug submission to include an abbreviated EUND submission. These additions would allow application of the data protection provisions to this new type of submission.

Regulatory and non-regulatory options considered

The options outlined below were considered in the development of the proposed regulatory framework.

1. The status quo

Currently, EUNDs cannot be authorized for sale within the existing NDS framework. There are three regulatory options currently available to allow access to these unauthorized extraordinary use drugs.

(a) EUNDs can be obtained through the SAP, which provides an exemption from the Act and Regulations. Although the SAP was intended for single patient-single practitioner use, it has been and continues to be broadly interpreted to allow for the mass distribution or stockpiling of emergency use drugs by DND and the Public Health Agency of Canada (PHAC).

(b) According to section 30.1 of the Act, an interim order may be made to bring into effect temporary regulations to deal with a given emergency situation. This provision could allow Health Canada to recommend that the Minister enact interim orders to authorize the sale of an EUND for use in that particular emergency.

(c) A clinical trial application may be filed, under Part C, Division 5 of the Regulations, and the manufacturer could distribute the EUND for clinical testing, following the protocols set out in their clinical trial application.

The OAG has already raised concerns that the SAP is not an appropriate regulatory mechanism for the sale of EUNDs. When EUNDs are authorized for sale through the SAP, there is no pre-market review to assess the quality, safety and efficacy of the EUND, nor does the regulator have sufficient authority in the post-market period to protect the health and safety of patients. A drug obtained through the SAP is not subject to the same rules respecting good manufacturing practices, establishment licensing, labelling and adverse drug reaction reporting that apply to other new drugs. Finally, the use of the SAP for EUNDs takes resources away from the program’s mandate of providing access to non-marketed drugs for practitioners treating patients with serious or life-threatening conditions when conventional therapies have failed, are unsuitable or unavailable.

The use of interim orders during an emergency situation is a reactionary approach to regulation since the legislation requires that the Minister believe that immediate action is required to deal with a significant risk, direct or indirect, to health, safety or the environment. An interim order was used in October 2009 to allow the authorization of the pandemic H1N1 influenza vaccine for sale in Canada. It must be noted, however, that planning on the part of governments and prospective EUND manufacturers would be better facilitated if the regulatory requirements were known in advance of the actual emergency. It is important to note that, even if the proposed EUND amendments are made, there may still be some instances where interim orders would be the only viable option.

The use of the clinical trial framework to sell EUNDs for use in emergency situation raises a number of concerns. Due to the sporadic and infrequent nature of the events which might require the use of EUNDs, it might be impractical to design open-ended trials for these drugs. If there is a wide-spread public health emergency, the situation may prove to be too chaotic to allow clinicians to follow good clinical practices, as required by the Regulations. Furthermore, it would difficult, if not logistically impossible, for a research ethics board to approve and monitor the ethical aspects of such a large, population-based clinical trial, as would be required by the Regulations. Manufacturing sites for drugs distributed for clinical trials are not required to hold an establishment licence, and the applicable good manufacturing practices requirements are not as stringent as for authorized new drugs.

Because of the concerns raised by the OAG and because of Health Canada’s commitment to introduce an appropriate regulatory framework for EUNDs, the status quo is not a viable option.

2. Amend the enabling legislation

Any future amendments to the Act might allow for a regulatory framework that would provide Health Canada the flexibility to grant authorization for sale of an EUND under a graduated licensing system, with pre- and post-market checks in place to ensure the health and safety of patients who may use the drug. In this scenario, an EUND would likely be evaluated in the same manner as other drugs, using an evidence-based approach to dealing with the safety and efficacy issues throughout the lifecycle of the drug.

The main disadvantage to this option is the uncertain timeframe associated with introducing and passing legislation. A delay in putting in place a means of authorizing EUNDs for sale may deter emergency preparedness efforts.

3. Create a new type of submission (chosen option)

Health Canada is recommending the creation of a new type of submission for EUNDs through amendments to the Regulations. The proposed EUND submission requirements would differ slightly from those for new drugs, but the structure of the submission and the operational processes within Health Canada would remain the same. Special consideration would be given to preclinical and clinical data requirements, labelling and post-market data collection and reporting for EUNDs. This approach would allow Health Canada to put into place an appropriate risk-based framework for authorizing EUNDs.

International approaches

When adequate and well-controlled efficacy studies in humans cannot be ethically conducted, the United States Food and Drug Administration allows for the approval of new drug products based on animal data through the Animal Efficacy Rule. Similarly, the European Medicines Agency has regulations which grant authorization and provide safeguards to ensure as best as possible the quality, safety and efficacy of these drugs via the Market Authorization under Exceptional Circumstances.

The proposed EUND Regulations are aligned with other regulators’ approaches in terms of the criteria for consideration, the drug submission requirements, the conditions pertaining to post-market surveillance and the labelling requirements. The scientific considerations and the risk-management approaches are similar, but differences between the Food and Drugs Act and the enabling legislation in other jurisdictions would preclude true harmonization of Canadian regulations with international regulations.

