CANADA RNA BIOCHEMICAL INC. Applicant v. CANADA (MINISTER OF HEALTH), AND ATTORNEY GENERAL OF CANADA, 2020 FC 668

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: A . 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? B . 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

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 additionalinformation as is "“necessary to make the determination.”" The NNHPD’s practice is to send such requests in the form of an InformationRequest 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-makersin understanding and applying the NHP Regulations. Such guidelines have long been recognized as being appropriate, helpful, and evenpersuasive.

They do not, however, have force of law and cannot amend, limit or qualify statutory or regulatory provisions: Maple LodgeFarms Ltd v Canada, (SCC), [1982] 2 SCR 2 at pp 3–4, 6–7, aff’g (FCA), [1981] 1 FC 500 (CA) atpp 513–514; Canada (Information Commissioner) v Canada (Minister of Citizenship and Immigration), 2002 FCA 270 at para 37. Atissue 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 forSafety and Efficacy of Finished Natural Health Products (Version 2.0).

This 2006 Guideline included an epigraph noting the role of thedirectorate, 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 qualitywhile 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 recommendedconditions of use, its appropriateness for self-care and the existing totality of evidence related to the NHP.”" It goes on to provide furtherdetail on what is meant by "“recommended conditions of use,”" "“self-care”" and "“totality of evidence.”" The 2006 Guideline also setsout an approach in which the "“health claims”" of a product are divided into two categories: traditional use claims and non-traditionaluse claims.

A "“health claim”" is a statement about the expected benefit to the consumer of taking an NHP, such as "“maintains healthygums”" 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 Medicineused 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.

Othertypes 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 theCertified Tribunal Record. It was accepted for filing by Direction of Prothonotary Aalto acting as Case Management Judge, subject toarguments on its admissibility. No such arguments were made before me. The Minister, appropriately in my view, focused theirsubmissions 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. "“Traditionalmedicines”" 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 ProductsMaking Modern Health Claims.

C-RNA’s 2013 application for a product licence was made as a "“non-traditional”" application.

ThePathway for Licensing Natural Health Products Making Modern Health Claims document is therefore the guideline of relevance, and Iwill 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 aresafe and effective when used under their recommended conditions of use.”" It describes a risk-based approach to assessing safety andefficacy, in which the type and amount of evidence to be filed in support of an application varies depending on the proposed healthclaims 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 thesecategories, and in particular the assignment of Boluoke to the high-level risk category, is the source of some of C-RNA’s arguments. The2012 Guideline provides guidance on the nature of evidence that can be filed to show the safety and efficacy of the product, including atable 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 forBoluoke [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 manyyears ago and that rejection was not challenged, C-RNA choosing to file its 2013 application instead. I consider the 2006 applicationrelevant 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 were not recommended since they were not available in Canada and/or did not have an appropriately validated reference range predictive of bleeding. There were also concerns about the feasibility of collecting data during the professional use term, in part because such data was again likely to be directed to patients with a hypercoagulable state and therefore would not establish safety in a healthy population. C.

Reconsideration/Reassessment and Refusal [ 58 ] C-RNA requested reconsideration of the 2015 refusal pursuant to

section 9 of the NHP Regulations . That

section provides that if an applicant requests reconsideration of a refusal, the Minister shall give the applicant an " “opportunity to be heard in respect of the application,” " and shall reconsider the application after that opportunity: NHP Regulations , ss 9(2)–(3). After the reconsideration, a licence is to be granted if the requirements of

section 7 are met, or a " “final notice” " setting out reasons for refusal will be issued: NHP Regulations , s 10. [ 59 ] C-RNA’s request for reconsideration raised two primary issues: (1) the classification of lumbrokinase as a " “high risk” " product; and (2) a concern that the NNHPD " “selectively ignored” " much of the evidence. With respect to each of these, C-RNA raised a number of sub-arguments.

In addition to its substantive concerns, C-RNA made requests regarding the selection of the reviewing officers, and requested a face-to-face meeting to present and answer questions. [ 60 ] On receipt of the reconsideration request, Health Canada conducted an internal review. Prior to convening a meeting with C-RNA, it concluded that there were concerns with how the evidentiary requirements and the Prescription Drug List criteria were communicated to C-RNA before the 2015 refusal. Health Canada therefore decided to " “reinstate” " the application.

