Date: 20090505
Docket: T-394-08
Citation: 2009 FC 452
Ottawa, Ontario, May 5, 2009
PRESENT: The Honourable Mr. Justice Phelan
BETWEEN:
APOTEX
INC.
Applicant
and
MINISTER OF HEALTH and
ATTORNEY
GENERAL OF CANADA
Respondents
REASONS FOR JUDGMENT AND JUDGMENT
I. INTRODUCTION
[1]
Apotex
Inc. (Apotex), a generic pharmaceutical manufacturer, seeks judicial review of
a decision by the Minister of Health (Minister) to refuse to issue a Notice of
Compliance (NOC) for Apotex’s version of aspirin.
[2]
More
specifically, the NOC application, which – if granted – would permit the sale
of a drug, dealt with Apotex’s Abbreviated New Drug Submission (ANDS) for its
acetylsalicylic acid (ASA) 81 mg enteric-coated tablets (Apo-ASA).
[3]
The
relief Apotex initially sought was a mandamus order to issue a NOC; a
relief which it conceded was not available. It revised its relief sought to the
following:
Remedy
In the alternative, an order in the
nature of mandamus compelling the Minister to consider the safety and
efficacy of the Apo-ASA submission without restricting such consideration to
the mere application of the standards for bioequivalence set out in the Report
“B” Guidelines and to provide Apotex an intelligible explanation of why the
ANDS is not sufficient to demonstrate Apo-ASA to be safe or why the ANDS is not
sufficient to demonstrate Apo-ASA to be effective, and compelling the Minister
to, or in the alternative compelling the Minister to consider whether to,
thereafter submit any issue still in dispute to an Appeal Panel pursuant to the
Minister’s Appeal Procedures and the agreement between the Minister and Apotex
dated May 24, 2005.
II. BACKGROUND
[4]
ASA,
or aspirin, has been available as a medicine in Canada for several
decades and is commonly available over the counter in strengths of 325 and 650
mg as well as 80 or 81 mg for paediatric use.
[5]
In
Apotex’s ANDS filing, it included both a fasted and a fed bioequivalence study,
as required in the Report B Guidelines (Guidelines). In a bioequivalence study,
the new drug is measured against a comparator or reference drug – which, in
this case, was Bayer ASA 81 mg enteric-coated tablets (B-ASA).
[6]
Apotex
filed an ANDS for its Apo-ASA with the Therapeutic Products Directorate (TPD).
[7]
Apotex’s
fasted study met the Minister’s bioequivalence standards. However, the fed
study included two subjects for which the data did not meet the Minister’s
standards. The results for these two subjects were outside the range of
deviation established by the Guidelines, e.g. 80-125% of the AUC (area under
the curve).
[8]
It
was Apotex’s position that the reference drug was defective and that this was
the reason for the difference between Apo-ASA and B-ASA. The Apo-ASA delivered
more of the drug to the subject than did the B-ASA.
[9]
As
a result of Apotex’s position, it excluded the results from these two subjects
from the data analysis when submitting its ANDS.
[10]
The
TPD issued a Notice of Non-Compliance (NON) on January 26, 2007, indicating,
along with some minor deficiencies, the major deficiency of the data exclusion
in the fed study. The minor deficiencies were resolved prior to this hearing, leaving
the issue in dispute: the problem of the fed study and the Minister’s refusal
to accept Apotex’s position.
[11]
Apotex’s
response to the NON was to repeat its position regarding the B-ASA reference
drug. It also claimed that the Grubbs test (an analysis method) for outliers
supported the exclusion of the problematic data. However, it recognized that
another analysis method provided a different perspective in that it did not
identify the two excluded subjects’ data as outliers.
[12]
Apotex
also submitted an expert opinion that the apparent lack of bioequivalence could
be attributed to the occasional failure of the reference drug.
[13]
On
October 5, 2007, the TPD issued a NON Withdrawal letter (NONW) which had the
effect of considering Apotex’s ANDS withdrawn without prejudice to its right to
re-file.
[14]
Apotex
then asked for a reconsideration in which it asserted that its product was safe
and that a failure to prove bioequivalence was not fatal to an application.
[15]
On
January 15, 2008, TPD’s Director General informed Apotex that the Office of
Science had completed its review and that the Director General confirmed that
the NONW was upheld.
