CITATION: Batten v. Boehringer Ingelheim (Canada) Ltd., 2017 ONSC 53

COURT FILE NO.: CV-13-475701CP

DATE: 20170105

ONTARIO

SUPERIOR COURT OF JUSTICE

BETWEEN:

ALBERT C. BATTEN and THE ESTATE OF MARGARET JANE HAMILTON, on behalf of her Estate Representative Wendy Nelson, and WENDY NELSON, personally

Plaintiffs

– and –

BOEHRINGER INGELHEIM (CANADA) LTD., BOEHRINGER INGELHEIM PHARMACEUTICALS, INC., BOEHRINGER INGELHEIM PHARMA GMBH & CO. KG, and BOEHRINGER INGELHEIM INTERNATIONAL GMBH

Defendants

Bryan C. McPhadden, Venessa Vuia and Karol Pawlina for the Plaintiffs

Scott Maidment, Calie Adamson, and Anna Tombs for the Defendants

Proceeding under the Class Proceedings Act, 1992

HEARD: November 28, 29, and 30, 2016

PERELL, J.

CORRIGENDUM

The following paragraphs replace the corresponding paragraphs in the original Reasons for Decision issued on January 5, 2017.

[27] Boehringer Ingelheim Pharmaceuticals, Inc. is a Connecticut corporation with its head office located at Ridgefield, Connecticut. In the United States, it was the sponsor of Pradaxa® and obtained the approval of the United States Food and Drug Administration (“FDA”) to sell the drug in the United States. It operates a website www.pradaxa.com that provides health information, safety information, and a medication guide about Pradaxa®.

[63] It is alleged that Boehringer promoted Pradaxa® as being more effective than warfarin in preventing stroke and systemic embolism and providing a convenient alternative to warfarin therapy because Pradaxa® did not require blood monitoring or dose adjustments and it did not require dietary restrictions.

REASONS FOR DECISION

A. INTRODUCTION AND OVERVIEW

[1] The Plaintiffs, Albert C. Batten, the Estate of Margaret Jane Hamilton, and Wendy Nelson, in her personal capacity and as estate representative of the late Mrs. Hamilton, bring a proposed class action under the Class Proceedings Act, 1992, S.O. 1992, c. 6 against: (a) Boehringer Ingelheim (Canada) Ltd. (“Boehringer-Canada”); (b) Boehringer Ingelheim Pharmaceuticals, Inc.; (c) Boehringer Ingelheim Pharma GmbH & Co. KG; and (d) Boehringer Ingelheim International GmbH. I shall refer to the Defendants collectively as “Boehringer”.

[2] Boehringer-Canada is a pharmaceutical company that manufactures and distributes in Canada, dabigatran, a drug marketed as Pradaxa® (formerly Pradax®). Pradaxa® is an anticoagulant. Its Product Monograph specifies that Pradaxa® is indicated for: hip and knee surgery; venous thromboembolism events (deep vein thrombosis or “DVT”); pulmonary embolism (“PE”); and atrial fibrillation (“AF”), which is a serious heart condition that causes strokes and heart attacks. The use of anticoagulants for the treatment of AF to prevent strokes and heart attacks is long established, and Pradaxa® has become the predominant choice of an anticoagulant for AF treatment.

[3] Up until April 2016, when Praxbind® (the drug idarucizumab) was approved for sale in Canada, Pradaxa® was sold without an antidote. Mr. Batten, the Hamilton Estate, and Ms. Nelson allege that using Pradaxa® carried the risk of excessive bleeding and that Boehringer breached a duty to warn that there was no antidote for the drug.

[4] Mr. Batten, the Hamilton Estate, and Ms. Nelson bring a motion for certification of their duty to warn claim. In their Statement of Claim, under the headings of failure to warn and negligence, they plead most every kind of products liability claim and they join claims of breach of express warranty, breach of implied warranty, breach of statutes, waiver of tort, and unjust enrichment. This plethora of causes of action, however, is not being pursued for the purposes of the certification of the action. The Plaintiffs pursue only their duty to warn claim, a type of claim that has often satisfied the criteria for certification as a class action. See among others: Wilson v. Servier Canada Inc. (2000), 2000 CanLII 22407 (ON SC), 50 O.R. (3d) 219 (S.C.J.), leave to appeal ref'd (2000), 2000 CanLII 29052 (ON SC), 52 O.R. (3d) 20 (Div. Ct.), leave to appeal to S.C.C. ref'd [2001] S.C.C.A. No. 88; Heward v. Eli Lilly & Co., 2007 CanLII 2651 (ON SC), [2007] O.J. No. 404 (S.C.J.), leave to appeal to Div. Ct. granted 2007 CanLII 26607 (ON SC), [2007] O.J. No. 2709 (S.C.J.), appeal dismissed 2008 CanLII 32303 (ON SCDC), [2008] O.J. No. 2610 (Div. Ct.); Goodridge v. Pfizer Canada Inc., 2010 ONSC 1095; Parker v. Pfizer, 2012 ONSC 361, leave to appeal refused 2012 ONSC 6604 (Div. Ct.).

[5] Notwithstanding that pharmaceutical class actions have come to be often certified, Boehringer, nevertheless, resists the certification motion, and it brings a cross-motion to have the action dismissed for the failure of the Statement of Claim to plead a cause of action. However, because of the very narrow or circumscribed way that the Plaintiffs now wish to advance their proposed class action, it is not necessary to address the cross-motion, and I shall, therefore, adjourn the cross-motion and address just the certification motion.

[6] As will become most apparent during the discussion and analysis portion of these Reasons for Decision, it was wise for Mr. Batten, the Hamilton Estate, and Ms. Nelson to focus on just the duty to warn cause of action since the very broad scope of the original action would have confronted enormous difficulties. The difficulties were: (a) very serious pleading deficiencies, some of which were likely insolvable; (b) the speculative joinder of: Boehringer Ingelheim Pharmaceuticals, Inc., Boehringer Ingelheim Pharma GmbH & Co. KG, and Boehringer Ingelheim International GmbH, discussed below, seemingly for the purposes of fishing for claims against them and to secure discovery rights; (c) showing that there was some basis in fact for the proposed common issues; and (d) showing that there was some-basis-in-fact for a class action being the preferable procedure for Class Members to pursue their claims rather than proceed by individual actions.

[7] Unfortunately, for Mr. Batten, the Hamilton Estate, and Ms. Nelson, there are similar fundamental problems to their duty to warn class action that persist into their much more focused proposed class action. As the discussion below with reveal, making their duty to warn claim fit within the criteria for certification has proved difficult for the Plaintiffs. The fundamental problem is that as their duty to warn claim narrowed to the failure to adequately warn about the absence of an antidote, Mr. Batten, the Hamilton Estate, and Ms. Nelson were unable to connect the dots between the duty to warn and the consequent harm suffered in a way that would satisfy the criteria for certification as a class action. Having focused on the absence of an antidote as the subject-matter of the warning, unlike the Plaintiffs in other duty to warn cases involving pharmaceuticals that have been certified, Mr. Batten, the Hamilton Estate, and Ms. Nelson have been unable to posit a common failure to warn issue that would justify a class proceeding.

[8] I, therefore, dismiss the certification motion. The parties have agreed that there shall be no costs of the motion.

B. EVIDENTIARY BACKGROUND

[9] Mr. Batten, the Hamilton Estate, and Ms. Nelson supported their motion for certification with affidavits from: (a) Mr. Batten, sworn September 6, 2014. Mr. Batten was cross-examined; (b) Mr. Stanley North, sworn January 24, 2014 and June 23, 2016. Mr. North was cross-examined; (c) Dr. Leeor Zeev Sommer, sworn November 13, 2013. Dr. Sommer was cross-examined; (d) Ms. Lisa Staffieri, sworn July 5, 2016. Ms. Staffieri was not cross-examined; and (e) Mr. Peter E. Tuovi, sworn October 17, 2014. Mr. Tuovi was not cross-examined.

[10] Mr. North is a graduate of the University of Waterloo (B.Sc., 1990) and McGill University (M.Sc., Molecular Biology, 1993). He was a regulatory affairs assistant and associate at Agriculture Canada, then worked at Nordic Merrel Dow Research and Berlex Canada from 1988 to 2007. He is the principal and owner of Stan North Consultation, which he founded in 2007. Mr. North provides advice and services to clients in the pharmaceutical, biotech, medical device, and natural health product industries with respect to regulatory matters. He is a member and a former director (2007-2009) of the Canadian Association of Professional Regulatory Affairs.

[11] Dr. Sommer is a graduate of the University of Toronto (B.Sc., 1996, MD, 2000). Since 2005, he has an appointment as a lecturer at the University of Toronto, Department of Family and Community Medicine. Dr. Sommer has a specialty in emergency medicine, and since 2003, he has been on staff in the emergency departments at Peel Memorial Hospital (2003-2006), St Joseph’s Health Centre, Toronto (2003-to date) and North York General Hospital (2003-to present). He is a member of the Canadian College of Family Physicians, Canadian Association of Emergency Physicians, Ontario Medical Association, Canadian Medical Association, College of Physicians and Surgeons of Ontario, Canadian Medical Protective Association, and Canadian Emergency Ultrasound Society.

[12] Ms. Staffieri is a legal assistant with McPhadden Samac Tuovi, lawyers for the Plaintiffs.

[13] Mr. Tuovi is a lawyer with McPhadden Samac Tuovi, lawyers for the Plaintiffs.

[14] Boehringer opposed the motion for certification with affidavits from: (a) Ms. Nancy Chaves, sworn April 28, 2016. Ms. Chaves was not cross-examined; (b) Dr. Anil Chopra, sworn March 30, 2016. Dr. Chopra was cross-examined; (c) Ms. Anne Tomalin, sworn April 25, 2016. Ms. Tomalin was cross-examined; and (d) Dr. Zaev Wulffhart, sworn April 5, 2016 and April 8, 2016. Dr. Wulffhart was cross-examined.

[15] Ms. Chaves is a law clerk at McMillan LLP, lawyers for Boehringer.

[16] Dr. Chopra is a graduate of the University of Toronto (B.Sc. 1985, MD, 1989). He completed a Fellowship in Emergency Medicine at the University of Toronto in 1994 and since that time has served as a physician in the Emergency Department of the University Health Network (“UHN”) (Toronto General Hospital, Toronto Western Hospital, Princess Margaret Cancer Care Centre, and the Toronto Rehab Centre). Since 2006, he has served as the Head and Medical Director of the UHN’s Emergency Department. He is a member of Thrombosis Canada, which is an international organization aiming to educate physicians in the prevention and treatment of thrombotic vascular disease. Dr. Chopra has prescribed Pradaxa®, and he has treated patients in the Emergency Department who were bleeding while on anticoagulants, including Pradaxa®. He chaired a committee charged with developing a protocol to govern the use of Praxbind® (Pradaxa®’s antidote) for the Emergency Department. In 2011, Dr. Chopra published a peer reviewed research paper on the subject of, “New Anticoagulants for Atrial Fibrillation: The Beginning of a New Era in Stroke Prevention”.

[17] Ms. Tomalin is a graduate of York University (B.A., English, 1970; B.Sc., Chemistry, 1980). She received a Regulatory Affairs Certification from the Regulatory Affairs Professional Society for U.S. Regulatory Affairs (1997), European Regulatory Affairs (2001), and Canadian Regulatory Affairs (2005). She is the President and Founder of TPIreg, a consulting company that provides training services to pharmaceutical companies in regulatory affairs. She has worked in-house at pharmaceutical companies including Wyeth Ltd. and Hoffman-LaRoche Limited, as well as Searle Canada (a unit of Monsanto, Inc.). She teaches Regulatory Affairs at Humber College in Toronto. She served on the executive of the Pharmaceutical Sciences Group and the Canadian Association of Professional Regulatory Affairs, which are industry associations focusing on regulatory issues.

[18] Dr. Wulffhart is a graduate of the University of Witwatersrand Medical School, Johannesburg, South Africa (Bachelor of Medicine and Bachelor of Surgery, 1984). He is a licentiate of the Medical Council of Canada (1987). He is a Fellow of the American College of Cardiology, a Fellow of the Royal College of Physicians – Cardiology, a Fellow of the Royal College of Physicians – Internal Medicine and a member of the Canadian Cardiovascular Society. Between 1993 and 1996, Dr. Wulffhart was a lecturer at the University of Toronto Faculty of Medicine, and he became an Assistant Professor in 1996 in the area of general cardiology, which appointment has continued since that time. He has participated in numerous medical research trials and published numerous abstracts and articles. Since 2001, Dr. Wulffhart has been a staff cardiologist at the Southlake Regional Health Centre, where he was Director of the Heart Rhythm Program from 2001-2013 and Head of the Cardiology Division from 2008 to 2013. Since 2013, he has served as the Physician Leader of Southlake’s Regional Cardiac Program, which is Ontario’s largest centre for the treatment of AF.

C. FACTUAL BACKGROUND

1. The Proposed Representative Plaintiffs

[19] Albert C. Batten is 81 years of age and was diagnosed with AF. In May 2012, his doctor prescribed Pradaxa® for treatment. For several years previously, Mr. Batten had been prescribed warfarin, another anticoagulant, without problems, but with the inconvenience of the constant monitoring that a warfarin prescription entails.

[20] On July 7, 2012, while taking Pradaxa®, Mr. Batten experienced blood in the stool. At the time, he was also taking aspirin and indomethacin, a nonsteroidal anti-inflammatory drug, both of which are known to cause gastrointestinal bleeding. He attended at an emergency department and was released to go home. His medical problems continued, however, and he was hospitalized from July 16 to July 19, 2012. He stopped taking Pradaxa® and resumed taking warfarin.

[21] Wendy Nelson is the estate executor and daughter of the late Margaret Jane Hamilton. Mrs. Hamilton died at 87 years of age. She had been prescribed Pradaxa® for the treatment of AF. Mrs. Hamilton began using Pradaxa® on or about April 2012, and on May 16, 2013, while home alone, she suffered an intracranial cerebral hemorrhage (ICH) from which she died in the hospital a few hours later.

[22] There are four other proposed Representative Plaintiffs to represent Class Members in various provinces; namely: (1) Marilyn Tanguay, a British Columbia resident, as personal representative of the Estate of Gladys Chouinard; (2) Dimitre Stoianov Karpuzov, an Alberta resident; (3) Edward McAlpine, a Manitoba resident; and (4) Dawn Rae Downton, a Nova Scotia resident, as executor of the Estate of Marion Wiseman. For the purposes of the certification motion, it is not necessary to discuss their personal circumstances and without meaning any disrespect to them, I shall not refer to them again.

2. The Defendants

[23] Mr. Batten, the Hamilton Estate, and Ms. Nelson sue: (a) Boehringer-Canada; (b) Boehringer Ingelheim Pharmaceuticals, Inc.; (c) Boehringer Ingelheim Pharma GmbH & Co. KG; and (d) Boehringer Ingelheim International GmbH.

[24] Boehringer-Canada is a Canadian corporation with its registered office at Burlington, Ontario. It was the sponsor for Pradaxa® in Canada, which is to say that it is registered with Health Canada to seek a drug approval, and if approval is granted, to market the drug in Canada. It was granted an approval and it manufactured and distributed Pradaxa® in Canada.

[25] Boehringer Ingelheim International GmbH is a German corporation with its registered office located at Ingelheim am Rhein, Germany. It owns the Canadian patent for the manufacture of Pradaxa®.

