2019 QCCA 801, 2019 QCCA 801

Brousseau c. Laboratoires Abbott limitée 2019 QCCA 801 COURT OF APPEAL CANADA PROVINCE OF QUEBEC REGISTRY OF QUEBEC No.: 200-09-009393-163 (200-06-000107-089) DATE: MAY, 8 2019 CORAM: THE HONOURABLE ALLAN R. HILTON, J.A. SIMON RUEL, J.A. SUZANNE GAGNÉ, J.A. ANGÈLE BROUSSEAU JEAN-CLAUDE PICARD APPELLANTS – Plaintiffs v.

ABBOTT LABORATORIES LIMITED RESPONDENT – Defendant JUDGMENT * [ 1 ] The appellants Angèle Brosseau and Jean-Claude Picard appeal the judgment of the Superior Court, District of Quebec, rendered on October 19, 2016 by the Honourable Madam Justice Suzanne Hardy-Lemieux that dismissed their class action. [ 2 ] For the reasons of Ruel, J.A., with which Hilton and Gagné, JJ.A. concur, THE COURT: [ 3 ] DISMISSES the appeal, with legal costs. ALLAN R. HILTON, J.A. SIMON RUEL, J.A. SUZANNE GAGNÉ, J.A. Mtre David Bourgoin BGA INC.

Mtre Maxime Ouellette AUGER GARNIER For the appellants Mtre Michel Gagné Mtre Emmanuelle Poupart Mtre Steeves Bujold Mtre Andrée-Anne Labbé McCARTHY TÉTRAULT For the respondent Date of hearing: September 20, 2018

REASONS OF RUEL, J.A. * Overview [ 4 ] The appellants appeal a judgment of the Superior Court that dismissed their class action. [1] The appellants are seeking damages from Abbott Laboratories Limited (“Abbott”) for the breach of its duty to warn, as a pharmaceutical manufacturer, of the neuropsychiatric side effects of Biaxin, a widely-used antibiotic that has been marketed by Abbott in Canada since 1992. [ 5 ] The action is based primarily on the extra-contractual liability of manufacturers, under articles 1468 , 1469 and 1473 of the Civil Code of Québec , [2] for safety defects in a thing by reason of the lack of sufficient indications as to the risks and dangers it involves or as to the means to avoid them. [ 6 ] The main issue in this appeal is whether the appellants have proved that Biaxin presents a danger of neuropsychiatric side effects, triggering Abbott’s duty, as a pharmaceutical manufacturer, to warn users.

If the answer to this question is affirmative, the Court must then determine whether Abbott breached its duty to warn users of that danger or of the means to avoid it. [ 7 ] The trial judge concluded that the appellants had not demonstrated a causal link between the ingestion of Biaxin and the neuropsychiatric effects observed concomitantly with the use of the medication. [ 8 ] The appeal should be dismissed, but for reasons that differ from those of the trial judge. [ 9 ] In order to obtain redress against a manufacturer under the regime of extra-contractual liability for safety defects in things, a user must prove, on a balance of probabilities: (1) that the thing presents a danger, (2) that the user sustained an injury, and (3) that there is a causal link, namely that the injury represents the concrete realization of the danger.

If the user is able to prove the foregoing, the manufacturer’s liability is presumed. [ 10 ] The manufacturer can exonerate itself if it proves that it fulfilled its duty to warn by providing users with adequate information regarding the dangers of its product. Where applicable, it may rely on the fact that the user knew or could have known of the danger.

If it proves that, according to the state of knowledge at the time that it manufactured or marketed the product, the existence of the danger could not have been known, it will also be able to exonerate itself if it proves that it was not neglectful of its duty to warn when it became aware of the danger. [ 11 ] Here, the evidence does not establish that Biaxin has the capacity to cause neuropsychiatric side effects. Nonetheless, some users have reported very serious neuropsychiatric side effects concomitant with taking Biaxin. Five class action members presented convincing evidence in that regard.

As a precautionary measure and given the widespread use of this medication to treat certain serious bacterial infections, the manufacturer should inform users of serious side effects reported after the ingestion of this medication. [ 12 ] In the case at bar, however, from the moment Biaxin was marketed, Abbott adequately informed users of the risks of neuropsychiatric side effects, and it continued to do so thereafter as and when the state of knowledge evolved. [ 13 ] The successive Biaxin monographs, which were approved by Health Canada in connection with the marketing of the medication, mentioned various types of neuropsychiatric side effects. [ 14 ] Given that the medication’s capacity to cause neuropsychiatric side effects could not be established, notwithstanding rigorous testing and surveillance over nearly thirty years, and that the prevalence of such side effects is very low, Abbott was justified in including these side effects in the “Adverse Reactions”

section of

Part I of the successive Biaxin monographs, rather than in the “Warnings and Precautions”

section of that same part, which addresses serious and proven effects that can endanger users’ immediate health. [ 15 ] By including the information in its successive Biaxin monographs, Abbott discharged its duty to inform the learned intermediaries, that is, pharmacists and physicians, of the risks and dangers of the medication’s use. These intermediaries should read the information set out in the monographs and, in turn, inform their patients thereof, based on their professional judgment, having regard, in particular, to the level of risk. [ 16 ] The appellants’ action was also based on contractual liability under

section 53 of the Consumer Protection Act , [3] which deals with liability for latent defects and which includes, as a latent defect, the lack of instructions necessary for the protection of the user against risks or dangers of which the user would otherwise be unaware. [ 17 ] This ground must be rejected, because the sale of prescription medications by a pharmacist is not a consumer contract giving rise to the manufacturer’s liability under

section 53 of the Consumer Protection Act . Background 1. The relevant evidence [ 18 ] Biaxin is an antibiotic manufactured by Abbott and marketed in tablet form in Canada since 1992. Its active medicinal ingredient is clarithromycin. [ 19 ] Biaxin is used primarily to treat certain bacterial respiratory and skin infections. It is only available with a prescription. It is a widely-used antibiotic that has been prescribed millions of times, in Canada and throughout the world, since it was brought to market over 20 years ago.

[ 20 ] At trial, five members of the class described various neuropsychiatric effects, some very serious, that occurred concomitantly with their ingestion of Biaxin. These events took place between 2005 and 2011. [ 21 ] The testimony of these five class members has several common elements and can be summarized as follows. [ 22 ] Each member received a prescription for Biaxin from a physician to treat a respiratory infection, such as pneumonia, bronchitis or pharyngitis.

One of the members was told by his physician that the medication could cause side effects that were identified as nausea, headaches, stomach cramps and diarrhea. In the other cases, the physicians did not mention the potential side effects of taking the medication. [ 23 ] The members quickly purchased the Biaxin from their pharmacist.

Most of them received a pharmaceutical information sheet from their pharmacist mentioning the potential side effects of Biaxin, or were verbally informed of the side effects by their pharmacist, namely, diarrhea, stomach aches, vomiting, nausea, dizziness or headaches. [ 24 ] None of the members was informed by their physician or pharmacist of potential neuropsychiatric side effects. [ 25 ] Each member began taking Biaxin on the day they purchased it.

After one or several days, depending on the case, they noted a change in their behaviour that manifested itself in different ways: strange sensations, insomnia, nightmares, aggressiveness, incoherent speech and actions, and/or confusion. At the same time, they continued to take the prescribed doses of Biaxin. [ 26 ] These symptoms increased as the days progressed, ultimately leading to a variety of reactions ranging in intensity among the members. Some suffered from suicidal thoughts, hallucinations or psychosis, while others inflicted serious injuries on themselves.

The majority of these reactions required hospitalization. [ 27 ] For example, Ms. Brousseau slashed her left wrist with a kitchen knife. Another member, Mr. Audet, stabbed himself with a knife, jumped out of a window and inflicted wounds on his own throat with a piece of glass. These are the most striking cases. [ 28 ] The neuropsychiatric symptoms disappeared when the Biaxin was stopped. One of the class members, Ms. Laroche, received a second Biaxin prescription a short time after her hospitalization. The same symptoms reappeared a few days after she took the Biaxin, leading to a second hospital stay.

