Canada RNA Biochemical Inc. v. Canada (Health)

Canada RNA Biochemical Inc. v. Canada (Health)
Court (s) Database
Federal Court Decisions
Date
2020-06-04
Neutral citation
2020 FC 668
File numbers
T-1304-16
Decision Content
Date: 20200604
Docket: T-1304-16
Citation: 2020 FC 668
Ottawa, Ontario, June 4, 2020
PRESENT: Mr. Justice McHaffie
BETWEEN:
CANADA RNA BIOCHEMICAL INC.
Applicant
and
CANADA (MINISTER OF HEALTH), AND ATTORNEY GENERAL OF CANADA
Respondents
JUDGMENT AND REASONS
I. Overview
[1] Lumbrokinase is an enzyme complex derived from earthworms. It has “fibrinolytic” properties, meaning that it enhances the breakdown of blood clots. Such products are often termed “blood thinners,” although they do not actually thin the blood. Canada RNA Biochemical Inc (C-RNA) sought a natural health product (NHP) licence for its oral lumbrokinase capsules, branded Boluoke. C-RNA emphasized Boluoke’s fibrinolytic properties and sought to label it for its ability to “reduce blood viscosity” and “improve circulation.”
[2] As evidence of the safety and efficacy of Boluoke, C-RNA filed information on the longstanding use of earthworms in Traditional Chinese Medicine, research and clinical studies, and the approval and safety record of Boluoke in other countries. The Natural and Non-Prescription Health Product Directorate (NNHPD) of Health Canada was concerned that the fibrinolytic properties of lumbrokinase entailed a potential risk of internal bleeding. This was of particular concern in the non-prescription context of NHPs. Health Canada found that the information and evidence filed by C-RNA did not satisfy these concerns, since it did not adequately demonstrate safety in healthy populations. Health Canada therefore refused both C‑RNA’s initial application and a subsequent application, and upheld that refusal on a reassessment.
[3] C-RNA argues that the refusal of its application was unreasonable. It argues that Health Canada misinterpreted the Natural Health Products Regulations, SOR/2003-196 [NHP Regulations], by reading in terms such as “healthy population” and “risk/benefit” that are not found in the regulations. C‑RNA also argues that Health Canada was unreasonable in categorizing Boluoke as a “high risk” product, in doing so based on evidence of intravenous drugs when Boluoke is an oral capsule, and in adopting an overly stringent approach to the evidence that effectively treated its product as a non-NHP drug rather than an NHP. It further claims that Health Canada ignored relevant evidence and that its refusal to accept that Boluoke was safe was unreasonable.
[4] I conclude that Health Canada’s refusal of C-RNA’s application was reasonable. Health Canada’s approach to the NHP Regulations is consistent with the text, context and purpose of the regulations, and it thoroughly and reasonably considered the evidence filed by C-RNA. It reached a consistent and reasoned view on the adequacy of the safety evidence, and it is not this Court’s function to stand as a scientific review panel to second-guess that decision.
[5] C-RNA also argues that the refusal was procedurally unfair. It relies on numerous aspects of Health Canada’s review, including non-disclosure of information and documents, the use of new guidelines that were not in place at the time of the original application, and irregularities in the reconsideration process.
[6] I also conclude that the process that led to the refusal was fair. C-RNA had notice of Health Canada’s concerns and ample opportunity to address them. C-RNA was not improperly persuaded to re-submit its application, and fairness did not require that Health Canada disclose the information and internal documents C-RNA says it should have been given. There is also no indication that C-RNA was prejudiced by the application of certain guidelines instead of others, and in any case, the standard ultimately applicable was, throughout, the one set out in the NHP Regulations. The reconsideration process, while not “textbook” as the Minister concedes, gave C-RNA the required opportunity to be heard before reconsideration, and the final decision was made after a fair reassessment of the application by an appropriate officer. What is required is fairness, not perfection, and C-RNA was given a fair process.
[7] The application for judicial review is therefore dismissed.