[26] Boehringer Ingelheim Pharma GmbH & Co., KG is a German corporation with its registered office located in Ingelheim am Rhein, Germany. It owns the trademark Pradaxa® which it licensed to Boehringer-Canada and to Boehringer Ingelheim Pharmaceuticals, Inc.

[27] Boehringer Ingelheim Pharmaceuticals, Inc. is a Connecticut corporation with its head office located at Ridgefield, Connecticut. In the United States, it was the sponsor of Pradaxa® and obtained the approval of the United States Food and Drug Administration (“FDA”) to sell the drug in the United States. It operates a website www.pradaxa.com that provides health information, safety information, and a medication guide about Pradaxa®.

[28] Boehringer-Canada does not operate a website providing information about Pradaxa®. As the internet and the website www.pradaxa.com are universally accessible, I conclude that Canadian Class Members would have received health and safety information from Boehringer Ingelheim Pharmaceuticals, Inc.’s website.

3. Procedural History of the Pradaxa® Class Actions

[29] On March 7, 2013, Mr. Batten commenced his proposed class action against Boehringer-Canada, Boehringer Ingelheim Pharmaceuticals, Inc., Boehringer Ingelheim Pharma GmbH & Co. KG and Boehringer Ingelheim International GmbH (collectively “Boehringer”), the Defendants in the case at bar. Mr. Batten also included claims against: Boehringer Ingelheim Vetmedica, Inc.; Boehringer Ingelheim Corporation; Boehringer Ingelheim USA Corporation; and; Bidachem S.P.A., but the claims against these Defendants were discontinued in 2015.

[30] Pradaxa® class actions were also commenced in British Columbia, Alberta, Manitoba, Ontario, Québec, and Nova Scotia. In October 2015, an agreement was reached between the various Class Counsel in the parallel class actions. Boehringer was also a party to the agreement. It was agreed that Mr. Batten would seek certification of a national class action in Ontario. If certification was granted, then all the Pradaxa® alass actions, other than the one in Ontario, would be discontinued. If certification was refused in Ontario, the other class actions could be resumed within 100 days.

[31] McPhadden Samac Tuovi LLP and Siskinds LLP are the proposed Class Counsel for the Ontario action. McMillan LLP is the lawyer of record for Boehringer.

[32] There were parallel proceedings in the United States District Court, Southern District of Illinois, in a multi-district litigation known as MDL 2385. McPhadden Samac Tuovi LLP and Siskinds LLP have worked closely with the Plaintiff Steering Committee that prosecuted the actions in the United States.

[33] In their Amended Statement of Claim, Mr. Batten, the Hamilton Estate, and Ms. Nelson plead that Boehringer breached its duty to warn consumers of dangers inherent in the use of Pradaxa® of which it had knowledge or ought to have had knowledge. They also plead a breach of the duty to manufacture Pradaxa® free of defects that are likely to give rise to injury in the ordinary course of its use and a breach of the duty to design Pradaxa® to avoid safety risks and to make the product reasonably safe for its intended purposes.

[34] However, as noted above, for purposes of certification, Mr. Batten, the Hamilton Estate, and Ms. Nelson seek to certify only the common issues of whether Boehringer failed to adequately warn about the lack of an antidote for Pradaxa®. The Plaintiffs are no longer pursuing the claim of waiver of tort and are no longer proposing common issues regarding negligent design and negligent manufacture, and they are not advancing the plethora of other causes of action and breaches of statute that were pleaded.

[35] To make the point that the focus of the Plaintiffs’ claim as a class action changed fundamentally in the run up to the certification motion, I note that the first formulation of their common issues was in their notice of motion dated October 2014. About a year later, in September 2015, they substantially reformulated the questions in an amended notice of motion. The common issues were again substantially reformulated in their factum, and further revisions were discussed during the argument of the certification motion.

[36] For the purposes of this certification motion, the pertinent portions of the Amended Statement of Claim are set out in Schedule “A” to these Reasons for Decision.

4. The Duty to Warn

[37] As mentioned several times, for the purposes of certification, Mr. Batten, the Hamilton Estate, and Ms. Nelson focus on Boehringer’s duty to warn. To understand both the factual background that follows and also the legal analysis later in this decision, it is necessary to describe the law associated with a duty to warn.

[38] As explained by Justice Huddart of the British Columbia Court of Appeal in Harrington v. Dow Corning Corp., 2000 BCCA 605, affg. 1996 CanLII 3118 (BC SC), [1996] B.C.J. No. 734 (S.C.), leave to appeal to S.C.C. ref'd. [2001] S.C.C.A. No. 21, at paras. 42 to 46, typically the four steps in a products liability class action are: (1) determining whether the product is defective or whether, although non-defective, the product has a propensity to injure; (2) determining what the manufacturer knew about the dangerousness of its product; (3) given the state of the art and the extent of the risks inherent in the product’s use, determining the reasonableness of the warning whether made directly to the consumer or to a learned intermediary; and (4) determining individual causation and damages. The first step, known as the general causation step, determines whether the product is capable of causing harm. The second step is part of determining whether the manufacturer had a duty of care not to sell the product or to sell it only with an appropriate warning. The third step focuses on the adequacy of the warning. The fourth step will determine individual causation and the quantification of the compensation for the consequent harm.

[39] In Hollis v. Dow Corning Corp., 1995 CanLII 55 (SCC), [1995] 4 S.C.R. 634 at para. 21, Justice La Forest explained the rationale for a manufacturer's duty to warn. He stated:

21. The rationale for the manufacturer's duty to warn can be traced to the "neighbour principle", which lies at the heart of the law of negligence, and was set down in its classic form by Lord Atkin in Donoghue v. Stevenson, 1932 CanLII 536 (FOREP), [1932] A.C. 562 (H.L.). When manufacturers place products into the flow of commerce, they create a relationship of reliance with consumers, who have far less knowledge than the manufacturers concerning the dangers inherent in the use of the products, and are therefore put at risk if the product is not safe. The duty to warn serves to correct the knowledge imbalance between manufacturers and consumers by alerting consumers to any dangers and allowing them to make informed decisions concerning the safe use of the product.

[40] A manufacturer of a product has a duty to warn consumers of dangers inherent in the use of the product of which the manufacturer has knowledge or ought to have knowledge: Hollis v. Dow Corning Corp., supra, at para. 20; Lambert v. Lastoplex Chemicals Co., 1971 CanLII 27 (SCC), [1972] S.C.R. 569 at p. 574; Bow Valley Husky (Bermuda) Ltd. v. Saint John Shipbuilding Ltd., 1997 CanLII 307 (SCC), [1997] 3 S.C.R. 1210. The warnings must be reasonably communicated and detailed to give the consumer a full indication of each of the specific dangers that arise from the ordinary use of the product: Hollis v. Dow Corning Corp., supra, at paras. 20-21; Lambert v. Lastoplex Chemicals Co., supra, at pp. 574-75.

[41] If a product, although suitable for the purpose for which it is manufactured, is at the same time dangerous to use, the manufacturer of the product has a duty of to warn of the attendant dangers in using the product. In Lambert v. Lastoplex Chemicals Co., supra, Justice Laskin stated:

Manufacturers owe a duty to consumers of their products to see that there are no defects in manufacture which are likely to give rise to injury in the ordinary course of use. Their duty does not, however, end if the product, although suitable for the purpose for which it is manufactured and marketed, is at the same time dangerous to use; and if they are aware of its dangerous character they cannot, without more, pass the risk of injury to the consumer.

The duty to warn is a continuing duty, requiring manufacturers to warn not only of dangers known at the time of sale, but also of dangers discovered after the product has been sold and delivered; see Rivtow Marine Ltd v. Washington Iron Works, 1973 CanLII 6 (SCC), [1974] S.C.R. 1189, at p. 1200, per Ritchie J. All warnings must be reasonably communicated, and must clearly describe any specific dangers that arise from the ordinary use of the product. …

[42] The manufacturer's duty to alert consumers about dangers associated with the use of a product is a continuing duty, requiring manufacturers to warn not only of dangers known at the time of sale, but also of dangers discovered after the product has been sold and delivered: Hollis v. Dow Corning Corp., supra, at para. 20; Rivtow Marine Ltd. v. Washington Iron Works, 1973 CanLII 6 (SCC), [1974] S.C.R. 1189 at p. 1200. In the case of medical products, given their substantial risk of harm from improper use, the standard of care is correspondingly high and there will almost always be a heavy onus on the manufacturer to provide clear, complete and current information concerning the dangers inherent in the ordinary use of its product: Hollis v. Dow Corning Corp., supra, at para. 23.

[43] There is a high standard of care. In Buchan v. Ortho Pharmaceutical (Can.) Ltd. (1986), 1986 CanLII 114 (ON CA), 54 O.R. (2d) 92 (C.A.), Justice Robins stated at para. 18:

Once a duty to warn is recognized, it is manifest that the warning must be adequate. It should be communicated clearly and understandably in a manner calculated to inform the user of the nature of the risk and the extent of the danger; it should be in terms commensurate with the gravity of the potential hazard; and it should not be neutralized or negated by collateral efforts on the part of the manufacturer. The nature and extent of any given warning will depend on what is reasonable having regard to all the facts and the circumstances relevant to the product in question.

[44] In cases involving highly technical products intended to be used under the supervision of experts or where the nature of the product is such that the consumer will not realistically receive information directly from the manufacturer without the intervention of a learned intermediary, the duty of the manufacturer is discharged if the manufacturer provides the learned intermediary (for example, physicians or surgeons), rather than the consumers, with an adequate warning of the potential dangers associated with the use of its product: Hollis v. Dow Corning Corp., supra, at paras. 28-29; Buchan v. Ortho Pharmaceutical (Canada) Ltd., supra, at paras. 23, 59.

[45] In the context of manufacturers of pharmaceuticals and medical devices the learned intermediary is the physician that prescribes the drug or medical device. The legal theory here is that where a consumer places primary reliance on the judgment of a learned intermediary, then the manufacturer will satisfy its duty to warn the consumer by adequately warning the learned intermediary of the risks inherent in the use of the product. In Hollis v. Dow Corning Corp., supra, Justice La Forest stated at para. 27:

As a general rule, the duty to warn is owed directly by the manufacturer to the ultimate consumer. However, in exceptional circumstances, a manufacturer may satisfy its informational duty to the consumer by providing a warning to what the American courts have, in recent years, termed a "learned intermediary”. …. The rationale for the rule was outlined by Wisdom J. in Reyes v. Wyeth Laboratories, 498 F. 2d 1264 (5th Cir., 1974), at p. 1276, certiorari denied 419 U.S. 1096 ( 1974), a suit against a manufacturer of oral polio vaccine, in the following terms:

Prescription drugs are likely to be complex medicines, esoteric in formula and varied in effect. As a medical expert, the prescribing physician can take into account the propensities of the drug, as well as the susceptibilities of his patient. His is the task of weighing the benefits of any medication against its potential dangers. The choice he makes is an informed one, an individualized medical judgment bottomed on a knowledge of both patient and palliative. Pharmaceutical companies then, who must warn ultimate purchasers of dangers inherent in patent drugs sold over the counter, in selling prescription drugs are required to warn only the prescribing physician, who acts as a “learned intermediary” between manufacturer and consumer. [Footnotes omitted.]

[46] The rationalization for the learned intermediary rule for pharmaceutical products is summarized by Patricia Peppin in "Drug/Vaccine Risks: Patient Decision-Making and Harm Reduction in the Pharmaceutical Company Duty to Warn Action", (1991) 70 Can. Bar Rev. at p. 484:

… (1) [T]he patient places primary reliance on the physician’s judgment and advice because the physician must prescribe; (2) direct communication between the manufacturer and the consumer is "difficult if not virtually impossible"; (3) such direct communication would interfere unduly with the doctor-patient relationship; and (4) direct warnings would be read after the purchase, creating the possibility that the patient would be frightened and not take the drug ...

Quoted in Bow Valley Husky (Bermuda) Ltd. v. Saint John Shipbuilding Ltd. (1995), 1995 CanLII 9867 (NL CA), 126 D.L.R. (4th) 1 (Nfld. C.A.), aff’d 1997 CanLII 307 (SCC), [1997] 3 S.C.R. 1210.

5. Antigoagulants, Pradaxa® (dabigatran), Atrial Fibrillation (“AF”), and Strokes

[47] The ability of the blood to coagulate; i.e., to clot and seal off a wound and to stop the bleeding is critically important for health, but clotting can also be dangerous as blood clots can block blood vessels and deprive body organs from the oxygen contained in the blood, which, in turn, leads to heart attacks and strokes.

[48] Coagulation is a complex process, and two of the substances that play an important role are vitamin K and thrombin. Anticoagulants are substances that interfere with the coagulation process, and the anticoagulant drug warfarin inhibits the ability of the body to use vitamin K. In comparison, the anticoagulant drug dabigatran inhibits the ability of the body to use the protein thrombin, which is the main active principle in plasma.

[49] In June 2008, Health Canada approved Pradaxa® (dabigatran) for use in Canada.

[50] Pradaxa® is a prescription drug found on the Prescription Drug List. It was the first of a class of drugs known as Novel Oral Anticoagulants (“NOACs”). It was introduced for anticoagulation therapy as an alternative to warfarin, which had been prescribed since 1954. Warfarin is a vitamin K antagonist and produces an anticoagulant effect for up to 48 hours by reducing vitamin K. After the approval of Pradaxa®, Health Canada approved two competing NOACs, Xarelto and Eliquis.

[51] Pradaxa® is indicated for, among other things, the prevention of stroke and systemic embolism in patients with AF. AF is the most common arrhythmia (heart rhythm disturbance). It affects approximately 350,000 Canadians. Approximately 6% to 10% of the population over the age of 65 have AF, and 25% of people over the age of 75 will develop AF. AF is at epidemic levels, it is increasing, and it is estimated that by 2050, the number of patients with AF will likely double. The most serious consequence of AF is its propensity for causing strokes.

[52] People with AF are at risk of having the flow of blood slow or stagnate in areas of the heart. Blood clots can then form, and the clots account for the increased risk of stroke associated with AF. The risk of stroke increases significantly with advancing age, from 1.5% per year for people in their 50s to 24% per year for people in their 80s.

[53] Strokes that arise from AF are often fatal (20%), and when not fatal they can cause temporary or permanent disabilities (60%). The strokes attributable to AF have a higher mortality and morbidity rate as compared to strokes from other causes.

[54] The treatment of patients with AF has two goals. One goal is to treat the rhythm disorder and the second goal is to prevent strokes, and it is for this second goal that anticoagulants play a prominent role. Anticoagulants reduce the risk of clot formation, and thereby reduce the risk of stroke.

[55] Historically, and before the development of the NOACs, the treatment for AF has involved the administration of warfarin (also known by the brand name Coumadin among others) or aspirin (also known as acetylsalicylic acid), both of which have limitations and risks.

[56] Warfarin patients require frequent access to medical services for close medical monitoring, routine coagulation tests, and frequent dose adjustments. Since warfarin acts as a vitamin K antagonist, patients must abide by dietary restrictions, including the need to avoid green leafy vegetables that contain vitamin K, which reduces warfarin’s effectiveness in stroke prevention. These requirements made warfarin extremely inconvenient for patients to use and physicians to prescribe.

[57] A patient taking warfarin must maintain an International Normalized Ratio (“INR”) between 2 and 3, which is difficult for the patient to do. The INR is a measurement of how long it takes blood to form a clot. An INR below 2 is associated with an increased risk of stroke – obviously a dangerous risk - and an INR above 3 is associated with an increased risk of bleeding - also obviously a dangerous risk. A patient’s INR fluctuates due to dietary changes, interactions with other medications, alcohol consumption, or as a result of genetic variability in the patient’s ability to metabolize warfarin.