On September 24, 2015, the NNHPD sent a " “final notice” " on the reconsideration, advising that " “[t]he submission will recommence at Assessment and this letter

will serve as a Submission Reinstatement Notice.” " The NNHPD indicated that during this further assessment it might require more information, and offered the opportunity to meet with the NNHPD if still requested. [ 61 ] C-RNA took the NNHPD up on the offer of a meeting, and a meeting was arranged for December 2, 2015. At that meeting, representatives from C-RNA met with NNHPD staff, and provided a written and oral presentation.

The presentation set out C-RNA’s case for licensing, raised issues with NNHPD’s " “actions and rationales” " to date, and asked the question " “what would it take for NNHPD to approve lumbrokinase?” " At the conclusion of the meeting, the parties agreed that the NNHPD would look to complete its review of the application by the end of January 2016. [ 62 ] The NNHPD sent another IRN on February 1, 2016. The IRN again stated that the evidence filed was insufficient to support the safe use of lumbrokinase and asked for further evidence.

The IRN provided a specific response to four studies that had been raised in C- RNA’s application, and noted that the majority of the evidence that C-RNA provided " “pertains to conditions that infringe on the principles and factors used in establishing prescription status for health products and are insufficient to support the safe use of this product in the target subpopulation.” " The IRN set out further detail on the principles for determining prescription status, and stated that the recommended uses proposed for Boluoke were not acceptable, as the conditions (blood viscosity and hemorheology) evoke considerations that could not be addressed without involvement of a health care practitioner. [ 63 ] C-RNA responded to the 2016 IRN, restating its case, responding to the identified concerns regarding the studies, but providing no new information. [ 64 ] On July 8, 2016, Health Canada sent a final notice to C-RNA indicating that it upheld the decision to refuse to issue a product licence.

The decision attached an Issue Analysis

Summary (IAS) prepared by an " “Impartial Reviewer” " who was a Manager with NNHPD, which included a recommendation to uphold the refusal. That recommendation was accepted by an Acting Director General at NNHPD, who upheld the decision and reasons communicated in the 2015 Notice of Refusal.

The IAS sets out reasons similar to those set out in the 2015 refusal: The clinical trials involving LK [lumbrokinase] have been conducted predominantly in individuals with more serious health conditions such as ischemic cerebrovascular disease or diabetic with complications (including peripheral neuropathy, coronary heart disease, diabetes nephrosis, dementia, etc.).

As a result, there is a scarceness of studies conducted in otherwise healthy individuals such as those envisioned as typically [ sic ] consumers for NHPs and of the available studies where extrapolation to an otherwise healthy person may be broached (e.g., Liu 2007; Deng 2000; Pan 2008; Yan 2008), there are limitation[s] . […] Therefore, in contextualising all of the available information to the safety of LK when utilised in otherwise healthy persons, it is necessary to bear in mind the prevailing assumptions and expectations regarding NHPs.

NHPs are intended for conditions where the consumer is to able to self-manage both the risks of the condition and of the product, used limited practitioner oversight and/or on-going involvement . … A key aspect of NNHPD’s current mandate is to ensure that Canadians have access to NHPs that are safe, effective and of high quality. Consequently, access could be defined as not specific to a particular product and more so to a range of products.

Within the range of available products, each should be associated with favourable benefit-to-risk enabling the consumer to self-select the most appropriate product for managing their health needs . … [Emphasis added.] [ 65 ] The IAS included a list of references and an appendix that summarized clinical evidence reviewed in the prior assessment, and referred to the SEAR prepared in the assessment of Boluoke. The SEAR contains a review and analysis of the evidence submitted by C- RNA. It appears to have been a " “working document,” " updated over time as more information was submitted.

In particular, the first 46 pages of the SEAR appear to have been prepared during the initial assessment of the application. The remaining 26 were prepared during the reassessment and include analysis of studies previously considered in the initial assessment. [ 66 ] Having reviewed the regulatory and factual framework, I turn to the specific issues raised by C-RNA. V. Analysis A. Health Canada’s Decision was Reasonable [ 67 ] C-RNA argues that Health Canada misinterpreted the NHP Regulations , and that it unreasonably refused its application.

