Apotex Inc. v. Canada (Health)

Apotex Inc. v. Canada (Health)
Court (s) Database
Federal Court Decisions
Date
2017-09-25
Neutral citation
2017 FC 857
File numbers
T-2011-15
Notes
A correction was made on November 30, 2017.
Decision Content
Date: 20170925
Docket: T-2011-15
Citation: 2017 FC 857
Ottawa, Ontario, September 25, 2017
PRESENT: The Honourable Mr. Justice Roy
BETWEEN:
APOTEX INC.
Applicant
and
MINISTER OF HEALTH AND ATTORNEY GENERAL OF CANADA
Respondents
JUDGMENT AND REASONS
I. Overview [1] In what is in the process of becoming a veritable saga concerning its Apo-Omeprazole Magnesium Tablets [or Apo-Omeprazole], the applicant is once again before this Court on a judicial review application, presumably pursuant to section 18.1 of the Federal Courts Act (RSC, 1985, c F-7). The relief sought is concerned with the decision of the Minister of Health [the Minister or the respondent] to cancel the reconsideration of Apotex’s submission concerning a Notice of Compliance [NOC] in respect of Apotex’s Apo-Omeprazole (omeprazole magnesium) Tablets and to treat its submission as withdrawn. That is the decision of the Minister of November 16, 2015, cancelling the reconsideration which the applicant wants squashed; the applicant also seeks that the Minister continue to process its submission without fettering her discretion “by insisting on strict compliance with policies and guidelines which do not have force of law”. The applicant seeks an alternative remedy:
• to direct the Minister to submit its preferred question to a reconsideration panel;
• to direct that it be afforded two hours to argue its case relative to its preferred question;
• to direct that it be permitted to make submissions to the Reconsideration Panel concerning “missed opportunities” for dispute prevention and/or earlier resolution of the dispute;
• to direct the Minister’s delegates to be prohibited from having ex parte discussions with the Reconsideration Panel.
[2] The applicant, Apotex Inc. [Apotex], manufactures and distributes pharmaceutical products, primarily generic versions of drugs that were first marketed by other manufacturers. All drug manufacturers must obtain a NOC from the Minister of Health to sell new drug products in Canada (section C.08.002(1) of the Food and Drug Regulations, CRC, c 870 [Regulations]). A NOC can be obtained in several ways. In this case, the mechanism for seeking a NOC for a generic version of an existing approved drug is the “abbreviated new drug submission” [or ANDS]. If the ANDS meets the requirements of the Food and Drugs Act [the Act], RSC, 1985, c F-27 and the Food and Drug Regulations, the Minister issues a NOC (para C.08.004(1)(a)).
[3] One of the criteria that an ANDS must meet is demonstrating that the drug is “bioequivalent” to the existing drug, referred to as the “Canadian reference product” [or CRP]. Bioequivalence is not defined in the Regulations, but Health Canada has published guidelines on how companies can demonstrate bioequivalence. For our purpose, it will suffice to refer to the notion of “bioequivalent” as described by Dr. Scott Appleton, who testified by affidavit for the respondent. Dr. Appleton holds degrees in pharmacology and toxicology, including a Doctorate (Ph. D.), as well as a Post-Doctoral Fellowship from Tulane University. He described bioequivalence at para 22 of his affidavit:
The generic drug is considered to be bioequivalent to the CRP once it has been determined that it can be expected to have the same systemic effects as the CRP when administered to patients under the conditions specified in the labeling of the "innovative drug".
[4] Apotex originally filed an ANDS in 2000 for “Apo-Omeprazole” tablets, an anti-ulcer drug. That submission was understood to be approved on March 7, 2003, given that the examination of the submission had been completed but placed on patent hold. In other words, the NOC would not issue until requirements of the Patented Medicines (Notice of Compliance) Regulations (SOR/93-133) were met, which, as I understand it, was on the expiration of a patent owned by AstraZeneca Canada Inc. (Apotex Inc. v Canada (Health), 2012 FCA 322 [Apotex], at para 4). Health Canada later revoked approval because the ANDS lacked a study showing bioequivalence to the CRP when the drug is taken with a high calorie/high fat meal. Eventually, in 2013, Apotex submitted a high calorie/high fat study (OMEC03), but the Minister refused to issue a NOC because she was not satisfied with the results of the study and the study design.