II. Issues
[8] C-RNA structured its submissions to address three aspects of Health Canada’s refusal to grant an NHP licence: Health Canada’s interpretation of the NHP Regulations; the fairness of the process; and the reasonableness of Health Canada’s refusal. The first and third of these go to the substantive merits of the decision, while the second is a matter of procedural fairness. I will therefore address the issues as follows:
Was Health Canada’s decision to refuse a licence for C-RNA’s Boluoke lumbrokinase product unreasonable, and in particular:
(1) did Health Canada err in its interpretation of and approach to the NHP Regulations; and/or
(2) was the refusal unreasonable in light of the information filed in support of the application?
Was the process leading to Health Canada’s decision to refuse a licence for C‑RNA’s Boluoke lumbrokinase product unfair?
[9] To assess these issues, it is necessary to consider in some depth both the regulatory framework applicable to NHPs and the history of C-RNA’s applications for a product licence for Boluoke. I will consider these matters before turning to C-RNA’s particular arguments.
III. The Natural Health Products Regulatory Framework
A. The Regulatory Context
[10] Promulgated under the Food and Drugs Act, RSC 1985, c F-27 [FDA], the NHP Regulations created a new scheme for the approval and regulation of NHPs. As the Federal Court of Appeal has said, this scheme is “legally and operationally discrete” from the regime for the regulation of other drugs under the Food and Drug Regulations, CRC, c 870: Canada (Health) v The Winning Combination Inc, 2017 FCA 101 at para 8. I use the term “other drugs” to mean drugs that are not NHPs, since NHPs fall within the FDA definition of “drug”: FDA, ss 2 (“drug”), 37(1.1)(b); Mancuso v Canada (National Health and Welfare), 2015 FCA 227 at para 4.
[11] The intention to treat NHPs distinctly from other drugs is seen from the regulations themselves. With a few exceptions, the provisions of the Food and Drug Regulations do not apply to NHPs: NHP Regulations, ss 3, 60, 96–103.1; Winning Combination (FCA) at para 8.
[12] The Regulatory Impact Analysis Statement (RIAS) that accompanied the NHP Regulations, while not part of the regulations, is a useful tool to understand how they are intended to work: RIAS, SOR/2003-196, Canada Gazette Part II, Vol 137, No 13 at p 1571; Mounted Police Association of Ontario v Canada (Attorney General), 2015 SCC 1 at para 113. The RIAS describes the goals that the regulations intended to accomplish:
These Regulations are intended to provide Canadians with ready access to natural health products that are safe, effective, and of high quality, while respecting freedom of choice and philosophical and cultural diversity.
[13] The parties stressed different aspects of this balanced statement of purpose. The Minister highlighted the fundamental importance of safety, while C-RNA submitted that Health Canada had lost sight of its mandate of “respecting freedom of choice and philosophical and cultural diversity.” Both of the principles are important to the NHP context. That said, the NHP Regulations and the regulatory context in which they were promulgated emphasize the importance of safety.
[14] The NHP Regulations arose in the wake of recommendations contained in a 1998 report from the House of Commons Standing Committee on Health: RIAS at p 1572; House of Commons, Standing Committee on Health, Natural Health Products: A New Vision (November 1998) (Chair: Joseph Volpe). C‑RNA relies on this Report, noting that it sets out as a “guiding principle” that “NHPs are different in nature from and must not be treated strictly as either food or pharmaceutical products.” I agree that this principle is reflected in the NHP Regulations and must be recognized in their interpretation: see, e.g., Winning Combination (FCA) at para 14.
[15] However, another relevant guiding principle in the Report is that “[s]afety of NHPs is of primary concern.” Indeed, the Report underscores that the common objective of the Standing Committee members was that “the health of Canadians must remain as the most vital criterion underlying any regulatory analysis” [emphasis added]. Notably, while the Minister is expressly required by the NHP Regulations to evaluate safety and prevent injury to health, the importance of “freedom of choice and philosophical and cultural diversity” exists only as an underlying principle rather than an identified criterion for evaluation. A review of the Standing Committee Report, the RIAS, and the NHP Regulations themselves confirms that while the regulations are intended to treat NHPs under a process and principles distinct from those for other drugs, they are not intended to do so at the expense of the health (broadly considered) or safety of Canadians.
[16] This is consistent with the objective of the FDA, the enabling statute of the NHP Regulations. The Supreme Court of Canada has described the FDA’s objective as being “to encourage bringing safe and effective medicines to market to advance the nation’s health”: AstraZeneca Canada Inc v Canada (Minister of Health), 2006 SCC 49 at para 12. This description applies equally to the NHP Regulations: Winning Combination (FCA) at para 58.