They disappeared after she stopped the treatment. [ 29 ] None of the members who testified had any history of psychiatric or mental illness, except for Mr. Audet, who had suffered a major depression in previous years and who had been showing signs and symptoms of depression for several weeks before he took the Biaxin. All the members stated that they never again took Biaxin and never again experienced such symptoms.

Some of the members’ treating physicians expressed the opinion that the neuropsychiatric symptoms experienced by their patients were probably caused by the ingestion of Biaxin. [ 30 ] Several members stated that they would not have agreed to take Biaxin had they been informed of the potential neuropsychiatric side effects. [ 31 ] Based on their experiences and backed by their experts, the appellants argue that there is a non-coincidental association between the ingestion of Biaxin and the members’ neuropsychiatric symptoms.

In their view, Abbott did not adequately highlight the risk of neuropsychiatric side effects in the Biaxin monographs. [ 32 ] Abbott, backed by its experts, argues that no causal link, or even association, has been established between the ingestion of Biaxin and the psychiatric side effects. In any event, Abbott is of the view that the neuropsychiatric side effects were sufficiently disclosed in the successive Biaxin monographs. 2. Splitting of the action [ 33 ] The action in this case was split.

This is a matter that must be addressed, because the effect of splitting the action was to direct the trial judge’s analysis to the issue of causation. [ 34 ] In her judgment authorizing the class action, the judge identified the following common issues, among others: determining the intensity of Abbott’s duty, as a drug manufacturer, to provide information on Biaxin’s neuropsychiatric side effects; and determining whether Abbott committed a fault by inadequately disclosing those side effects. [4] [ 35 ] The judge also identified the following as an issue to be dealt with collectively: [ translation ] “[w]hether or not there is a causal link between the fault or faults Abbott committed and the damages the applicants and the members of the class suffered”. [5] [ 36 ] Abbott was of the view that this last issue created a difficulty in that it would oblige the court to deal with causation for each individual case collectively, which would result in a much longer evidentiary process. [ 37 ] Abbott therefore asked the trial judge to order that individual causation between the damages the class members allegedly suffered and the faults it allegedly committed be determined at a later stage, that of the individual claims. [ 38 ] The judge partially granted this request and amended the collective issue regarding the causal link as follows: [ translation ] “[w]hether or not there is a causal link between the fault or faults Abbott committed and the existence of damages”. [6] The trial judge was of the view that phrasing the issue in this manner did not result in skirting individual or specific causation. [7] [ 39 ] As for the appellants, they asked the trial judge to split the action so that the determination of the quantum of damages and the determination of Abbott’s liability would be dealt with in two separate hearings.

Abbott contested this request, because, in its view, the same experts would have to be heard on two separate occasions.

[ 40 ] The judge was of the opinion that [ translation ] “if the Court concludes that Abbott did not commit a fault or that there is an insufficient causal link between the fault, as determined, and the generic damages alleged, the hearing will end at that point without continuing on to an unnecessary additional step”. [8] [ 41 ] The judge therefore agreed to split the action [ translation ] “so that the debate on liability could be heard prior to and separate from all questions regarding the quantum and the method for awarding the damages claimed”. [9] 3.

The trial judgment [ 42 ] The judge framed the debate as bearing on the [ translation ] “determination of the intensity of Abbott’s duty to warn about the neuropsychiatric side effects caused to patients who are prescribed the medication Biaxin®”. [10] [ 43 ] According to the judge, the case required the determination of three matters in dispute: (1) the existence of a causal link between the ingestion of Biaxin and the neuropsychiatric effects experienced; (2) if applicable, the intensity of the duty of the manufacturer of a pharmaceutical product to warn about its potential side effects; and (3) where appropriate, the criteria for assessing the damages. [11] [ 44 ] The judge gave a lengthy description of the evidence provided by the five class members who testified about the effects they experienced concomitantly with taking Biaxin, as well as the evidence provided by the parties’ experts. [ 45 ] The judge noted that the fault alleged against Abbott [ translation ] “was, in essence, that it failed to provide consumers of Biaxin® with information that its use is prone to cause neuropsychiatric side effects”. [12] [ 46 ] The trial judge, however, was of the view that [ translation ] “such an action cannot be allowed unless there is proof of a causal link between the fault and the alleged damages”. [13] [ 47 ] The judge therefore approached the case from the perspective of causation. [14] She pointed out that legal causation is not identical to scientific causation. [15] Legal causation is established on a balance of probabilities, taking into account all the evidence, namely, the factual and statistical evidence as well as the evidence that the judge is entitled to presume. [16] [ 48 ] Based on her analysis of the legal principles, the trial judge found that [ translation ] “the applicants have the burden of establishing a causal link between the ingestion of Biaxin® and the neuropsychiatric effects they experienced.

This burden cannot be discharged by relying on mere possibilities. It must be met by a preponderance of evidence”. [17] [ 49 ] At trial, the appellants had argued that the mention of psychiatric problems in Biaxin’s monograph was sufficient to establish causation. The judge did not share that view, stating that [ translation ] “the mention of certain undesirable side effects in a monograph does not, in and of itself, lead to the conclusion that this is a causal link the manufacturer has acknowledged.” [18] [ 50 ] The judge examined the testimony of the class members, whose honesty she did not doubt.

She was of the opinion, however, that the evidence in these five individual cases could not constitute a preponderance of evidence regarding causation. [ 51 ] She indicated that [ translation ] “the abundant scientific literature filed by Abbott’s experts has convinced the Court that the use of the Naranjo algorithm combined with the case method analysis is not the appropriate method for establishing a causal link in the case at bar”. [19] [ 52 ] The judge relied on the reports and testimony of Dr. Frédéric Calon and Dr.

Mitchell Levine, experts for the defence, according to whom [ translation ] “the blood-brain barrier and the size of the clarithromycin molecule is such that the possibility of this molecule penetrating the brain and causing the side effects described by the class members is infinitesimal”. [20] [ 53 ] Relying on the same expert evidence, she noted that the fever experienced by infected individuals can reduce the protection afforded by the blood-brain barrier, but that the quantity of clarithromycin that could make its way into the brain is tiny and could not provoke the neuropsychiatric side effects that the class members experienced. [21] [ 54 ] The judge concluded as follows [ translation ]: [327] Based on its analysis of the evidence, the Court concludes that the applicants did not discharge their burden of proving, on a balance of probabilities, that the psychiatric side effects experienced after taking Biaxin® were more probable than not. [328] The Court cannot base its decision on coincidences that, at the very most, would indicate a weak possibility of causation versus the weight of the evidence which establishes that there is very likely no causal link. [329] Considering the Court’s conclusion, there is no need to rule on Abbott’s duty to warn or on the criteria for awarding damages.