Benefits and costs

Baseline

The baseline for comparison of costs and benefits is the current situation whereby drugs that would be EUNDs are obtained through the SAP. The regulations which govern the SAP are intended to allow a single practitioner to treat a single patient with a drug that is not currently marketed in Canada. The program has been broadly interpreted to authorize the sale of drugs to DND, PHAC, provinces and territories and municipalities for emergency preparedness stockpiling. There are no fees charged to manufacturers that provide drugs through this program, nor is a robust pre- or post-market data analysis conducted.

Health Canada (regulator)

Pharmaceutical industry

F/P/T/M governments

Canadian public (EUND recipients)

Costs

- a one-time cost of $40,000 to develop guidance documents and templates

- $20,000 every five years to evaluate and review EUND Regulations

- $1.5 million, less user fees collected, to review an estimated three EUND submissions each year

- cost of preparing an EUND submission, including the cost of additional animal studies and development and implementation of post-market plan for data collection

- user fees collected by Health Canada, including a one-time fee of $52,900 and annual fees ranging from $1,000 to $26,625

- P/T/M departments or health units may be responsible for collecting data on EUND use for the manufacturer analysis and submission to regulators

- cost would depend on type of emergency situation and level of use of EUND

- no change in cost to Canadian public

Benefits

- would meet the Department’s commitment to Canadians to provide an appropriate regulatory pathway for EUND-type drugs

- authorization of EUNDs for sale would allow manufacturers to market directly to government buyers

- formalized post-market data collection may allow for broader market authorization through regular submission pathway

- would have more confidence in the safety and quality of the EUNDs they purchase, knowing that risk-based regulatory reviews were required in both the pre- and post-market periods

- would have more confidence in the safety and quality of the EUNDs they receive, knowing that risk-based regulatory reviews were required in both the pre- and post-market periods

Neither government nor industry stakeholders are expected to incur significant costs compared to the baseline, particularly because the number of drugs submitted through the EUND pathway is anticipated to be very low and because any additional costs would generally constitute normal business activities associated with drug development and approval.

Canadians would benefit from having access to extraordinary use drugs that have undergone a pre-market review. The proposed amendments would allow Health Canada to meet their commitments to provide an appropriate route for regulatory review and authorization for sale of EUNDs.

The benefits and costs to specific stakeholders are outlined below. A comparison is made to the baseline situation described above.

Health Canada

Costs

The regulatory amendment would present additional costs to Health Canada. According to Health Canada’s document of July 2007, Cost Recovery Framework: Official Notice of Fee Proposal for Human Drugs and Medical Devices, the cost of reviewing an EUND submission is expected to be at par with an NDS review: approximately $404,635 for a pharmaceutical and $522,347 for a biologic.

Review for a second EUND indication for a previously authorized drug would likely focus on pre-clinical data only, using in vitro or animal models to predict the effectiveness of the EUND in humans under the recommended conditions of use. Although there is no comparable activity in the current cost recovery framework, the cost to Health Canada of reviewing clinical data only for a pharmaceutical is approximately $95,641, and that for a biologic is approximately $132,426. Despite the differences in the type of data required, the cost to review a new EUND indication for a previously authorized drug is expected to be at par with these costs.

A small portion of the submission review costs would be recovered through fees charged to manufacturers as part of Health Canada’s Cost Recovery Initiative.

The development of new forms, templates and guidance documents for manufacturer and Health Canada use is expected to cost $37,500 to $45,000 in salary dollars over six months. This would be a one-time cost to Health Canada. The maintenance and review of these documents, approximately every five years as per the Performance Measurement and Evaluation Plan, would cost about $20,000 in salary dollars every five-year cycle.

Benefits

The proposed regulatory amendment would satisfy Health Canada’s commitment to provide a regulatory mechanism for granting market authorization to extraordinary use drugs that, for ethical or logistical reasons, cannot be studied under traditional clinical trials and as such cannot be granted market authorization under C.08.002(2).

Pharmaceutical industry

Costs

The preparation of an EUND submission that includes robust and definitive animal and in vitro studies represents a cost to industry, as do the creation and implementation of a required post-market surveillance and data collection plan. An association representing pharmaceutical manufacturers has stated it would be difficult to estimate such costs without knowing the details of the proposed regulatory requirements. The costs would also vary, depending on the details of the individual EUND submission.

No changes are being proposed to existing user fees regulations under the Financial Administration Act, but established user fees would be charged to EUND manufacturers. A summary of fees that would apply is provided in the table below:

Type of user fee

Amount of fee ($)

Frequency of payment

Establishment licensing

Would range from 0 to 25,625, depending on type of activities undertaken and which fees were previously paid for that site

Paid on an annual basis

Drug evaluation

52,900

One-time fee, per submission

Authority to sell

1,000

Paid on an annual basis

Benefits

Authorization under the proposed regulatory amendment would enable manufacturers to sell their authorized drugs directly to federal, provincial, territorial and municipal government purchasers.