[5] Apotex pursued a reconsideration process offered by Health Canada, but the Minister ultimately refused reconsideration after the parties could not agree on a proper question to put to an external expert panel. Health Canada wanted to focus on bioequivalence and the only study, actually conducted in 1998, offered to demonstrate bioequivalence under fed conditions, the main reason why the approval given earlier had been revoked through a “Notice of Non-Compliance Withdrawal Letter” [or NONW] of February 9, 2009. In fact, the need to consider bioequivalence under fat fed conditions goes back to December 2008 when the Minister advised Apotex that its original examination was not completed in spite of the letter of March 2003. I note that this initial ANDS, which did not include a fat fed study resulted in the notice of Notice of Non-Compliance Withdrawal Letter on February 9, 2009. The Minister denied a request for reconsideration on July 27, 2009. An ANDS was resubmitted in 2013. It is that process which started in 2013 that gives rise to this latest judicial review application.
[6] The record at the time the decision was made to refuse reconsideration, on November 16, 2015, shows that Apotex’s proposed questions focused on whether Apo-Omeprazole was “safe and effective” rather than “bioequivalent”. During the hearing of this case, Apotex’s counsel suggested that the company knew it had to show bioequivalence, but hesitated to use that term in proposing reconsideration questions because it was concerned the Minister was fettering her discretion by strictly applying the bioequivalence standards in the guidelines. That was certainly not evident on the face of the exchanges, over a number of weeks, between Apotex and the Minister’s agents. Rather, the evidence points in the direction of Apotex seeking to circumvent the requirement to show bioequivalence.
[7] Apotex is asking the Court to quash the Minister’s November 16, 2015, decision to cancel the reconsideration process. The applicant argues that the Minister’s proposed question results from the fettering of the Minister’s discretion and does not meet its legitimate expectations. The respondent argues firmly that the question submitted by the Minister does not signal any fettering of its discretion and the applicant cannot validly expect that its question will prevail. Furthermore, the respondent argues that the matter cannot be returned for the reconsideration to take place on the basis that the question proposed by the Minister would be reasonable. In the view of the respondent, that is an alternative that is not possible since it is not a remedy sought by the applicant in its notice of application of December 1, 2015.
[8] For the reasons that follow, there is no fettering of discretion and the legitimate expectations of the applicant are not defeated.
II. Legislative and policy framework [9] Setting out the legislative and policy framework within which a manufacturer like Apotex obtains a NOC provides necessary context for the facts. There are three key legislative and policy aspects to this file: obtaining a NOC for an ANDS; meeting the “bioequivalence” criterion; and the reconsideration process.
[10] A NOC following an abbreviated new drug submission is based on less information than would be the case for a completely new drug, but the Canadian reference product and the drug for which compliance is sought must be, inter alia, bioequivalent. The requirement for a drug manufacturer to obtain a NOC before selling a new drug in Canada is set out under subsection C.08.002(1) of the Regulations. That provision provides that an ANDS, but also other types of submissions, must be “satisfactory” to the Minister for her to issue the NOC:
C.08.002 (1) No person shall sell or advertise a new drug unless
C.08.002 (1) Il est interdit de vendre ou d’annoncer une drogue nouvelle, à moins que les conditions suivantes ne soient réunies :
(a) the manufacturer of the new drug has filed with the Minister a new drug submission, an extraordinary use new drug submission, an abbreviated new drug submission or an abbreviated extraordinary use new drug submission relating to the new drug that is satisfactory to the Minister;
a) le fabricant de la drogue nouvelle a, relativement à celle-ci, déposé auprès du ministre une présentation de drogue nouvelle, une présentation de drogue nouvelle pour usage exceptionnel, une présentation abrégée de drogue nouvelle ou une présentation abrégée de drogue nouvelle pour usage exceptionnel que celui-ci juge acceptable;
(b) the Minister has issued, under section C.08.004 or C.08.004.01, a notice of compliance to the manufacturer of the new drug in respect of the submission; and
b) le ministre a délivré au fabricant de la drogue nouvelle, en application des articles C.08.004 ou C.08.004.01, un avis de conformité relativement à la présentation;
(c) the notice of compliance in respect of the submission has not been suspended under section C.08.006.
c) l’avis de conformité relatif à la présentation n’a pas été suspendu aux termes de l’article C.08.006.