The second paragraph of

section 53 of the Consumer Protection Act also requires a causal link in order for the Court to analyze the duty to warn. Given the absence of such a causal link, the Court is not required to examine this situation. Analysis

Section 53 of the Consumer Protection Act [ 55 ] I will deal first with

section 53 of the Consumer Protection Act which, in my opinion, does not apply to the specific facts of this case. [ 56 ]

Section 53 of the Consumer Protection Act includes the duty for a manufacturer to provide information about the risks and

dangers of goods, a duty that arises from the contractual relationship between the consumer and the merchant. [22] [ 57 ] The first paragraph of

section 53 states the following: “A consumer who has entered into a contract with a merchant is entitled to exercise directly against the merchant or the manufacturer a recourse based on a latent defect in the goods forming the object of the contract, unless the consumer could have discovered the defect by an ordinary examination.” [ 58 ] Under the second paragraph of

section 53 of the Consumer Protection Act , the same is true “where there is a lack of instructions necessary for the protection of the user against a risk or danger of which he would otherwise be unaware.” Pursuant to the third paragraph of

section 53 , “[t]he merchant or the manufacturer shall not plead that he was unaware of the defect or lack of instructions.” [ 59 ] The Consumer Protection Act applies to “every contract for goods or services entered into between a consumer and a merchant in the course of his business.” [23] It therefore targets consumer contracts. [ 60 ] To be considered a consumer, one must be a natural person who obtains goods or services for personal, non-business, purposes. [24] A merchant, on the other hand, is a person who ordinarily carries on business on his own behalf. [25] [ 61 ] It should be noted that pharmacists [ translation ] “simultaneously [carry on] professional and business activities”, [26] activities which, depending on their nature, can give rise to the application of the Consumer Protection Act . [ 62 ] Pharmacies have a

section that is inaccessible to consumers, in which prescription medications, as well as non-prescription medications that nevertheless need to be sold under the control of a pharmacist, are prepared, kept, and distributed or sold by the pharmacist within the practice of his professional activities. [27] [ 63 ] They also have a

section accessible to the public that contains, among other things, over-the-counter medications, such as acetaminophen and ibuprofen, which only require pharmaceutical oversight. [28] Several pharmacies also have a commercial

section where various products, such as cosmetics, food or household products, are offered for sale. [29] [ 64 ] Professor Marie-Ève Arbour has explained the hybrid nature of a pharmacist’s activities as follows [ translation ]: […] Pharmacists perform a legally hybrid act which comprises both the sale of a product and the provision of a health care service. In some circumstances, the sale of medication is incidental when compared with the pharmacist’s larger advisory role, thereby excluding the application of the [ Consumer Protection Act ].

Moreover, the answer to the question of whether or not the [ Consumer Protection Act ] applies to pharmacists could very well be a hybrid one, depending more or less on the act the professional performs—based on the ultimate nature of that act—such that the sale of over-the-counter medications could give rise to its application, while, on the contrary, the sale of prescription medications could exclude it because of the overriding health care component of the service provided. [30] [ 65 ] The sale of prescription medications, as in the case at bar, calls on the professional judgment of a physician, who prescribes medication he considers necessary because of the patient’s condition, and that of a pharmacist, who determines and ensures the proper use of medications, particularly to identify and prevent possible pharmacotherapeutic problems. [31] [ 66 ] In my opinion, in this specific context, these health professionals are not acting as merchants within the meaning of the Consumer Protection Act .

Thus, the sale of prescription medications by a pharmacist is not a consumer contract giving rise to the manufacturer’s liability under

section 53 of the Consumer Protection Act . [ 67 ] It should also be noted that the fact that the Consumer Protection Act does not provide a means of exoneration based on the state of scientific knowledge at the time a product is manufactured (as is found in the second paragraph of

article 1473 of the Civil Code of Québec [32] ) seems difficult to reconcile with the specific way in which medications are developed. [ 68 ] In my view, the legislature could not have wanted to burden pharmaceutical manufacturers with an irrefutable presumption of knowledge of all the potential risks and dangers that appear after a medication is brought to market. [33] [ 69 ] As will be seen below, the development of medications for purposes of receiving marketing approval is a highly complex process that requires clinical human trials in its last phases. [ 70 ] Although certain harmful effects may be identified at the clinical trial stage, a better understanding of the risks and dangers of a medication comes with use within a large population and with progress in scientific and medical knowledge over time; indeed, pharmaceutical manufacturers are required to rigorously monitor new side effects. [34] [ 71 ] In order to resolve the appeal regarding drug manufacturers’ duty to warn, the Court must therefore turn to the extra-contractual regime set out in the Civil Code of Québec . 2.

Did the appellants prove that Biaxin presents a danger of neuropsychiatric side effects, triggering Abbott’s duty, as a pharmaceutical manufacturer, to warn users? If so, did Abbott breach its duty to warn users of that danger or of the means to avoid it? a.

Legal considerations of the extra-contractual liability of manufacturers for safety defects in things [ 72 ] The liability regime applicable to safety defects in things is the extra-contractual regime set out in articles 1468 , 1469 and 1473 of the Civil Code of Québec . [ 73 ] This is the legal framework the appellants invoked and it is the one that applies to the case at bar. [ 74 ] The liability regime applicable to safety defects in things was discussed at great length in the recent judgment of this Court in

Imperial Tobacco Canada ltée c. Conseil québécois sur le tabac et la santé . [35] [ 75 ] The trial judge did not have the benefit of the principles enunciated by this Court in that case.

It is useful, for purposes of this judgment, to set out the applicable principles, tailored to the nature of the matter before the Court and the issues that have been raised. [ 76 ] The regime applicable to safety defects in things, as set out in articles 1468 , 1469 and 1473 of the Civil Code of Québec , is a no- fault regime, in the nature of a safety guarantee. [36] [ 77 ] The regime applies, notably, to things that have no defects, but which, by virtue of their nature, nevertheless have inherent dangers that must be disclosed to users.

This is the case for prescription medications, which, even [ translation ] “when administered as they should, can nevertheless have side effects of which users must be warned”. [37] [ 78 ] Under

article 1468 of the Civil Code of Québec , the manufacturer “is bound to make reparation for injury caused to a third person by reason of a safety defect in the thing”. [ 79 ]

Article 1469 of the Civil Code of Québec describes the concept of safety defect as follows (emphasis added): 1469. A thing has a safety defect where, having regard to all the circumstances, it does not afford the safety which a person is normally entitled to expect, particularly by reason of a defect in design or manufacture, poor preservation or presentation, or the lack of sufficient indications as to the risks and dangers it involves or as to the means to avoid them. 1469.

Il y a défaut de sécurité du bien lorsque, compte tenu de toutes les circonstances, le bien n’offre pas la sécurité à laquelle on est normalement en droit de s’attendre, notamment en raison d’un vice de conception ou de fabrication du bien, d’une mauvaise conservation ou présentation du bien ou, encore, de l’absence d’indications suffisantes quant aux risques et dangers qu’il comporte ou quant aux moyens de s’en prémunir. [ 80 ] By establishing this regime, the legislature sought to protect users against a product’s dangers to which they are exposed by a manufacturer.

Dangers must be evaluated based on the circumstances, including the nature of the product, its use, the target population, and the seriousness or foreseeability of an injury, the whole having regard to the reasonable expectations that ordinary users may have with respect to the safety of the product in question. [38] [ 81 ] According to

article 1469 of the Civil Code of Québec , the lack of sufficient indications as to the dangers a thing involves or as to the means to avoid them is therefore considered to be a safety defect. [ 82 ] Indeed, when a manufacturer provides users with adequate information on a product’s dangers, users can make an informed choice whether or not to purchase it, use it or stop using it or they can ask the manufacturer or the learned intermediaries questions so as to avoid or protect against the occurrence of the risks and dangers it involves. [39] [ 83 ] The information must be specific and the manufacturer’s warnings must be sufficient for users to [ translation ] “fully realize the danger and the risk associated with using the thing as well as the potential consequences thereof and to know what to do (or not do) in order to protect against those consequences or remedy them, as the case may be”. [40] [ 84 ] As for the intensity of the manufacturer’s duty to warn, it [ translation ] “is directly proportional to the extent of the potential danger and injury resulting from the use of the thing”. [41] [ 85 ] As such, [ translation ] “a product intended for ingestion, or implantation or introduction into the body, requires a particularly high degree of information, especially when the injury liable to result from its use is serious or there is a considerable probability that it will occur.” [42] [ 86 ] In short, [ translation ] “manufacturers have a duty to inform users of the product’s risks and dangers and of the manner in which to protect against them, such that if a manufacturer breaches this duty, the product will not afford the safety that a person is normally entitled to expect, and the manufacturer’s liability will arise”. [43] [ 87 ] In order to obtain redress under