Manufacturers would also have the assurance that Health Canada is committed to working in a collaborative manner during an emergency to ensure that information regarding adverse events and drug effectiveness is exchanged in a timely manner to protect the health and safety of Canadians.

Formalized post-market data collection and analysis may provide future opportunities for broader market authorization through C.08.002(2).

Federal, provincial, territorial or municipal governments

Costs

Although the proposed regulations place the responsibility of collecting and analyzing and post-market data on EUND use and submitting it to Health Canada, in an actual emergency situation, health care workers in the affected communities would be best situated to do the actual data collection. Thus, federal, provincial, territorial and municipal health units would be responsible for carrying out post-market surveillance and data collection for the EUNDs they purchase and use. Valid cost estimates can only be known following an emergency scenario and via the details of a purchase agreement.

Benefits

Government purchasers of EUNDs would have more confidence in the safety and quality of the EUNDs they purchase, knowing that risk-based regulatory reviews were required in both the pre- and post-market periods.

Recipients of EUND

Costs

Currently, drugs that would be EUNDs could be purchased by the government from a manufacturer if authorized under the SAP. Under the proposed amendments, drugs that would be EUNDs would still be purchased from manufacturers by the government, so the expected cost to Canadians would remain the same.

Benefits

Canadians who receive CBRN medical countermeasures or get a vaccine against pandemic influenza would have more confidence in the safety and quality of the drugs they receive, knowing that risk-based regulatory reviews were required in both the pre- and post-market periods

Rationale

Health Canada seeks to amend the Regulations, thereby creating a new type of drug submission. In designing the proposed regulatory framework, the concerns raised by the OAG in a 2005 report would be taken into account, as well as those of various stakeholders within the broader community. The proposed Regulations would allow Health Canada to grant market authorization for drugs needed for emergency preparedness and to ensure that these drugs receive appropriate pre-market review and post-market follow-up.

Health Canada’s approach to EUNDs would be consistent with that of other international regulators, allowing Health Canada to take into account extraordinary conditions of use for these drugs and yet still make sound, evidence-based decisions.

The restriction of sales to government purchasers only would address a variety of concerns raised by stakeholders, ranging from preventing inappropriate off-label use to implementing a product recall. With public health officials (or senior medical staff, in the case of DND) as decision makers regarding EUND stockpiles, Canadians would have access to drugs at the appropriate times. The distribution of EUNDs by government officials might facilitate the collection of post-market data, especially in cases of wide-spread use of EUNDs (e.g. during an influenza pandemic).

The proposed amendments require that every EUND carry a statement on the label to inform health care professionals and patients that “Health Canada has authorized the sale of this Extraordinary Use New Drug for [naming purpose] based on limited clinical testing in humans.” Health Canada would work with manufacturers to ensure that information leaflets for patients are written in plain language.

Provisions have been added to require manufacturers to monitor product safety, collect data to establish the efficacy of the EUND in the post-market period and provide updated safety and efficacy information to Health Canada on an annual basis, or as requested by the regulator.

Health Canada would commit to providing up-to-date safety information to health care providers in a timely manner, especially in an emergency period during which EUNDs would be used.

Consultation

In October 2007, a letter to stakeholders was sent out to a wide range of Health Canada’s stakeholders. The letter solicited feedback on Health Canada’s proposal to amend the Regulations with respect to EUNDs. Feedback was received from 21 stakeholders, including pharmaceutical companies and industry associations; professional associations of physicians, nurses and pharmacists; members of academia; patient advocacy groups; and private citizens. Most of the comments were positive, suggesting that the Canadian public believes there is a need for special measures to authorize drugs for extraordinary use, but concerns were expressed about the risk of using these drugs, which will not have been studied to the same extent as other new drugs.

Please note that Health Canada carefully considered all stakeholder comments during the regulatory drafting process. A summary of stakeholder comments is provided below.

Scope of EUND Regulations

A number of stakeholders had concerns about the scope of the proposed Regulations, and some called for a clear definition of the term “extraordinary use.”

Although the term EUND is not defined explicitly, a list of inclusion criteria, which would serve as a definition of EUND, is included in C.08.002.01(1) of the proposed amendments. These are the conditions that would need to be met in order for a drug to be considered under the EUND submission process.

Other stakeholders indicated that the proposed amendments should be expanded to cover natural health products and diagnostic medical devices that might prove useful in public health emergencies such as a pandemic.

Natural health products and medical devices are covered by different regulations under the Food and Drugs Act, so those products fall outside the scope of the proposed amendments to the Food and Drug Regulations.

Harmonization of submission requirements with international regulators

Several industry stakeholders indicated that the requirements set by Health Canada should be harmonized with those in other jurisdictions, namely the United States and the European Union.