[17] While the regimes for NHPs and other drugs are “legally and operationally discrete,” they do not exist in isolation from each other. The borderline between NHPs and other drugs is drawn by the definition of “natural health product” in subsection 1(1) of the NHP Regulations, and by subsection 2(2), which states that a substance is not an NHP if the Food and Drug Regulations require it to be sold by prescription. Prior to 2012, such prescription drugs were listed on Schedule F to the Food and Drug Regulations; they are now listed on the Prescription Drug List: Food and Drug Regulations, s A.01.010 (“prescription drug”, “Prescription Drug List”); FDA, s 29.1. The RIAS for the NHP Regulations at page 1577 notes that subsection 2(2) “clearly distinguishes prescription drugs from NHPs” and states:
This clarifies the original policy intent of the NHP Regulations to regulate substances that are safe for over-the-counter use. It was not the intent of the Regulations to take substances off Schedule F or to regulate substances that require a prescription or have a narrow margin of safety.
[18] In deciding whether a drug should be on the Prescription Drug List, the Minister is to consider the need for practitioner supervision, and whether the “level of uncertainty” respecting the drug justifies such supervision: Food and Drug Regulations, s C.01.040.3. Thus, if a substance that is sold for treatment, mitigation or prevention of a health condition (i.e., a drug) presents issues or uncertainties that suggest it should be used under medical supervision, then it may be considered for inclusion on the Prescription Drug List, which would take it outside the NHP Regulations: FDA, s 2 (“drug”); Food and Drug Regulations, s C.01.040.3; NHP Regulations, s 2(2). This is one of the issues that arose in Health Canada’s review of Boluoke.
[19] This context provides the backdrop for the particular provisions in the NHP Regulations at issue in this matter, namely sections 5(g) and 7. These sections are found in Part 1 of the NHP Regulations, which deals with product licences.
B. The Regulatory Provisions at Issue
[20] NHPs can only be sold in Canada under a product licence: NHP Regulations, s 4. Section 5 of the NHP Regulations sets out what must be filed as part of an application for a product licence, including information regarding the “safety and efficacy” of the NHP. At the time of C‑RNA’s application for a product licence, subsection 5(g) read as follows:
Licence Application
Demande
5 An application for a product licence shall be submitted to the Minister and shall contain the following information and documents:
5 La demande de licence de mise en marché est présentée au ministre et comporte les renseignements et documents suivants :
[…]
[…]
(g) information that supports the safety and efficacy of the natural health product when it is used in accordance with the recommended conditions of use;
g) les renseignements montrant l’innocuité et l’efficacité du produit lorsqu’il est utilisé selon les conditions d’utilisation recommandées;
[Emphasis added.]
[Je souligne.]
[21] In 2018, an amendment to the English version of subsection 5(g) changed the word “supports” to “demonstrates,” such that the provision now reads “information that demonstrates the safety and efficacy of the natural health product…” While information that “demonstrates” safety and efficacy might at first blush suggest a higher standard than information that simply “supports” it, a closer reading shows that the terms are synonymous in this context and that the amendment was simply a clarification rather than a substantive change.
[22] Significantly, other provisions in the regulations—both before and after the amendment—refer to an applicant or licensee having to provide information “demonstrating” that the NHP is safe and efficacious: NHP Regulations, ss 11(2)(c), 16, 17(1)(b), 17(2)(a). This includes section 11, dealing with applications to amend a product licence, which must include “information demonstrating that the natural health product is safe and efficacious after the change”: NHP Regulations, s 11(2)(c). It would be incongruous if a different standard of safety and efficacy information was required when a licence application is first filed than when it is amended. This is particularly so since the French version, which was not amended, uses the same verb “montrer” in each section: NHP Regulations, ss 5(g), 11(2)(c).
[23] The RIAS for the amending regulation confirms that the amendment was designed to address one of many identified discrepancies between French and English versions of various regulations: RIAS, Regulations Amending Certain Department of Health Regulations (Miscellaneous Program), SOR/2018-69, Canada Gazette Part II, Vol 152, No 8, p 775 at p 779. I also refer for completeness to the principle that amendments are not deemed to involve a change in the law: Interpretation Act, RSC 1985, c I-21, ss 45(2)–(3).