article 1468 of the Civil Code of Québec , the user must prove, on a balance of probabilities: (1) that the thing involves a danger, (2) that he has suffered an injury, and (3) that there is a causal link between the injury and the danger. [44] [ 88 ] In principle, the user does not have the burden of proving the specific cause of the safety defect. More specifically, he does not have to prove, under

article 1469 of the Civil Code of Québec , that the safety defect results from a defect in design or manufacture, or from the lack of sufficient indications as to the risks and dangers, although he may certainly attempt to provide such proof or paint the broad strokes thereof. [45] [ 89 ] With respect to the sufficiency of the indications as to the risks and dangers, it is truly only the manufacturer who can present comprehensive evidence on this subject. [46] The burden in this regard, therefore, does not lie on the user, although, in practice, the user may provide

summary evidence to that effect. [ 90 ] As for causation, the user must establish that the injury represents the concrete realization of the danger. [47] [ translation ] “[T]he injury [must] be an expression of the realization of the danger the user risked by using the product”. [48] [ 91 ] In a matter involving the use of medication, as in the case at bar, causation is established by showing a cause and effect relationship between the risk and the injury suffered, which entails proving, on a balance of probabilities, that the risk of a particular side effect of the medication has in fact materialized. [49] [ 92 ] Within the scope of a class action dealing with a safety defect in medication, causation may, in some cases, be proved collectively, particularly where the capacity of the medication to cause a specific side effect has been established.

[ 93 ] In other cases, users may have to prove causation individually. [50] For example, in a case involving the ingestion of a prescription drug, as in the case at bar, if the risk of a particular side effect is very rare, it may be necessary to determine whether there is a cause and effect relationship between the risk of a particular side effect and the injury suffered, taking into account the user’s medical history and other factors that may explain his condition. [ 94 ] Causation can be established through presumptions of fact. [51] In such a case, the court must take only serious, precise and concordant presumptions into consideration. [52] The court can apply such presumptions to a class action, just as to any other civil action. [53] [ 95 ] Such presumptions of fact, however, cannot be established where “[t]he evidence [points] in different and sometimes opposite directions” or the expert evidence is disputed. [54] [ 96 ] A presumption that the manufacturer is liable will arise where the user proves, on a balance of probabilities, the existence of a danger, an injury and a causal link. [55] [ 97 ] In addition to the ordinary means of defending against extra-contractual civil liability (absence of injury or causation, fault of the victim, fault of another person, superior force), a manufacturer has two specific means of exoneration that are set out in

article 1473 of the Civil Code of Québec . [56] [ 98 ] First, the manufacturer can exonerate itself by proving that the user knew or could have known of the defect, or could have foreseen the injury (first paragraph of

article 1473 of the Civil Code of Québec ). If the manufacturer proves that it adequately warned the user as to the risks and dangers of the thing or as to the means to avoid them, it will be able to avail itself of this means of exoneration. [57] [ 99 ] Second, the manufacturer can exonerate itself if it proves that “ according to the state of knowledge at the time that [it] manufactured [...] the thing, the existence of the defect could not have been known, and that [it] was not neglectful of [its] duty to provide information when [it] became aware of the defect”, both of these conditions being cumulative (second paragraph of

article 1473 of the Civil Code of Québec ). [58] [ 100 ] This second means of exoneration, which deals with the insufficiency of the available knowledge, seeks to share the risks associated with technological innovation.

Indeed, the potential dangers a product entails may not be known when it is brought to market and may appear over time as and when the product is used and scientific knowledge or techniques evolve. [59] [ 101 ] This is particularly true of pharmaceutical manufacturers, who deal with medications that, despite comprehensive pre-market trials, have side effects that may reveal themselves through use.

I will come back to this point. [ 102 ] The duty to inform in these circumstances is therefore an ongoing one, such that warnings must be provided to users as and when knowledge of the risks and dangers of using the medication evolves. [60] b.

The liability of manufacturers in connection with the safety of medications [ 103 ] In a case involving the extra-contractual civil liability of a pharmaceutical manufacturer in connection with a medication’s safety, a series of specific contextual considerations will have an impact on proving the danger, the causal link and the existence and intensity of the duty to warn, and on the specific means of defence that apply, particularly the defence based on technological innovation. [61] [ 104 ] Moreover, a pharmaceutical manufacturer’s informational duty regarding the safety of a drug, as implemented by the provisions of the Civil Code of Québec , draws from other sources, including federal law governing the development, approval and marketing of drugs, [62] and the solutions proposed by the Supreme Court and courts in other Canadian jurisdictions regarding the duty to warn of manufacturers of pharmaceutical products or medical equipment. i.

Proof of the existence of a danger and correlative duty to warn [ 105 ] In cases involving a manufacturer’s liability for a safety defect in medication, there are two principal ways of proving the existence of a danger. [ 106 ] First, the plaintiff can prove the medication’s capacity to cause a particular undesirable side effect. [ 107 ] Second, even in the absence of compelling evidence of the medication’s capacity to cause such a side effect, the documented presence of a serious side effect that has occurred concomitantly with the ingestion of the medication can establish the presence of a danger. [ 108 ] Proof that a danger exists in connection with the ingestion of a drug triggers a duty to warn about the risks the drug entails and the means users can take to avoid them, a duty that can give rise to the manufacturer’s civil liability for a safety defect in a thing, provided the other conditions for liability are satisfied (the existence of an injury and a causal link). [ 109 ] Evidence that the medication has the capacity to cause an undesirable side effect therefore establishes the existence of a danger, facilitates proof of causation, gives rise to a duty to warn and, where applicable, may increase the intensity of the pharmaceutical manufacturer’s duty to warn. [ 110 ] The court must evaluate whether the medication has a propensity, i.e., the capacity, to cause the alleged injury. [63] Courts in common law jurisdictions have used the expression “general causation”. [64] Consequently, the plaintiff must present evidence that, on a balance of probabilities, establishes the medication’s capacity to cause an undesirable side effect. [65]

[ 111 ] A drug’s capacity to cause an undesirable side effect therefore provides an indication of its inherent risks and dangers. [66] [ 112 ] This notion has been applied in common law jurisdictions to cases dealing with the liability of pharmaceutical manufacturers based on the duty to warn. [67] It is useful, and it is appropriate to adapt it for purposes of Quebec law. [ 113 ] In order not to cause confusion with the notion of specific causation, which must be shown in order to establish the liability of a manufacturer in connection with a safety defect in medication, I will use the expression “capacity of the medication to cause a side effect” rather than “general causation”. [ 114 ] What type of evidence is required in order to prove the capacity of a medication to cause a side effect? [ 115 ] The evidence may be scientific or technical, such as expert epidemiological, toxicological or statistical evidence, [68] because the question is whether the medication has the capacity to cause side effects.

The evidence can include a demonstration of a biological mechanism of action explaining or making it probable that the medication can cause the alleged side effect. [ 116 ] By adopting this approach in all cases, however, there is a risk of favouring a scientific demonstration over a civil demonstration on the balance of probabilities, the latter being the standard that applies. [69] [ 117 ] Thus, lay evidence, pre- and post-market data, including the results of animal testing and human clinical trials, as well as presumptions of fact can be considered in order to establish that a medication has the capacity to cause side effects. [70] However, in this type of case, which involves extensive technical considerations, expert evidence still plays an important role. [71] [ 118 ] If the medication is shown to have the capacity to cause a side effect, the existence of a danger will have been established. [72] This triggers, on the part of the manufacturer, a duty to warn whose intensity is necessarily high. [ 119 ] As indicated, however, even absent compelling evidence of the medication’s capacity to cause a side effect, the documented presence of a serious side effect that has occurred concomitantly with the ingestion of the medication can establish the existence of a danger that the manufacturer must disclose. [ 120 ] Given the nature of the product—a drug designed for ingestion—pharmaceutical manufacturers have to meet a high standard of care with regard to adequate consumer warnings. [73] [ 121 ] As the Ontario Court of Appeal stated in Wise v.