As indicated earlier in this document, the United States’ Animal Efficacy Rule and the European Union’s Market Authorization under Exceptional Circumstances regulation were taken into account as the submission requirements were developed. The proposed EUND Regulations would be aligned with these other two frameworks in terms of scientific and risk management approaches, but harmonization would not be possible due to differences in the enabling legislation and the structure of regulations in the three jurisdictions.

Labelling

Comments were received regarding special labelling requirements that should be in place for EUNDs. Several stakeholders asked that there be a special warning on the label and/or accompanying package insert, detailing the special conditions under which the EUND was authorized.

The proposed Regulations include EUND-specific labelling requirements in C.01.004(1)(c)(vi) and in C.04.019(b)(vi). Health Canada is currently developing a guidance document which would provide further information about labelling requirements for EUNDs.

Post-market surveillance, studies and reporting

Stakeholders from all sectors expressed concerns regarding the issuance of an authorization for the sale of a drug for which there was little or no clinical efficacy data. There were numerous questions concerning the conduct of post-market adverse drug reaction surveillance and ongoing clinical trials.

The proposed Regulations include a requirement to monitor and establish the safety and effectiveness of the new drug under the conditions of use recommended that includes procedures for gathering and analyzing data. Further information regarding the requirements for the collection of data and adverse drug reaction reporting in the post-market period would be provided in a guidance document.

Appropriate use of EUNDs

Many stakeholders asked questions about the decision-making process around the recommendation to use EUNDs in an emergency situation, and several stakeholders also expressed concerns about inappropriate off-label use of these drugs, which will not have been fully tested in humans.

The sale of EUNDs in Canada would be restricted to federal, provincial, territorial and municipal governments. The government organization(s) responsible for the health and safety of the people who are in need of EUND treatment would recommend the use of EUNDs, and health care professionals would be responsible for distributing and/or administering the drug. Government officials might also facilitate the collection of post-market data regarding the effectiveness of the EUND.

Ethical considerations

Stakeholders expressed concerns around effective, timely communication of the risks involved in using drugs which have not been fully tested in humans. Most conceded that an informed consent process, similar to that used in clinical trials, would not be possible or appropriate for EUNDs, but there was a call for a concerted effort to provide plain-language information to patients and to provide updated safety information as soon as practical.

The proposed Regulations would require that a statement be placed on the EUND label, indicating that “Health Canada has authorized the sale of this Extraordinary Use New Drug for [naming purpose] based on limited clinical testing in humans.” Further guidance would be provided regarding the requirements for information to health care professionals and plain-language information that would be made available to patients. The proposed post-market reporting requirements of adverse drug reactions and updated clinical results would allow Health Canada to issue warnings on an as-needed basis.

Pricing of EUNDs and patent and data protection

Some stakeholders wanted to know whether current government policies on pricing and patent and data protection would remain in place for EUNDs.

The Patented Medicines Price Review Board policies would not be affected by the proposed regulatory amendments, so current policies on pricing would continue to apply to all patented drugs, including EUNDs with valid patents. Proposed consequential amendments to the Patented Medicines (Notice of Compliance) Regulations would not mark a change in policy direction and would only serve in bringing EUNDs in the existing regulatory framework. The data protection provisions in C08.004.1 would also apply to EUNDs.

A 75-day consultation period will follow pre-publication in the Canada Gazette, Part I. Stakeholders, including the following, will be directly notified of the pre-publication: the pharmaceutical industry and associations; deans and registrars of Pharmacy, Medicine and Dentistry; provincial and territorial Ministries of Health; associations of municipal governments; academic institutions; research centres; hospitals; and professional associations of physicians and dentists.

The results of all consultations will be analyzed and all recommendations, including comments received during the pre-publication of the proposed Regulations in the Canada Gazette, Part I, will be taken into account in the development of this proposal.

Implementation, enforcement and service standards

These amendments do not alter existing compliance mechanisms under the provisions of the Act enforced by the Health Products and Food Branch Inspectorate. Inspections, compliance verification, and investigations of EUND facilities would be conducted using the same approach as for other types of drugs to ensure that the applicable good manufacturing practices are followed.

Under normal circumstances, the service standards for EUND-related submissions would be the same as those for other new drugs, as outlined in the Health Canada guidance documents, Management of Drug Submissions and Priority Review of Drug Submissions. Should there be an immediate need for the drug, as in the case of an influenza pandemic, human resources would be reallocated, and Health Canada would streamline the review process as much as possible.