[58] The pharmacokinetic effect of warfarin is idiosyncratic and poorly predictable, which is to say determining the optimum dosage for a particular patient is difficult. Because of the significance of genetic makeup, determining the appropriate dosage of warfarin is patient specific. For example, some patients will require a daily dose of 12-15 mg of warfarin to achieve an INR between 2 and 3, while others will require a daily dose of only 1 mg of warfarin to achieve the same INR. And some patients metabolize warfarin so quickly that it is not effective at all.

[59] It is estimated that patients who are treated with warfarin are within the therapeutic range for stroke prevention only 50% of the time; the other 50% of the time, they are either at an increased risk of stroke or an increased risk of bleeding.

[60] Historically, some AF patients with a lower risk of stroke were not prescribed warfarin because of an increased risk of intracranial hemorrhage (“ICH”), bleeding in the brain, a devastating form of bleeding that was associated with warfarin use. Because these patients were not receiving warfarin due to the risks of ICH, they did not have access to effective protection from stroke.

[61] Aspirin’s efficacy in stroke prevention is substantially less than that of warfarin and the risk of bleeding when on aspirin is significant. Aspirin is in the top three categories of drugs that result in emergency department visits due to its adverse consequences.

[62] In contrast to warfarin and aspirin, Pradaxa®: has a wider therapeutic range; has a fixed dosing regimen; has minimal drug interactions; has no food interactions, and has a predictable anticoagulant response with a rapid onset and a faster decline of effectiveness. Patients taking Pradaxa® can consume green leafy vegetables and other vitamin K rich foods, without increasing their risk of stroke. There is no need or utility to measuring the INR of patients taking Pradaxa®.

[63] It is alleged that Boehringer promoted Pradaxa® as being more effective than warfarin in preventing stroke and systemic embolism and providing a convenient alternative to warfarin therapy because Pradaxa® did not require blood monitoring or dose adjustments and it did not require dietary restrictions.

[64] A major benefit of using Pradaxa® over warfarin is the reduced rate of ICH. There is at least 50% lower frequency of ICH with Pradaxa® use than with warfarin use. The introduction of Pradaxa® and the other NOACs resulted in a larger percentage of AF patients receiving anticoagulant therapy for stroke prevention because Pradaxa® and other NOACs have a significantly lower risk of ICH as compared to warfarin. With the development of Pradaxa® and the other NOACs, a higher proportion of AF patients are being prescribed anticoagulation therapy, resulting in fewer strokes and reducing the mortality and morbidity associated with AF.

[65] Testing a lower and a higher dose of Pradaxa®, an extensive clinical trial known as the RE-LY TRIAL, studied Pradaxa® in 18,133 patients. The study found there were significant clinical advantages to Pradaxa® over warfarin: namely: (a) the risk of first stroke or systemic embolism (blood clot to another part of the body other than the brain) for patients taking Pradaxa® was reduced by 35% when compared to warfarin; (b) the lower dose of Pradaxa® had a similar efficacy to warfarin, but with a lower risk of bleeding; (c) both tested doses of Pradaxa® had a significant reduction in ICH and life-threatening bleeding as compared to warfarin; (d) the lower dose of Pradaxa® had a lower risk of bleeding (including GI bleeding) than warfarin; and (e) both doses of Pradaxa® had a similar all-cause mortality to warfarin.

[66] Based on the findings of the RE-LY Trial, Pradaxa® was accepted, approved and introduced rapidly into clinical practice for the treatment of stroke prevention in AF. Pradaxa® was introduced into the Canadian Cardiovascular Society (“CCS”) Guidelines in 2010 as a first choice over warfarin for stroke prevention. The 2014 CCS Guidelines recommend that when oral anticoagulant therapy is indicated for patients with non-valvular AF, most patients should receive a NOAC in preference to warfarin. In 2014, the CCS Guidelines introduced a decision tree algorithm for physicians to assess the individual patient’s risk of stroke and, therefore, the therapeutic benefit of anticoagulation.

[67] In determining whether a particular patient will benefit from anticoagulant therapy, a clinician must first assess the patient’s risk of stroke and the risks of bleeding; the greater the risk of stroke, the more benefit the patient will receive from anticoagulation. A physician will also consider the presence of a variety of conditions, such as very poor renal function (measured by creatinine clearance), patients with prosthetic mechanical heart valves, and those patients with rheumatic valvular heart disease. Patients with these particular characteristics would have to use warfarin because NOACs are contraindicated.

[68] Physicians must engage in a complex decision making process in deciding whether to recommend a NOAC or warfarin. When considering anticoagulant therapy for AF patients, physicians use a scoring system to assess an individual patient’s risk of stroke and, therefore, the therapeutic benefit of anticoagulation. Clinically relevant scoring systems include the Congestive Heart Failure, Hypertension, Age > 75, Diabetes Mellitis and Prior Stroke or Transient Ischemic Attack index (“CHADS2”) and the Congestive Heart Failure, Hypertension, Diabetes Mellitis, Stroke, Vascular Disease, Age 65 to 74 years, Sex Category index (“CHADSVASC”).

[69] If a determination is made that a particular patient will benefit from anticoagulant therapy, the physician must then balance this benefit against the risk of hemorrhage, which is associated with all anticoagulants. The risk of major hemorrhage depends upon individual patient characteristics. Physicians use a scoring system to predict a patient’s individual bleeding risk. The CCS Guidelines recommend that physicians use the Hypertension, Abnormal Renal/Liver Function, Stroke, Bleeding History or Predisposition, Labile INR, Elderly (age >65), Drugs/Alcohol Concomitantly score schema (“HAS-BLED”). A high HAS-BLED score indicates to the physician that a particular patient may be at an increased risk for bleeding. A physician will use this information to either use the lower dose of Pradaxa® or consider using warfarin, aspirin, or nothing.

6. Anticoagulants and the Risk of Bleeding

[70] Bleeding may result in death, and all anticoagulants, including warfarin, Pradaxa® and the other NOACs, are associated with an increased risk of bleeding. It should, however, be kept in mind – indeed it needs to be emphasized - that anticoagulants do not cause bleeding, which rather is caused by a variety of disease states, can take many forms, and can occur in any location in the human body.

[71] The point is subtle - but the point is important for this certification motion – although warfarin, Pradaxa® and the other NOACs do not “cause” bleeding, they all “propagate” bleeding, which is to say that the all are associated with the bringing about of the risks of prolonged or persistent bleeding. As their description or nomenclature suggests, all anticoagulants work to prevent blood coagulation, which explains how they propagate bleeding without causing bleeding. In a sense, although warfarin, Pradaxa® and the other NOACs do not cause bleeding in the first instance, they do cause bleeding in the sense of causing bleeding to continue or to be prolonged. To foreshadow the discussion later in the analysis, the subtle point about propagating but not causing bleeding is important because it makes it extremely difficult for the Plaintiffs to articulate common issues to satisfy the tests for certifying a class action.

[72] The evidence about coagulants and their benefits and risks, which were highly dependent on the idiosyncrasies of the patients, compound the Plaintiffs’ difficulties in articulating a satisfactory common issue. The evidence about antidotes and the need for them further compounded the Plaintiffs’ difficulties in articulating a satisfactory common issue. To understand the role of antidotes, it is important to note that Pradaxa® has a biological half-life of approximately 12-14 hours; i.e., after 12-14 hours it loses its efficacy. Thus, a patient who last consumed Pradaxa® 12 to 24 hours before presenting at an emergency department would experience little remaining anticoagulation effect. In contrast, warfarin, unlike Pradaxa®, which wears off relatively quickly, has a much longer anticoagulant effect, lasting up to 48 hours. For warfarin, it could take 16 hours to produce a reduction in INR with a therapeutic level being reached by the second day.

[73] The outcome of any bleeding for any patient on warfarin, Pradaxa®, or any other anticoagulant will be dependent on individualized factors such as the patient’s underlying diagnosis, the state of the patient’s health, size of the bleed, location of the bleed, timing of last anticoagulant dose, time to presentation, patient co-morbidity, and co-medications. The measures applied for the management of bleeding will differ depending upon each patient’s particular circumstances. In the majority of cases, no reversal agent for an anticoagulant will be necessary.

[74] In the great majority of cases, there is no material difference in the management of bleeding as between Pradaxa® patients and warfarin patients. Most patients who present with bleeding while taking any anticoagulant have mild to moderate transient bleeding, such as a nosebleed and skin bruising. These types of bleeding can typically be managed with conservative measures such as local compression. A minority of patients taking an oral anticoagulant will have a major bleeding episode. Major bleeding may require resuscitation with intravenous fluids and blood products, and may require interventional procedures such as surgery, cauterization, or an endoscopic procedure. The blood products that may be transfused to treat bleeding include Prothrombin Complex Concentrate (“PCC”), a concoction of blood clotting factors and proteins made from human blood plasma or Fresh-Frozen Plasma (“FFP”).

[75] However, because anticoagulants propagate bleeding, there may be circumstances in which reversing their anticoagulant effect is called for. In the case of warfarin, as already noted, its anticoagulant effect can be long-lasting. It is, therefore, appropriate in some circumstances to reverse the anticoagulant effect of warfarin by administering both vitamin K and a PCC or FFP. The administration of vitamin K reverses that anticoagulant effect of warfarin, which is a vitamin K antagonist.

[76] However, the evidence suggested that it takes longer to reverse the longer-lasting anticoagulant effect of warfarin by the administration of vitamin K than it takes Pradaxa® to lose its anticoagulant effect because of its shorter biological half-life. If the patient has taken Pradaxa® in the previous one to two hours, activated charcoal might be given to the patient to absorb any free remaining drug in the stomach or intestines, but the vast majority of patients could safely wait till the anticoagulant effect of Pradaxa® has worn off.

[77] Studies show that in patients who have major bleeding while taking either warfarin or Pradaxa®, all-cause mortality is lower with Pradaxa® than with warfarin. The mortality rate from major bleeding is higher for warfarin patients than for Pradaxa® patients. Even without an antidote or reversal agent for Pradaxa®, fewer patients are expected to die from a Pradaxa®-associated major bleed than a warfarin-associated major bleed.

[78] In any event, regardless of the anticoagulant, reversal is not the immediate or automatic response to a patient presenting with bleeding. That is because reversal of the anticoagulant carries very serious risks, including an increased risk of stroke. The Pradaxa® Product Monograph states that all temporary discontinuations should be avoided, unless medically indicated. Thus, the decision to apply a reversal agent of an anticoagulant will depend on the site of the bleeding, the nature of the bleeding, the underlying disease state, and the adequacy of the conventional means to arrest bleeding and the dangers of discontinuing the administration of an anticoagulant.

[79] Pradaxa® did not have an approved specific reversal agent until May of 2016, when Praxbind® was approved. The other NOACs do not have an approved reversal agent.

[80] Following the approval of Praxbind®, administration of a reversal agent for Pradaxa® became an option for physicians treating a bleeding Pradaxa® patient. It, however, was never envisioned that Praxbind® would be used in every case of bleeding, and the use of Praxbind® will not be appropriate for the great majority of patients who experience bleeding while on Pradaxa®. Praxbind® may be appropriate for patients in rare cases where very rapid reversal of the anticoagulation effect of Pradaxa® is necessary. Whether the use of Praxbind® is appropriate in any particular case is a matter of the treating physician’s professional judgment and the circumstances of the particular patient.

7. Regulatory Process for Drug Marketing

[81] Health Canada is responsible for approving drugs for sale in Canada. A drug is licensed for sale by Health Canada issuing a Notice of Compliance (“NOC”) after an elaborate submission and review process.

[82] Pursuant to the Food and Drugs Act, R.S.C. 1985, F.27, and its regulations, the manufacturer, described as the sponsor, must file a New Drug Submission ("NDS"). The NDS contains detailed information about: the chemistry of the drug; the manufacturing process; the results of pre-clinical and clinical testing; information about the proposed indications, dosage, and conditions of use; the drug’s claimed therapeutic value; and warnings about potential side effects and risks. The NDS submissions by the manufacturer include a draft Product Monograph.

[83] The NDS/NOC process includes an extensive review of the manufacturer’s submission and a review of the proposed Product Monograph for the drug. The Health Canada reviewers are physicians, pharmacologists, or other scientists. In determining whether to approve or reject a submission, the reviewers will scrutinize: whether the drug can be made consistently; whether the product quality can be assured; whether the efficacy of the drug is acceptable based on a randomized controlled trial(s), and whether the safety profile of the drug is acceptable based on the risk/benefit analysis.

[84] The Product Monograph is subject to a review by Health Canada’s Therapeutic Products Directorate. The Directorate is staffed by scientific experts with extensive clinical and or medical expertise. The Product Monograph provides pertinent information about the nature and uses of the drug including cautions and warnings. The Product Monograph summarizes the results of the studies submitted to Health Canada. Health Canada's publication, "Guidance for Industry: Product Monograph" describes the role of the Product Monograph as follows:

A Product Monograph is a factual, scientific document on the drug product that, devoid of promotional material, 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. A Product Monograph should include appropriate information respecting the name of the drug, its therapeutic or pharmacologic classification, its actions and/or clinical pharmacology, and its indications and clinical uses. The monograph should also include contraindications, warnings, precautions, adverse reactions, drug interactions and effects on laboratory tests, symptoms and treatment of overdosage, dosage and administration, storage and stability, pharmaceutical information, dosage forms, pharmacology, toxicology, microbiology, special handling instructions, information on clinical trials, information for the consumer, references, and the dates of the initial printing and current revision.

From a medical and scientific standpoint, the prime objective of a Product Monograph is to provide essential information that may be required for the safe and effective use of a new drug.

[85] A Product Monograph consists of three distinct parts; that is: (1) Part I: Health Professional Information, which provides information to healthcare professionals for the prescribing, dispensing, and administering of the medication; (2) Part II: Scientific Information, which provides highly detailed scientific research information such as the drug’s chemical composition, toxicology and data from clinical trials; and (3): Part III: Consumer Information, which provides information for the consumer about the medication, how to use it and what are the side effects.

[86] Within a Product Monograph, any particular risk can be profiled with greater or lesser prominence. The most prominent warnings take the form of “boxed warnings,” found in Part I and repeated in Part III that highlight serious risks that are clinically significant or life-threatening. Other serious risks will be presented within the WARNINGS AND PRECAUTIONS section in Parts I and III.

[87] If satisfied that the drug and its Product Monograph satisfies the requirements of the Food and Drugs Act, Health Canada will issue a NOC as well as a Drug Identification Number (“DIN”) that permits the sponsor to sell the drug in Canada. When a NOC is issued, Health Canada also prepares a "Summary Basis of Decision" ("SBD"). The SBD explains why Health Canada authorized the drug for sale in Canada. The document includes regulatory, safety, effectiveness, and quality (chemistry and manufacturing) considerations.

[88] Health Canada is also responsible for the post-marketing surveillance of drugs once they have been marketed, including monitoring drug safety and ensuring that drug manufacturers comply with the regulations, which include reporting and recordkeeping obligations about the effects of the drug on patients. For example, manufacturers are required to deliver expedited adverse drug reaction (ADR) reports of all serious adverse drug reactions that occur in Canada and all serious and unexpected ADRs that occur outside of Canada. ADRs may also be submitted by patients, health professionals or others.

