Vol. 145, No. 8 — April 13, 2011

Registration

SOR/2011-88 March 25, 2011

FOOD AND DRUGS ACT

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

P.C. 2011-452 March 25, 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(1319 — New Drugs for Extraordinary Use).

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):

1. (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:

1. (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:

1. (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):

1. (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:

1. (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:

1. (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,
   
2. (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:

1. (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;
   
2. (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

1. (a) the new drug is intended for
   
   1. (i) emergency use in situations where persons have been exposed to a chemical, biological, radiological or nuclear substance and action is required to treat, mitigate or prevent a life-threatening or other serious disease, disorder or abnormal physical state, or its symptoms, that results, or is likely to result, from that exposure, or
      
   2. (ii) preventative use in persons who are at risk of exposure to a chemical, biological, radiological or nuclear substance that is potentially lethal or permanently disabling; and
      
   (b) the requirements set out in paragraphs C.08.002(2)(g) and (h) cannot be met because
   
   1. (i) exposing human volunteers to the substance referred to in paragraph (a) would be potentially lethal or permanently disabling, and
      
   2. (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

1. (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
   
2. (b) sufficient information and material to enable the Minister to assess the safety and effectiveness of the new drug, including the following:
   
   1. (i) the information and material described in paragraphs C.08.002(2)(a) to (f) and (i) to (m),
      
   2. (ii) information respecting the pathophysiological mechanism for the toxicity of the chemical, biological, radiological or nuclear substance and describing the new drug(ii) information respecting the pathophysiological mechanism for the toxicity of the chemical, biological, radiological or nuclear substance and describing the new drug’
      
   3. (iii) detailed reports of in vitro studies respecting the toxicity and activity of the new drug in relation to the recommended purpose,
      
   4. (iv) detailed reports of studies, in an animal species that is expected to react with a response that is predictive for humans, 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,
      
   5. (v) information confirming that the end point of animal studies is clearly related to the desired benefit in humans,
      
   6. (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,
      
   7. (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,
      
   8. (viii) information, if any, respecting the effectiveness of the new drug in humans for the purpose or under the conditions of use recommended,
      
   9. (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
      
   10. (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

1. (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;
   
2. (b) samples of the ingredients of the new drug;
   
3. (c) samples of the new drug in the dosage form in which it is proposed to be sold; and
   
4. (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

1. (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
   
2. (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:

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

1. (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,

1. (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
   
2. (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,

1. (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
   
2. (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):

1. (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

1. (a) shall adhere to the plan referred to in subparagraph C.08.002.01(2)(b)(ix); and
   
2. (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 information respecting the drug’s safety and effectiveness.

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

1. (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.

REGULATORY IMPACT ANALYSIS STATEMENT

(This statement is not part of the Regulations.)

Executive summary

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 regulatory framework for new drug submissions 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 for new drugs cannot be met.

Previously, access to quantities of military medical countermeasures and other emergency preparedness drugs that did not have an NOC could only be requested by public health officials or senior medical staff from the Department of National Defence (DND) through the Special Access Programme (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 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 EUND regulatory amendments work towards meeting this commitment by providing a framework under which the safety, efficacy and quality of pandemic vaccines could be assessed; the vaccines could subsequently be authorized for sale.

During the recent H1N1 influenza pandemic, the Interim Order Respecting the Sale of the Vaccine for the Novel Influenza A H1N1 Virus was signed by the Minister of Health, allowing Health Canada to authorize the sale the pandemic influenza vaccine using a standard of evidence which differed from that which is usually required for new drugs. This interim order, which was in effect from October 2009 to October 2010, was required because permanent EUND Regulations, which had undergone an initial round of stakeholder consultations in 2007, were not in place when the pandemic occurred. The pre- and post-market requirements outlined in the interim order were consistent with those contained in these EUND Regulations, and the lessons learned from the regulatory measures taken during the 2009–2010 H1N1 pandemic have been taken into account in finalizing these Regulations.

Objectives

The purpose of these regulatory amendments is to create a regulatory mechanism by which Health Canada can 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 will 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 will be followed in the post-market period for safety and efficacy. In bringing about the regulatory changes, Health Canada is meeting its commitment to the OAG to have a route of regulatory authorization for the sale of military medical countermeasures.

Description

The regulatory amendments 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 have been 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 have been made.

Overview of the new regulatory framework

The Regulations set out to define the term Extraordinary Use New Drug (EUND) by detailing the criteria which a new drug must meet before the manufacturer can 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 apply to EUNDs as well. Because of the nature and intended purpose of these drugs, manufacturers are only 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 must meet the following inclusion criteria:

1. (a) The drug must be intended for
   
   1. (i) emergency use in situations where persons have been exposed to a chemical, biological, radiological or nuclear substance and action is required to treat, mitigate or prevent a life threatening or other serious disease, disorder or abnormal physical state, or its symptoms, that results, or is likely to result, from that exposure, or
      
   2. (ii) preventative use in persons who are at risk of exposure to a chemical, biological, radiological or nuclear substance that is potentially lethal or permanently disabling.
      