Abbott Laboratories Limited , “an association between a product and a dangerous condition may give rise to a duty to warn even if the association has not been demonstrated to be causal.” [74] This is a specific application of the precautionary principle. [75] [ 122 ] In Hollis v.

Dow Corning Corp ., the Supreme Court of Canada found a manufacturer of breast implants liable because it had failed to disclose the occurrence of ruptures, even though the number of ruptures was statistically very small—l ess than 0.1% —and their cause was unknown. [76] [ 123 ] The Supreme Court dismissed the manufacturer’s argument that the duty to warn arose only once the manufacturer had reached definitive conclusions regarding the cause and effect of the danger. [77] [ 124 ] On the contrary, it is precisely because there were unexplained ruptures that the manufacturer should have included information in its literature disclosing those ruptures and their effects on the human body. [78] [ 125 ] Thus, even where evidence does not establish the capacity of a medication to cause side effects, but the side effects of the medication are revealed in pre- or post-market studies, or otherwise within the scope of the continuous monitoring of the side effects of the medication, a court may find that a danger exists and that there is a correlative duty to warn. [ 126 ] Factors such as the nature of the medication, and the severity, intensity or frequency of side effects reported in conjunction with taking the medication may establish the existence of a danger and give rise to a duty to warn. [79] [ 127 ] All serious risks or dangers a medication entails should be disclosed, regardless of how low the probability is that they will materialize. [80] A pharmaceutical manufacturer’s failure to do so may give rise to its extra-contractual civil liability towards users. [ 128 ] Once the existence of a danger and the pharmaceutical manufacturer’s correlative duty to warn have been shown, the intensity of the duty will vary depending on the circumstances.

As the Ontario Court of Appeal stated in Buchan v. Ortho Pharmaceutical (Canada) Ltd. : Whether a particular warning is adequate will depend on what is reasonable in the circumstances. But the fact that a drug is ordinarily safe and effective and the danger may be rare or involve only a small percentage of users does not necessarily relieve the manufacturer of the duty to warn.

While a low probability of injury or a small class of endangered users are factors to be taken into account in determining what is reasonable, these factors must be balanced against such considerations as the nature of the drug, the necessity for taking it, and the magnitude of the increased danger to the individual consumer.

Similarly, where medical evidence exists which tends to show a serious danger inherent in the use of a drug, the manufacturer is not entitled to ignore or discount that information in its warning solely because it finds it to be unconvincing; the manufacturer is obliged to be forthright and to tell the whole story.

The extent of the warning and the steps to be taken to bring the warning home to physicians should be commensurate with the potential danger—the graver the danger, the higher the duty. [81] [ 129 ] The circumstances that can affect the intensity of the duty to warn include: evidence of the medication’s capacity to cause an undesirable side effect; the nature of the medication; the nature of the illness being treated; the need to take the medication in order to

treat the illness; and the severity, intensity or frequency of the side effects reported, even where there is no evidence of the medication’s capacity to cause a side effect. [82] ii.

The continuous nature of the duty to inform [ 130 ] The fact that the pharmaceutical manufacturer’s duty to warn is not static—it changes over time—is another important consideration. [ 131 ] The development and marketing of drugs are costly and complex processes involving years of scientific and medical research and requiring manufacturers to undergo rigorous regulatory approval mechanisms in each jurisdiction in which they wish to distribute or sell the medication.

In our country, the regulator is Health Canada. [ 132 ] Although medications carry risks of side effects, regulators may nevertheless authorize their marketing if the beneficial effects outweigh the deleterious ones. [83] [ 133 ] The process of developing drugs is such that the existence or extent of certain side effects may not be fully known or appreciated when regulators approve them for marketing. [ 134 ] As the Ontario Court of Appeal stated in Buchan , “[i] n the present state of human knowledge, many drugs are clearly incapable of being made totally safe for their intended or ordinary use, even though they have been properly manufactured and are not impure or defective.” [84] [ 135 ] In short, a pharmaceutical manufacturer’s duty to inform as regards a drug’s safety changes over time. [ 136 ] Pharmaceutical manufacturers have a duty to warn patients about the potentially dangerous side effects they know or should know about at the time of marketing, and continuously thereafter, as scientific knowledge and post-market data develop. [85] [ 137 ] As indicated, under the second paragraph of

article 1473 of the Civil Code of Québec , a pharmaceutical manufacturer can exonerate itself if it proves that the safety defect could not have been known at the time the medication was manufactured and that it was not otherwise negligent with respect to its duty to inform. iii.

The impact of regulatory requirements on a pharmaceutical manufacturer’s duty to warn [ 138 ] Drug manufacturers are subject to a series of federal regulatory requirements that must be considered in connection with their extra-contractual duty to warn about the risks of the medications they develop and market. [ 139 ] When a manufacturer wishes to market a new drug, it must submit a New Drug Submission to Health Canada. [86] A draft monograph is filed with this application [87] and is examined by Health Canada’s Health Products and Food Branch. [88] [ 140 ] A monograph is “a factual, scientific document on the drug product that […] describes the properties, claims, indications, and conditions of use for the drug, and that contains any other information that may be required for optimal, safe, and effective use of the drug.” [89] [ 141 ] If the New Drug Submission and monograph are deemed compliant, Health Canada will issue a Notice of Compliance and the manufacturer will be entitled to sell the drug in Canada. [90] [ 142 ] In order to be considered compliant, the monograph must, inter alia , include all the representations to be made in respect of the new drug; [91] fulfil the requirements for adequate directions for use; [92] identify the information that is to be provided to a member of the health profession, upon request, and to consumers; and establish parameters for advertising and promotional materials. [93] [ 143 ] Following the approval, the manufacturer must revise the monograph each time updates are necessary (for example, to add new post-market side effects). [94] [ 144 ] Since 2004, a monograph must contain three parts. [ 145 ]

Part I presents health professional information,

Part II presents scientific information and

Part III contains consumer information. [95] [ 146 ] Health Canada prepares guidance documents that help the pharmaceutical industry draft monographs and that indicate the information each Part should contain. [96] [ 147 ]

Part I of a monograph contains a

section entitled “Warnings and Precautions” that must indicate “information about all serious effects that may pose a hazard to the patient”. [97] This information must be classified under subheadings. [98] Health Canada states that “[b]ehavioural changes (e.g., suicidal ideation) should be included in this section.” [99] [ 148 ] The “Warnings and Precautions”

section of

Part I also contains a box that should set out “[c]linically significant or life- threatening safety hazards when taking the drug”. [100] In technical jargon, this box is referred to as a “black box”. [101] Health Canada specifies that the text in the black box should generally not exceed 20 lines. [102] [ 149 ]

Part I must also include, under the “Adverse Reactions” section, information on “all types of adverse drug reactions (ADRs) including those identified during clinical trials and as a result of post-market surveillance.” [103] [ 150 ] As for

Part III, it also contains a

section entitled “Warnings and Precautions” that must include a box setting out, in lay language, the same information that is provided in the box in

Part I. [104]

[ 151 ] In addition,

Part III contains a

section entitled “Side Effects and What To Do About Them” that sets out “a brief

summary of the self-limiting and serious side effects”. [105] It is understood that this is not a complete list of side effects. [106] [ 152 ] The manufacturer selects the side effects from

Part I that it considers appropriate to include in

Part III based, notably, on the frequency with which they occur and on scientific evidence regarding a causal relationship. [ 153 ] Mr. Frédéric Poitras, a clinical pharmacy expert called by the defence, testified that

Part III of a drug’s monograph is not systematically provided to patients. Certain pharmaceuticals are packaged by the manufacturer (for example, a box containing a blister pack), and

Part III is included. In such cases,

Part III is provided directly to patients. [ 154 ] Other products, however, are supplied in bulk to pharmacists and are therefore not accompanied by a monograph. In these cases, the pharmacist will provide patients with an information sheet. These information sheets, which are generated by software programs, do not set out all the side effects of a drug and are a

summary of the information found in

Part III. They also contain a paragraph inviting users to consult the manufacturer’s literature for more complete information. [ 155 ] It is also worth noting that

Part III of a drug’s monograph is available for online consultation. [ 156 ] The fact that a regulated entity satisfies the regulatory requirements, however, does “not have the effect of exempting it from the ordinary law of civil liability.” [107] [ 157 ] Indeed, in Buchan , the Ontario Court of Appeal stated that a drug manufacturer’s general duty to warn under the common law is separate from any regulatory scheme under the Food and Drugs Act . [108] [ 158 ] In short, a pharmaceutical manufacturer will not have satisfied its civil duty to warn merely because it has satisfied the regulatory requirements established by Health Canada. [109] [ 159 ] That being said, compliance with statutory or regulatory standards may tend to indicate that the manufacturer has satisfied its duty to warn. [110] For example, in Andersen v.