[89] As new information about a drug becomes available, or as changes are made by the manufacturer, a follow-up submission to Health Canada may be required. If the manufacturer expands the indications for a drug, a supplemental NDS (“SNDS”) must be filed. For a change to identify adverse events or to take risk management measures, the manufacturer must file a NOC submission and the changes can be implemented only after Health Canada issues a No Objection Letter (NOL).

[90] After a drug has been approved, Health Canada's Marketed Health Products Directorate (MHPD) monitors ADRs including the required reports from manufacturers and also spontaneous reports of ADRs from healthcare professionals across Canada.

8. Regulatory History of Pradaxa®

[91] Health Canada first approved Pradaxa® for sale in June of 2008. The same year, Pradaxa® was approved by European regulators for sale in Europe. It was approved for sale in the United States in 2010. There is no evidence that Pradaxa® is ineffective for any of its approved uses, and Health Canada’s marketing approval of Pradaxa® has never been suspended or withdrawn.

[92] Boehringer-Canada submitted an NDS for Pradaxa® with Health Canada on June 19, 2007, and Pradaxa® was approved as of June 10, 2008 for the prevention of venous thromboembolic events (VTE) in patients who have undergone elective total hip replacement or total knee replacement surgery.

[93] Boehringer-Canada submitted a SNDS for Pradaxa® to Health Canada on December 23, 2009 for the prevention of stroke, systemic embolism and reduction in vascular mortality in patients with AF. Health Canada gave it a priority review, which Health Canada reserves for circumstances where the drug could be prescribed for a serious, life-threatening, or severely debilitating disease or condition for which there is substantial evidence of clinical effectiveness that the drug provides: (1) effective treatment, prevention or diagnosis of a disease or condition for which no drug is presently marketed in Canada; or (2) a significant increase in efficacy and or significant decrease in risk such that the overall benefit risk profile is improved over existing therapies, preventatives or diagnostic agents for a disease or condition that is not adequately managed by a drug marketed in Canada. The drug was approved as of October 26, 2010.

[94] Around the world, once approved for use by the regulator, Pradaxa® became a very popular prescription drug. For example, in the United States, the 2013 sales for Pradaxa® totaled $825 million.

[95] Shortly after Pradaxa® was approved for sale in Canada and in the United States, adverse events began to be reported to the FDA in the United States and to Health Canada in Canada, respectively. By the end of December 2011, there were thousands of reports, most of them involving life-threatening bleeding or blood clots in the elderly. There were hundreds of reports of rectal hemorrhages, cerebrovascular events, and deaths linked to Pradaxa®. In Canada, in 2014, the Canadian Vigilance Adverse Reaction Online Database had 818 reports of “bleeding” or “hemorrhage.”

[96] On June 26, 2014, Pradaxa® was granted further approval for the treatment of VTE and DVT and pulmonary embolism (“PE”) and the prevention of recurrent DVT and PE.

[97] Pradaxa® did not have an approved specific reversal agent until May of 2016, when Praxbind® was approved.

9. The Pradaxa® Product Monograph

[98] Using the Pradaxa® Product Monograph dated May 14, 2013 as the illustration, I have set out the pertinent portions of the Product Monograph in Schedule “B” to these Reasons for Decision.

[99] As may be seen, the excerpt is extensive. It is necessary to include this large excerpt because the nature of the Plaintiffs’ allegations about the failure to warn requires the alleged deficiencies to be put into the context of the totality of information provided by Boehringer in its Product Monograph and because, as noted above, the nature of the allegations at the certification motion changed from the much broader allegations made at the outset of the proposed class action and narrowed to a failure to warn claim associated with an alleged inadequate notice of the absence of an antidote.

[100] Although the whole excerpt from the Product Monograph must be read to understand the parties’ arguments, it is helpful to summarize some of the more important aspects of it.

[101] In this regard, the Product Monograph has always been copiously replete with warnings about bleeding, including a warning that “major or severe bleeding may occur” and “may lead to disabling, life-threatening or even fatal outcomes.” The WARNINGS AND PRECAUTIONS section of Part I begins with a warning about the risks of all anticoagulants as follows:

As with all anticoagulants, PRADAXA (dabigatran etexilate) should be used with caution in circumstances associated with an increased risk of bleeding. Bleeding can occur at any site during therapy with PRADAXA. The possibility of a hemorrhage should be considered in evaluating the condition of any anticoagulated patient. An unexplained fall in hemoglobin and/or hematocrit or blood pressure should lead to a search for a bleeding site.

Patients at high risk of bleeding should not be prescribed PRADAXA (see CONTRAINDICATIONS).

Should severe bleeding occur, treatment with PRADAXA must be discontinued and the source of bleeding investigated promptly.

[102] Part I of the Pradaxa® Product Monograph discusses bleeding in: the CONTRAINDICATIONS section, the WARNINGS AND PRECAUTIONS section, the ADVERSE REACTIONS section, the DOSAGE AND ADMINISTRATION section, and the OVERDOSAGE section. Part I refers to common ADRs that include “anemia, epistaxis (nosebleeds), gastrointestinal hemorrhage, urogenital hemorrhage hematoma (abnormal collection of blood outside of a blood vessel), hematuria (the presence of blood in urine), wound hemorrhage, wound secretion, post-procedural hematoma, post-procedural hemorrhage, traumatic hematoma, post-procedural discharge. Part I provides information regarding bleeding risks and advises that should severe bleeding occur, treatment with Pradaxa® must be discontinued and the source of bleeding investigated promptly.

[103] There are pages and pages of text and charts discussing bleeding and its association with anticoagulants and with bleeding. The text notes that although rare in frequency in clinical trials, major or severe bleeding may occur and, regardless of location, may lead to disabling, life-threatening or even fatal outcomes.

[104] Part II of the Pradaxa® Product Monograph discusses bleeding in the CLINICAL TRIALS section and provides a great deal of information.

[105] Part III of the Product Monograph discusses bleeding under numerous headings and identifies numerous serious side effects, many of which are bleeding related. Part III, states in bold that major or severe bleeding can occur in any part of the body while taking Pradaxa® and also that although rare, major or severe bleeding may occur and regardless of its location, may become disabling, life-threatening or even lead to death.

[106] The Product Monograph advises that bleeding was the most relevant side effect and that bleeding occurred in approximately 14% of patients treated short-term for elective hip or knee replacement surgery and in long-term treatment in 16.5% of patients with AF treated for the prevention of stroke and systemic embolism.

[107] Until the approval of Praxbind®, every version of the Canadian Product Monograph for Pradaxa® since the launch of the product indicated under the OVERDOSAGE Section of Part I that there is no antidote for this drug.

[108] After Praxbind® was approved, the Product Monograph of Pradaxa® was revised.

10. The Experts’ Evidence

(a) Stanley North

[109] For the time before the introduction of Praxbind®, the Plaintiffs asked Mr. North to provide an opinion regarding the adequacy of the statements in the Product Monograph for Pradaxa® about the lack of a reversal agent (antidote), and the prominence given to those statements.

[110] Mr. North reviewed all the iterations of the Product Monograph for Pradaxa® to determine whether the lack of an antidote was ever profiled and if so, when and how it was profiled. He considered whether any references to the lack of an antidote were adequate and timely, given the state of Boehringer’s knowledge.

[111] Mr. North observed that in Canada, for its Product Monographs, Boehringer warned about the lack of an antidote for the anticoagulant effects of Pradaxa® in only the OVERDOSAGE section of the Product Monograph and not under the WARNINGS AND PRECAUTIONS section.

[112] Mr. North noted that in January 2012, in the United States, Boehringer revised the Product Monograph to include information about the lack of an antidote in both the OVERDOSAGE and WARNINGS AND PRECAUTIONS sections of the Product Monograph. The warning in the Product Monograph in the United States stated:

A specific reversal agent for dabigatran is not available. Dabigatran can be dialyzed (protein binding is low, with the removal of about 60% of drug over 2-3 hours); however the amount of data supporting this approach is limited. Activated prothrombin complex concentrates (PCCs, e.g., FEIBA), or recombinant Factor VIIa, or concentrates of coagulation factors II, IX or X may be considered, but their use has not been evaluated in clinical trials. Protamine sulfate and vitamin K are not expected to affect the anticoagulant activity of dabigatran. Consider administration of platelet concentrates in cases where thrombocytopenia is present or long-acting antiplatelet drugs have been used.

[113] Subsequent versions of the U.S. label continued to include the statement about the lack of a reversal agent in the OVERDOSAGE section and a warning in the WARNINGS AND PRECAUTIONS section. In his report, Mr. North noted that the Australian label for Pradaxa® underwent a similar process of revision comparable to what had occurred in the United States.

[114] Although Mr. North had not read the evidence of the Plaintiffs’ emergency medicine expert (Dr. Sommer) and had no independent knowledge of how bleeding events are managed by physicians, it was Mr. North’s opinion that the statements in the Canadian Product Monograph were inadequate to alert healthcare professionals and the public about the lack of an antidote for Pradaxa®.

[115] More particularly, Mr. North concluded that it is not sufficient for the information concerning the lack of a reversal agent to be found only in the OVERDOSAGE section of Part I. Mr. North submitted that since Pradaxa® users can experience excessive bleeding in numerous circumstances unrelated to overdosing, reference to the absence of an antidote only with respect to overdosing was inadequate. Rather, in his opinion, the absence of an antidote should have been profiled in the WARNINGS AND PRECAUTIONS section of Part I and arguably, in a Boxed Warning. It was his opinion that the warning should also have included in Part III of the Product Monograph so that patients could become aware of this risk independent of any information, if any, provided by their physician.

[116] It was Mr. North’s opinion that the fact there was no antidote to Pradaxa® qualified as a clinically significant or life-threatening safety hazard and would thus properly belong in a Boxed Warning.

[117] During cross-examination, Mr. North admitted that a physician would be better placed to know whether simple cessation of Pradaxa® would be adequate to address bleeding. He admitted that: it would not be appropriate for all information in Part I of the Product Monograph to be included in Part III and that where information is placed is ultimately determined by Health Canada. He also admitted that for some drugs that carry a risk of bleeding it would be appropriate to put the absence of a reversal agent only in the OVERDOSAGE section and that the decision would depend on the particular drug.

[118] Boehringer argues that I should reject Mr. North’s evidence about the adequacy of the warnings in the Pradaxa® Product Monograph in its entirety. I, think, however, that would go too far. What I will say is that Mr. North’s evidence is very weak in making a connection between any harm being suffered by the alleged deficiencies in the warnings contained in the Product Monograph. Mr. North did not take into account the reviewing role of Health Canada or the circumstance that most drugs do not have a reversal agent and he had done no research into the practice of physicians in prescribing anticoagulants and the significance, if any, of the absence of an antidote for Pradaxa® to an emergency department doctor responding to a bleeding event. Mr. North spoke to no physician before he prepared his reports, and he was unaware of the evidence that a reversal agent for Pradaxa® would only be useful in very rare cases.

(b) Dr. Leeor Zeev Sommer

[119] Dr. Sommer delivered a very short report of 41 paragraphs of which the opinion portion comprised 18 paragraphs. As an emergency department physician, his opinion was that when confronted with a patient suffering from major bleeding, he felt that it was far more difficult to manage patients taking Pradaxa® who presented with excessive bleeding because there was no way to measure the state of the anticoagulants of the drug as was the case for warfarin, for which the INR could be measured. It was his opinion that there were no treatment options for the patient on Pradaxa® because there was no antidote and no simple way to reverse its anticoagulant effect, as was the case for warfarin, which had the reversal agent of vitamin K.

[120] I found Dr. Sommer’s evidence unhelpful and unconvincing, and I very much prefer the evidence of Dr. Wulffhart and Dr. Chopra set out below. Dr. Wulffhart’s, and particularly, Dr. Chopra’s, detailed and cogent opinions demonstrated that Dr. Sommer was wrong in his analysis of the comparative treatment options for a patient presenting with excessive bleeding on warfarin and a patient presenting with excessive bleeding on Pradaxa®. While Dr. Sommer was correct in his description of anticoagulation, he was wrong in his general assessment about the need for reversal agents when a patient on a anticoagulant presents with excessive bleeding, and he was wrong in suggesting that there were no treatment options to respond to excessive bleeding presented by a patient on Pradaxa®. While Dr. Sommer was correct in stating that there was no comparable measure like INR for Pradaxa®, he missed the point that given the short biological half-life of the drug, very little purpose would be accomplished by having a test and that in most cases what the emergency doctor needed to know is when did the patient last take the drug.

[121] And Dr. Sommer was certainly wrong in suggesting that the choice of administering vitamin K or any reversal agent was an easy matter. As Dr. Chopra’s evidence revealed, the decision to reverse warfarin with vitamin K (or to reverse Pradaxa® with Praxbind®) is bursting with serious and dangerous problems including precipitating the lethal stroke or heart attack that warfarin and Pradaxa® were prescribed to prevent.

(c) Dr. Anil Chopra

[122] In his testimony, Dr. Chopra described in detail the nature of coagulation, anticoagulation, natural and pharmaceutical anticoagulants, and how physicians make treatment decisions about how to treat patients on anticoagulant drugs that present with bleeding. Some of the evidence is already described earlier in this judgment.

[123] Dr. Chopra said that when faced with a bleeding patient taking Pradaxa®, even a patient who just recently consumed the drug, emergency room physicians have non-antidote measures available to effectively manage bleeding, as they do in the case of warfarin patients. Dr. Chopra said that most patients who present with bleeding while taking an anticoagulant have simple bleeding, such as nosebleeds or bruising, and this bleeding can typically be managed with conservative measures such as compression. Regardless of whether the patient is on an anticoagulant, other measures for patients presenting with bleeding are cauterization and the transfusion of PCC or FPP. In these cases, no reversal agent would be necessary.

[124] Dr. Chopra said that in other cases of patients admitted with serious bleeding, the availability of an antidote would be meaningless. He testified that for patients who are admitted with ICH, approximately 30 to 50 percent die in hospital, and some come in so sick after their bleeding that giving them a drug to reverse their coagulation status is essentially futile and would not alter their outcome.

[125] Dr. Chopra said that a physician had to exercise great care on an individual case-by-case basis to determine whether it was medically advisable to move beyond conservative measures to apply a reversal agent to an anticoagulant because this might not be necessary and could expose the patient to a risk of stroke or thromboembolism. He said that in the vast majority of patients, the benefits of stroke prevention were far greater than the risks of major bleeding. He said that there must be good reason to reverse the anticoagulant effect of warfarin and the physician must be sure that reversal, in all of the specific circumstances relevant to that patient, will not cause more harm than good.

[126] Dr. Chopra said that in the great majority of cases, there is no material difference in the management of bleeding as between a Pradaxa® patient and a warfarin patient. He said that for the vast majority of patients on Pradaxa®, they could safely wait for the anticoagulant effect of the drug to wear off even if surgery was required.

[127] Dr. Chopra’s evidence revealed that in the circumstances when it would be medically desirable to manage the bleeding by reversing an anticoagulant, treating the patient on warfarin was problematic because unlike Pradaxa® there was no alternative of just administering PCC and FPP and waiting until the drug wore off (likely just a few hours) because given the longer-lasting effect of warfarin (up to 48 hours), there might be a need to reverse the warfarin by administering vitamin K. The administration of vitamin K, however, presented serious challenges and risks. In his report, Dr. Chopra stated:

A physician would typically wait for INR test results before administering any reversal agent, however. There are two reasons for this. First, the INR results will allow the physician to determine whether reversal of warfarin is indicated for that patient. Second, the INR results allow the physician to determine the appropriate dose of vitamin K that is needed for that patient. Appropriate dosing of vitamin K is critically important. If the patient requires reversal and the reversal dose is too low, the reversal effect will be inadequate. On the other hand, if the dose is too high, this can be dangerous for the patient, as it will increase the patient's risk of clotting and having a stroke or pulmonary embolism in the near future unless adequate early anticoagulation is reintroduced. This is particularly problematic for patients on warfarin because it can significantly delay the ability to re-anticoagulate these patients with warfarin for stroke prevention or treatment of venous thromboembolism (e.g. deep vein thrombosis or pulmonary embolism). Depending upon the dose of vitamin K administered, it can take up to 2 weeks for warfarin patients to reacquire effective anticoagulation from warfarin.