(d) [Repealed, SOR/2014-158, s. 10]
d) [Abrogé, DORS/2014-158, art. 10]
...
(…)
(2) A new drug submission shall contain sufficient information and material to enable the Minister to assess the safety and effectiveness of the new drug, including the following:
(2) La présentation de drogue nouvelle doit contenir suffisamment de renseignements et de matériel pour permettre au ministre d’évaluer l’innocuité et l’efficacité de la drogue nouvelle, notamment :
…
(…)
It is clear that the ultimate purpose of the Regulations is to establish the safety and effectiveness of a new drug one wishes to sell or advertise in Canada. Not only does that transpire from the Regulations, but the Supreme Court of Canada, in another case involving omeprazole (but not omeprazole magnesium), commented that “(t)he FDA objective is 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, [2006] 2 SCR 560, para 12).
[11] If an innovator wishes to bring to market a new drug, its submission must include, pursuant to C.08.002(1):
(g) detailed reports of the tests made to establish the safety of the new drug for the purpose and under the conditions of use recommended;
(h) substantial evidence of the clinical effectiveness of the new drug for the purpose and under the conditions recommended;
As Justice Layden-Stevenson noted in Reddy Cheminor Inc.v Canada (Attorney General), 2003 FTC 542, 233 FTR 271, this kind of information is typically voluminous; the evidence in that case suggested that it could range from 100 to 300 volumes of data.
[12] There is fortunately a less expensive route that is made available in appropriate cases: the abbreviated new drug submission [or ANDS]. If a manufacturer wishes to copy a marketed drug, as opposed to bringing to market a completely new drug, it may avoid providing voluminous detailed reports and data demonstrating the required safety and effectiveness. The Regulations allow for a comparison with the Canadian reference product, a term defined in the Regulations in the following fashion:
C.08.001.1 For the purposes of this Division,
C.08.001.1 Les définitions qui suivent s’appliquent au présent titre.
Canadian reference product means
produit de référence canadien Selon le cas :
(a) a drug in respect of which a notice of compliance is issued under section C.08.004 or C.08.004.01 and which is marketed in Canada by the innovator of the drug,
a) une drogue à l’égard de laquelle un avis de conformité a été délivré en application des articles C.08.004 ou C.08.004.01 et qui est commercialisée au Canada par son innovateur;
(b) a drug, acceptable to the Minister, that can be used for the purpose of demonstrating bioequivalence on the basis of pharmaceutical and, where applicable, bioavailability characteristics, where a drug in respect of which a notice of compliance has been issued under section C.08.004 or C.08.004.01 cannot be used for that purpose because it is no longer marketed in Canada, or
b) une drogue jugée acceptable par le ministre et qui peut être utilisée pour la détermination de la bioéquivalence d’après les caractéristiques pharmaceutiques et, le cas échéant, les caractéristiques en matière de biodisponibilité, lorsqu’une drogue pour laquelle un avis de conformité a été délivré en application des articles C.08.004 ou C.08.004.01 ne peut être utilisée à cette fin parce qu’elle n’est plus commercialisée au Canada;
(c) a drug, acceptable to the Minister, that can be used for the purpose of demonstrating bioequivalence on the basis of pharmaceutical and, where applicable, bioavailability characteristics, in comparison to a drug referred to in paragraph (a); (produit de référence canadien)
c) une drogue jugée acceptable par le ministre qui peut être utilisée pour la détermination de la bioéquivalence d’après les caractéristiques pharmaceutiques et, le cas échéant, les caractéristiques en matière de biodisponibilité, par comparaison à une drogue visée à l’alinéa a). (Canadian reference product)
[my emphasis]
[13] The brand name drug (it is typically the case) marketed by the innovator is copied, and the “generic drug” will receive a NOC as long as it satisfies the conditions prescribed by the Regulations. It is C.08.002.1 that is particularly relevant. I reproduce it in its entirety in view of its importance in this case:
C.08.002.1 (1) A manufacturer of a new drug may file an abbreviated new drug submission or an abbreviated extraordinary use new drug submission for the new drug where, in comparison with a Canadian reference product,
C.08.002.1 (1) Le fabricant d’une drogue nouvelle peut déposer à l’égard de celle-ci une présentation abrégée de drogue nouvelle ou une présentation abrégée de drogue nouvelle pour usage exceptionnel si, par comparaison à un produit de référence canadien :
(a) the new drug is the pharmaceutical equivalent of the Canadian reference product;
a) la drogue nouvelle est un équivalent pharmaceutique du produit de référence canadien;
(b) the new drug is bioequivalent with the Canadian reference product, based on the pharmaceutical and, where the Minister considers it necessary, bioavailability characteristics;
b) elle est bioéquivalente au produit de référence canadien d’après les caractéristiques pharmaceutiques et, si le ministre l’estime nécessaire, d’après les caractéristiques en matière de biodisponibilité;
(c) the route of administration of the new drug is the same as that of the Canadian reference product; and
c) la voie d’administration de la drogue nouvelle est identique à celle du produit de référence canadien;
(d) the conditions of use for the new drug fall within the conditions of use for the Canadian reference product.