As previously noted, C-RNA separated these two arguments in its submissions. I will address the arguments using that structure, while recognizing that they are not entirely independent. [ 68 ] Each of these arguments goes to the merits of the refusal and the reasons for it. Such issues are reviewed on a reasonableness standard: Winning Combination (FC) at paras 28–29; North American Nutriceutical Inc v Canada (Attorney General) , 2012 FC 1044 at paras 78–79 . [ 69 ] In oral submissions, C-RNA argued that the correctness standard should apply to Health Canada’s

interpretation of the NHP Regulations . I disagree. Even prior to the Supreme Court of Canada’s decision in Vavilov , issued after the hearing of this matter, it was clearly recognized that deference should presumptively be given to administrative decision-makers on questions of

interpretation of their " “home statute” " : Canada (Human Rights Commission) v Canada (Attorney General) , 2018 SCC 31 at para 27 ; Canada (Minister of Citizenship and Immigration) v Vavilov , 2019 SCC 65 at para 25 ; Winning Combination (FC) at para 28. There is no basis under either

the pre-Vavilov or post-Vavilov framework to depart from that presumption in this case. Both Health Canada’s

interpretation and itsapplication of the NHP Regulations are thus reviewable on the reasonableness standard. Vavilov simply confirms this: Vavilov at paras16–17, 23–25.

(1) Health Canada did not err in its

interpretation of the NHP Regulations [70] I agree with C-RNA that the NHP Regulations are to be interpreted using the "“modern”" approach to

interpretation that hasprevailed since at least Re Rizzo & Rizzo Shoes Ltd, (SCC), [1998] 1 SCR 27. There, Justice Iacobucci adoptedProfessor Driedger’s formulation that "“the words of

an Act are to be read in their entire context and in their grammatical and ordinarysense harmoniously with the scheme of the Act, the object of the Act, and the intention of Parliament”": Rizzo at para 21. In the case of aregulation, part of the interpretive context is the statute under which the regulations are promulgated—in this case, the FDA: Bristol-Myers Squibb Co v Canada (Attorney General), 2005 SCC 26 at paras 37–38. [71] The Supreme Court has confirmed that this analytical framework applies whether it is a court or an administrative decision-makerthat is interpreting the legislative provision: Vavilov at paras 117–124. While an administrative

interpretation may not bear theformalities of a court decision, and may even be implicit, a reasonable

interpretation should be consistent with the text, context andpurpose of the legislation: Vavilov at paras 121–123. [72] C-RNA asserts that Health Canada unreasonably interpreted the NHP Regulations by introducing terms and requirements not foundin the regulations: (

a) the need to demonstrate safety in a "“healthy population”"; (

b) reference to "“over-the-counter”" and "“self-care”"as the model for use of NHPs; and (

c) a requirement that the "“benefits”" of Boluoke outweigh its "“risks.”" For the following reasons, Idisagree that Health Canada’s

interpretation of the NHP Regulations was unreasonable. (a) "“Healthy population”" [73] C-RNA argues that the NHP Regulations do not require it to show safety or efficacy in a "“healthy population,”" and that HealthCanada has unreasonably read that term into the regulations by requiring evidence of safety in such a population. C-RNA notes thatsubsection 5(

g) of the NHP Regulations only refers to demonstrating safety and efficacy of the NHP when used in accordance with the"“recommended conditions of use.”" C-RNA argues that adding a requirement to show safety in a "“healthy population”" narrows theregulations, contrary to the general policy of making NHPs more available rather than less. [74] I do not consider Health Canada’s

interpretation of subsection 5(

g) unreasonable. While subsection 5(

g) refers to safety when theNHP is used in accordance with the "“recommended conditions of use,”" this cannot be considered in isolation from its context. Thatcontext includes, significantly, that NHPs are necessarily sold without a prescription, since prescription products are excluded from thedefinition of NHPs: NHP Regulations, s 2(2).

As a result, they can be taken without medical supervision as part of an individual’sprogram of "“self-care”" or "“self-medication.”" [75] Importantly, Health Canada’s concern about the evidence of safety in a healthy population was connected to the difficulties of self-diagnosing whether one is in a hypercoagulable state. If a member of the Canadian public cannot themselves assess whether they are in ahypercoagulable state, they cannot determine whether they fall within the group for whom the product is recommended, or in a group forwhom the product presents potential safety risks.

In such circumstances, it is not unreasonable to conclude that the requirement to fileevidence demonstrating safety includes evidence that the NHP is safe for the general population. [76] To recognize this context in assessing whether there is adequate evidence of a product’s "“safety”" is not improperly readingrestrictions into the NHP Regulations as C-RNA suggests. It is interpreting and applying the regulations based on their "“text, contextand purpose,”" as required by the modern principle of

interpretation: Rizzo at para 21; Vavilov at para 120. Indeed, it would beunreasonable, and potentially even reckless, for Health Canada not to consider this non-prescription context in assessing whether thesafety of an NHP was adequately established. [77] C-RNA asserts that many consumers consult with health professionals, including natural health care professionals in particular,regarding the use of NHPs. Be that as it may, the availability of NHPs without a prescription means that they may be readily purchasedand taken without such oversight or advice.