Decision-making related to the administration of a reversal agent to warfarin patients is both patient-specific and disease-specific. Thus, it is not consistent with the appropriate medical standard of care to administer a reversal agent to every warfarin patient who presents in the ED with bleeding. In general, it may be said that treatment of warfarin patients should include a reversal agent if the following factors are present: (1) persistent, major or critical bleeding; (2) an unstable bleeding patient; or, (3) no evidence that normal progression of clotting is curtailing the bleeding. Nevertheless, depending upon patient-specific and disease-specific factors, a reversal agent might not be administered to a warfarin patient or, if administered, might not be administered immediately. Among other things, the risk of reversal is greater in some special patient populations. In the case of patients with mechanical heart valves, for example, it may be more harmful to reverse an elevated INR. A prudent physician would not administer a reversal agent to a warfarin patient with a mechanical heart valve unless absolutely necessary as it could lead to a fatal valve-related thrombosis (clot) or stroke.

If the bleeding was very severe or significantly impacting the patient's condition, then a physician may recommend vitamin K and PCC for reversal, depending upon the INR. In the case of such a patient on Pradaxa®, however, one would expect the anticoagulant effect to wear off in the next 12 to 24 hours or less (depending upon the timing of the last Pradaxa® dose), and this is typically a self-limited condition which can be managed conservatively over this time period.

[128] Dr. Chopra stated that the absence of an approved specific reversal agent for Pradaxa® did not render Pradaxa® inferior to warfarin from a patient safety point of view. He said that the studies indicated the opposite, and that patients who had major bleeding while taking either warfarin or Pradaxa®, had lower all-cause mortality with Pradaxa® than with warfarin notwithstanding the absence of an antidote for Pradaxa®.

[129] Dr. Chopra said the ability to administer a reversal agent in late presenters on warfarin who have critical bleeding was of unproven benefit and likely unprovable because the outcome is a moving target in terms of the time of presentation and intervention because it depends on numerous individual patient factors.

[130] Dr. Chopra stated that in cases where a reversal agent might have been indicated had the patient been on warfarin, to determine whether the administration of vitamin K would have had any material effect one would need to know, among other things: (a) the disease state that caused the bleeding, (b) the location of the bleed in the patient's body, (c) the amount of time that passed between the onset of bleeding and the presentation of the patient, (d) the seriousness or extent of the bleeding, (e) the patient's age, (f) any co-medications, and (g) any comorbidities. It would also be necessary to know whether the bleeding stopped spontaneously or whether surgical intervention occurred, and whether the intervention was successful.

[131] Dr. Chopra said that Praxbind® had been used only twice at the UHN Emergency Department and in both cases the hospital’s staff haematologist felt that the use of Praxbind® was actually inappropriate.

[132] Dr. Chopra said that an important clinical judgment issue facing doctors considering administering a reversal agent to an anticoagulated patient (whether the agent is Praxbind® for Pradaxa® or vitamin K for warfarin) was the risks associated with stopping the patient’s anticoagulation which was indicated to prevent life-threatening blood clots. He said: “So when you use Praxbind® in antidote, the anticoagulation effect of the drug Pradaxa® goes away very quickly and the patient very soon becomes at risk of having a stroke, of having a pulmonary embolism, of having a deep vein thrombosis, all of which can be potentially life threatening.” He said that these risks meant that the use of Praxbind® would not be appropriate for the great majority of patients who experienced bleeding while on Pradaxa®.

(d) Dr. Zaev Wulffhart

[133] Dr. Wulffhart, whose clinical practice and research work involved the use of anticoagulants, was asked to provide an opinion about their use, including Pradaxa®, for the prevention of strokes in patients with AF and to opine on the risks and benefits of the various anticoagulants.

[134] In his evidence Dr. Wulffhart described much of the medical evidence about AF and about anticoagulants that I have set out above, and he described how the introduction of NOACs had a major impact upon the treatment of AF.

[135] Dr. Wulffhart said that a physician’s recommendation about the administration of an anticoagulant and dosing decisions for AF treatment were based on patient-specific factors including an assessment of the individual patient’s risk of stroke and the individual patient’s risk of bleeding, both of which are patient specific.

[136] Dr. Wulffhart said that the introduction of the NOACs had revolutionized the treatment of stroke prevention. It was Dr. Wulffhart’s opinion that the introduction of Pradaxa® presented AF patients with a treatment option that was more effective in the prevention of strokes and is superior in terms of its overall risk profile. He said that the risk of stroke with AF was about 5 to 6% per year on no anticoagulants, about 2% on warfarin, and about 1.0 to 1.5% on Pradaxa®. He said that Pradaxa® has become preferred over warfarin and aspirin for the prevention of strokes in AF patients.

[137] Dr. Wulffhart testified that the lack of an antidote for Pradaxa® was well known because it had routinely been discussed in medical journals and at medical educational conferences and the absence of an antidote was common knowledge amongst doctors prescribing the drug. He said that this aspect of the drug was so well known that he could not imagine any competent Canadian physician to have prescribed Pradaxa® in ignorance of it.

[138] It was Dr. Wulffhart’s opinion that the absence of a specific reversal agent for Pradaxa® was appropriately and adequately disclosed in the OVERDOSAGE section found in Part I of the Pradaxa® Product Monograph. He said prescribing physicians typically considered whether there was an antidote or reversal agent for a particular drug by looking in the OVERDOSAGE section of a product monograph.

[139] Dr. Wulffhart testified that the choice of an anticoagulant involves a complex risk-benefit analysis, and that it is only in rare cases that a reversal agent for Pradaxa® is likely to be of benefit. He said that his practice was to inform patients about the lack of an antidote for Pradaxa® or for the other NOACs, none of which have an antidote, but that his practice was to encourage the patient to take the drug notwithstanding the absence of an antidote. He said that he told patients that the risk of having a life-threatening bleed or intracranial hemorrhage on Pradaxa® is much less than it is on warfarin, which has an antidote.

[140] Dr. Wulffhart also said that the availability of the antidote was unlikely to make any difference to a patient being treated for AF. He would encourage them to take a drug that had a lower risk of bleeding in the first place rather than succumbing to the fear of not having an antidote which might not make any difference. He said that more than 95% of his patients were comfortable with the lack of a reversal agent for the NOACs because of the convenience of NOACs over warfarin and because a NOAC materially reduces the risk of stroke and ICH relative to warfarin. He said about 3-5% of his patients preferred warfarin because they felt more comfortable with the knowledge that bleeding can be actively reversed. He said, however, that this was not the best decision in terms of overall risk-benefit.

[141] For the circumstance where a patient presented in an emergency department suffering from bleeding, Dr. Wulffhart strongly disagreed with Dr. Sommer’s view about the significance to warfarin having an antidote and Pradaxa® (until recently) not having an antidote.

(e) Anne Tomalin

[142] Ms. Tomalin described the regulatory regime in Canada and described the information about bleeding contained in the various Pradaxa® Product Monographs in great detail.

[143] Ms. Tomalin reviewed the evidence of Dr. Chopra and Dr. Wulffhart and opined that physicians and patients were adequately informed of the recognized risk of bleeding in the Product Monograph.

[144] Ms. Tomalin noted that Health Canada’s Product Monograph Guideline recommends that information on any available antidote be placed under the OVERDOSAGE section of the Product Monograph. She testified that noting the absence of an antidote in Part III of the Product Monograph was not required by any regulation or principle of regulatory practice.

[145] In her opinion, the approach taken by Boehringer-Canada in disclosing the lack of an antidote for Pradaxa® was appropriate and in accord with the regulatory requirements in Canada. She noted that although the United States and Australian labels were revised to include information about the lack of antidote in the WARNINGS AND PRECAUTIONS section, no change was made to the European label and that Health Canada had reviewed the Pradaxa® Product Monograph at least five times after the United States’ label revision was made without directing any change to the Product Monograph.

D. DISCUSSION AND ANALYSIS: CERTIFICATION

1. Introduction

[146] Mr. Batten, the Hamilton Estate, and Ms. Nelson seek to certify as a class action a breach of duty to warn product’s liability negligence claim against: (a) Boehringer-Canada; (b) Boehringer Ingelheim Pharmaceuticals, Inc.; (c) Boehringer Ingelheim Pharma GmbH & Co. KG; and (d) Boehringer Ingelheim International GmbH. Before addressing the criteria for certification and whether they are satisfied, I shall first address the matter of the joinder of all of the Defendants other than Boehringer. After the matter of the joinder of the Defendants is discussed, I shall proceed to analyze the certification criteria. In that discussion, I shall assume that all of the Defendants were properly joined and I shall continue to refer to the collective of Boehringer as referring to all of them.

2. The Joinder of Boehringer Ingelheim Pharmaceuticals, Inc., Boehringer Ingelheim Pharma GmbH & Co. KG, and Boehringer Ingelheim International GmbH

[147] In addition to suing Boehringer-Canada, Mr. Batten, the Hamilton Estate, and Ms. Nelson sue (a) Boehringer Ingelheim Pharmaceuticals, Inc., (b) Boehringer Ingelheim Pharma GmbH & Co. KG, and (c) Boehringer Ingelheim International GmbH as several; i.e., independent co-defendants.

[148] To be clear, for the purposes of the certification motion, although their Statement of Claim is replete with vague, undifferentiated, and not particularized allegations of a joint endeavor, the Plaintiffs disavow that they are relying on any allegation of enterprise liability, vicarious liability, or the piercing the corporate veil. For the purpose of the certification motion, the Plaintiffs submit that Boehringer Ingelheim Pharmaceuticals, Inc., Boehringer Ingelheim Pharma GmbH & Co. KG, and Boehringer Ingelheim International GmbH are sued for their own discrete failures to warn about the dangers of there being no antidote in the Pradaxa® Product Monograph.

[149] For example, although at present, Mr. Batten, the Hamilton Estate, and Ms. Nelson do not have any evidence that Boehringer Ingelheim Pharmaceuticals, Inc. had responsibility for disseminating information about Pradaxa® on a worldwide scale, including to Canadian residents, their position is that if Boehringer Ingelheim Pharmaceuticals, Inc. did have this responsibility, then it had a duty to adequately warn of any dangers associated with Pradaxa®, such as the lack of an antidote. Although at present, the Plaintiffs do not have any evidence that Boehringer Ingelheim Pharmaceuticals, Inc., which distributed Pradaxa® in the United States, also distributed it in Canada, their position is that if it did distribute the drug in Canada, then it would be a necessary party.

[150] Mr. Batten, the Hamilton Estate, and Ms. Nelson explain why, in their view, Boehringer Ingelheim Pharmaceuticals, Inc. is a necessary party in paragraphs 53-55 of their factum, as follows:

53. [Boehringer Ingelheim Pharmaceuticals, Inc.] is a necessary defendant to this action primarily because its role as a sponsor and distributor of Pradaxa in the U.S. means that it has in its power, possession, or control, documents that will inform the extent to which [Boehringer-Canada] failed to warn Class Members about the risk of irreversible excessive bleeding. The full extent to which [BOEHRINGER-CANADA], or Health Canada, relied on information originating with [Boehringer Ingelheim Pharmaceuticals, Inc.] (or the other Boehringer foreign defendants) in submitting to Health Canada its new drug submission regarding Pradaxa and in updating Health Canada regarding product vigilance cannot be known until discoveries. What is known now is that [Boehringer-Canada] is under a duty to report to Health Canada regarding worldwide adverse events. As the U.S. is the largest pharmaceutical drug market in the world, it stands to have the greatest number of such reports of any jurisdiction. In order to determine whether [Boehringer-Canada] fulfilled its reporting or warning obligations to Health Canada and, in turn, to Canadian consumers, it will be necessary to obtain [Boehringer Ingelheim Pharmaceuticals, Inc.]’s productions and evidence regarding adverse event reports in the U.S. It will also be necessary to ascertain from [BOEHRINGER INGELHEIM PHARMACEUTICALS, INC.] the extent to which it conveyed such information to [BOEHRINGER-CANADA], to physicians with patients resident in Canada and to residents of Canada. From [BOEHRINGER-CANADA], the plaintiff herein will obtain evidence about whether it related that information to Health Canada and to Canadian consumers.

54. Beyond that, [BOEHRINGER INGELHEIM PHARMACEUTICALS, INC.] owes a duty of care to Canadian Class Members if

a. [BOEHRINGER INGELHEIM PHARMACEUTICALS, INC.] distributed any of the Pradaxa that was consumed by Canadians, intending that it be consumed by Canadians or, at a minimum knowing that Pradaxa would be ingested by Canadians;

b. Canadian Class Members relied on health and safety information regarding Pradaxa that was published by [BOEHRINGER INGELHEIM PHARMACEUTICALS, INC.] (as, for instance, on the www.pradaxa.com website);

c. [BOEHRINGER INGELHEIM PHARMACEUTICALS, INC.] was involved in the development of Pradaxa with the intention that it be consumed by Canadians or knowing that it would be consumed by Canadians, and if it participated in the decision to introduce Pradaxa into the stream of commerce without first making available a reversal agent to correct excessive bleeding;

d. [BOEHRINGER INGELHEIM PHARMACEUTICALS, INC.] neglected to detect or report a signal to [BOEHRINGER-CANADA] or to Health Canada;

e. [BOEHRINGER INGELHEIM PHARMACEUTICALS, INC.] made or participated in the decision not to warn Health Canada, Canadian health-care professionals, and Canadian Class Members about the risk of irreversible excessive bleeding caused by Pradaxa.

55. The plaintiff herein will argue that [BOEHRINGER INGELHEIM PHARMACEUTICALS, INC.] is a necessary defendant by virtue of having owed and breached a duty of care to Canadians. The fact that Canadians would be capable of being harmed as a proximate result of any failures of [BOEHRINGER INGELHEIM PHARMACEUTICALS, INC.] to detect and/or report a signal of irreversible bleeding and the lack of a reversal agent is arguably foreseeable within the meaning of the Anns test establishing a duty of care.

[151] Mr. Batten, the Hamilton Estate, and Ms. Nelson make similar arguments about Boehringer Ingelheim Pharma GmbH & Co. KG, and about Boehringer Ingelheim International GmbH.

[152] There is no doubt that there is a proximate relationship between the Canadian Plaintiffs and Boehringer-Canada, which applied for the regulatory approval and which is distributing Pradaxa® in Canada and this proximate relationship gives rise to a duty of care between the Plaintiffs and Boehringer-Canada, but it is not readily apparent why associated and parent companies outside of Canada and associated companies involved in obtaining approvals in other countries who are at a more remote level of proximity should have a duty of care to Canadian consumers.

[153] In other words, the claims against Boehringer Ingelheim Pharmaceuticals, Inc., Boehringer Ingelheim Pharma GmbH & Co. KG, and Boehringer Ingelheim International GmbH cannot be justified on the basis of enterprise liability and the claims might not survive a duty of care analysis based on the Defendants’ more remote proximity and public policy factors negating a duty of care. For instance, it is not readily apparent why the foreign licensor of a patent or the licensor of trademark has a foreseeable duty of care about what is said in the Product Monograph of the Canadian licensee who would be obliged to obtain the Canadian regulator’s approval for the content of its Product Monograph.