[24] I therefore read the word “supports” in subsection 5(g) as it read prior to 2018 as being synonymous with the word “demonstrates.” The meaning of the provision as a whole, and in particular whether it creates a test the applicant must meet, is discussed further below.
[25] The “recommended conditions of use” referred to in subsection 5(g) are defined in the regulations as meaning its recommended use or purpose, dosage form, route of administration, dose, duration of use and risk information: NHP Regulations, s 1(1) (“recommended conditions of use”). Subsection 5(f) requires a product licence application to include the recommended conditions of use for the NHP.
[26] The other provision of particular relevance to C-RNA’s arguments is section 7 of the NHP Regulations, which reads as follows:
Issuance and Amendment
Délivrance et modification
7 The Minister shall issue or amend a product licence if
7 Le ministre délivre ou modifie la licence de mise en marché si les conditions suivantes sont réunies :
(a) the applicant submits an application to the Minister that is in accordance with section 5 or subsection 11(2), as the case may be;
a) le demandeur présente au ministre une demande conforme à l’article 5 ou au paragraphe 11(2), selon le cas;
(b) the applicant submits to the Minister all additional information or samples requested under section 15;
b) le demandeur fournit au ministre les renseignements complémentaires ou les échantillons demandés en vertu de l’article 15;
(c) the applicant does not make a false or misleading statement in the application; and
c) le demandeur ne fait pas de déclaration fausse ou trompeuse dans sa demande;
(d) the issuance or amendment of the licence, as the case may be, is not likely to result in injury to the health of a purchaser or consumer.
d) la délivrance ou la modification de la licence ne risque pas de causer un préjudice à la santé de l’acheteur ou du consommateur.
[Emphasis added.]
[Je souligne.]
[27] For a product licence to be issued, subsection 7(a) requires the application to be “in accordance with section 5.” To be “in accordance with section 5,” the application must, among other things, contain the information demonstrating safety and efficacy required by subsection 5(g). Health Canada treats subsection 7(a) as including a substantive requirement to demonstrate safety and effectiveness. This can be seen in Health Canada’s Safety and Efficacy Class Review Assessment Report (SEAR), used in the assessment of NHP product applications. The SEAR form used by Health Canada includes check boxes relating to a potential refusal of an application, including “Insufficient information to support the safety of the product (7a)” and “Insufficient information to support the efficacy of the product (7a)” [emphasis in original]. The SEAR form also contains other boxes related to subsections 7(b), (c) and (d). C-RNA’s application was refused pursuant to subsection 7(a) based on it containing insufficient information to support the safety of Boluoke.
[28] C-RNA submits that subsections 5(g) and 7(a) do not create a substantive standard but only an administrative requirement to file information of safety and efficacy. The substantive requirement for safety, C-RNA argues, is found in subsection 7(d), which requires that approval of the NHP is “not likely to result in injury to the health of a purchaser or consumer.” In support of this proposition, it relies on the decision of Justice Russell in Winning Combination Inc v Canada (Health), 2016 FC 381, which was reversed in part by Winning Combination (FCA).
[29] I do not believe that Justice Russell went so far as to conclude that subsection 5(g) was a purely administrative requirement: Winning Combination (FC) at paras 137–142. In this regard, I agree with the Minister that C-RNA’s reliance on paragraphs 42 to 46 of the decision is misplaced, as those paragraphs simply summarize the applicant’s arguments. In any case, to the extent that Justice Russell’s decision might be read in this way, it was overtaken by the Court of Appeal’s conclusion that in exercising their discretion under section 7 of the NHP Regulations, the Minister “must be satisfied that the product is safe and effective, albeit to different standards than in the assessment of new drugs” [emphasis added]: Winning Combination (FCA) at para 58. In my view, this statement and the structure of the NHP Regulations both indicate that to be satisfied under subsection 7(a) that an application complies with section 5, the Minister must be satisfied not just that the applicant has filed information on safety and effectiveness, but that the information demonstrates that the NHP is safe and effective when used in accordance with the recommended conditions of use. This accords with the Minister’s approach as seen in the SEAR and in its refusal of C-RNA’s application.