St-Jude Medical Inc ., in concluding that the manufacturer had acted in accordance with the standard of care, the judge of the Ontario Superior Court of Justice took into consideration the fact that Health Canada had approved the medical device in question (a heart valve). [111] [ 160 ] Compliance with statutory or regulatory standards is therefore relevant, but not conclusive in and of itself, when determining whether a pharmaceutical manufacturer acted diligently with respect to its duty to warn. [112] iv.

The learned intermediary [ 161 ] As a general rule, the manufacturer’s warning regarding the product must be made directly to the user. [113] In very specific circumstances, however, the learned intermediary rule provides an exception to this rule.

The Supreme Court stated the following in this regard, in Hollis : Generally, the [learned intermediary] rule is applicable either where a product is highly technical in nature and is intended to be used only under the supervision of experts, or where the nature of the product is such that the consumer will not realistically receive a direct warning from the manufacturer before using the product.

In such cases, where an intermediate inspection of the product is anticipated or where a consumer is placing primary reliance on the judgment of a “learned intermediary” and not the manufacturer, a warning to the ultimate consumer may not be necessary and the manufacturer may satisfy its duty to warn the ultimate consumer by warning the learned intermediary of the risks inherent in the use of the product. [114] [ 162 ] The manufacturer can avail itself of this exception only where the intermediate’s knowledge of the risks approximates that of the manufacturer. [115] Thus, the scope of the learned intermediary exception is narrow. [116] [ 163 ] The learned intermediary rule, however, does apply in the particular context of the purchase of prescription drugs.

In Buchan , the Ontario Court of Appeal explained that: […] prescription drugs are more likely to be complex medicines, esoteric in formula and varied in effect and, by definition, are available only by prescription. The prescribing physician is in a position to take into account the propensities of the drug and the susceptibilities of his patient. He has the duty of informing himself of the benefits and potential dangers of any medication he prescribes, and of exercising his independent judgment as a medical expert based on his knowledge of the patient and the product.

In taking the drug, the patient is expected to, and it can be presumed does, place primary reliance on his doctor’s judgment. [117] [ 164 ] In accordance with these principles, a prescription drug manufacturer will satisfy its informational duty if it adequately warns the learned intermediaries, that is, the physicians and pharmacists. [118] [ 165 ] The learned intermediary rule, which developed in the United States and under the common law, has been applied in a number of Quebec judgments, [119] although it has not yet been formally confirmed in decisions of this Court. [120] [ 166 ] The legitimacy of this rule, however, has been brought into question in the United States due to the rise in direct-to-consumer advertising by pharmaceutical companies. [121] [ 167 ] These concerns seem much less relevant in Canada, where the advertisement of prescription drugs to the general public is limited to their name, price and quantity. [122] It should also be noted that, in Canada, these drugs are exempt from several packaging and labelling requirements, precisely because of the fact that a learned intermediary will inevitably intervene between the manufacturer and the user. [123]

[ 168 ] Authors Thérèse Leroux and Michelle Giroux write that in order to determine whether or not the learned intermediary rule applies in Quebec, the following question must be answered: [ translation ] “Is the obligation to provide sufficient indications, set out in

article 1469 [of the Civil Code of Québec ], satisfied by providing information to intermediaries?” [124] [ 169 ] In my opinion, the Court should answer this question in the affirmative and confirm that the learned intermediary rule applies in Quebec law as regards the manner in which a manufacturer of prescription drugs discharges its duty to warn. [ 170 ]

Article 1469 of the Civil Code of Québec does not specify that the indications as to the risks and dangers a thing involves must be provided directly to the user in all cases. [125] In certain circumstances, they can be provided to a learned intermediary. [ 171 ] It is important to emphasize that the Court’s acknowledgement that the learned intermediary rule applies in Quebec law is made within the specific context of the purchase of prescription drugs, where the intervention of learned intermediaries—the physician and the pharmacist—is inevitable. [ 172 ] Therefore, Abbott will have discharged its duty to warn if it can show that it adequately informed physicians and pharmacists of the risks of neuropsychiatric side effects in connection with the ingestion of Biaxin. c.

Application [ 173 ] The trial judge dismissed the class action because, in her opinion, the appellants did not establish causation between the ingestion of Biaxin and the neuropsychiatric side effects they experienced. [ 174 ] The appellants’ arguments deal largely with causation. They submit, in particular, that the judge erred with respect to their burden of proof. According to them, they were required to prove legal, not scientific, causation between Biaxin and the neuropsychiatric side effects.

Moreover, they were entitled to rely on presumptions in order to prove legal causation. [ 175 ] The appellants also contend that the primary issue was the respondent’s duty to warn about the potential side effects of Biaxin— a question they say the judge skirted—and that the judge should have concluded that the respondent breached this duty by inadequately reflecting the neuropsychiatric side effects in

Part I and

Part III of the drug’s monograph. [ 176 ] The trial judge essentially relied on the evidence of Abbott’s experts to the effect that the blood-brain barrier and the size of the clarithromycin molecule is such that the possibility of this molecule penetrating the brain and causing psychiatric side effects is infinitesimal. [ 177 ] She made this finding notwithstanding the evidence provided by the five class members, whom she found to be honest and who experienced serious psychiatric side effects concomitantly with taking Biaxin. [ 178 ] In my view, this finding with respect to the blood-brain barrier is still relevant, but it must be considered within the analytical framework that applies to the extra-contractual liability of manufacturers for safety defects in products. [ 179 ] The judge’s finding concerns Biaxin’s capacity to cause neuropsychiatric side effects, which is one of the means of establishing a danger that gives rise to the manufacturer’s duty to warn. [ 180 ] Let us consider the evidence in that regard. [ 181 ] According to the plaintiffs’ experts, Ms.

Karine Desharnais, a psychiatric pharmacy expert, and Dr. Jacques Bouchard, an expert in psychiatry, there is a probable link between the ingestion of Biaxin and the neuropsychiatric symptoms the class members experienced.

These experts relied on the elements in the patients’ files and used the Naranjo algorithm, a questionnaire that can be used to identify the cause of a drug’s side effects in specific cases. [ 182 ] It should be noted that prior to being retained in this file, these experts had never heard of or observed, in their practice, neuropsychiatric side effects in connection with the ingestion of Biaxin. [ 183 ] Dr. Frédéric Calon, who holds a Ph.D. in pharmacy, was called by the defence and was recognized as an expert in neuropharmacology and a specialist with respect to the blood-brain barrier. Dr.

Calon stated that, given the physical and chemical properties of clarithromycin, and given the mechanism of action of the blood-brain barrier, which is a dynamic interface separating blood flow from brain cells, the clarithromycin molecule does not reach the brain and therefore cannot cause neuropsychiatric side effects. [ 184 ] According to Dr. Calon, the inability of clarithromycin to cross the blood-brain barrier was demonstrated experimentally in animal studies.