This ready access and broad availability of NHPs is one of the features and goals of the NHPRegulations. I therefore do not view Health Canada’s insistence on satisfactory evidence showing safety in a "“healthy population”" tobe adding words to or misinterpreting the regulations. [78] I reach this conclusion whether the "“recommended conditions of use”" in C-RNA’s application are limited to use by those in a"“hypercoagulable state”" or not.

As noted above, C-RNA’s application form identified the recommended use and purpose as being to"“reduce blood viscosity”" and "“improve circulation/hemorrheology,”" without further limitation or reference to a hypercoagulablestate.

Elsewhere, C-RNA states that it is seeking claims to reduce blood viscosity and improve circulation "“in hypercoagulable bloodstate.”" Various iterations of these health claims were put forward during the assessment process. [79] If the recommended use is not limited to a particular class of patients, the requirement to demonstrate safety when used inaccordance with the "“recommended conditions of use”" would cover anyone that might seek to reduce blood viscosity or improvecirculation. Demonstrating safety in only a subset of that population, namely those with hypercoagulable states, would clearly beinsufficient.

Even if the recommended use is considered limited to those in hypercoagulable states, it is reasonable for Health Canada torequire evidence of safety in a healthy population. The non-prescription context, the inability for a member of the public to assesswhether they are in a "“hypercoagulable state,”" and the fundamental statutory and regulatory focus on safety as a priority supports thereasonableness of requiring that safety be demonstrated in healthy populations. [80] Such a requirement does not "“narrow”" the regulations, as C-RNA argues.

While the NHP Regulations implemented a differentapproach to approval of NHPs so that they could be available for use by Canadians, the policy of the regulations is not to make NHPsavailable regardless of safety concerns. To the contrary, safety remains a central requirement for regulatory approval. Ensuring that aproduct is safe for all those who may take it before it is licensed is in no way contrary to the basic policy of the NHP Regulations.

[ 81 ] C-RNA relies on Apotex v Canada (Health) , 2013 FC 1217 [ Apo-Telmisartan ], in which Justice Kane rejected

interpretation arguments based on the " “broad scheme” " of the Food and Drug Regulations in favour of the " “ordinary meaning” " : Apo-Telmisartan at paras 98–144 . I agree with the Minister that this case does not assist C-RNA. Justice Kane applied the Rizzo principles to the regulatory

interpretation question before her, considering the words of the regulations and other interpretive tools such as drafting conventions, as well as the context of the regulatory and statutory scheme: Apo-Telmisartan at paras 98, 108–109, 125–128, 139–144 . The same Rizzo approach applies here, but beyond that, the

interpretation of " “medicinal ingredients” " in the context of the Food and Drug Regulations is of little assistance in assessing the requirement to file evidence of safety in the NHP Regulations . The same is true of C-RNA’s reference to paragraphs 136 to 150 of Apotex Inc v Canada (Health) , 2015 FC 1161 [ Apo-APIPL ], in which Justice Manson applied the Rizzo interpretive principles to the particular regulatory issue before him. [ 82 ] C-RNA’s related argument that Health Canada did not define " “healthy population” " is unpersuasive.

Health Canada’s communications included detailed descriptions of identified shortcomings in the studies filed. It was clear that Health Canada was concerned that the evidence filed related mainly to subjects with a hypercoagulable state and that it was looking for evidence showing safety among the broader population, not limited to those under medical care for blood conditions.

Indeed, as early as 2011, Health Canada advised C-RNA that " “[t]he evidence must support the safety in the general health population and not a subpopulation which will be monitored closely by a physician[.]” " C-RNA’s stated concern in its submission on reconsideration that the guidance documents do not define " “healthy populations” " seems largely to be a semantic argument rather than any real attempt to address the concerns raised by Health Canada.

I see no basis on which a licence applicant could have reasonably misunderstood what Health Canada was looking for. [ 83 ] Finally, I am also unpersuaded by C-RNA’s argument that the requirement for evidence showing safety in healthy populations inappropriately shifts the NHP Regulations from being " “use-based” " to being " “user-based.” " Both the " “recommended conditions of use” " and the assessments of safety and efficacy necessarily imply consideration of who may be using the product.