[30] I also do not agree that in showing safety, an applicant need only show that the NHP is not “likely to result in injury to the health of a purchaser or consumer,” the standard set out in subsection 7(d). The NHP Regulations use the term “safe when used in accordance with the recommended conditions of use” and the term “likely to result in injury to health” to mean two different things. This can be seen from the appearance of the two terms in different provisions that empower the Minister to stop sales of NHPs, with different procedural requirements. If the Minister has grounds to believe an NHP is no longer “safe,” they may stop sales, but only after requesting further information and providing the licensee an opportunity to respond: NHP Regulations, ss 16, 17(1)(a)–(b). However, if the Minister has grounds to believe an NHP may cause “injury to health,” they must suspend the product licence (thereby stopping sales) without giving the licensee an opportunity to be heard: NHP Regulations, s 19; see also s 4(3)(a).
[31] The Minister’s ability to stop sales if no longer satisfied that the product is “safe when used in accordance with the recommended conditions of use” confirms that this is a substantive requirement that must be established by a licensee. The different procedural requirements arising when concerns about “safety” and “injury to health” arise confirms that they represent different substantive standards. An applicant must therefore show not only that their product is not likely to cause “injury to health” (subsection 7(d)), but that it is “safe when used under the recommended conditions of use” (subsections 5(g) and 7(a)). While a product that is safe when used under the recommended conditions of use will presumably not cause injury to health, I do not believe that this renders subsection 7(d) redundant. Notably, safety is set out jointly with efficacy in subsection 5(g), an issue addressed further below in discussing the “risk-benefit” analysis. However, subsection 7(d) confirms that if a product is “likely to cause injury,” no licence can be granted, regardless of the efficacy of the product.
[32] As a final note in reviewing the provisions, subsection 7(b) refers to section 15 of the NHP Regulations. That section says that where the information and documents submitted with a licence application under section 5 are “insufficient to enable the Minister to determine whether the product licence should be issued,” the Minister may request that the applicant provide such additional information as is “necessary to make the determination.” The NNHPD’s practice is to send such requests in the form of an Information Request Notice (IRN).
C. The Minister’s Guidelines
[33] Over time, the NNHPD has published a number of guidance documents to assist industry, the public, and its own decision-makers in understanding and applying the NHP Regulations. Such guidelines have long been recognized as being appropriate, helpful, and even persuasive. They do not, however, have force of law and cannot amend, limit or qualify statutory or regulatory provisions: Maple Lodge Farms Ltd v Canada, [1982] 2 SCR 2 at pp 3–4, 6–7, aff’g [1981] 1 FC 500 (CA) at pp 513–514; Canada (Information Commissioner) v Canada (Minister of Citizenship and Immigration), 2002 FCA 270 at para 37. At issue in this matter are guidelines issued in 2006 and 2012.
(1) The 2006 Guideline
[34] In 2006, the NNHPD (then known as the Natural Health Products Directorate) issued a guidance document entitled Evidence for Safety and Efficacy of Finished Natural Health Products (Version 2.0). This 2006 Guideline included an epigraph noting the role of the directorate, using language that parallels that of the RIAS, as referenced in paragraph [12]
above:
“Our role is to ensure that Canadians have ready access to natural health products that are safe, effective and of high quality while respecting freedom of choice and philosophical and cultural diversity.” – Natural Health Products Directorate
[35] The 2006 Guideline states that evaluation of an NHP for safety and efficacy “includes an assessment of its recommended conditions of use, its appropriateness for self-care and the existing totality of evidence related to the NHP.” It goes on to provide further detail on what is meant by “recommended conditions of use,” “self-care” and “totality of evidence.” The 2006 Guideline also sets out an approach in which the “health claims” of a product are divided into two categories: traditional use claims and non-traditional use claims. A “health claim” is a statement about the expected benefit to the consumer of taking an NHP, such as “maintains healthy gums” or “reduces blood cholesterol.”
[36] Traditional use claims are those based on the knowledge, skills, theories, beliefs and experiences indigenous to different cultures. Such traditional use claims must be introduced with qualifiers identifying the traditional use, such as “In Traditional Chinese Medicine used to…” Non-traditional use claims do not use such qualifiers, and are established based on scientific evidence such as clinical trials. The 2006 Guideline identified types of evidence that might be used to support traditional use claims and non-traditional use claims. Other types of NHPs, including homeopathic medicines, are addressed under other guidelines.