d) les conditions thérapeutiques relatives à la drogue nouvelle figurent parmi celles qui s’appliquent au produit de référence canadien.
(2) An abbreviated new drug submission or an abbreviated extraordinary use new drug submission shall contain sufficient information and material to enable the Minister to assess the safety and effectiveness of the new drug, including the following:
(2) La présentation abrégée de drogue nouvelle ou la présentation abrégée de drogue nouvelle pour usage exceptionnel doit contenir suffisamment de renseignements et de matériel pour permettre au ministre d’évaluer l’innocuité et l’efficacité de la drogue nouvelle, notamment :
(a) the information and material described in
a) les renseignements et le matériel visés :
(i) paragraphs C.08.002(2)(a) to (f), (j) to (l) and (o), in the case of an abbreviated new drug submission, and
(i) aux alinéas C.08.002(2)a) à f), j) à l) et o), dans le cas d’une présentation abrégée de drogue nouvelle,
(ii) paragraphs C.08.002(2)(a) to (f), (j) to (l) and (o), and subparagraphs C.08.002.01(2)(b)(ix) and (x), in the case of an abbreviated extraordinary use new drug submission;
(ii) aux alinéas C.08.002(2)a) à f), j) à l) et o) et aux sous-alinéas C.08.002.01(2)b)(ix) et (x), dans le cas d’une présentation abrégée de drogue nouvelle pour usage exceptionnel;
(b) information identifying the Canadian reference product used in any comparative studies conducted in connection with the submission;
b) les renseignements permettant d’identifier le produit de référence canadien utilisé pour les études comparatives menées dans le cadre de la présentation;
(c) evidence from the comparative studies conducted in connection with the submission that the new drug is
c) les éléments de preuve, provenant des études comparatives menées dans le cadre de la présentation, établissant que la drogue nouvelle :
(i) the pharmaceutical equivalent of the Canadian reference product, and
(i) d’une part, est un équivalent pharmaceutique du produit de référence canadien,
(ii) where the Minister considers it necessary on the basis of the pharmaceutical and, where applicable, bioavailability characteristics of the new drug, bioequivalent with the Canadian reference product as demonstrated using bioavailability studies, pharmacodynamics studies or clinical studies;
(ii) d’autre part, si le ministre l’estime nécessaire d’après les caractéristiques pharmaceutiques et, le cas échéant, d’après les caractéristiques en matière de biodisponibilité de celle-ci, est bioéquivalente au produit de référence canadien selon les résultats des études en matière de biodisponibilité, des études pharmacodynamiques ou des études cliniques;
(d) evidence that all test batches of the new drug used in any studies conducted in connection with the submission were manufactured and controlled in a manner that is representative of market production; and
d) les éléments de preuve établissant que les lots d’essai de la drogue nouvelle ayant servi aux études menées dans le cadre de la présentation ont été fabriqués et contrôlés d’une manière représentative de la production destinée au commerce;
(e) for a drug intended for administration to foodproducing animals, sufficient information to confirm that the withdrawal period is identical to that of the Canadian reference product.
e) dans le cas d’une drogue destinée à être administrée à des animaux producteurs de denrées alimentaires, les renseignements permettant de confirmer que le délai d’attente est identique à celui du produit de référence canadien.