Performance measurement and evaluation

Performance measurement and evaluation of the EUND submission and review framework would be part of the Health Products and Food Branch’s (HPFB) Human Drug Activities (HDA) strategic evaluation. Many indicators for measuring changes in outputs and outcomes of the proposed regulatory amendments would be drawn from HPFB’s existing Program Activity Architecture. The establishment of these proposed Regulations and the development of supporting guidance documents have been identified as the relevant outputs. The desired immediate outcomes would include the filing of EUND submissions by manufacturers and a regulatory mechanism that allows for the authorization for the sale of EUNDs such as CBRN medical countermeasures and pandemic influenza vaccines. Benchmarks for intermediate outcomes include a reduction of CBRN medical countermeasure requests through SAP, the compliance of EUND NOC holders to their post-market commitments and the availability of an authorized pandemic influenza vaccine for the Canadian market. Short-, medium- and long-term evaluation would be done through document and literature review, key interviews and collecting performance data, most of which is available from Health Canada or other government sources, to see if the targets have been met. Although performance measurement and evaluation is a continuous process in Health Canada, the EUND regulatory framework would undergo a complete evaluation around the fifth anniversary of the promulgation of these proposed amendments as part of Cycle 2 of the HDA evaluation.

Contacts

Barbara Wong
Regulatory Unit
Office of Policy and International Collaboration
Biologics and Genetic Therapies Directorate
Health Canada
Address Locator 0702A
Health Protection Building, 2nd Floor
200 Tunney’s Pasture Driveway
Tunney’s Pasture
Ottawa, Ontario
K1A 0K9
Fax: 613-952-5364
Email: barbara_wong@hc-sc.gc.ca

Colette Downie
Marketplace Framework Policy Branch
Industry Canada
C.D. Howe Building, Floor 10E, Room 1046A
235 Queen Street
Ottawa, Ontario
K1A 0H5
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Email: colette.downie@ic.gc.ca

PROPOSED REGULATORY TEXT

Notice is hereby given that the Governor in Council, pursuant to subsection 30(1) (see footnote a) of the Food and Drugs Act (see footnote b), proposes to make the annexed Regulations Amending the Food and Drug Regulations(1319 — New Drugs for Extraordinary Use).

Interested persons may make representations with respect to the proposed Regulations within 75 days after the date of publication of this notice. All such representations must cite the Canada Gazette, Part I, and the date of publication of this notice, and be addressed to Barbara Wong, Biologics and Genetic Therapies Directorate, Health Products and Food Branch, Department of Health, Health Protection Building, Room 2146, 200 Tunney’s Pasture Driveway, Address Locator 0702A, Tunney’s Pasture, Ottawa, Ontario K1A 0K9 (fax: 613-952-5364; e-mail: barbara_wong@hc-sc.gc.ca).

Ottawa, March 25, 2010

JURICA ČAPKUN
Assistant Clerk of the Privy Council

REGULATIONS AMENDING THE FOOD AND DRUG
REGULATIONS (1319 — NEW DRUGS FOR
EXTRAORDINARY USE)

AMENDMENTS

1. Paragraph C.01.004(1)(c) of the Food and Drug Regulations (see footnote 1) is amended by striking out “and” at the end of subparagraph (iv), by adding “and” at the end of subparagraph (v) and by adding the following after subparagraph (v):

(vi) in the case of a new drug for extraordinary use in respect of which a notice of compliance has been issued under section C.08.004.01, the following statement, displayed in capital letters and in a legible manner:

“HEALTH CANADA HAS AUTHORIZED THE SALE OF THIS EXTRAORDINARY USE NEW DRUG FOR [naming purpose] BASED ON LIMITED CLINICAL TESTING IN HUMANS.

SANTÉ CANADA A AUTORISÉ LA VENTE DE CETTE DROGUE NOUVELLE POUR USAGE EXCEPTIONNEL AUX FINS DE [indication de la fin] EN SE FONDANT SUR DES ESSAIS CLINIQUES RESTREINTS CHEZ L’ÊTRE HUMAIN.”.

2. Subsection C.01.014.1(3) of the Regulations is replaced by the following:

(3) In the case of a new drug, a new drug submission, an extraordinary use new drug submission, an abbreviated new drug submission or an abbreviated extraordinary use new drug submission filed under section C.08.002, C.08.002.01 or C.08.002.1 shall be regarded as an application for a drug identification number.

3. The portion of subsection C.01.014.2(1) of the Regulations before paragraph (a) is replaced by the following:

C.01.014.2 (1) Subject to subsection (2), if a manufacturer or importer has provided all the information described in subsection C.01.014.1(2) or section C.08.002, C.08.002.01 or C.08.002.1, as the case may be, in respect of a drug, the Director shall issue to the manufacturer or importer a document that

4. Paragraph C.01.015(2)(a) of the Regulations is replaced by the following:

(a) a notice of compliance in respect of the drug in the form of a tablet has been issued under section C.08.004 or C.08.004.01;

5. Paragraph C.01.062(5)(a) of the Regulations is replaced by the following:

(a) a drug for which a notice of compliance has been issued under section C.08.004 or C.08.004.01;

6. Paragraph C.04.019(b) of the Regulations is amended by striking out “and” at the end of subparagraph (iv), by adding “and” at the end of subparagraph (v) and by adding the following after subparagraph (v):

(vi) in the case of a new drug for extraordinary use in respect of which a notice of compliance has been issued under section C.08.004.01, the following statement, displayed in capital letters and in a legible manner:

“HEALTH CANADA HAS AUTHORIZED THE SALE OF THIS EXTRAORDINARY USE NEW DRUG FOR [naming purpose] BASED ON LIMITED CLINICAL TESTING IN HUMANS.