   (b) 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):
   
   1. (i) exposing human volunteers to the substance referred to in paragraph (a) would be potentially lethal or permanently disabling, and
      
   2. (ii) the circumstances in which exposure to the substance occurs are sporadic and infrequent.

Submission requirements

If a drug meets the inclusion criteria, then the manufacturer may file an EUND submission with Health Canada. The submission must 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 will provide further information on submission requirements in a guidance document, the first draft of which will be released for consultation in late 2011.

Under these amendments, an abbreviated EUND submission can be filed for a subsequent-entry (generic) product if the inclusion criteria, set out in C.08.002.01(1), are met. The provisions regarding data protection in C.08.004.1 will apply to EUNDs, as well as the PM(NOC) Regulations. The abbreviated EUND submission must contain the same 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 is required to submit a post-market plan with the EUND submission, 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 will be required to 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 apply to EUNDs as well.

Authorization and restriction of sales

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

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

Minor changes have been made to the definitions under the PM(NOC) Regulations in order to ensure that those Regulations apply to EUND submissions. The amendments enable an innovative manufacturer, referred to as a first person, to list patents related to EUND submissions in accordance with the provisions currently outlined in the PM(NOC) Regulations. In addition, the PM(NOC) Regulations are 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 have been made 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 allow application of the data protection provisions to this new type of drug submission.

Regulatory and non-regulatory options considered

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

1. Make no changes

Previously, EUNDs could not be authorized for sale within the NDS framework. There were three regulatory options available to allow access to these unauthorized extraordinary use drugs.

1. (a) EUNDs could be obtained through the SAP, which provided 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).
   
2. (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.
   
3. (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.

In 2005, the OAG 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 or are unsuitable or unavailable.

The use of interim orders during an emergency situation is a reactionary approach to regulation since the enabling 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 license, 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, continuing with the status quo was 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 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 chose to create a new type of submission for EUNDs through amendments to the Regulations. The EUND submission requirements differ slightly from those for new drugs, but the structure of the submission and the operational processes within Health Canada remain the same. Special consideration will be given to preclinical and clinical data requirements, labelling and post-market data collection and reporting for EUNDs. This approach allows 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 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 preclude true harmonization of Canadian regulations with international regulations.

Benefits and costs

Baseline

The baseline for comparison of costs and benefits is the situation whereby EUNDs that were 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.

Costs and benefits	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 3 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 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 analyze and submit to regulator — actual cost will depend on type of emergency situation and level of use of EUND	— no change in cost to Canadian public
Benefits	— will meet the department’s commitment to Canadians to provide an appropriate regulatory pathway for EUND-type drugs	— authorization of EUNDs for sale will allow manufacturer to market directly to government buyers — formalized post-market data collection could lead to broader market authorization through regular submission pathway	— will have more confidence in the safety and quality of the EUNDs they purchase, knowing that risk-based regulatory reviews are required in both the pre- and post-market periods	— will have more confidence in the safety and quality of the EUNDs they receive, knowing that risk-based regulatory reviews are 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 low, comprising a very small percentage of stakeholders’ overall workload, and because any additional costs would generally constitute normal business activities associated with drug development and approval.

Canadians will benefit from having access to extraordinary use drugs that have undergone a pre-market review. The amendments will 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 will 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 will 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.

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 will 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, will cost about $20,000 in salary dollars every five-year cycle.

Benefits

The regulatory amendment will 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 is difficult to estimate such costs without knowing the details of the proposed regulatory requirements. The costs will also vary, depending on the details of the individual EUND submission.

A summary of fees that would apply to EUNDs is provided in the table below:

Type of User Fee	Amount of Fee ($)	Frequency of Payment
Establishment Licensing	Ranges from 0 to 25,625, depending on type of activities undertaken and which fees are already being paid for that site	To be paid on an annual basis
Drug Evaluation Fee	52,900	One-time fee, per submission
Authority to Sell Fee	1,000	To be paid on an annual basis

Benefits

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

Manufacturers will 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 Regulations give manufacturers 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 are going to be best situated to do the actual data collection. Thus, federal, provincial, territorial and municipal health units would take on the responsibility 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 will have more confidence in the safety and quality of the EUNDs they purchase, knowing that risk-based regulatory reviews are required in both the pre- and post-market periods.

Recipients of EUNDs

Costs

Previously, EUNDs could be purchased by the government from a manufacturer if authorized under the SAP. Under these new regulatory amendments, EUNDs will still be purchased from manufacturers by the government, so the cost to Canadians is expected to remain the same.