In other words, there is no use without a user, and it is not inappropriate to consider both elements of that equation in assessing safety. (b) " “Over-the-counter” " and " “self-care” " [ 84 ] C-RNA’s argument that other terms used by Health Canada, such as " “over-the-counter” " and " “self-care,” " are not found in the NHP Regulations is of no merit. While the term " “over-the-counter” " is not used in the NHP Regulations (or, for that matter, the FDA or the Food and Drug Regulations ), it is commonly used to describe non-prescription products and is fair shorthand for drugs available without a prescription.

The fact that NHPs are by definition available without a prescription comes directly and expressly out of the regulations: NHP Regulations , s 2(2). Thus all NHPs are intended to be available for OTC use. Referring to NHPs as " “non- prescription” " products or being for " “non-prescription use” " would clearly be consistent with the NHP Regulations .

I fail to see how using the term " “over-the-counter” " or OTC changes this in any way. [ 85 ] Similarly, the term " “self-care” " —along with related terms such as self-medication, self-diagnosis, self-manage, or self-direct— simply describe the context in which many Canadians take NHPs and other OTC medications. They are terms used in both the RIAS and the underlying Standing Committee Report that C-RNA relies on.

I see nothing unreasonable in Health Canada’s use of those terms or its reliance on the context those terms describe in making a decision on NHP licensing. (c) " “Risk vs benefit” " [ 86 ] C-RNA argues that Health Canada inappropriately required it to demonstrate that the benefits of Boluoke outweighed the risks of the product.

Such an assessment is contemplated in both the 2006 Guideline (which indicates that the " “totality of evidence…must be in support of the benefits of the product outweighing any risks” " ) and the 2012 Guideline (which indicates that the " “benefit-to-risk profile of a product is always considered prior to a product licensing decision being made” " ).

C-RNA asserts that the NHP Regulations contain no risk-benefit requirement or analysis, and that it was unreasonable to impose one. [ 87 ] I do not agree that it is unreasonable for Health Canada to consider the balance between risk and benefit in considering whether to licence an NHP. Subsection 5(

g) requires an applicant to file evidence demonstrating the " “safety and efficacy” " of the NHP. In my view, the reference to " “safety” " in the context of the NHP Regulations inherently implies consideration of risks to health. This is so even though, as C-RNA submits, something can be considered " “safe” " even if it has associated risks. Similarly, " “efficacy” " implies consideration of benefit, as the efficacy of the product is its ability to bring about the desired health benefit, i.e. , the health claim made by the product.

Thus the introduction to the 2012 Guideline that correlates safety to risk and efficacy to benefit is not unreasonable: This guidance document provides information to help product licence applicants determine the evidence (type and amount of data) to provide as part of a product licence application to support the safety (risk) and efficacy (benefit) of natural health products (NHPs) that make modern health claims. [Emphasis added; footnote omitted.] [ 88 ] I agree with C-RNA that the concepts of safety and efficacy as set out in subsection 5(

g) are interrelated. However, I do not agree with its contention that efficacy implies safety, particularly for an NHP, or that an efficacious NHP is necessarily safe. To the contrary, a product might be very effective in bringing about a particular health result, and yet be unsafe because it also poses other health risks.

Similarly, a product may be very safe, but have little or no efficacy in bringing about a particular health claim. [ 89 ] Rather, the concepts of safety and efficacy are interrelated in part because what is considered acceptably safe for a health product may depend on the product’s effectiveness. Put more plainly, we might accept a somewhat greater safety risk in a product that works very well, or accept a lower health benefit in a product that is very safe. At the same time, a product that is dangerous may be unacceptable regardless of how effective it is.

While less relevant in the circumstances of this case, it is worth noting, as the 2012 Guideline does, that safety and efficacy are also interrelated because an ineffective product may impact health by not treating a condition in the manner expected, or causing a consumer to forego other treatment options. [ 90 ] C-RNA is correct that this balancing between safety and efficacy is not spelled out in the NHP Regulations . No particular approach

to assessing safety and efficacy is set out. Rather, the assessment is left to the Minister. As the Federal Court of Appeal noted, " “[t]hese are matters for the Minister to decide” " : Winning Combination (FCA) at para 58. [ 91 ] The Minister has clearly taken an approach to safety and efficacy that includes consideration of a balancing between the two. This approach is set out in both the 2006 and 2012 Guidelines.