SANTÉ CANADA A AUTORISÉ LA VENTE DE CETTE DROGUE NOUVELLE POUR USAGE EXCEPTIONNEL AUX FINS DE [indication de la fin] EN SE FONDANT SUR DES ESSAIS CLINIQUES RESTREINTS CHEZ L’ÊTRE HUMAIN.”.

7. The portion of section C.05.003 of the Regulations before paragraph (a) is replaced by the following:

C.05.003. Despite sections C.01.014, C.08.002, C.08.002.02 and C.08.003, no person shall sell or import a drug for the purposes of a clinical trial unless

8. Paragraph C.05.005(g) of the Regulations is replaced by the following:

(g) if the drug has not been assigned a drug identification number under subsection C.01.014.2(1) or, in the case of a new drug, a notice of compliance has not been issued under section C.08.004 or C.08.004.01, the chemistry and manufacturing information in respect of the drug, including its site of manufacture; and

9. Paragraphs (a) and (b) of the definition “Canadian reference product” in section C.08.001.1 of the Regulations are replaced by the following:

(a) a drug in respect of which a notice of compliance is issued under section C.08.004 or C.08.004.01 and which is marketed in Canada by the innovator of the drug,

(b) a drug, acceptable to the Minister, that can be used for the purpose of demonstrating bioequivalence on the basis of pharmaceutical and, where applicable, bioavailability characteristics, where a drug in respect of which a notice of compliance has been issued under section C.08.004 or C.08.004.01 cannot be used for that purpose because it is no longer marketed in Canada, or

10. Paragraphs C.08.002(1)(a) and (b) of the Regulations are replaced by the following:

(a) the manufacturer of the new drug has filed with the Minister a new drug submission, an extraordinary use new drug submission, an abbreviated new drug submission or an abbreviated extraordinary use new drug submission relating to the new drug that is satisfactory to the Minister;

(b) the Minister has issued, under section C.08.004 or C.08.004.01, a notice of compliance to the manufacturer of the new drug in respect of the submission;

11. The Regulations are amended by adding the following after section C.08.002:

C.08.002.01 (1) A manufacturer of a new drug may file an extraordinary use new drug submission for the new drug if

(a) the new drug is intended for emergency use in situations where immediate action is required to treat, mitigate or prevent a life-threatening or other serious disease, disorder or abnormal physical state, or its symptoms, in human beings that results from exposure to a chemical, biological, radiological or nuclear substance; and

(b) the requirements set out in paragraphs C.08.002(2)(g) and (h) cannot be met because

(i) exposing human volunteers to the substance referred to in paragraph (a) would be potentially lethal or permanently disabling, and

(ii) the circumstances in which exposure to the substance occurs are sporadic and infrequent.

(2) Subject to subsections (3) and (5), an extraordinary use new drug submission shall contain

(a) an attestation, signed and dated by the senior executive officer in Canada of the manufacturer filing the submission and by the manufacturer’s senior medical or scientific officer, certifying that the conditions referred to in paragraphs (1)(a) and (b) are met, together with sufficient supporting information to enable the Minister to determine that those conditions are met; and

(b) sufficient information and material to enable the Minister to assess the safety and effectiveness of the new drug, including the following:

(i) the information and material described in paragraphs C.08.002(2)(a) to (f) and (i) to (m),

(ii) information respecting the pathophysiological mechanism for the toxicity of the chemical, biological, radiological or nuclear substance and describing the new drug’s ability to treat, mitigate or prevent that mechanism,

(iii) detailed reports of in vitro studies respecting the toxicity and activity of the new drug in relation to the recommended purpose,

(iv) detailed reports of studies establishing the safety of the new drug, and providing substantial evidence of its effect when used for the purpose and under the conditions of use recommended, in an animal species that is expected to react with a response that is predictive for humans,

(v) information confirming that the end point of animal studies is clearly related to the desired benefit in humans,

(vi) information demonstrating that there is a sufficient understanding of the pharmacokinetics and pharmacodynamics of the new drug in animals and in humans to enable inferences to be drawn in respect of humans so as to allow for the selection of an effective dose in humans,

(vii) information respecting the safety of the new drug in humans, including detailed reports of clinical trials, if any, establishing the safety of the new drug,

(viii) information, if any, respecting the effectiveness of the new drug in humans for the purpose or under the conditions of use recommended,

(ix) a plan for monitoring and establishing the safety and effectiveness of the new drug under the conditions of use recommended that includes procedures for gathering and analyzing data, and

(x) any available assessment reports regarding the new drug prepared by regulatory authorities in countries other than Canada.

(3) Reports referred to in subparagraph (2)(b)(iii) or information referred to in subparagraph (2)(b)(vi) may be omitted if the extraordinary use new drug submission includes a detailed scientific explanation as to why the reports are or the information is not available.