In fact, no biological mechanism of action can explain how clarithromycin could cause neuropsychiatric side effects. [ 185 ] The evidence and witnesses presented by the defence indicated an extremely low prevalence of neuropsychiatric side effects concomitantly with the ingestion of Biaxin, a drug that has been prescribed tens of millions of times in Canada over more than 25 years. [ 186 ] Witnesses for the defence commented on the reports prepared by Abbott and filed with the Irish Medicines Board (“IMB”), the regulator that acts on behalf of the European Union, in connection with post-market surveillance of clarithromycin (marketed as “Klacid” in Europe). [ 187 ] The IMB had noted reports of some suicides in Abbott’s post-market surveillance.

The IMB had therefore asked Abbott to file further reports regarding the neuropsychiatric effects of clarithromycin. [ 188 ] In a report submitted to the IMB on August 20, 2008, Abbott indicated that animal studies had demonstrated that there was no central nervous system toxicity from clarithromycin, except at very high and fatal doses. These studies show that clarithromycin does not penetrate the animal brain.

[ 189 ] The report sent to the IMB on December 1, 2008 deals with clinical studies, that is, pre- and post-market human trials. It is a meta-analysis, i.e., a compilation of clinical analyses of the potential toxicity of clarithromycin as regards neuropsychiatric side effects. [ 190 ] The witnesses for both parties explained that, in the hierarchy of scientific sources for assessing causation of a side effect, a meta-analysis is the most reliable. [ 191 ] The meta-analysis examined 126 clinical studies in which a large number of subjects were assessed.

Indeed, a total of 22,573 subjects were covered by the meta-analysis, of which 14,032 received clarithromycin, while 8,541 received a placebo or a comparator agent (another antibiotic). These studies made it possible to assess the statistical prevalence of neuropsychiatric side effects in connection with the ingestion of clarithromycin, such that the existence of a causal link (from a scientific point of view) could be evaluated. [ 192 ] The meta-analysis confirmed the very low prevalence of neuropsychiatric effects in connection with the ingestion of clarithromycin.

A total of 238 “neuropsychiatric events” occurred in the “clarithromycin” group. [ 193 ] Statistically, an equivalent number of neuropsychiatric events occurred in the comparator group for two types of infections treated.

In the group treated for a specific infection (“MAC” or “ mycobacterium avium complex”, which particularly affects patients suffering from HIV) , the meta-analysis showed that the placebo group reported more neuropsychiatric effects than the “clarithromycin” group, the explanation being that the medication probably relieved these seriously ill patients. [ 194 ] As for the review of post-market data, the meta-analysis indicated that reports of neuropsychiatric side effects were extremely rare. [ 195 ] The meta-analysis concluded that it was not possible, based on the clinical and post-market data, to establish a link between the ingestion of clarithromycin and neuropsychiatric side effects, and that, in its monographs, Abbott had adequately informed professionals and patients about the neuropsychiatric side effects that occurred concomitantly with the ingestion of Biaxin. [ 196 ] None of the experts, whether for the plaintiffs or the defendant, proposed a biological mechanism of action that could provide a probable explanation for the neuropsychiatric side effects in connection with the ingestion of Biaxin. [ 197 ] In fact, the neuropsychiatric side effects of Biaxin reported in Canada are very rare.

The number of Biaxin prescriptions made between 1992 and 2011 is estimated at nearly 30 million. [126] For the same period, 312 cases of neuropsychiatric side effects, ranging in severity, were disclosed to Abbott. [127] [ 198 ] Therefore, the evidence considered as whole does not show, on a balance of probabilities, that Biaxin has the capacity to cause neuropsychiatric side effects. [ 199 ] The analysis, however, does not end there. [ 200 ] Even though Biaxin’s capacity to cause neuropsychiatric side effects has not been established, one must consider the other factors that have an impact on determining whether a danger exists and, if the danger exists, on the intensity of the manufacturer’s correlative duty to warn. [ 201 ] The neuropsychiatric side effects reported concomitantly with the ingestion of Biaxin, while very rare, are extremely serious.

Such effects have been reported and, in fact, are mentioned in the successive Biaxin monographs. The existence of such effects was the basis for the in-depth investigation requested by the IMB, on behalf of the European Union.

Biaxin is a routinely used antibiotic, with millions of doses having been prescribed in Canada since it was brought to market. [ 202 ] The widespread use of Biaxin justifies the public being informed of the potential serious risks in connection with the ingestion of this medication. [ 203 ] It is possible that science does not currently provide a means for proving the capacity of a drug to cause undesirable side effects. [ 204 ] In the case at bar, although the appellants were unable to provide such proof, they presented evidence that serious neuropsychiatric side effects occurred concomitantly with the ingestion of Biaxin in at least five instances. [ 205 ] The judge found these witnesses to be honest and forthright.

She rejected the evidence provided by Abbott’s expert, Dr.

Emmanuel Stip, who stated that the neuropsychiatric problems experienced by the five class members could be explained by medical causes other than the ingestion of Biaxin. [ 206 ] Consequently, although the danger linked to the ingestion of Biaxin is statistically very weak, I consider that the appellants established the existence of this danger which triggers Abbott’s duty, as a pharmaceutical manufacturer, to warn. [ 207 ] It is evident that the class members suffered damages, which were to be quantified at a subsequent stage. [ 208 ] The only remaining matter is the causal link, namely, proof that the injury the class members suffered is the concrete realization of the danger that Biaxin may cause neuropsychiatric side effects. [ 209 ] The lack of evidence of the drug’s capacity to cause these side effects is relevant, but does not entirely settle the matter of causation. [ 210 ] The specific evidence of the neuropsychiatric effects experienced by the five class members concomitantly with the ingestion of Biaxin is troubling.

According to the plaintiffs’ experts, based on a detailed examination of the medical history of the class members and after applying the Naranjo algorithm, there is no probable cause, other than the ingestion of Biaxin, for the neuropsychiatric side effects the class members experienced.

[ 211 ] As for Abbott’s experts, they presented thorough and convincing scientific evidence that clarithromycin cannot, by reason of its physical and chemical properties, penetrate the blood-brain barrier and induce psychiatric side effects. [ 212 ] In the case at bar, given that there is no evidence of Biaxin’s capacity to cause the side effects, only an individual examination of the class members’ medical records would allow one to set aside other possible causes for the neuropsychiatric side effects they experienced, for example, the presence of a pre-existing psychiatric condition, the existence of a vulnerability or other medical condition that could give rise to these symptoms, or the prior or simultaneous ingestion of illegal drugs or other substances that could explain these side effects. [ 213 ] In short, in this particular case, causation is largely an individual question. [ 214 ] Nonetheless, it is not necessary to move on to this step, because, in my opinion, Abbott did not breach its informational duty towards users of Biaxin. [ 215 ] In the case at bar, the intensity of Abbott’s duty to inform may be characterized as intermediate. [ 216 ] In this regard, one must consider the fact that Biaxin’s capacity to cause neuropsychiatric side effects has not been established on a balance of probabilities.

There is currently no biological mechanism of action that can provide a probable explanation for the neuropsychiatric side effects. Moreover, such side effects are very rare. [ 217 ] Nonetheless, given that Biaxin is a medication that is widely used to treat relatively common infections, patients certainly do not expect to experience psychoses or delirium.

Although the reported neuropsychiatric side effects are extremely rare, they are very serious. [ 218 ] The plaintiffs’ experts expressed the opinion that Biaxin’s monographs do not adequately warn physicians and pharmacists about the neuropsychiatric symptoms that may result in connection with the ingestion of this medication. [ 219 ] Dr. Bouchard testified that, since the time Biaxin was brought to market, he never received any disclaimers, warnings or precautions from Abbott with respect to neuropsychiatric side effects. [ 220 ] Given the severity of these side effects, Ms.