[16]
Thereafter
there was a series of communications in which Apotex continued to explain why
the NOC should be issued. The Minister responded once confirming that no NOC
would be issued and otherwise did not respond to further entreaties.
[17]
The
crux of the Minister’s position was set forth in the January 26, 2007 NON:
Current TPD practice does not allow for
the exclusion of data from the statistical analysis without a valid
physiological or clinical justification. Further, the justification provided
for the exclusion of data from subject 02 and 23 due to a purported product
failure is not acceptable.
The NON concluded that the standards for
bioequivalence had not been proven and as such the safety and efficacy of the
Apo-ASA had not been proven either. Lastly, the NON specified that Apotex could
conduct a second comparative bioavailability (bioequivalency) study but the
results thereof would be combined with the existing study.
[18]
In
the subsequent NONW, the TPD set out its concern that Apotex’s product caused
the non-equivalence due to its concentration of SA and that there was no
failure of the reference product. The NONW also varied the statement made in the
NON by permitting a new study to replace the existing study, rather than necessitating
the combination of the two results.
[19]
The
Minister’s letter of February 11, 2008 closed off further debate in confirming
that full consideration had been given, that the decision was consistent with
TPD policy, and consequently no NOC would be issued based on the existing submitted
data.
[20]
Apotex
raises three issues in this judicial review:
a.
Whether
the Minister fettered his discretion by rigidly following its Guidelines;
b.
Whether
there were no intelligible reasons for the Minister’s decision that the product
was not safe and effective; and
c.
Whether
there was unfairness in the system used by the Minister, particularly as there
was a legitimate expectation of improvement and fair treatment in the system as
well as of an external appeal, all of which is said to flow from a Settlement
Agreement.
III. ANALYSIS
A. Standard
of Review
[21]
The
real issue in dispute is the decision that the ANDS did not have enough data to
satisfy the Minister that Apo-ASA was safe and effective. This is a largely
factual determination by an expert body and therefore is reviewable on a
standard of reasonableness (Dunsmuir v. New Brunswick, 2008 SCC
9).
[22]
The
issues of intelligibility of the reasons and of legitimate expectation are
matters of fairness. As such, they are issues determined either outside the
realm of a standard of review analysis or are subject to a correctness standard
(see Dunsmuir, above, and Baker v. Canada (Minister of
Citizenship and Immigration), [1999] 2 S.C.R. 817).
B. Fettering
Discretion
[23]
The
regulatory scheme governing NOCs is saturated with Ministerial discretion. The
key provision is C.08.002(1) of the Food and Drug Regulations (FDA Regs):
|
C.08.002. (1) No person
shall sell or advertise a new drug unless
(a) the manufacturer of the new drug has
filed with the Minister a new drug submission or an abbreviated new drug
submission relating to the new drug that is satisfactory to the Minister;
(b) the Minister has issued, pursuant to
section C.08.004, a notice of compliance to the manufacturer of the new drug
in respect of the new drug submission or abbreviated new drug submission;
(c) the notice of compliance in respect of
the submission has not been suspended pursuant to section C.08.006; and
(d) the manufacturer of the new drug has
submitted to the Minister specimens of the final version of any labels,
including package inserts, product brochures and file cards, intended for use
in connection with that new drug, and a statement setting out the proposed
date on which those labels will first be used.
|
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) le
fabricant de la drogue nouvelle a, relativement à celle-ci, déposé auprès du
ministre une présentation de drogue nouvelle ou une présentation abrégée de
drogue nouvelle que celui-ci juge acceptable;
b) le
ministre a, aux termes de l'article C.08.004, délivré au fabricant de la
drogue nouvelle un avis de conformité relativement à la présentation de
drogue nouvelle ou à la présentation abrégée de drogue nouvelle;
c) l'avis
de conformité relatif à la présentation n'a pas été suspendu aux termes de
l'article C.08.006;
d) le
fabricant de la drogue nouvelle a présenté au ministre, sous leur forme
définitive, des échantillons des étiquettes—y compris toute notice jointe à
l'emballage, tout dépliant et toute fiche sur le produit—destinées à être
utilisées pour la drogue nouvelle, ainsi qu'une déclaration indiquant la date
à laquelle il est prévu de commencer à utiliser ces étiquettes.