I cannot conclude that this approach to assessing the regulatory requirements of " “safety” " and " “efficacy” " and exercising the discretion to issue a product licence is unreasonable in the context of the NHP Regulations .

Nor is expressing this through the commonly understood language of " “risk-benefit,” " or requiring an applicant to demonstrate that an NHP’s health benefits outweigh its risks before it is licensed, unreasonable. [ 92 ] I also note that C-RNA does not appear to have raised any concern with having to demonstrate that the benefits of Boluoke outweighed its risks at any time during the regulatory process, or to have argued that such a requirement is contrary to the NHP Regulations . Health Canada’s 2013 refusal of C-RNA’s first application included reference to the need for the benefit to outweigh the risk.

So did its 2014 IRN and the 2015 refusal. As set out above, this approach has been in the Minister’s Guidelines since at least 2006. Yet despite raising a number of criticisms during the process, C-RNA did not challenge the need for a positive risk-benefit balance.

While the Minister did not object to C-RNA raising the issue on this judicial review, applicants are generally precluded from raising new arguments on judicial review that have not been raised before the administrative decision-maker: Alberta (Information and Privacy Commissioner) v Alberta Teachers’ Association , 2011 SCC 61 at paras 22–26 . [ 93 ] I therefore reject C-RNA’s arguments that Health Canada unreasonably interpreted the NHP Regulations .

(2) Health Canada’s refusal of the application was reasonable [ 94 ] C-RNA argues that Health Canada acted unreasonably in its assessment of Boluoke by (

a) treating it as a " “high risk” " product under the 2012 Guideline; (

b) applying too high a standard for evidence of safety; (

c) refusing to license Boluoke when licences had been issued for other oral fibrinolytic enzyme products; (

d) failing to accept the potential for mitigation of safety risks; and (

e) ignoring evidence that favoured a finding that Boluoke is safe. While C-RNA asserted that a number of these matters also raised issues of procedural fairness, I find that they go to the merits of the decision rather than the process by which that decision was reached and are therefore more appropriately considered to be challenges to the substantive reasonableness of the decision.

For the reasons below, I disagree that any of C-RNA’s arguments shows Health Canada’s decision to be unreasonable. [ 95 ] In assessing these arguments, which invoke both the particular health concerns flagged by Health Canada and its review and assessment of the scientific evidence, I am particularly mindful of the caution that the Court is " “not to act as an academy of science” " : Greenpeace Canada v Canada (Attorney General) , 2016 FCA 114 at paras 60–61 . The Court does not sit in review of the scientific judgment of those to whom the legislation assigns the task of assessing safety and efficacy.

As a general observation, I view a significant portion of C-RNA’s arguments on reasonableness as an invitation to do just that. (

a) Treatment of Boluoke as a " “high risk” " product [ 96 ] As noted above, Health Canada’s 2012 Guideline classifies NHPs making modern health claims into one of three risk categories, and provides guidance on the nature of the evidence expected to demonstrate safety and efficacy in each category. The 2012 Guideline describes the high risk category as follows: High Level of Risk: This level applies to those products/ingredients that, through their intended use, present a serious health risk .

This category includes NHPs with the narrowest safety margin and effective dose range, as well as those used for treatment, cure, and prevention of serious diseases that require supervision by a health care practitioner , or are debilitating or potentially life threatening without effective treatment (refer to

section 2.4.1. for the definition of serious disease/condition claims). High level of risk includes, but is not limited to,

schedule A disease/conditions. [Emphasis added.] [ 97 ] Lumbrokinase was considered to be a " “high risk” " product based on Health Canada’s concerns about its fibrinolytic activity and resulting concerns about internal bleeding, and the associated concern that the conditions that it is generally used to treat are conditions that usually involve health practitioner supervision.

The IAS that gave the reasons for the final refusal stated the following: A general concern of substances that may enhance the breakdown of forming/formed clots (fibrinolytics) or inhibit platelet aggregation (anti-thrombotics) to prevent initial clot formation is the risk of internal bleeding , which may be tolerable when considered in the context of potentially life-threatening conditions (e.g., treatment of myocardial infarctions or pulmonary embolisms).

However, in the context of an NHP, where the majority of evidence relates to the purported efficacy of a substance as an anti-platelet therapy, a reasonable assumption would be that the substance is inherently riskier. … Similarly, the trepidation with LK are typical of the therapeutic class (e.g., fibrinolytic agents).