(3) The manufacturer of a new drug shall, at the request of the Minister, provide the Minister, where for the purposes of an abbreviated new drug submission or an abbreviated extraordinary use new drug submission the Minister considers it necessary to assess the safety and effectiveness of the new drug, with the following information and material:
(3) Le fabricant de la drogue nouvelle doit, à la demande du ministre, lui fournir, selon ce que celui-ci estime nécessaire pour évaluer l’innocuité et l’efficacité de la drogue dans le cadre de la présentation abrégée de drogue nouvelle ou de la présentation abrégée de drogue nouvelle pour usage exceptionnel, les renseignements et le matériel suivants :
(a) the names and addresses of the manufacturers of each of the ingredients of the new drug and the names and addresses of the manufacturers of the new drug in the dosage form in which it is proposed that the new drug be sold;
a) les nom et adresse des fabricants de chaque ingrédient de la drogue nouvelle et les nom et adresse des fabricants de la drogue nouvelle sous sa forme posologique proposée pour la vente;
(b) samples of the ingredients of the new drug;
b) des échantillons des ingrédients de la drogue nouvelle;
(c) samples of the new drug in the dosage form in which it is proposed that the new drug be sold; and
c) des échantillons de la drogue nouvelle sous sa forme posologique proposée pour la vente;
(d) any additional information or material respecting the safety and effectiveness of the new drug.
d) tout renseignement ou matériel supplémentaire se rapportant à l’innocuité et à l’efficacité de la drogue nouvelle.
(4) For the purposes of this section, in the case of an abbreviated new drug submission, a new drug for extraordinary use in respect of which a notice of compliance has been issued under section C.08.004.01 is not a Canadian reference product.
(4) Pour l’application du présent article, dans le cas d’une présentation abrégée de drogue nouvelle, la drogue nouvelle pour usage exceptionnel à l’égard de laquelle un avis de conformité a été délivré en application de l’article C.08.004.01 n’est pas un produit de référence canadien.
[my emphasis]
[je souligne]
[14] The scheme of the Regulations appears to be relatively straight forward. The goal is to have safe and effective medicines; in order to achieve that goal the manufacturer may bring an ANDS if the conditions are met, one of which being that the new drug is bioequivalent with the Canadian reference product. As I read para C.08.002.1(1) and (2), this is not a discretionary option. The goal is for medicines to be safe and effective, and the way to get there passes through section C.08.002.1, which includes bioequivalence. As I read the Regulations, those requirements cannot be circumvented.
[15] The Minister must therefore consider the bioequivalence between the Canadian reference product and the new drug in its generic version. If the generic product is bioequivalent to the reference product, which has already been approved, then it should be acceptable despite not providing “detailed reports of the tests made to establish the safety of the new drug for the purpose and under the conditions of use recommended” and “substantial evidence of the clinical effectiveness of the new drug for the purpose and under the conditions of use recommended” (para C.08.002 (2)(g) and (h)), which undeniably constitutes a heavy burden. But bioequivalent it must be.
[16] The quid pro quo is that the ANDS does not include the voluminous information described at C.08.002(2)(g) and (h) as seen at C.08.002.1(2)(a)(i). If the requirements of C.08.002.1 are satisfied by a generic manufacturer, it will not have to present the extensive evidence that was required of the innovator. Pursuant to subsection C.08.004(1), the Minister must issue a NOC if the ANDS complies with subsection C.08.002.1 as set out above. The NOC that would be issued in those circumstances “shall constitute a declaration of equivalence for that new drug” (C.08.004(4)).
[17] The ANDS is submitted to the Therapeutic Products Directorate [or TPD] at Health Canada. It is naturally the Minister of Health who has the authority to issue the NOC; this authority is typically delegated to the Director General of the TPD.
III. Context [18] It is helpful to put this case in its broader context before considering further the mechanism of “reconsideration” that is the subject of the challenge in this case.
[19] The NOC sought by Apotex in the early 2000’s had received a positive reception from Health Canada. On March 7, 2003, Health Canada wrote to Apotex to confirm that the examination of the ANDS for Apo-Omeprazole (Omeprazole magnesium) was completed. It is not disputed that this signalled a positive examination, but the final determination could not be communicated in view of the fact that there was a patent in place.