Desharnais was of the view that the side effects should be listed in the “Warnings and Precautions”

section of

Part I of the monograph (health professional information), which is presented in a condensed form in a similar

section of

Part III of the monograph (patient information). [ 221 ] According to the experts for the defence, an analysis of the various Biaxin monographs prepared by Abbott and approved in Canada over the years indicates that the side effects on the nervous system were included in

Part I of the monograph as of 1992. [ 222 ] As and when the state of knowledge progressed, particulars of the nature of the neuropsychiatric side effects were included in the monographs.

These monographs were developed in cooperation with Health Canada and ultimately approved by it. [ 223 ] As a result, Abbott is of the view that it provided sufficient information to professionals and patients about the dangers and risks of the medication. [ 224 ] I agree with this view, which is supported by the evidence. [ 225 ] The evidence reveals that the Biaxin monograph was amended 36 times between 1992, the date on which Health Canada approved the first monograph, and 2011. [ 226 ] Before 2004, Health Canada did not require that monographs be divided into three Parts. [128] The information was grouped under different sections, including “Warnings” and “Adverse Reactions”. [129] [ 227 ] The very first version of the Biaxin monograph, dated 1992, refers to the following side effects on the nervous system: “dizziness, vertigo, nervousness, insomnia, somnolence and depression”. [130] Under the subheading “Others”, the monograph also mentions that seizures, hallucinations, confusion and vertigo were reported, not in connection with Biaxin, but with erythromycin, another antibiotic in the same family. [131] [ 228 ] The 1993 Biaxin monograph adds anxiety, nightmares, confusion and hallucinations to this list. [132] [ 229 ] The 1996 Biaxin monograph adds psychosis. [133] [ 230 ] From 1998 to 2005, the Biaxin monographs contained the following list of side effects on the nervous system: “dizziness, vertigo, tinnitus, nervousness, anxiety, insomnia, nightmares, somnolence, depression, confusion, disorientation, depersonalization, hallucinations and psychosis”. [134] [ 231 ] From 2007 to 2011, the Biaxin monographs contained a list of psychiatric problems under the heading “Adverse Reactions” of

Part I, which included insomnia, nightmares, disorientation, confusional state, depersonalisation, hallucinations and psychotic disorders. [135] [ 232 ] The occurrence of neuropsychiatric problems was never mentioned in the “Warnings and Precautions”

section of

Part I of the Biaxin monograph, nor was it mentioned in

Part III of the successive monographs. [ 233 ] The decision as to what must be included in each Part of a product’s monograph is made jointly by the pharmaceutical company and Health Canada. [136] Moreover, when the manufacturer submits a New Drug Submission , Health Canada carefully examines the information contained in the manufacturer’s proposed monograph and approves the monograph if it satisfies the requirements. [137] [ 234 ] According to Ms. Anne Tomalin, an expert in regulatory affairs in the pharmaceutical industry, the inclusion of side effects or

effects resulting from drug interactions in the “Warnings and Precautions”

section of

Part I of the monograph is intended to provide serious warnings to health professionals about certain effects of the medication that they must absolutely consider. [ 235 ] In essence, the information will be included in the “Warnings and Precautions”

section when there is a scientific consensus regarding the probability that the medication can cause the side effect. Others factors to consider include the severity of the problem, the frequency of the side effects and the plausibility of a mechanism of action explaining the occurrence of those effects. [ 236 ] The decision to include a side effect in the “Warnings and Precautions”

section of a monograph is the result of a scientific judgment call. The decision is made by the manufacturer in cooperation with Health Canada and with the latter’s approval. [ 237 ] As regards Biaxin, based on pre- and post-market clinical data, and based on the case reports collected over more than 25 years, which indicate that neuropsychiatric side effects are very rare, that there is no evidence that the medication can cause the side effects and that there is no evidence of a mechanism of action, there was no reason to include a reference to neuropsychiatric side effects in the “Warnings and Precautions”

section of

Part I of the Biaxin monographs. [ 238 ] Such neuropsychiatric side effects were reported and may nevertheless occur, which is why they were described in the “Adverse Reactions”

section of

Part I of the successive Biaxin monographs. [ 239 ] As regards the side effects listed in the “Adverse Reactions”

section of

Part I, Ms. Tomalin indicated that the threshold is lower than for the “Warnings and Precautions” section. [ 240 ] As a matter of fact, the side effects listed in the “Adverse Reactions”

section are those that have occurred concomitantly with the ingestion of Biaxin. The purpose of this

section is to inform physicians and pharmacists that there may potentially be a relationship between these side effects and the medication. [ 241 ] As for

Part III, it contains the same information as

Part I, but in plain language so that consumers can properly understand it. Ms. Tomalin explained that

Part III will not list all the side effects found in

Part I. The selection will be based on the frequency of the side effect, the weight of scientific evidence regarding causation, the ability of patients to recognize the reaction and the need to act if the side effect occurs. [ 242 ] In short, Abbott and its experts are of the view that the reference to the neuropsychiatric side effects in the “Adverse Reactions”

section of

Part I provides sufficient warning to health professionals about the potential neuropsychiatric side effects of Biaxin. [ 243 ] There was therefore no requirement to mention neuropsychiatric problems in the “Warnings and Precautions”

section of

Part I or in

Part III of the Biaxin monograph. Health Canada agreed with these decisions when it approved the successive Biaxin monographs. [ 244 ] There is nothing in the evidence to suggest that Abbott minimized the information provided to Health Canada or the potential risks associated with taking Biaxin.

On the contrary, it responded to Health Canada’s requests and proposed several annotated versions of the Biaxin monograph until it was approved. [ 245 ] It also provided highly detailed responses to the requests made by the IMB, on behalf of the European Union, regarding a possible relationship between cases of neuropsychiatric problems and the ingestion of Biaxin. [ 246 ] For these reasons, I am of the opinion that the information provided by Abbott in the Biaxin monographs constitutes sufficient warning under the circumstances, considering that: there is no evidence of the capacity to cause the undesirable side effects, there is no mechanism of action to explain the neuropsychiatric side effects, and the frequency of these reported side effects is infinitesimal. [ 247 ] Abbott disclosed the information it had—according to the state of knowledge at the relevant times—on the neuropsychiatric side effects that were reported in connection with taking Biaxin. [ 248 ] Moreover, it was not negligent in the exercise of its duty to inform, given that it disclosed the state of its knowledge to Health Canada throughout the life of the medication and that Health Canada approved the successive Biaxin monographs after in-depth verifications. [ 249 ] In the case at bar, the monograph provides sufficient information to health professionals on the benefits and risks of Biaxin.

They should read the information set out in the monograph and inform their patients thereof, based on their professional judgment, having regard, in particular, to the level of risk. [ 250 ] The pharmaceutical information sheet for Biaxin, which is usually provided to patients, states that [ translation ] “[f]or more information, consult the manufacturer’s literature, where you will find additional information about uncommon side effects as well as contraindications associated with this product”. [138] [ 251 ] Patients are therefore informed that they must consult additional documents in order to find out more about uncommon side effects, or ask their physician or pharmacist questions. [ 252 ] It is for these reasons that I would dismiss the appeal, with legal costs.

SIMON RUEL, J.A.

[2] Civil Code of Québec , CQLR, c. CCQ-1991. [7] Brousseau c. Laboratoires Abbott ltée , 2013 QCCS 6747 , para. 17 . [27] Pharmacy Act , CQLR, c. P-10, s. 17; Regulation respecting the terms and conditions for the sale of medications , CQLR, c. P- 10, r. 12, ss. 1, 3-5 and Schedules I and II; Règlement sur la tenue des pharmacies , RLRQ, c. P-10, r. 24, s. 5 (note that this regulation exists only in French). [28] Regulation respecting the terms and conditions for the sale of medications , CQLR, c. P-10, r. 12, ss. 1, 4, 6 and

Schedule III; Règlement sur la tenue des pharmacies , RLRQ, c. P-10, r. 24, ss. 1 and 6 (note that this regulation exists only in French). [31] Pharmacy Act , CQLR, c. P-10, s. 17.