(4) Any information or material that is necessary to enable the Minister to assess the safety and effectiveness of the new drug shall, at the request of the Minister, be added to the extraordinary use new drug submission, including

(a) the names and addresses of the manufacturers of each of the ingredients of the new drug and the names and addresses of the manufacturers of the new drug in the dosage form in which it is proposed to be sold;

(b) samples of the ingredients of the new drug;

(c) samples of the new drug in the dosage form in which it is proposed to be sold; and

(d) any information omitted by virtue of subsection (3).

(5) If an extraordinary use new drug submission is in respect of a new purpose for a new drug for which a notice of compliance has been issued under section C.08.004, the information and material referred to in subparagraph (2)(b)(i) may be omitted unless any of it is different from that which was originally submitted.

C.08.002.02 Despite sections C.08.002 and C.08.003, no manufacturer or importer shall sell a new drug for extraordinary use in respect of which a notice of compliance has been issued under section C.08.004.01 except to

(a) the Government of Canada or the government of a province for the use of a department or agency of that government, on receipt of a written order signed by the minister responsible for the department or by the person in charge of the agency, or by their duly authorized representative; or

(b) a municipal government, or an institution of such a government, on receipt of a written order signed by a senior official of the government or institution or by his or her duly authorized representative.

12. (1) The portion of subsection C.08.002.1(1) of the Regulations before paragraph (a) is replaced by the following:

C.08.002.1 (1) A manufacturer of a new drug may file an abbreviated new drug submission or an abbreviated extraordinary use new drug submission for the new drug where, in comparison with a Canadian reference product,

(2) The portion of subsection C.08.002.1(2) of the Regulations before paragraph (b) is replaced by the following:

(2) An abbreviated new drug submission or an abbreviated extraordinary use new drug submission shall contain sufficient information and material to enable the Minister to assess the safety and effectiveness of the new drug, including the following:

(a) the information and material described in

(i) paragraphs C.08.002(2)(a) to (f) and (j) to (l), in the case of an abbreviated new drug submission, and

(ii) paragraphs C.08.002(2)(a) to (f) and (j) to (l) and subparagraphs C.08.002.01(2)(b)(ix) and (x), in the case of an abbreviated extraordinary use new drug submission;

(3) The portion of subsection C.08.002.1(3) of the Regulations before paragraph (a) is replaced by the following:

(3) The manufacturer of a new drug shall, at the request of the Minister, provide the Minister, where for the purposes of an abbreviated new drug submission or an abbreviated extraordinary use new drug submission the Minister considers it necessary to assess the safety and effectiveness of the new drug, with the following information and material:

(4) Section C.08.002.1 of the Regulations is amended by adding the following after subsection (3):

(4) For the purposes of this section, in the case of an abbreviated new drug submission, a new drug for extraordinary use in respect of which a notice of compliance has been issued under section C.08.004.01 is not a Canadian reference product.

13. (1) The portion of subsection C.08.003(1) of the Regulations before paragraph (b) is replaced by the following:

C.08.003. (1) Despite section C.08.002, no person shall sell a new drug in respect of which a notice of compliance has been issued to the manufacturer of that new drug and has not been suspended under section C.08.006, if any of the matters specified in subsection (2) are significantly different from the information or material contained in the new drug submission, extraordinary use new drug submission, abbreviated new drug submission or abbreviated extraordinary use new drug submission, unless

(a) the manufacturer of the new drug has filed with the Minister a supplement to that submission;

(2) Subsection C.08.003(3) of the Regulations is replaced by the following:

(3) A supplement to a submission referred to in subsection (1), with respect to the matters that are significantly different from those contained in the submission, shall contain sufficient information and material to enable the Minister to assess the safety and effectiveness of the new drug in relation to those matters.

(4) If a supplement to an extraordinary use new drug submission or an abbreviated extraordinary use new drug submission concerns a matter specified in subparagraph (2)(h)(iii), the supplement shall contain the attestation and supporting information referred to in paragraph C.08.002.01(2)(a).

14. Section C.08.003.1 of the Regulations is replaced by the following:

C.08.003.1 In examining 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 Minister may examine any information or material filed with the Minister by any person pursuant to Division 5 or section C.08.002, C.08.002.01, C.08.002.1, C.08.003, C.08.005 or C.08.005.1 to establish the safety and effectiveness of the new drug for which the submission or supplement has been filed.

15. The Regulations are amended by adding the following after section C.08.004:

C.08.004.01 (1) Subject to section C.08.004.1, the Minister shall, after completing an examination of an extraordinary use new drug submission or an abbreviated extraordinary use new drug submission or a supplement to either submission,

(a) if that submission or supplement complies with section C.08.002.01, C.08.002.1 or C.08.003, as the case may be, and section C.08.005.1, issue a notice of compliance; or

(b) if that submission or supplement does not comply with section C.08.002.01, C.08.002.1 or C.08.003, as the case may be, or section C.08.005.1, notify the manufacturer that the submission or supplement does not so comply.