[37] I note that the Minister initially objected to C-RNA filing the 2006 Guideline on this application, since it was not part of the Certified Tribunal Record. It was accepted for filing by Direction of Prothonotary Aalto acting as Case Management Judge, subject to arguments on its admissibility. No such arguments were made before me. The Minister, appropriately in my view, focused their submissions on responding to C-RNA’s arguments regarding the guideline.
(2) The 2012 Guidelines
[38] In 2012, as part of an announced new approach to NHPs, the 2006 Guideline was replaced by two separate guidance documents. These two documents addressed concepts similar to the two categories of health claims described in the 2006 Guideline. “Traditional medicines” were addressed in a new guideline titled Pathway for Licensing Natural Health Products used as Traditional Medicines. Products that made “modern health claims” were addressed in a new guideline titled Pathway for Licensing Natural Health Products Making Modern Health Claims. C-RNA’s 2013 application for a product licence was made as a “non-traditional” application. The Pathway for Licensing Natural Health Products Making Modern Health Claims document is therefore the guideline of relevance, and I will refer to it as the “2012 Guideline.”
[39] The 2012 Guideline states that its policy objective is to “provide reasonable assurance that NHPs offered for sale in Canada are safe and effective when used under their recommended conditions of use.” It describes a risk-based approach to assessing safety and efficacy, in which the type and amount of evidence to be filed in support of an application varies depending on the proposed health claims of the product and its overall risk profile.
[40] The approach described in the 2012 Guideline includes a categorization of products into low, medium and high levels of risk. The “high level of risk” category applies to NHPs with the narrowest safety margin and effective dose range, and those used for treatment, cure, and prevention of serious diseases, including those listed in Schedule A (now Schedule A.1) to the FDA. The introduction of these categories, and in particular the assignment of Boluoke to the high-level risk category, is the source of some of C-RNA’s arguments. The 2012 Guideline provides guidance on the nature of evidence that can be filed to show the safety and efficacy of the product, including a table setting out evidence that will be accepted as meeting minimum criteria for evidence for each risk category.
IV. C-RNA’s Application for an NHP Product Licence for Boluoke
[41] C-RNA filed two applications for NHP product licences for Boluoke, one in 2006 and a second in 2013 after the first was refused. C-RNA seeks judicial review only of the refusal of its second application. This is appropriate, as the 2006 application was rejected many years ago and that rejection was not challenged, C-RNA choosing to file its 2013 application instead. I consider the 2006 application relevant to the procedural fairness issues raised by C-RNA, and its argument that the second application should have been considered pursuant to the 2006 Guideline. I will therefore briefly summarize the process leading to its refusal. However, the substantive decision under review is the 2015 refusal of the second application, as reconsidered and affirmed in 2016.
A. The First Application
[42] C-RNA’s first product licence application for Boluoke was filed in March 2006. The application sought approval of Boluoke as a “traditional claim” NHP to “reduce blood viscosity” and “improve circulation.” The application included information regarding the manufacturing process, and an evidence summary identifying various scientific studies and providing narrative overviews of the product and the science. It also attached copies of materials regarding the use of earthworms in food and traditional medicine, and proposed labelling for Boluoke.
[43] The NNHPD issued an IRN to C-RNA in April 2009 that classified Boluoke as a “Non-Traditional” NHP. While not set out in the IRN, it appears that the classification of Boluoke as “Non-Traditional” was because it was not just earthworms, which had been used in Traditional Chinese Medicine, but an extraction using non-traditional methods of the enzyme complex contained in earthworms. The IRN stated that the evidence C-RNA had filed was not considered adequate to support safety and efficacy, noting in part that animal or in vitro evidence was provided as the sole source of safety or efficacy evidence. C-RNA was asked to provide further evidence to support the safety and efficacy of lumbrokinase according to the recommended conditions of use, and reference was made to the criteria in the 2006 Guideline for assessing evidence.