[20] On December 5, 2008, Apotex was advised that its ANDS was not “approvable at this time”. The reason for the position change was that the earlier decision was based on the ingestion of the tablet in circumstances where the person was fasting (OMEC14) and where the meal was low in fat and calories (OMEC13 and OMEC16). It appears that with greater experience with this kind of medication, Health Canada came to the realization that submissions had to include the full spectrum, from fasted to standard fed conditions. That includes not only low fat/low calorie meals, but also high fat meals. Thus, the satisfaction of the bioequivalence requirement needed evidence under both fasted and standard fed conditions, which the ANDS did not provide.
[21] The letter went on to request that Apotex submit a high fat fed pharmacokinetic study, or a high fat fed pharmacodynamics study in patients or any other scientific rationale with data that would support evidence of bioequivalence. Given the delay in reaching a negative conclusion, Health Canada offered its assistance in discussing an appropriate study design and committed to quickly consider the evidence in the context of the entirety of the submission and to perform an expeditious review in order to decide on the disposition of the submission.
[22] Two things appeared to be very clear. Health Canada was insisting on bioequivalence and evidence of bioequivalence had to be under both fasted and high fat fed conditions. We now know that Apotex never produced satisfactory evidence of bioequivalence under high fat fed conditions in its initial ANDS.
[23] Non-compliance was found by the Minister and reconsideration was denied. Apotex challenged on judicial review more than a year later. Apotex sought to argue before this Court that it was entitled to its NOC because it claimed that it had acquired a vested right. In Apotex Inc. v Canada (Health), 2011 FC 1308; 400 FTR 28, my colleague Justice Robert Barnes reported that following the December 5, 2008, letter, the Minister issued a notice of non-compliance withdrawal letter for Apo-Omeprazole Tablets. A request for reconsideration of the decision to issue the Notice of Non-Compliance was also denied, this time on July 28, 2009. The Challenge to the three “decisions” was brought on August 26, 2010. Apotex had argued that the “decisions” were “unlawful, unreasonable, unfair, discriminatory, illogical, scientifically untenable and biased” (para 14). Barnes J. concluded that the application was out of time. Nevertheless, my colleague considered if Apotex had a vested right in view of the March 7, letter. If there is a vested right to a NOC, arguably there may be an entitlement to bring judicial review at any time to enforce the vested right. He concluded:
[33] It seems quite obvious to me that until a NOC is issued, a proponent enjoys no vested interest in a favourable outcome at least with respect to issues that properly fall within the Minister’s lawful discretion (ie. pertaining to public safety and efficacy). There is no legal significance attaching to an application for a NOC that has been placed on patent hold. The Minister is fully entitled to revisit scientific issues at any point in the process up to the actual issuance of a NOC. It is only at that point that the Minister’s examination is completed in accordance with C.08.004 of the Food and Drug Regulations, RSC 1985, c F-27.
[24] Apotex appealed (2012 FCA 322; 443 NR 291). The Federal Court of Appeal agreed with the Federal Court that Apotex’s application was out of time. Furthermore, the Court rejected the argument that the Minister is compelled to issue a NOC once Apotex was notified that the submission was satisfactory, at the time, for the purpose of the Regulations. The purpose of the Act and the Regulations being to bring safe and effective medicines to market, the Court of Appeal found that it would be absurd to “construe the Regulations in such a way that the Minister could be compelled to issue a NOC even if she was not satisfied that the drug in question is safe and effective” (para 30). Moreover, the Court of Appeal did not accept that Apotex had a legitimate expectation that the NOC would be issued once the patent hold was over: the legitimate expectation doctrine does not confer substantive rights of the nature sought.
[25] As can be seen, the Federal Court of Appeal was insistent that the safety and effectiveness of the drug was the governing principle. The Minister was entitled to come to the conclusion that more was needed in order to be satisfied of the safety and effectiveness. That in effect was the long and short of it. The concerns about safety and efficacy were found to be bona fide:
[44] Before leaving this point, I have considered Apotex’ submission that it was “unfair and arbitrary” for the Minister’s officials to prefer the negative result of a 2008 review of its submission over the positive result obtained in 2002 when, it alleges, there had been no material change in circumstances. I have also considered its argument that the conduct of the Minister’s officials gives rise to a reasonable apprehension of bias.
[45] Apotex’ evidence on these points was addressed by the Minister.