[154] Moreover, there is strong evidence in the case at bar that the real purpose of the joinder of the various Boehringer co-Defendants is to fish for a cause of action and to obtain documentary discovery to bolster the claims against Boehringer-Canada. A plaintiff may not plead for the purpose of using the examinations for discovery for what is colloquially referred to as a “fishing expedition”. The plaintiff must plead material facts that lay the foundation for a cause of action before the examinations for discovery and not frame his or her pleadings for the purpose of providing a basis for searching or probing for the foundation of a cause of action at the examinations for discovery: McMahon v. Healey, [1946] O.J. No. 391 (H.C.J.); Rose Park Wellesley Investment Ltd. v. Sewell, 1972 CanLII 354 (ON SC), [1973] 1 O.R. 102 (Ont. S.C.); Basdeo (Litigation guardian of) v. University Health Network, [2002] O.J. No. 263 (S.C.J.); Lysko v. Braley (2006), 2006 CanLII 11846 (ON CA), 79 O.R. (3d) 721 (C.A.).

[155] Because I am adjourning Boehringer’s pleadings motion and because I shall be dismissing the certification motion, I shall not rule on whether Boehringer Ingelheim Pharmaceuticals, Inc., Boehringer Ingelheim Pharma GmbH & Co. KG, and Boehringer Ingelheim International GmbH are necessary, proper, or improperly joined defendants. For the purposes of the certification motion, I will simply assume that all of the Defendants have been properly joined.

3. The General Principles for Certification

[156] The court is required to certify the action as a class proceeding where the following five-part test in s. 5 of the Class Proceedings Act, 1992 is met: (1) the pleadings disclose a cause of action; (2) there is an identifiable class of two or more persons that would be represented by the representative plaintiff; (3) the claims of the Class Members raise common issues; (4) a class proceeding would be the preferable procedure for the resolution of the common issues; and (5) there is a representative plaintiff who: (a) would fairly and adequately represent the interests of the class; (b) has produced a plan for the proceeding that sets out a workable method of advancing the proceeding on behalf of the class and of notifying class members of the proceeding, and (c) does not have, on the common issues for the class, an interest in conflict with the interests of other class members.

[157] For an action to be certified as a class proceeding, there must be a cause of action shared by an identifiable class from which common issues arise that can be resolved in a fair, efficient, and manageable way that will advance the proceeding and achieve access to justice, judicial economy, and the modification of behaviour of wrongdoers: Sauer v. Canada (Attorney General), 2008 CanLII 43774 (ON SC), [2008] O.J. No. 3419 (S.C.J.) at para. 14, leave to appeal to Div. Ct. refused, 2009 CanLII 2924 (ON SCDC), [2009] O.J. No. 402 (Div. Ct.).

[158] On a certification motion, the question is not whether the plaintiff's claims are likely to succeed on the merits, but whether the claims can appropriately be prosecuted as a class proceeding: Hollick v. Toronto (City), 2001 SCC 68, [2001] 3 S.C.R. 158 at para. 16.

[159] The test for certification is to be applied in a purposive and generous manner, to give effect to the important goals of class actions -- providing access to justice for litigants; promoting the efficient use of judicial resources; and sanctioning wrongdoers to encourage behaviour modification: Western Canadian Shopping Centres Inc. v. Dutton, 2001 SCC 46, [2001] 2 S.C.R. 534 at paras. 26 to 29; Hollick v. Toronto (City), supra at paras. 15 and 16.

[160] The representative plaintiff must come forward with sufficient evidence to support certification, and the opposing party may respond with evidence of its own to challenge certification: Hollick v. Toronto (City), supra at para. 22.

[161] The purpose of a certification motion is to determine how the litigation is to proceed and not to address the merits of the plaintiff's claim; there is to be no preliminary review of the merits of the claim: Hollick v. Toronto (City), supra at paras. 28 and 29. However, the plaintiff must show “some-basis-in-fact” for each of the certification criteria other than the requirement that the pleadings disclose a cause of action: Hollick v. Toronto (City), supra at paras. 16-26. Certification will be denied if there is an insufficient evidentiary basis for the facts on which the claims of the class members depend: Williams v. Canon Canada Inc., 2011 ONSC 6571, aff’d 2012 ONSC 3992 (Div. Ct.); Chadha v. Bayer Inc. (2003), 2003 CanLII 35843 (ON CA), 63 O.R. (3d) 22 (C.A.), leave to appeal to S.C.C. ref’d [2003] S.C.C.A. No. 106; Ernewein v. General Motors of Canada Ltd., 2005 BCCA 540 (C.A.), leave to appeal to S.C.C. ref’d, [2005] S.C.C.A. No. 545; Taub v. Manufacturers Life Insurance Co. (1998), 1998 CanLII 14853 (ON SC), 40 O.R. (3d) 379 (Gen. Div.), aff’d (1999), 1999 CanLII 19922 (ON SC), 42 O.R. (3d) 576 (Div. Ct.).

[162] In particular, there must be a basis in the evidence before the court to establish the existence of common issues: Dumoulin v. Ontario, [2005] O.J. No. 3961 (S.C.J.) at para. 25; Fresco v. Canadian Imperial Bank of Commerce, 2009 CanLII 31177 (ON SC), [2009] O.J. No. 2531 (S.C.J.) at para. 21; Singer v. Schering-Plough Canada Inc., 2010 ONSC 42 at para. 140. In order to establish commonality, evidence that the alleged misconduct actually occurred is not required; rather, the necessary evidence goes only to establishing whether the questions are common to all the class members: Pro-Sys Consultants v. Microsoft, 2013 SCC 57 at para. 110.

[163] On a certification motion, evidence directed at the merits may be admissible if it also bears on the requirements for certification but, in such cases, the issues are not decided on the basis of a balance of probabilities but rather on that of the much less stringent test of "some-basis-in-fact": Hollick v. Toronto (City), supra at paras. 16-26; Cloud v. Canada, 2004 CanLII 45444 (ON CA), 73 O.R. (3d) 401 (C.A.) at para. 50, leave to appeal to the S.C.C. ref'd, [2005] S.C.C.A. No. 50 , rev'g (2003), 2003 CanLII 72353 (ON SCDC), 65 O.R. (3d) 492 (Div. Ct.). The evidence on a motion for certification must meet the usual standards for admissibility: Martin v. Astrazeneca Pharmaceuticals PLC, supra; Williams v. Canon Canada Inc., supra; Ernewein v. General Motors of Canada Ltd., supra; Schick v. Boehringer Ingelheim (Canada) Ltd., 2011 ONSC 63 at para.13. While evidence on a certification motion must meet the usual standards for admissibility, the weighing and testing of the evidence is not meant to be extensive and if the expert evidence is admissible the scrutiny of it is modest: Griffin v. Dell Canada Inc., 2009 CanLII 3557 (ON SC), [2009] O.J. No. 418 (S.C.J.) at para. 76. In a class proceeding, the close scrutiny of the evidence of experts should be reserved for the trial judge: Stanway v. Wyeth Canada Inc., 2011 BCSC 1057, aff’d 2012 BCCA 260.

[164] The some-basis-in-fact test sets a low evidentiary standard for plaintiffs, and a court should not resolve conflicting facts and evidence at the certification stage or opine on the strengths of the plaintiff’s case; the focus at certification is whether the action can appropriately go forward as a class proceeding: Pro-Sys Consultants v. Microsoft, supra; McCracken v. CNR Co., 2012 ONCA 445.

4. Cause of Action Criterion

(a) General Principles

[165] The first criterion for certification is that the plaintiff's pleading discloses a cause of action. The "plain and obvious" test for disclosing a cause of action from Hunt v. Carey Canada, 1990 CanLII 90 (SCC), [1990] 2 S.C.R. 959 is used to determine whether a proposed class proceeding discloses a cause of action for the purposes of s. 5(1)(a) of the Class Proceedings Act, 1992.

[166] Thus, to satisfy the first criterion for certification, a claim will be satisfactory, unless it has a radical defect or it is plain and obvious that it could not succeed: Anderson v. Wilson (1999), 1999 CanLII 3753 (ON CA), 44 O.R. (3d) 673 (C.A.) at p. 679, leave to appeal to S.C.C. ref'd, [1999] S.C.C.A. No. 476; 176560 Ontario Ltd. v. Great Atlantic & Pacific Co. of Canada Ltd. (2002), 2002 CanLII 6199 (ON SC), 62 O.R. (3d) 535 (S.C.J.) at para. 19, leave to appeal granted, 2003 CanLII 36393 (ON SCDC), 64 O.R. (3d) 42 (S.C.J.), aff'd (2004), 2004 CanLII 16620 (ON SCDC), 70 O.R. (3d) 182 (Div. Ct.).

[167] In a proposed class proceeding, in determining whether the pleading discloses a cause of action, no evidence is admissible, and the material facts pleaded are accepted as true, unless patently ridiculous or incapable of proof. The pleading is read generously and it will be unsatisfactory only if it is plain, obvious, and beyond a reasonable doubt that the plaintiff cannot succeed: Hollick v. Toronto (City), supra at para. 25; Cloud v. Canada (Attorney General) supra at para. 41; Abdool v. Anaheim Management Ltd. (1995), 1995 CanLII 5597 (ON SCDC), 21 O.R. (3d) 453 (Div. Ct.) at p. 469.

[168] In the case at bar, as noted above, I have serious reservations about the joinder of causes of action against Boehringer Ingelheim Pharmaceuticals, Inc., Boehringer Ingelheim Pharma GmbH & Co. KG, and Boehringer Ingelheim International GmbH but there is no doubt that there is cause of action against Boehringer-Canada. I, therefore, conclude that the first criterion for certification is satisfied in the case at bar.

5. Identifiable Class Criterion

[169] The definition of an identifiable class serves three purposes: (1) it identifies the persons who have a potential claim against the defendant; (2) it defines the parameters of the lawsuit so as to identify those persons bound by the result of the action; and (3) it describes who is entitled to notice: Bywater v. Toronto Transit Commission, [1998] O.J. No. 4913 (Gen. Div.).

[170] In defining class membership, there must be a rational relationship between the class, the causes of action, and the common issues, and the class must not be unnecessarily broad or over-inclusive: Pearson v. Inco Ltd. (2006), 2006 CanLII 913 (ON CA), 78 O.R. (3d) 641 (C.A.) at para. 57, rev'g 2004 CanLII 34446 (ON SCDC), [2004] O.J. No. 317 (Div. Ct.), which had aff'd [2002] O.J. No. 2764 (S.C.J.).

[171] Mr. Batten, the Hamilton Estate, and Ms. Nelson propose the following definition for the classes:

(1) All persons throughout Canada who ingested Pradaxa® and their estates, administrators or other legal representatives (“the Class”); and

(2) All persons who have a derivative claim on account of a family relationship with a person in (1) (“the Family Class”).

[172] More than 800 people have reported Pradaxa® bleeding events to Health Canada.

[173] In proposed pharmaceutical or medical device products liability class actions, defining the class by reference to those who were prescribed the drug or medical device is a conventional technique, and in my opinion, the class definition in the immediate case is technically satisfactory. I conclude that the identifiable class criterion is satisfied.

6. Common Issues Criterion

(a) General Principles

[174] The third criterion for certification is the common issues criterion. For an issue to be a common issue, it must be a substantial ingredient of each class member's claim and its resolution must be necessary to the resolution of each class member's claim: Hollick v. Toronto (City), supra at para. 18.

[175] With regard to the common issues, success for one member must mean success for all. All members of the class must benefit from the successful prosecution of the action, although not necessarily to the same extent. The answer to a question raised by a common issue for the plaintiff must be capable of extrapolation, in the same manner, to each member of the class. See: Western Canadian Shopping Centres Inc. v. Dutton, supra at para. 40; Ernewein v. General Motors of Canada Ltd., supra at para. 32; Merck Frosst Canada Ltd. v. Wuttunee, 2009 SKCA 43 at paras. 145-46 and 160, leave to appeal to S.C.C. refused, [2008] S.C.C.A. No. 512; McCracken v. Canadian National Railway Co., supra, at para. 183.

[176] In Pro-Sys Consultants v. Microsoft, supra at para. 106, the Supreme Court of Canada describes the commonality requirement as the central notion of a class proceeding which is that individuals who have litigation concerns in common ought to be able to resolve those common concerns in one central proceeding rather than through an inefficient multitude of repetitive proceedings.

[177] An issue is not a common issue if its resolution is dependent upon individual findings of fact that would have to be made for each class member: Fehringer v. Sun Media Corp., [2003] O.J. No. 3918 (Div. Ct.) at paras. 3, 6. Common issues cannot be dependent upon findings which will have to be made at individual trials, nor can they be based on assumptions that circumvent the necessity for individual inquiries: Nadolny v. Peel (Region), [2009] O.J. No. 4006 (S.C.J.) at paras. 50-52; Collette v. Great Pacific Management Co., 2003 BCSC 332, [2003] B.C.J. No. 529 (B.C.S.C.) at para. 51, varied on other grounds (2004) 2004 BCCA 110, 42 B.L.R. (3d) 161 (B.C.C.A.); McKenna v. Gammon Gold Inc., 2010 ONSC 1591, [2010] O.J. No. 1057 (S.C.J.) at para. 126, leave to appeal granted 2010 ONSC 4068, [2010] O.J. No. 3183 (Div. Ct.), varied 2011 ONSC 3882 (Div. Ct.).

[178] The common issue criterion presents a low bar: Carom v. Bre-X Minerals Ltd. (2000), 2000 CanLII 16886 (ON CA), 51 O.R. (3d) 236 (C.A.) at para. 42; Cloud v. Canada (Attorney General), supra, at para. 52; 203874 Ontario Ltd. v. Quiznos Canada Restaurant Corp., 2009 CanLII 23374 (ON SCDC), [2009] O.J. No. 1874 (Div. Ct.), aff’d 2010 ONCA 466, [2010] O.J. No. 2683 (C.A.), leave to appeal to S.C.C. refused [2010] S.C.C.A. No. 348.

[179] An issue can be a common issue even if it makes up a very limited aspect of the liability question and even though many individual issues remain to be decided after its resolution: Cloud v. Canada (Attorney General) supra. A common issue need not dispose of the litigation; it is sufficient if it is an issue of fact or law common to all claims and its resolution will advance the litigation for (or against) the class: Harrington v. Dow Corning Corp., supra.

[180] In the context of the common issues criterion, the some-basis-in-fact standard involves a two-step requirement that: (1) the proposed common issue actually exists; and (2) the proposed issue can be answered in common across the entire class: Hollick v. Toronto (City), supra; Fulawka v. Bank of Nova Scotia, 2012 ONCA 443; McCracken v. Canadian National Railway Company, supra; Williams v. Canon Canada Inc., supra; Martin v. Astrazeneca Pharmaceuticals PLC, 2012 ONSC 2744; Good v. Toronto Police Services Board, 2014 ONSC 4583 (Div. Ct.); Dine v. Biomet, 2015 ONSC 7050, aff’d 2016 ONSC 4039 (Div. Ct.).

(b) The Proposed Common Issues

[181] In their Notice of Motion, Mr. Batten, the Hamilton Estate, and Ms. Nelson propose the following common issues:

(1) Can ingesting Pradaxa® cause an increased risk of excessive and irreversible bleeding?