Hence, the categorization of LK as high risk, in the absence of likely or certain evidence of bleeding is not an unreasonable postulation given its therapeutic applications and fibrinolytic activity . […] The predominant uses of LK as evidenced in the submitted clinical trials and reflected through the clinical experiences of the experts (when LK is administered to cancer patients, persons with atherosclerosis, blocked veins, blood clots, etc.) , its ability to significantly influence not only tPA and the absence of clinical trial investigating its pharmacokinetics contribute to the gaps in the evidence.

While efficacy of LK is not the focus of the IAS, the information on its clinical applications includes a report of it effects being comparable to warfarin (Su et al. 2006), a prescription drug that is used to treat or prevent blood

clots in veins or arteries, which can reduce the risk of stroke, heart attack, or other serious conditions. … [Emphasis added; typographical errors corrected.] [ 98 ] C-RNA argues that there was no basis to consider Boluoke as " “high risk.” " It states that Boluoke does not claim to treat or cure a serious disease, that it ought to properly be considered a " “food,” " and that Health Canada’s decision to categorize Boluoke as high risk was based on information related to intravenous fibrinolytic products that are not comparable to Boluoke as an oral capsule. [ 99 ] I disagree that the categorization of Boluoke as high risk was unreasonable.

With respect to the question of health claims, C-RNA’s licence application states that Boluoke is to be used to " “reduce blood viscosity” " and " “improve circulation/hemorrheology.” " Its proposed amendments to these claims were variations on one or both of these themes.

As noted above, elements of C-RNA’s application also indicated that it sought approval of these claims specifically " “in hypercoagulable blood state.” " Either way, the claims indicate that they are intended to provide a health benefit in connection with blood viscosity and/or coagulation, even if they do not expressly use the words " “treat,” " " “cure” " or " “prevent.” " Indeed, as early as 2011, Health Canada gave its view that the claims " “reduce blood viscosity” " and " “improve circulation” " related to the fibrinolytic activity of lumbrokinase.

It maintained this position throughout, noting in its final rejection in 2016 that " “it is clear that the therapeutic benefits for LK are directed towards cardiovascular health.” " [ 100 ] The scientific primer agreed to by the parties indicates that patients with high blood viscosity (hyperviscosity) can have neurologic complaints such as loss of vision, and can be associated with various acute and chronic conditions including being a factor associated with heart disease and stroke.

Similarly, hypercoagulable states are associated with a predisposition to develop blood clots, which can result in pulmonary embolism, cerebral venous thrombosis, heart attack and stroke. Based on these descriptions, it is not unreasonable to associate lumbrokinase with the " “treatment, cure and prevention of serious diseases.” " Indeed, I note that " “thrombotic and embolic disorders” " are expressly listed on

Schedule A (now

Schedule A.1) to the FDA , referred to in the 2012 Guideline as indicating a high risk categorization. Again, this association is reasonable even if the health claims are not phrased as " “will treat blood hyperviscosity” " or " “for prevention of pulmonary embolism.” " [ 101 ] The same is true of Health Canada’s decision not to treat Boluoke as a food. The 2012 Guideline does indicate that demonstrating food use of a medicinal ingredient can support the safety of the ingredient.

However, while earthworms have traditionally been used as a food, the same cannot be said of Boluoke, which contains a refined extract derived from earthworms. The conclusion that Boluoke is a high risk product is not inconsistent with the possibility that safety of other NHPs may be shown through evidence of their use as a food. [ 102 ] C-RNA’s asserts that Health Canada’s concern about internal bleeding, and thus its high risk categorization, was based on a comparison to intravenous drugs and an " “erroneous assumption” " that Boluoke would be administered intravenously.

It points to the passage from the 2011 IRN underlined at paragraph [45] above, suggesting that the problems with the NNHPD’s analysis began with this error. [ 103 ] I believe C-RNA significantly misreads the passage. As I read it, there is no assumption that Boluoke will be administered intravenously. To the contrary, Health Canada is assessing the " “potential safety concerns for oral products ” " and the absence of evidence " “demonstrating long-term oral safe use of fibrinolytic enzymes” " [emphasis added].

Health Canada appears to be underscoring the serious nature of fibrinolytics as evidenced by the fact that they are used to treat patients with serious conditions, and are therefore administered intravenously and under medical supervision. In other words, the reason that fibrinolytics raised safety concerns for self-care is not that they are administered intravenously, but that they present such risks and are used to treat such serious conditions that they are generally seen in a medical setting in which they are administered intravenously and under physician care.