[46] On the whole of the evidence I find that Apotex has failed to establish that the Minister’s safety and efficacy concerns were not bona fide. The evidence is consistent with there being significant uncertainty within the Therapeutic Products Directorate of Health Canada about the appropriate bioequivalence requirements to be applied to proton pump inhibitors. Such scientific uncertainty does not detract from the bona fides of the Minister’s safety and efficacy concerns.
[26] While Health Canada was steadfast that bioequivalence had to be established on the full spectrum (from fasting to high fat fed meals) in order to be satisfied that the drug is bioequivalent, and thus was safe and effective, it was also willing to assist in creating a study that could prove to be appropriate. It stated plainly that any other scientific rationale with data that would support evidence of bioequivalence would be received. The data thus produced would be reviewed expeditiously. Obviously, nothing happened and OMEC03 was not produced. A Notice of Non-Compliance Withdrawal Letter with respect to that first submission was issued and, as noted by Barnes J., reconsideration was denied on July 27, 2009. It took more than a year to apply to this Court on judicial review, which was found to be fatal in and of itself. Moreover, the two federal courts commented on the ability of the Minister to seek more information to ascertain bioequivalence.
[27] Finally, on February 4, 2013, Apotex refiled its ANDS; this time it included the 1998 fed study with a high fat meal, the OMEC03 study, after it sought to offer a study that was found to be inadequate. It was not successful and notice of non-compliance was issued on November 28, 2013.
[28] In the end, the various chapters in this particular episode boil down to this. Apotex was on its way to approval for its Apo-Omeprazole Tablets on March 7, 2003, on the basis of studies that did not include high fat/high calorie meals. However, the regulator concluded on December 5, 2008, that approval could not be given because bioequivalence was not demonstrated: evidence of bioequivalence under both fasted and standard fed conditions was found to be necessary. Instead of providing the evidence of bioequivalence, Apotex chose to challenge the decision arguing that rights had vested; it was unsuccessful before this Court and the Federal Court of Appeal. Apotex ultimately submitted its 15-year old OMEC03 study as its only study meant to satisfy the concerns about bioequivalence.
[29] The Notice of Non-Compliance of November 28, 2013, is explicit that not only the standards to determine bioequivalence between Apotex’s new drug and the Canadian reference product under high fat fed conditions were not met, but equally important Health Canada complained that the test meal (760 calories instead of the required 1000) was not a standard high calorie/high fat meal; indeed, the sampling protocol was not adequate, the study was not adequately powered and three enteric-coated tablets were administered instead of only one. The letter offers precise guidance concerning what would be required in the design and implantation of a new study. There was no new study and there has not been a new one.
IV. Reconsideration [30] Instead of devising a new study with a view to satisfy Health Canada’s requirement that there be bioequivalence under high fat/high calorie fed meal or challenging the refusal on judicial review, Apotex chose to seek “reconsideration”.
[31] As the document “Guidance for Industry – Reconsideration of Final Decisions Issued for Human Drug Submissions” states, Health Canada has put in place a policy the purpose of which is to resolve drug submission-related disputes; it applies to ANDS.
[32] If the Minister issues a notice of non-compliance withdrawal for a drug submission, the sponsor can request a reconsideration process described in a policy document.
[33] The Guiding Principles for Dispute Resolution require staff to “resolve disputes in a fair and timely manner, using the most appropriate dispute resolution mechanism.” The principles are fairness, accountability, and accessibility. The reconsideration process is a formal dispute resolution mechanism and is intended to be used when informal dispute resolution mechanisms have failed.
[34] The sponsor files the request for reconsideration and the Office of Science recommends to the Director General of the Therapeutic Products Directorate a process to be followed to address the reconsideration request, which could include referring the issues to an external panel, reviewing the issues within the Office of Science, or a combination.
[35] The Director General decides what process to follow and informs the sponsor. Here, the matter was to be handled by a reconsideration panel. Its composition is determined by the sponsor (Apotex) and by the affected Directorate (Therapeutic Products Directorate) each recommending a panel member with the Director General appointing the panel’s chair.
[36] The more difficult issue may well be the determination of the parameters, or mandate, of the Reconsideration Panel. In this case, Apotex and the Director General were incapable to reach an agreement on the question to be posed to the Panel, which led to the cancellation of the process on November 16, 2015. That constitutes the only decision which is the subject of the judicial review.