(2) Where an extraordinary use new drug submission or an abbreviated extraordinary use new drug submission or a supplement to either submission does not comply with section C.08.002.01, C.08.002.1 or C.08.003, as the case may be, or section C.08.005.1, the manufacturer who filed the submission or supplement may amend the submission or supplement by filing additional information or material.

(3) Subject to section C.08.004.1, the Minister shall, after completing an examination of any additional information or material filed in respect of an extraordinary use new drug submission or an abbreviated extraordinary use new drug submission or a supplement to either submission,

(a) if that submission or supplement complies with section C.08.002.01, C.08.002.1 or C.08.003, as the case may be, and section C.08.005.1, issue a notice of compliance; or

(b) if that submission or supplement does not comply with section C.08.002.01, C.08.002.1 or C.08.003, as the case may be, or section C.08.005.1, notify the manufacturer that the submission or supplement does not so comply.

(4) A notice of compliance issued in respect of a new drug for extraordinary use on the basis of information and material contained in a submission filed pursuant to section C.08.002.1 shall state the name of the Canadian reference product referred to in the submission and shall constitute a declaration of equivalence for that new drug.

16. Subsection C.08.004.1(1) of the Regulations is amended by adding the following in alphabetical order:

“abbreviated new drug submission” includes an abbreviated extraordinary use new drug submission. (présentation abrégée de drogue nouvelle)

“new drug submission” includes an extraordinary use new drug submission. (présentation de drogue nouvelle)

17. (1) The portion of subsection C.08.005.1(1) of the Regulations before paragraph (a) is replaced by the following:

C.08.005.1 (1) Every manufacturer who files a new drug submission, an extraordinary use new drug submission, an abbreviated new drug submission, an abbreviated extraordinary use new drug submission, a supplement to any of those submissions or a submission for the clinical testing of a new drug for veterinary use shall, in addition to any information and material that is required under section C.08.002, C.08.002.01, C.08.002.1, C.08.003 or C.08.005, include in the submission or supplement

(2) Subsection C.08.005.1(6) of the Regulations is replaced by the following:

(6) Every manufacturer who has filed a new drug submission, an extraordinary use new drug submission, an abbreviated new drug submission, an abbreviated extraordinary use new drug submission, a supplement to any of those submissions or a submission for the clinical testing of a new drug for veterinary use and who has any relating clinical case reports or raw data that were not included in the submission or supplement shall keep those reports or data and shall, within 30 days after receiving a written request from the Minister, submit them to the Minister.

18. (1) Subsection C.08.006(1) of the Regulations is replaced by the following:

C.08.006. (1) For the purposes of this section, evidence or new information obtained by the Minister includes any information or material filed by any person pursuant to Division 5 or section C.08.002, C.08.002.01, C.08.002.1, C.08.003, C.08.005 or C.08.005.1.

(2) The portion of subsection C.08.006(2) of the Regulations before paragraph (a) is replaced by the following:

(2) The Minister may, by notice to a manufacturer, suspend, for a definite or indefinite period, a notice of compliance issued to that manufacturer 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 if the Minister considers

(3) Subsection C.08.006(2) of the Regulations is amended by striking out “or” at the end of paragraph (e), by adding “or” at the end of paragraph (f) and by adding the following after paragraph (f):

(g) that, in the case of a new drug for extraordinary use, the manufacturer has not adhered to the plan referred to in subparagraph C.08.002.01(2)(b)(ix).

19. (1) The portion of section C.08.007 of the Regulations before paragraph ( a ) is replaced by the following:

C.08.007. (1) 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

(2) Section C.08.007 of the Regulations is amended by adding the following after subsection (1):

(2) A manufacturer or importer who sells a new drug for extraordinary use in accordance with section C.08.002.02 shall retain the written order for at least 15 years from the day on which the order was filled.

20. The Regulations are amended by adding the following after section C.08.008:

C.08.008.1 Where a manufacturer has received a notice of compliance issued in respect of an extraordinary use new drug submission, an abbreviated extraordinary use new drug submission or a supplement to either of those submissions, the manufacturer

(a) shall adhere to the plan referred to in subparagraph C.08.002.01(2)(b)(ix); and

(b) shall, before the first day of October in each year and whenever requested to do so by the Minister for the purposes of assessing the safety and effectiveness of the drug to which the notice of compliance relates, provide a report on the use of the drug, including a critical analysis of any available updated safety and efficacy information.

21. Paragraph C.08.009(1)(b) of the Regulations is replaced by the following:

(b) to suspend a notice of compliance issued under section C.08.004 or C.08.004.01,

COMING INTO FORCE

22. These Regulations come into force on the day on which they are registered.

[14-1-o]

Footnote a
S.C. 2005, c. 42, s. 2

Footnote b
R.S., c. F-27

Footnote 1
C.R.C., c. 870