I also note that of the three scientific papers cited by Health Canada in the 2011 IRN as sources for the " “concern of the safety of fibrinolytic enzymes,” " at least one bears a title indicating that it relates to " “combined use of nattokinase and aspirin,” " suggesting oral and not intravenous administration. [ 104 ] In any event, it is clear from both the identified passage and from the extensive later communications from Health Canada that the safety concern about the risk of internal bleeding stemmed from lumbrokinase’s activity as a fibrinolytic agent, not its route of administration.

This concern was based on the physiological mechanisms of action and evidence of potential bleeding risks arising in both pharmaceutical and natural fibrinolytics and intravenous and oral administration. There was no dispute that lumbrokinase has fibrinolytic activity, and that it shows this activity when administered orally. Indeed, this was the very ground on which C-RNA sought approval of Boluoke as an NHP. [ 105 ] Health Canada’s concern about risk of internal bleeding stemmed from demonstrated risks arising in products in the same therapeutic class.

While C-RNA sought to draw distinctions based on asserted mechanisms of action and other activity, its own application was based on the lumbrokinase being " “one of the most powerful fibrinolytic agents.” " As noted by Health Canada in the passage reproduced at paragraph [97] , the available evidence showed lumbrokinase to have effects similar to oral warfarin, a drug that is only available by prescription. [ 106 ] C-RNA’s demands that Health Canada produce specific evidence showing that oral lumbrokinase can cause internal bleeding, and its submission that Health Canada’s failure to do so shows that its assessment was unreasonable, show a misunderstanding of the nature of the concern and the onus that was on C-RNA.

Health Canada’s concern was reasonably based on its scientific assessment of the evidence before it, and it was not required to " “prove” " that lumbrokinase is unsafe. Rather, the onus was on C-RNA under the NHP Regulations to file information in support of its application demonstrating the safety and efficacy of lumbrokinase. This fundamental framework error seems to permeate much of C-RNA’s submissions to Health Canada and to this Court, in which the NNHPD is denounced as unreasonable for not producing studies showing the dangers of lumbrokinase.

Health Canada is not required to show that a product is unsafe; an applicant is required to show that it is safe. While Health Canada could clearly not manufacture safety concerns entirely out of thin air, there is no evidence that it did so. It raised a supported and reasonable concern about safety, based on reasoned reference to safety evidence of similar products, including oral fibrinolytics, and the product under review.

Having done so, the onus was on C-RNA to provide information to address that concern with evidence that satisfied Health Canada of Boluoke’s safety. [ 107 ] C-RNA also claims that the categorization of lumbrokinase as " “high risk” " is inconsistent with an entry in a chart apparently

prepared by a Health Canada official in about 2012. That chart compares various information with respect to lumbrokinase and nattokinase. The final row in the chart is entitled " “Previous Risk Classification,” " and the entry for lumbrokinase is " “[w]ould recommend Type III in health adults (product is not likely to cause any adverse health consequences)” " [emphasis in original], whereas the entry for nattokinase is a higher Type II risk. I am unable to draw any conclusions about the reasonableness of Health Canada’s categorization from this document.

I have no information about what the " “Previous Risk Classification” " row signified in the chart, when or whether it applied, or whether the stated recommendation was adopted. In any case, even if Health Canada’s risk assessment with respect to lumbrokinase changed, about which there is no information, this does not alone render the later categorization unreasonable. (

b) Applying too high a standard for evidence of safety [ 108 ] C-RNA argues that Health Canada’s approach to the evidence of safety effectively required it to meet the stringent standards applicable to non-NHP drugs under the Food and Drug Regulations . I see no evidence that Health Canada demanded an unduly stringent level of evidence. [ 109 ] As the Court of Appeal stated in Winning Combination (FCA) , the very existence of the NHP Regulations implies different regulatory standards for the assessment of the safety and efficacy of NHPs and of other drugs: Winning Combination (FCA) at paras 14, 45, 58.

However, this does not mean that the requirement to demonstrate safety and efficacy is a low hurdle, or that Health Canada is required to accept information that has scientific shortcomings, particularly in respect of a product for which there are identified safety concerns. [ 110 ] The various communications between Health Canada and C-RNA, including the 2015 Notice of Refusal, the subsequent 2016 IRN and the final refusal in 2016, as well as the SEAR prepared internally by Health Canada, set out the nature of Health Canada’s review of the various scientific and non-scie

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