[37] The Reconsideration Policy does not detail how the sponsor and Health Canada are to agree on the question put to the Reconsideration Panel. The Policy simply states that “the Office [of Science] will work with the sponsor and the review bureau/centre to draft specific questions to be posed” to the Scientific Advisory Committee or the Panel. However, the Policy provides clear indications of the type of issues that could go to a reconsideration panel. Thus, the Policy lists examples of issues that are generally appropriate for referral to an external panel:
- interpretation of available data;
- disagreement in applied methodology; and
- relative weights given to data impacting on the risk/benefit assessment of the submission information.
The Policy also indicates what issues are generally inappropriate for referral to an external panel:
- submission of false information;
- allegations of bias;
- matters in which regulatory policy/guidance or procedures are the dominant concern; and
- an issue on which the Directorate has available recent external independent expert opinion.
[38] Obviously, the Policy contemplates issues of a technical nature. Matters of regulatory policy or procedure are not contemplated. Furthermore, the Policy is focused on discrete issues to be brought before the Panel whose role is purely advisory:
The roles and responsibilities of the Panel, and the process for obtaining its advice will be the same as for the SAC outlined in Section 5.3.1(a). Consistent with its advisory role, the Panel will not be asked to make a decision on the submission; rather, advice will be solicited through one or more direct questions related to the specific outstanding issue(s) identified.
[my emphasis]
(Policy, 5.1.3(b) Reconsideration Panel)
[39] I fail to see how that process can be understood to suggest that it constitutes, for all intents and purpose, an appeal of sorts. It is rather a process put in place to address discrete issues of a technical nature where the Director General of the Therapeutic Products Directorate plays a central role. She appoints the panel chair; she will receive the advice of a panel; she will make the reconsideration decision. The Panel members have expertise relevant to the resolution of the matter raised, not on matters of regulatory guidance or procedure. Issues around data, methodology and weight to be given to data impacting on the risk/benefit assessment are apposite. Are not matters in which regulatory policy or procedures are the dominant concern.
[40] In a sense, the Director General is not wrong to say that it is her process: she makes the final reconsideration decision and the advice is for her. She may also refuse a reconsideration filed for decisions that are not eligible. Indeed, her role is defined in the following fashion in the Policy:
The Director General of TPD or BGTD or his/her designate is responsible for:
• refusing Reconsiderations filed for decisions that are not eligible;
• deciding whether to consider information filed in the Request of Reconsideration;
• deciding on the process for the disposition of the Request for Reconsideration;
• deciding on the use and membership of the Scientific Advisory Committee or Reconsideration Panel (if applicable); and
• making the Reconsideration decision.
(Policy, 4. Roles and Responsibilities)
Obviously, a director general who would not be acting in good faith or would display bias, for instance, may well attract scrutiny on judicial review despite the high degree of discretion reposed in her. Fairness commands no less. But there is no such allegation here.
[41] I have not found any indication suggesting that the sponsor has an unhampered ability to raise whatever issue it sees fit. In fact, it is quite the opposite. Issues that may be ripe for reconsideration appear rather to be of a particular ilk. That may well be why the Policy requires that the Drug Submission sponsor work with the Office of Science in the Therapeutic Products Directorate to draft questions to be posed to the Reconsideration Panel. Contrary to what Apotex asserted, the reconsideration process is not adversarial with the Panel as a judge of the matter raised by a sponsor. It is rather a process where experts in a field will provide advice to a Director General on discrete issues that have been identified in questions agreed to by the sponsor and Office of Science of the TPD. It is a way to avoid disputes: as stated in the Policy, “(i)f, at any time during the Reconsideration process, the sponsor files a Notice of Application to the Federal Court to resolve the matter, the Directorate will terminate the Reconsideration process”. That reconsideration process resulted in an impasse in this case. While Apotex insisted that the question to be posed to the Reconsideration Panel had to turn on whether its new drug is safe and effective, the Therapeutic Products Directorate was of the view that the focus of the question had to be on bioequivalence.
V. The reconsideration process: the Question [42] Apo-Omeprazole belongs to a class of drugs termed “proton pump inhibitors” or “PPIs”. PPIs inhibit gastric acid production to address problems such as ulcers. PPIs are unstable in acidic conditions; therefore, they are made with an enteric coating for protection in the stomach so they can pass into the intestine where they are absorbed into the body. The Canadian reference product for the Apo-Omeprazole ANDS is “Losec”, wh