[44] C-RNA’s response to the 2009 IRN was not to file further evidence but to say that it “did not see the deficiencies you pointed out” and to summarize the information already provided. C‑RNA stated its belief that it “provided as complete a submission as can be expected from any natural health product applicant,” and asked that if the NNHPD still believed the submission insufficient, that it “please be very specific as to what kind of evidence you still require.”
[45] NNHPD issued another IRN in August 2011. It noted that the NNHPD had identified potential health risks associated with the use of three natural fibrinolytic enzymes, nattokinase, lumbrokinase and serratiopepsidase. Included in its discussion of this concern is the following passage referring to intravenous fibrinolytic agents, which C-RNA takes significant issue with:
Evidence of fibrinolytic activity in humans is limited, however, the existing evidence demonstrates adverse effects and/or expresses concern of the safety of fibrinolytic enzymes in humans (Hsia et al. 2009; Change [sic] et al. 2008; Kim et al. 2008). Additionally, fibrinolytic agents are generally administered intravenously and under supervision of a physician since they are used to treat patients with serious conditions (e.g. patients with myocardial infarction, acute thrombotic stroke, arterial thromboembolism) and thus are not considered appropriate for ‘self-care’. Furthermore, the serious contraindications for these products such as active internal bleeding, haemorrhagic cerebrovascular disease, bleeding diatheses, pregnancy, uncontrolled hypertension, invasive procedures in which haemostasis is important, and recent trauma – including vigorous cardiopulmonary resuscitation (Rang et al. 2009), are also considered potential safety concerns for oral products in the absence of clinical trials demonstrating long-term oral safe use of fibrinolytic enzymes.
[Emphasis added.]
[46] The 2011 IRN concluded that more clinical evidence was required to show that the health benefits of a product containing one of these enzymes outweighed the risks of their use without physician supervision. It indicated that adequate evidence had to be filed to “support the safety in the general healthy population and not a subpopulation which will be monitored closely by a physician (e.g. hypertensive patients, patients with acute myocardial infarction).” It also set out a series of reasons why the evidence in the licence application was insufficient.
[47] C-RNA responded to the 2011 IRN by providing a number of revisions to its application, as well as additional studies and references. C-RNA argued that the concerns about fibrinolytic enzymes did not apply to lumbrokinase as none of the research referenced by the NNHPD specifically implicated lumbrokinase as a high-risk enzyme preparation. It also contended that intravenous fibrinolytics would have no effect if administered orally, and that oral fibrinolytics had a safer profile.
[48] Another IRN issued in 2013 raised similar issues to those raised in the 2011 IRN, and set out a 14-point list of identified deficiencies in the studies filed by C-RNA. It referred C-RNA to the 2012 Guideline, which had been issued in the interim, and asked C-RNA to provide evidence to support the product’s safety and efficacy in humans taking into account the requirements for a “high risk” category product. C-RNA’s response to the 2013 IRN included its responses to the list of identified deficiencies, and expressed disagreement with the NNHPD’s analysis on a number of matters. It also provided additional references and supporting documents, and raised a concern that the NNHPD’s approach to the evidence was more suited to other drugs than NHPs.
[49] On September 17, 2013, the NNHPD issued a Notice of Refusal. The NNHPD noted that, due to the inconsistency and uncertainty in the data, it could not conclude that Boluoke did not pose a bleeding risk in a healthy sub-population due to its anti-coagulant, anti-platelet and fibrinolytic potential. The NNHPD found that it was not possible to establish a favourable “risk versus benefit profile” to support the health claims, and noted that the internal bleeding risk could not be mitigated for over-the-counter (OTC) use. In particular, the NNHPD noted that the majority of the clinical data is derived from “populations with hypercoagulable states” that is not directly applicable to a healthy subpopulation intended for OTC use.
[50] The term “hypercoagulable state” refers to a condition associated with a predisposition to develop blood clots. As explained in a helpful scientific primer agreed to by the parties and filed pursuant to an Order of Prothonotary Aalto, the blood coagulation system involves a balance between the coagulation (clot forming) system and the fibrinolytic (clot resolving) system. Where coagulation overbalances fibrinolysis, the system becomes hypercoagulable. Where the reverse occurs—a hypocoagulable state—there is a higher chance of bleeding. Health Canada’s concerns were thus in essence that if a coagulation system is already in balance (or is already hypocoagulable), introducing a fibrinolytic might render it hypocoagulable (or more so), with an associated risk of internal bleeding. Studies with subjects in a hypercoagulable state therefore may not demonstrate safety in those not in such a state.