Benefits

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

Rationale

Health Canada has amended 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 have been taken into account, as well as those of various stakeholders within the broader community. The EUND Regulations will 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 is consistent with that of other international regulators and will allow 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 will 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 will have access to drugs at the appropriate times. The distribution of EUNDs by government officials may facilitate the collection of post-market data, especially in cases of wide-spread use of EUNDs (e.g. during an influenza pandemic).

The Regulations 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 will 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 commits to providing up-to-date safety information to health care providers in a timely manner, especially in an emergency period during which EUNDs are used.

Consultation

Consultation prior to the pre-publication of these Regulations in the Canada Gazette, Part I, on April 3, 2010

In October 2007, a letter 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.

During this round of consultations, 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. Comments regarding risk communication, on-label use and post-market surveillance led to the addition of a number of risk-mitigating provisions, the most notable being the proposal to limit the sales of EUNDs to government purchasers. Other stakeholder comments, including those on broadening the scope of the amendment, harmonization with other regulators, labelling of EUNDs and patent and data protection issues, were summarized and addressed in the Regulatory Impact Analysis Summary that accompanied the proposed Regulations in the Canada Gazette, Part I.

Consultation following pre-publication of the Regulations in the Canada Gazette, Part I

The proposed amendments respecting EUNDs and the consequential amendments to the PM(NOC) Regulations were pre-published in the Canada Gazette, Part I, on April 3, 2010, followed by a 75-day comment period. The following stakeholders were notified, by email, of the proposed regulatory amendments and invited to submit written comments regarding the proposal: the pharmaceutical industry and associations; deans and registrars of pharmacy, medicine and dentistry; provincial and territorial ministries of health; association of municipal governments; academic institutions; research centres; hospitals; and professional associations of physicians and dentists.

Written submissions were received from six stakeholders, all from the pharmaceutical industry. More than 75% of the comments received were outside the scope of this regulatory amendment. These questions will be answered in a guidance document, which is currently being developed. Both internal and external stakeholders will have an opportunity to provide comment on a draft version of the guidance, as per current Health Canada practice, prior to the release of the final document.

No comments were received with regard to the amendments to PM(NOC) Regulations.

Inclusion criteria for EUNDs

One stakeholder raised a concern that the term “where immediate action is required” inclusion criteria for EUNDs in the proposed paragraph C.08.002.01(1)(a) would exclude prophylactic vaccines, such as those for smallpox or pandemic influenza. As a result of this comment, changes have been made to the wording of this section of the Regulations in order to clarify that prophylactic vaccines are to be included as EUNDs.

Submission requirements

Five of the six stakeholders asked specific questions regarding requirements of EUND submissions (e.g. criteria for choosing animal models and appropriate endpoints). Comments consistently advocated for harmonization with requirements of the regulators in the United States and Europe. These and other submission-related comments are outside the scope of these Regulations but will be considered as Health Canada prepares its guidance document to accompany the EUND Regulations.

Other comments

One stakeholder questioned whether it was appropriate to have an abbreviated submission process for EUNDs. A decision was made to have the same rules in place for all new drugs, including EUNDs. If there are specific safety concerns regarding a subsequent entry EUND, these concerns will be considered on a case-by-case basis during the review period, as is the case for other new drugs.

Three stakeholders commented regarding the length of the data protection period for EUNDs. One stakeholder commented that the period was too long, while two others indicated a preference for a longer protection period for EUNDs. The latter indicated that the data protection period should cover the entire period while the drug is considered an EUND, and the data protection period should start from the time the drug receives a “full” NOC for a new drug submission. Health Canada has determined that EUNDs, some of which may never accumulate sufficient post-market data to support a regular new drug submission, should be granted the same data protection period as other new drugs, starting from the time that the EUND NOC is issued.

Two stakeholders commented that sales of EUNDs to non-government buyers should be considered. It is important to note the origin of the restriction on sales — concerns about off-label use of EUNDs, raised by health care professionals, academics, private citizens and stakeholders from the pharmaceutical industry, led to the inclusion of this restriction in the regulations. Health Canada maintains that the limiting sales to government buyers will help facilitate safe and effective use of EUNDs during public health or military emergencies.

Implementation, enforcement and service standards

The new Regulations 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 will 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 will 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 will be part of the Health Products and Food Branch’s (HPFB) Human Drug Activities (HDA) strategic evaluation. Many indicators for measuring changes in out puts and outcomes of these regulatory amendments have been drawn from HPFB’s existing Program Activity Architecture. The establishment of these Regulations and the development of supporting guidance documents have been identified as the relevant outputs. The desired immediate outcomes 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 will 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 will undergo a complete evaluation around the fifth anniversary of the promulgation of these 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
Fax: 613-948-6393
Email: colette.downie@ic.gc.ca

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

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

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