[Emphasis added]
|
[24]
FDA
Reg C.08.004(1) provides that where a new drug submission or ANDS meets the
above regulation, the Minister shall issue a NOC. If it does not meet the above
regulation, the Minister shall notify the manufacturer that it does not comply.
[25]
Lastly,
FDA Reg C.08.002.1 provides that an ANDS is to contain sufficient information
and material to enable the Minister to assess the safety and effectiveness of
the drug. That information and material is to include evidence of comparative
studies and, where the Minister considers it necessary, bioavailability studies
showing the bioequivalence with a Canadian reference product.
[26]
The
precise wording of the applicable regulation is:
|
C.08.002.1. (1) A manufacturer of a new drug may file an abbreviated
new drug submission for the new drug where, in comparison with a Canadian
reference product,
(a) the new drug is the pharmaceutical
equivalent of the Canadian reference product;
(b) the new drug is bioequivalent with the
Canadian reference product, based on the pharmaceutical and, where the
Minister considers it necessary, bioavailability characteristics;
(c) the route of administration of the new
drug is the same as that of the Canadian reference product; and
(d) the conditions of use for the new drug
fall within the conditions of use for the Canadian reference product.
(2) An abbreviated new drug submission shall contain sufficient
information and material to enable the Minister to assess the safety and
effectiveness of the new drug, including the following:
(a) the information and material described
in paragraphs C.08.002(2)(a) to (f) and (j) to (l);
(b) information identifying the Canadian
reference product used in any comparative studies conducted in connection
with the submission;
(c) evidence from the comparative studies
conducted in connection with the submission that the new drug is
(i) the pharmaceutical equivalent of the Canadian
reference product, and
(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, pharmacodynamic studies or
clinical studies;
(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
(e) for a drug intended for administration
to food-producing animals, sufficient information to confirm that the
withdrawal period is identical to that of the 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 si, par comparaison à un produit de
référence canadien :
a) la
drogue nouvelle est un équivalent pharmaceutique du produit de référence
canadien;
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) la voie
d'administration de la drogue nouvelle est identique à celle du produit de
référence canadien;
d) les
conditions thérapeutiques relatives à la drogue nouvelle figurent parmi
celles qui s'appliquent au produit de référence canadien.
(2) La présentation abrégée 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 :
a) les
renseignements et le matériel visés aux alinéas C.08.002(2)a) à
f) et j) à l);
b) les
renseignements permettant d'identifier le produit de référence canadien
utilisé pour les études comparatives menées dans le cadre de la présentation;
c) les
éléments de preuve, provenant des études comparatives menées dans le cadre de
la présentation, établissant que la drogue nouvelle :
(i) d'une part, est
un équivalent pharmaceutique du produit de référence canadien,
(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) 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) 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.
|
[27]
The
FDA Regs explicitly require proof of a drug’s safety and efficacy to the
Minister’s satisfaction (on a reasonable basis). In order to assist
manufacturers and sponsors in satisfying the Minister, the department has
issued the Report B Guidelines which deal with the methodology for
bioequivalence studies for enteric-coated drugs.
[28]
The
Guidelines state that alternative approaches may be acceptable but should be
discussed in advance. Further, the foreword warns that Health Canada reserves
the right to require more and other information not prescribed in the
Guidelines to allow the department to adequately assess the “safety, efficacy
or quality of a therapeutic product”.
[29]
In
sum, the Guidelines set out the general approach to establishing
bioequivalency, they allow for exceptions where justified, and they warn that
there is no assurance of approval upon filing of the requestor’s submissions.
That flexibility is consistent with the general public law principle that
guidelines, policies, or similar non-legislated documents are permissible (even
encouraged) but that they must allow for exceptions where justified.
[30]
The
Minister’s analysis clearly stated its concerns with the Applicant’s
explanation for the bioequivalence issue. It assessed the evidence and relied
on the recommendations of scientific experts.
[31]
The
Applicant was given every opportunity, including a reconsideration, to submit
new or better evidence and submissions. It chose to merely reiterate the
arguments it had already made. Repetition did not and could not make the
problem disappear.
[32]
The
process followed showed that the Minister was not blindly following a policy
for the mere sake of doing so. The process showed that the Minister remained
open to new and better evidence.