(2) Is Pradaxa® ineffective and/or defective and/or unfit for the purpose for which it was intended as designed, researched, developed, tested, manufactured, marketed, packaged, labeled, promoted, distributed, licensed, sold, or otherwise placed into the stream of commerce in Canada by the Defendants or any of them?

(3) Did any of the Defendants owe a duty of care to the Class Members? If so, what was the standard of care? Did any of the Defendants breach the standard of care? If so, which of them, when and why?

(4) Did any of the Defendants have a duty to warn the Class Members of the risks of harm from Pradaxa®, and/or the lack of an antidote for bleeding caused by Pradaxa®? If so, did any of them fail to warn in a timely manner? If so, who, when and how?

(5) Are Class Members entitled to special damages for medical costs incurred in the treatment of health complications related to having ingested Pradaxa®?

(6) Are the Defendants liable for damages resulting from the purchase and ingestion of Pradaxa®? If yes, which Defendants are liable for such damages? Is each Defendant responsible in law for the acts or omissions of the other Defendant in respect of the sale and marketing of Pradaxa® in Canada?

(7) Are the Defendants liable for the subrogated health care costs of Class Members incurred in the treatment of conditions related to taking Pradaxa®?

(8) By virtue of waiver of tort, are the Defendants liable on a restitutionary basis: (a) to account to any of the Class, including the provincial insurers with subrogated or direct claims, for any part of the proceeds of the sale of Pradaxa®? Or in the alternative, (b) such that a constructive trust is to be imposed on the proceeds of the sale of Pradaxa® for the benefit of the Class, including provincial health insurers with subrogated or direct claims.

(9) If liability is found under the waiver of tort above, in what amount and for whose benefit is such an account to be made, or in what amount, and for whom are such proceeds held?

(10) Following a determination of any compensation owed by one or both of the Defendants to Class Members, should one or both of the Defendants pay punitive damages? Should punitive damages be assessed in aggregate? If so, in what amount and how should punitive damages be distributed?

[182] In their factum, Mr. Batten, the Hamilton Estate, and Ms. Nelson propose a different set of common issues, which for convenience of analysis, I have re-ordered as follows:

(1) Were any of the Defendants negligent in the marketing, packaging, labeling, and promotion of Pradaxa®?

(2) Did any of the Defendants have a duty to warn the Class Members of the risks of harm, namely from the lack of an antidote for Pradaxa®?

(3) Can the lack of an antidote for Pradaxa® give rise to or exacerbate dangerous or life-threatening events for persons who have ingested Pradaxa®?

(4) Are the Defendants liable for the subrogated healthcare costs of Class Members incurred in the treatment of conditions related to ingesting Pradaxa®?

(a) to account to any of the Class, including the provincial insurers with subrogated or direct claims, for any part of the proceeds of the sale of Pradaxa®? Or in the alternative,

(b) such that a constructive trust is to be imposed on the proceeds of the sale of Pradaxa® for the benefit of the Class, including provincial health insurers with subrogated or direct claims.

(5) Following a determination of any compensation owed by one or both of the Defendants to Class Members, should one or both of the Defendants pay punitive damages? Should punitive damages be assessed in aggregate? If so, in what amount and how should punitive damages be distributed?

[183] With the narrowing of the Plaintiffs’ claim to the duty to warn claim, I shall analyze the proposed common issues from the factum.

(c) Question 1: Were any of the defendants negligent in the marketing, packaging, labeling, and promotion of Pradaxa®?

[184] This question is no longer applicable to the narrowed duty to warn claim, and has been supplanted by the more specific and focused Question 2, to which I now turn.

(d) Question 2: Did any of the Defendants have a duty to warn the Class Members of the risks of harm, namely from the lack of an antidote for Pradaxa®?

[185] In my opinion, Question 2 fails the common issues criterion. In the immediate case, there is no basis in fact to conclude that a common issue about a duty to warn about the absence of an antidote actually exists. And, if this duty to warn did exist, there is no-basis-in-fact for concluding that the question of whether the Defendants had a duty to warn about the absence of an antidote can be answered in common across the class of persons who ingested Pradaxa®.

[186] Recognizing that Boehringer has a duty to warn of dangers inherent in the use of Pradaxa® of which it has knowledge or ought to have knowledge and without doing an analysis of the merits of the breach of the duty to warn claim; i.e., without assessing the merits of Mr. North’s argument that the information in the OVERDOSAGE section of Part I of the Product Monograph was inadequate and instead applying the very low threshold test of some-basis-in-fact for the existence of a duty to warn claim, there is no basis in fact for concluding that the failure to warn about the absence of an antidote for Pradaxa® is a source of harm and there is no-basis-in-fact for concluding that - as a class - persons who ingested Pradaxa® would suffer any harm from not being warned about the absence of an antidote for Pradaxa®.

[187] There is no basis in fact for concluding that a patient on Pradaxa® who experienced a bleeding event was at a greater risk of unstoppable bleeding because of the lack of an antidote than a patient on warfarin who experienced a bleeding event. The evidence was that there was no increased risk for developing life-threatening injuries for patients prescribed Pradaxa® rather than warfarin. Indeed, the evidence is that regardless of the prescribed anticoagulant, the physician treating a patient for excessive bleeding would use conventional methods to abate the bleeding and would resort to an antidote or reversal agent as a last resort, because a reversal agent to an anticoagulant carries the very serious risk of precipitating a devastating and perhaps life-ending stroke. For persons on anticoagulants, the same treatments for the known risk of bleeding would be used for persons on warfarin as for patients on Pradaxa®. The evidence, however, was that the patient presenting with bleeding who was on Pradaxa® without an antidote was in a preferable position to patient presenting with bleeding who was on warfarin.

[188] There was no-basis-in-fact to conclude that that the bleeding of a patient on Pradaxa® was more difficult to stop by conventional means than the bleeding of a patient on warfarin. The evidence was that in the overwhelming majority of cases, an antidote was not necessary for Pradaxa®, because unlike the much longer lasting warfarin, the effect of Pradaxa® would simply wear off and rarely would it be necessary to hasten that wearing-off process by a reversal agent. The evidence suggested that it takes longer to reverse the longer-lasting anticoagulant effect of warfarin by the administration of vitamin K, than it takes Pradaxa® to lose its anticoagulant effect because of the shorter biological half-life of Pradaxa®. If a patient had taken Pradaxa® in the previous one to two hours before being treated for bleeding, activated charcoal might be given to absorb any free remaining drug in the stomach or intestines, but the vast majority of patients could receive conventional treatments and safely wait till the anticoagulant effect of Pradaxa® had worn off.

[189] What the evidence establishes is that inherently all anticoagulants propagate bleeding and while there is a reversal agent for warfarin and until recently there was no reversal agent for Pradaxa®, for the very rare patient for whom it would be safe to reverse an anticoagulant (with the attendant risk of precipitating a blood clot and a stroke), the patient on Pradaxa®, unlike the patient on warfarin, would not need an antidote because unlike warfarin, the anticoagulant effect of Pradaxa® would likely have already worn off. Save for very few cases, an emergency room physician would stop the administration of the anticoagulant but would not apply a reversal agent because of the risks associated with doing so. There is no-basis-in-fact for concluding that the failure to warn about the absence of an antidote for Pradaxa® was a potential cause of harm and there is no-basis-in-fact for concluding that the failure to warn was a potential cause of harm across the class of patients prescribed Pradaxa®.

[190] There is no-basis-in-fact for concluding that the absence of an antidote for Pradaxa® created any undisclosed hazard for patients. The evidence was that the absence of an antidote was not an undisclosed hazard, because it was not a hazard for the reasons already expressed. And, it was common knowledge among the medical profession that the drug did not have an antidote. The evidence was that prescribing physicians treating patients for AF and emergency room physicians already knew about the absence of an antidote.

[191] Moreover, save in a few individual cases, for cardiologists prescribing an anticoagulant, the absence of an antidote for Pradaxa® was not a reason for not prescribing Pradaxa® or for favouring a prescription of warfarin. There is no-basis-in-fact for concluding that across the class of patients prescribed Pradaxa®, the Class Members would not have used Pradaxa® because of the absence of an antidote.

[192] In any event, if there was a failure to warn about the absence of an antidote, there was no-basis-in-fact for concluding that the failure applied commonly across a class of persons ingesting Pradaxa®. What was common to the class was that a physician had prescribed an anticoagulant that by its nature propagates bleeding but which was being prescribed to diminish the very grave risk of a stroke. However, the decision to prescribe an anticoagulant and the selection of the type of anticoagulant is based on patient-specific facts. The risks that a patient has of experiencing a stroke and his or her risk of experiencing a bleeding event, of which there is a wide range of variance in nature and intensity, are patient-specific. The need for an antidote for bleeding would depend on patient-specific factors, and the nature of a patient’s specific bleeding event would depend upon patient-specific factors. The need of a patient to be told about reversal agents or the absence of them is patient-specific and very much a matter of physician judgment on a case-by-case basis.

[193] If there was a common failure to warn, there is no common harm across the class because the individual Class Members would not be harmed by the absence of a warning because the absence of an antidote would not and ought not to have affected their decision to take Pradaxa® because their alternative would be to take warfarin which although it had an antidote, would take longer to reverse itself than it would take for Pradaxa® to naturally lose its operative effect.

[194] The case at bar is not like Parker v. Pfizer Canada Inc., 2012 ONSC 3681, where I certified a products liability failure-to-warn-action against the manufacturer of a smoking cessation drug that had a long list of neuropsychiatric adverse events including suicidal and homicidal ideation. In that case, the long list of neuropsychiatric adverse events did not eradicate a common complaint about a failure to warn. However, in the case at bar, there is no-basis-in-fact to conclude that the absence of an antidote was a danger in the ordinary use of Pradaxa®, and if the absence of an antidote was a danger in ordinary use, there is no-basis-in-fact to conclude that the absence of an antidote was a danger common to the Class Members. The case at bar is not a case where it could be said that there is some-basis-in-fact for concluding that all Class Members needed to be told by their physicians that that the drug they were taking had no antidote, and this is particularly true when the alternative of warfarin, which did have a reversal agent, would in most cases be less than the optimum choice of anticoagulant and might be disadvantageous and (more) harmful to the patient.

[195] I conclude that Questions 1 and 2 do not qualify as common issues.

[196] I wish to be clear that the conclusions in the immediate case are an application of existing principles to the particular circumstances of the immediate case. Although the standard is low, in the immediate case, based on their own evidence, the Plaintiffs did not satisfy me that there was some-basis-in-fact for the existence of common issues 1 and 2. In the immediate case, the absence of commonality arises from the particular nature of a duty to warn problem that involves an alleged failure to warn a learned intermediary about the absence of an antidote when there is no-basis-in-fact for concluding that the absence of an antidote was a hidden defect or that the absence of an antidote posed a common and material risk across the class. In contrast to the immediate case, most duty to warn cases simply involve an alleged failure by the defendant to warn about a hidden defect or potential risk of harm caused by the use of the product.

(e) Question 3: Can the lack of an antidote for Pradaxa® give rise to or exacerbate dangerous or life-threatening events for persons who have ingested Pradaxa®?

[197] Question 3 is apparently meant to be a general causation question, but it fails for the same reasons that questions 1 and 2 fail and for two additional reasons.

[198] The first additional reason is that there was no common class-wide potential injury or risk of injury arising from the absence of an antidote. The evidence is that Pradaxa® (or warfarin) does not give rise to dangerous or life-threatening events for persons who have ingested Pradaxa® (or warfarin) because, strictly speaking, anticoagulants do not cause dangerous or life threatening events; they are prophylactics prescribed to prevent dangerous life-threatening events, like a stroke from AF. However, as foreshadowed earlier, it can be said Pradaxa® (or warfarin) does exacerbate some life-threatening events; namely excessive bleeding, in the sense that anticoagulants by their nature interfere with the coagulation meant to stop bleeding. Nevertheless, across the class of persons taking Pradaxa® the absence of a reversal agent does not further exacerbate this problem, any more than the presence of vitamin K better ameliorates the problem across the class of persons taking warfarin. The point is that there is nothing generalized, i.e., common across the class, about the circumstances of a life-threatening bleeding event and the absence of an antidote, and whether the patient on Pradaxa® (or warfarin) needs a reversal agent is a patient-specific circumstance. Indeed, considerable care must be taken before administering a reversal agent to an anticoagulant because doing so may bring on the dangerous or life-threatening event for which the anticoagulant was meant to be prophylactic.

[199] The second additional reason why the causation issue in the case at bar fails the commonality tests is the absence of a methodology to prove general causation. Where a plaintiff seeks to address questions of causation on a class-wide basis as the foundation for his or her class action, there must be some evidence of a methodology that will enable the plaintiff to prove causation on a class-wide basis: Charlton v. Abbott Laboratories Ltd., 2015 BCCA 26, rev’g 2013 BCSC 1712; Chadha v. Bayer Inc., supra, at para. 52, aff’g (2001), 2001 CanLII 28369 (ON SCDC), 54 O.R. (3d) 520 (Div. Ct.), leave to appeal refused, [2003] 2 S.C.R. vi. Where no such methodology is put forward by the plaintiffs, there is not sufficient evidence before the court to show that the resolution of the proposed general causation common issue will efficiently advance the claim: Charlton v. Abbott Laboratories Ltd., supra at para. 84; Pro-Sys Consultants Ltd. v. Microsoft Corporation, supra at para. 115; AIC Limited v. Fischer, 2013 SCC 69 at para. 43.

[200] In Chadha v. Bayer Inc., supra, which was a competition conspiracy action, the Court of Appeal denied certification because there was no evidence that liability could be proved on a class-wide basis and thus there was no common issue. In Charlton, the defendants manufactured an antidepressant that contained sibutramine. There was some-basis-in-fact that sibutramine increased blood pressure and the risk of heart attacks and strokes in persons with a pre-existing cardiovascular condition. The plaintiffs, who as individuals had suffered strokes and heart attacks after being prescribed with drugs containing sibutramine, brought a proposed class action on behalf of patients prescribed with the drug. The expert evidence established that there was no methodology to establish that sibutramine had the potential to harm other than those with a pre-existing cardiovascular condition. Reversing the motions judge, the British Columbia Court of Appeal concluded that he had erred in certifying the class action.

[201] In the case at bar because of the particular nature of the duty to warn problem, there was no evidence of a methodology that would enable the Plaintiffs to prove causation on a class-wide basis, and this is another reason to conclude that question 3 is not certifiable.

(g) Question 4: Are the Defendants liable for the subrogated healthcare costs of Class Members incurred in the treatment of conditions related to ingesting Pradaxa®? (a) to account to any of the Class, including the provincial insurers with subrogated or direct claims, for any part of the proceeds of the sale of Pradaxa®? Or in the alternative, (b) such that a constructive trust is to be imposed on the proceeds of the sale of Pradaxa® for the benefit of the Class, including provincial health insurers with subrogated or direct claims.

[202] Putting aside that question 4 is ambiguous, unclear, and cryptic, in my opinion, the meaning that can be deciphered from it relates to the individual situations of the Class Members and is also dependent on the various legislative schemes of the provinces and territories. It is not a common issue. And, apart from being essentially an individual issue, assuming question 4 was amenable to class-wide treatment, it would add almost nothing to moving the action forward.

[203] Question 4 fails the test for certification as a common issue.

(h) Question 5: Following a determination of any compensation owed by one or both of the Defendants to Class Members, should one or both of the Defendants pay punitive damages? Should punitive damages be assessed in aggregate? If so, in what amount and how should punitive damages be distributed?