B. The Second Application
[51] After the 2013 refusal, there was a call between the NNHPD and C-RNA about a possible pathway for lumbrokinase to be licenced as part of a “professional use” program. There was little evidence filed before me regarding the nature of this program. An email exchange between Health Canada employees referred to a “Non-prescription Professional Use products framework,” suggesting that there was an existing or anticipated framework or program to cover non-prescription products with some degree of professional oversight. However, no framework documents, guidelines or other details were filed. In any case, based on the material filed and the subsequent discussion of the issue, the idea appears to have been some form of approval involving health professional monitoring or oversight for a period of time to allow for the accrual of post-market safety data before moving the product to OTC availability.
[52] C-RNA re-submitted its application on January 2, 2014, seeking an NHP licence for Boluoke in the “Non-traditional” category. C-RNA indicated in a cover letter that it had decided to “accept NHPD’s suggestion” and was re-submitting the application under “the new practitioner NHP category.” The application included new supporting evidence, but the bulk of the evidence came from its previous submissions. While the product licence application form itself contained the same health claims as the first application, namely “[t]o reduce blood viscosity” and “[t]o improve circulation/hemorrheology,” an attached Efficacy and Evidence Summary Report indicated that it was seeking claims that were limited to reducing blood viscosity and improving circulation “in hypercoagulable blood state.”
[53] The NNHPD issued an IRN on August 13, 2014. The IRN reiterated the view that, as communicated in the 2013 refusal:
…the body of clinical trial evidence for lumbrokinase is of insufficient quality to provide confidence that the product is not a risk with respect to internal bleeding. As internal bleeding is a serious health risk that cannot be mitigated through labeling and is not self-diagnosable, the NNHPD’s position is that the current evidence is not appropriate to support its safe use as an over-the-counter (OTC) product.
[54] The IRN also indicated that the NNHPD had examined the option of restricting the sale of lumbrokinase to health care professionals. To do so, it consulted with an “external practicing hematologist” to see if a post-market monitoring plan could be developed to manage risks and obtain post-market safety data. Based on this consultation, the NNHPD concluded that available tests could not predict bleeding risk, so practitioner oversight would be limited to reacting to symptoms suggestive of bleeding. Such a management strategy was not considered appropriate given the risk-benefit balance. The hematologist’s review of the clinical evidence was also said to reinforce the NNHPD’s view that the data did not support safety of lumbrokinase for general use. The NNHPD therefore asked C-RNA for additional clinical data.
[55] After some calls and email exchanges to try to clarify the concerns, C-RNA responded to the 2014 IRN in October. This response included a contention that Health Canada’s review of the evidence constituted “nit-picking” not based on facts, and a suggestion that the NNHPD had “veered off from its original founding principles.” C-RNA provided extensive submissions on these founding principles, and summarized the evidence on lumbrokinase and its safety. It also again criticized the assumption that lumbrokinase was a bleeding risk and the categorization as a “high risk” product. To counter the hematologist’s conclusions, C-RNA provided four expert reports that described potential monitoring tests and spoke to the safety of lumbrokinase. C-RNA also set out further risk mitigation strategies, including laboratory testing to identify patients who are hypercoagulable.
[56] On June 23, 2015, the NNHPD refused the second application. The 2015 Notice of Refusal repeated that the evidence was insufficient to support the safety of Boluoke for OTC use, as the clinical trial evidence was mainly limited to conditions of hypercoagulable state and did not support licensing to a health population. It again noted that the risk of internal bleeding was not self-diagnosable and could not be mitigated through labeling.
[57] With respect to a professional use option, the 2015 refusal noted that this would have to be a temporary measure for market access, since a product that needed ongoing monitoring and supervision would meet the Prescription Drug List criteria for regulation under the Food and Drug Regulations. The NNHPD concluded that licensing as a professional use NHP was not supported since there was no validated monitoring in Canada for lumbrokinase that could be used to monitor bleeding risk. The NNHPD considered the monitoring options discussed in the expert opinion reports, but concluded that they wer