[33]
It
is important to bear in mind that the Guidelines represent an indication of
what type of evidence will satisfy the “Minister’s opinion”. Any departure
therefrom must be justified.
[34]
The
Guidelines represent what the Minister is prepared to support by issuing a NOC.
It is the Minister who bears the responsibility for approval and is likely to
be held legally responsible (in whole or in part) in the case that harm results
from drugs approved despite a departure from established criteria.
[35]
It
is not unreasonable, nor is it intransigence, for the Minister to demand
compliance with the Guidelines in the absence of a clear indication that an
alternative approach is justified.
[36]
Apotex’s
reliance on Justice Lemieux’s decision in Delisle v. Canada (A.G.), 2006
FC 933, for the limitation/prohibition on non-statutory instruments is
misplaced. In Delisle, the applicable policy failed to reflect
Parliament’s intention to balance unproven science with humanitarian needs in
the use of experimental drugs. The Guidelines in this case are not designed,
nor are they required, to strike this type of public policy balance. These
Guidelines are principally scientific bench marks with ranges of acceptable
compliance.
[37]
Therefore,
the Minister’s decision not to accept Apotex’s demand for a NOC on the basis of
non-compliant data was not unreasonable. The record shows that the Minister
applied the Guideline requirements in a manner which recognized a possibility
of exceptions; but was not satisfied, on reasonable grounds, that an exception
should be granted.
[38]
The
Minister’s decision was based on a lack of evidence presented, and not on an
unreasonable refusal to vary the bioequivalence guidelines.
C. Absence
of Intelligible Reasons
[39]
The
Minister’s decision included lengthy and detailed reason for his concerns about
the bioequivalence data. The detailed notes of the reviewer are found at page
1155 of the Applicant’s Record.
[40]
The
Minister did not accept Apotex’s bare statement that the failure of the
bioequivalence data was the result of a defect in the reference drug. While the
Minister did not reject the claim as impossible, there was insufficient
evidence to satisfy him. This speaks to the reasonableness of the decision and to
its intelligibility.
[41]
The
Minister highlighted to Apotex what his concerns were and what data would be
necessary in order to satisfy the Minister that the drug was safe and
effective. There is no basis for a claim that the Minister did not provide
intelligible reasons.
[42]
In
the end, one is left with a difference of opinion between the Minister (and his
expert staff) and Apotex. It is not the Court’s role, in this instance, to
resolve that difference. It is sufficient that the Minister’s opinion or lack
of satisfaction is rationally based and adequately explained. It was.
D. Breach
of Procedural Fairness
[43]
Apotex’s
submissions on this point are that, as a result of a settlement of previous litigation,
it had a commitment from the Minister for a better and fairer system for
resolving differences of scientific opinion - including a better articulation
of the Minister’s rationale, and the availability of a scientific panel to
resolve disputes.
[44]
The
evidentiary basis of this claim included part of the settlement agreement, as
well as the procedure followed in this case. At issue is whether a new policy
which the Minister set complies with the settlement.
[45]
Firstly,
if there has been a breach of the terms of the settlement, that is a matter of
contract which is more properly the subject of an action in this Court.
Secondly, there is a lack of an evidentiary base upon which to make any
determination of non-compliance with an agreement, much less any conclusion as
to the legal ramifications flowing from alleged non-compliance.
[46]
Viewing
this matter as a whole, I can find no procedural unfairness in the process
followed. The Applicant knew what the issues were, had a full opportunity to
address those issues, and received a clearly reasoned expression of the
Minister’s opinion (which was formed on reasonable grounds).
[47]
Apotex
also complained that the witness put forward by the Minister was inadequate in that
she could not answer or refused to answer questions. Apotex asks that an
adverse inference be drawn against the Minister based on this.
[48]
The
witness in question was a “file” witness presented to prove the existence of
documents in the Respondent’s possession. To ask such a witness technical and
scientific questions was knowingly futile. If Apotex wished for a better
witness or for real answers to the technical and scientific questions, it took
no steps to accomplish this. This is not the basis for drawing an adverse
inference.
IV. CONCLUSION
[49]
For
all these reasons, this judicial review is dismissed with costs.
JUDGMENT
THIS COURT
ORDERS AND ADJUDGES that this
application for judicial review is dismissed with costs.
“Michael
L. Phelan”
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