[204] As drafted in the factum, question 5 is not certifiable as a common issue. However, a question about punitive damages is certifiable as a common issue. The appropriate question is: Does the conduct of the Defendants deserve an award of punitive damages if the other prerequisites for such an award were satisfied?

[205] In Waldman v. Thomson Reuters Corp., 2012 ONSC 1138, leave to appeal to Div. Ct. refused, 2012 ONSC 3436 (Div. Ct.), I explained that although a claim for the assessment of punitive damages will not be suitable for a common issue when the court cannot make a rational assessment about the appropriateness of punitive damages until after individual assessments of the compensatory losses of class members has been completed, nevertheless, the question of whether the defendant’s conduct was sufficiently reprehensible or high-handed to warrant punishment is capable of being determined as a common issue. This approach was endorsed in Chalmers (Litigation guardian of) v. AMO Canada Co., 2010 BCCA 560 and in other cases.

[206] Although the question of whether the conduct of the Defendants deserves an award of damages is an appropriate question for certification, nevertheless, in the immediate case, I would not certify the question because the certification of a question about punitive damages presupposes that there are common issues about the Defendants’ predicate liability and in the immediate case, there are no such questions. Put differently, a common issue about punitive damages is not certifiable in the absence of other certifiable common issues. If there are no common issues about liability, it is nonsensical to certify a common issues about the extent of the remedies.

[207] I, therefore, conclude that question 5 fails the test for certification.

[208] And, I conclude that the common issues criterion is not satisfied in the immediate case.

7. Preferable Procedure Criterion

[209] Since the case at bar fails the common issues criterion, it is axiomatic that it also fails the preferable procedure criterion. See O’Brien v. Bard, 2015 ONSC 2470.

8. Representative Plaintiff Criterion

[210] Since the case at bar fails the common issues and preferable procedure criterion, the issue of whether the Plaintiffs have satisfied the fifth and final criterion for certification is also unsatisfied. The fifth and final criterion for certification as a class action is that there is a representative plaintiff who would adequately represent the interests of the class without conflict of interest and who has produced a workable litigation plan.

[211] The representative plaintiff must be a member of the class asserting claims against the defendant, which is to say that the representative plaintiff must have a claim that is a genuine representation of the claims of the members of the class to be represented or that the representative plaintiff must be capable of asserting a claim on behalf of all of the Class Members as against the defendant: Drady v. Canada (Minister of Health), 2007 CanLII 27970 (ON SC), [2007] O.J. No. 2812 (S.C.J.) at paras. 36-45; Attis v. Canada (Minister of Health), [2003] O.J. No. 344 (S.C.J.) at para. 40, aff'd [2003] O.J. No. 4708 (C.A.).

[212] Provided that the representative plaintiff has his or her own cause of action, the representative plaintiff can assert a cause of action against a defendant on behalf of other Class Members that he or she does not assert personally, provided that the causes of action all share a common issue of law or of fact: Boulanger v. Johnson & Johnson Corp., [2002] O.J. No. 1075 (S.C.J.) at para. 22, leave to appeal granted, [2002] O.J. No. 2135 (S.C.J.), varied (2003), 2003 CanLII 45096 (ON SCDC), 64 O.R. (3d) 208 (Div. Ct.) at paras. 41, 48, varied 2003 CanLII 52154 (ON CA), [2003] O.J. No. 2218 (C.A.); Matoni v. C.B.S. Interactive Multimedia Inc., 2008 CanLII 1539 (ON SC), [2008] O.J. No. 197 (S.C.J.) at paras. 71-77; Voutour v. Pfizer Canada Inc., [2008] O.J. No. 3070 (S.C.J.); LeFrancois v. Guidant Corp., [2008] O.J. No. 1397 (S.C.J.) at para. 55.

[213] Whether the representative plaintiff can provide adequate representation depends on such factors as: his or her motivation to prosecute the claim; his or her ability to bear the costs of the litigation; and the competence of his or her counsel to prosecute the claim: Western Canadian Shopping Centres Inc. v. Dutton, supra at para. 41.

[214] In the immediate case, the Plaintiffs do not have claims that are representative of the claims of all Class Members for the reasons expressed above about the failure of the common issues criterion.

[215] I conclude that the representative plaintiff criterion is not satisfied.

E. CONCLUSION

[216] For the above reasons, the certification motion is dismissed without costs.

Perell, J.

Released: January 5, 2017

Schedule “A”

STATEMENT OF CLAIM

1. The plaintiff claims:

(a) damages in the amount of $100,000,000.00;

(b) aggravated damages in the amount of $25,000,000;

(c) punitive damages in the amount of$25,000,000;

(d) special damages on account of, inter alia, all, medical and other expenses for testing and treatment (including the subrogated claims of all Provincial and Territorial governmental providers of medical services) in such amount as is proven at trial;

(e) a declaration that the defendants were negligent in the design, development testing, research. manufacture, licensing, labelling, warning, marketing, distribution and sale of Pradaxa. Use of the term "Pradaxa" in this claim means the drug dabigatran, marketed formerly as "Pradax" and, as of January 2013, as "Pradaxa";

12. At all material times, the defendants, directly or through their agents, designed, researched, developed, tested, manufactured, marketed, packaged, labelled, promoted, distributed, licensed, and sold Pradaxa for use by patients throughout the world, including Ontario and the rest of Canada.

13. The plaintiffs plead that, by virtue of the acts described herein, each of the defendants is vicariously liable for the act and omissions of the others for the following reasons:

(a) Each was the agent of the other;

(b) Each defendant's business was operated so that it was inextricably interwoven with the business of the other;

(c) Each defendant entered into a common advertising and business plan with the other to distribute and sell Pradaxa;

(d) Each defendant operated pursuant to a common business plan to distribute and sell Pradaxa;

(e) Each defendant intended that the businesses be run as one business organization; and

(f) All or some of the defendants are related, associated or affiliated.

III. HARM CAUSED BY PRADAXA

20. Shortly after Pradaxa was first approved for sale in the United States, and Pradaxa approved for sale in Canada, adverse events came to be reported to the Food and Drug Administration ("FDA") and to Health Canada in the United States and Canada, respectively.

21. In the United States, within 12 weeks of initial marketing approval, Pradaxa was the suspected drug in 307 reported serious adverse events. Most of the adverse event reports involved serious bleeding or blood clots in the elderly. From October 2010 to the end of June 2011, there were almost 1,800 Pradaxa-associated "Serious Adverse Events" ("SAEs") reported to the FDA, including over 1,000 reports of life-threatening bleeding. As of December 31, 2011, the FDA received over 500 reports of deaths of people in the U.S. linked to Pradaxa. In addition, as of December 31, 2011, there were over 900 reports of gastrointestinal hemorrhages, over 300 reports of rectal hemorrhages, and over 200 reports of cerebrovascular accidents suffered by U.S. citizens associated with Pradaxa.

22. In Canada, the SAEs are known as Adverse Event Reports ("AERs"). The first AER regarding Pradaxa was submitted to Health Canada in March 2009.

23. As of February 2013, almost 1,000 AERs had been registered with Health Canada regarding Pradaxa.

24. More than 150 of those AERs registered with Health Canada indicated that death had resulted from Pradaxa.

25. The harm caused by Pradaxa has also come to the attention of regulators in other jurisdictions where it has been approved for sale:

a. On January 21, 2011, Pradaxa (under the brand name Prazaxa), in 75 mg and 110 mg doses only, was approved for sale in Japan to treat non-valvular atrial fibrillation. On August 11, 2011, Japan's pharmaceutical regulatory authority announced that it was requiring that a "boxed warning" be added to Pradaxa/Prazaxa to call attention to reports of severe hemorrhages in patients treated with Pradaxa/Prazaxa, including reports of fatalities.

b. On July 11, 2011, Pradaxa was approved for sale in New Zealand with lower dosing (lowered from 150mg to 110mg twice a day) required for patients over 80 years of age and recommended for patients with moderate renal impairment. On September 1, 2011, the New Zealand pharmaceutical regulatory authority issued a "Prescriber Update" entitled "Dabigatran - Is there a Bleeding Risk" in which physicians were alerted that Pradaxa had a higher incidence of gastrointestinal bleeds than warfarin and that there was no reversal agent to neutralize the anticoagulation effects of Pradaxa. A follow-up report issued in December 2011, indicated that among 10,000 New Zealanders who had taken Pradaxa, there were 78 reports of serious bleeding events associated with Pradaxa including 60 reports of gastrointestinal and rectal bleeding. Among the 78 serious events were 10 patient deaths and 55 hospitalizations. Three months later in March, 2012 the New England Journal of Medicine published two letters from physicians in New Zealand addressing bleeding events associated with Pradaxa. In one letter, physicians wrote, "We are concerned that the potential risks of this medication are not generally appreciated. The serious consequences of a lack of an effective reversal agent should not be underestimated."

26. The harms caused by Pradaxa have also been the subject of scientific scholarship. On July 25, 2011, the Archives of Internal Medicine published "The Use of Dabigatran [Pradaxa] in Elderly Patients", a report in which the authors concluded that "[t]he risk of major overdosage of ... [Pradaxa] in this [elderly] population is, however, much increased owing to frequent renal function impairment, low body weight, drug interactions that cannot be detected with a routine coagulation test and no antagonist available."

27. The harm caused by Pradaxa is two-fold. Like other anti-coagulants such as warfarin, it causes excessive bleeding, which can result in severe injury and death; unlike warfarin, however, in which such excessive bleeding can readily be stopped through the administration of vitamin K, there is no known antidote to excessive bleeding caused by Pradaxa. Elderly patients and patients with renal impairments are particularly vulnerable to the excess bleeding caused by Pradaxa.

RIGHTS OF ACTION

a. Failure to Warn

43. The defendants owed the plaintiffs and other Class Members a duty of care as follows:

a. to warn them and their treating healthcare professionals that ingestion of Pradaxa carried significant, and specifically identified, health risks including the risk of bleeding;

b. to warn them and their treating healthcare professionals that, unlike warfarin, there existed no antidote to excess bleeding caused by Pradaxa;

c. to ensure that prescribing physicians and other healthcare professionals were apprised and fully and regularly informed of all of the health risks associated with ingesting Pradaxa;

d. to warn them and their treating healthcare professionals that elderly patients, patients with impaired renal functions, and patients with a history of gastrointestinal bleeding are particularly vulnerable to the risks of unstoppable, excessive bleeding caused by Pradaxa;

e. to inform Health Canada fully, properly, and in a timely manner of the health risks and complaints, including those listed herein, associated with the ingestion of Pradaxa;

f. to provide truthful and complete information to Health Canada when submitting the New Drug Submission ("NDS") for Pradaxa;

g. to provide complete and accurate clinical and non-clinical data to Health Canada throughout the approval process for Pradaxa and subsequent to its approval, including when they submitted to Health Canada for approval the NDS for Pradaxa, when they submitted to Health Canada for approval the product monographs for Pradaxa, and subsequent to the issuance by Health Canada of the Notice of Compliance for Pradaxa;

h. promptly to report to Health Canada all of the adverse events that came to be reported to the defendants with regards to Pradaxa subsequent to its approval for sale in Canada;

i. to issue prompt, up-to-date, and accurate Health Professional Communications and Public Communications, which are the modes of communication through which manufacturers are required to communicate with healthcare professionals and the public, respectively, regarding the safety concerns affecting a health product;

j. to warn the plaintiffs, other Class Members, health care professionals, and Health Canada, that there existed an optimal range within which the blood concentration of Pradaxa needed to fall, and that accordingly, it was imperative that patients taking Pradaxa have their blood regularly monitored;

k. to provide truthful and complete information in the product monographs for Pradaxa, and particularly in Parts I and III of such monographs, which are directed to healthcare professionals and patients, respectively; and to advertise Pradaxa to healthcare professionals in a manner that adequately discloses the drug's risk of harm and the lack of an effective antidote in the event of bleeding caused as a side effect by Pradaxa.

44. The defendants breached their duty of care as follows:

a. The defendants' original labelling, product monograph, and prescribing information for Pradaxa failed to disclose, adequately or at all, that Pradaxa could cause excess bleeding;

b. The defendants' original labelling, product monograph, and prescribing information for Pradaxa failed to warn patients with renal impairments and elderly patients that they were particularly vulnerable to excess bleeding caused by Pradaxa;

c. The defendants' original labelling, product monograph, and prescribing information for Pradaxa failed to disclose, adequately or at all, that there is no drug, agent or means to reverse the anticoagulation effects of Pradaxa;

d. The defendants failed to warn the plaintiffs and other Class Members, healthcare professionals, and Health Canada, that Pradaxa was prone to cause excess bleeding, that elderly patients and patients with renal impairments were particularly vulnerable to harm from excess bleeding caused by Pradaxa, and that there was no known antidote for the excess bleeding caused by Pradaxa;

e. The defendants failed to advise prescribing physicians, such as the plaintiffs' physicians to instruct patients that Pradaxa was prone to cause excess bleeding, to monitor the renal function of patients being prescribed Pradaxa, to exclude those patients identified as having severe renal impairment or a history of gastro-intestinal bleeding, to monitor patients being administered Pradaxa for renal function and be alert to a decline in renal function, and to warn patients that there was no agent to reverse the anticoagulation effects of Pradaxa;

f. By marketing Pradaxa as requiring no monitoring, the defendants failed to warn the plaintiffs, other Class Members, healthcare professionals, and Health Canada, that it is necessary to assess the degree / or extent of anticoagulation in patients taking Pradaxa;

g. The defendants knowingly or recklessly provided misleading or incomplete information to Health Canada when submitting the NDS for Pradaxa. More particularly, but without limitation, the defendants did not disclose to Health Canada complete evidence regarding the clinical effectiveness of Pradaxa, the drug's contraindications and side effects, and the fact that there was no effective antidote for excessive bleeding caused by Pradaxa;

h. The defendants withheld important clinical and non-clinical data from Health Canada throughout the approval process for Pradaxa and subsequent to its approval, including when they submitted to Health Canada for approval the NDS for Pradaxa, when they submitted to Health Canada for approval the product monographs for Pradaxa, and subsequent to the issuance by Health Canada of the Notice of Compliance for Pradaxa;

i. The defendants failed promptly or at all to report to Health Canada all of the adverse events that came to be reported to the defendants with regards to Pradaxa subsequent to its approval for sale in Canada;

j. The defendants failed to issue prompt, up-to-date, and accurate Health Professional Communications and Public Communications;

k. The defendants knew that there existed an optimal range within which the blood concentration of Pradaxa needed to fall, and that, accordingly, it was imperative that patients taking Pradaxa have their blood regularly monitored; however, they willfully failed to alert the plaintiffs, other Class Members, healthcare professionals, and Health Canada about this fact;

l. The defendants knowingly or recklessly provided misleading or incomplete information in the product monographs for Pradaxa, and particularly in Parts I and III of such monographs, which are directed to healthcare professionals and patients, respectively; and

m. The defendants advertised Pradaxa to healthcare professionals in a manner that did not adequately or at all disclose the drugs risk of harm and the lack of an effective antidote in the event of bleeding caused as a side effect by Pradaxa.

45. Even if the defendants had properly warned physicians, pharmacists, or other healthcare professionals regarding the safe and effective use of Pradaxa, this fact alone would be insufficient to discharge the defendants' duty to warn the plaintiffs and other Class Members. This is so because:

a. The plaintiffs and other Class Members placed their primary reliance regarding the safety of Pradaxa, not on healthcare professionals, but on the defendants themselves;

b. The defendants advertised, promoted and marketed Pradaxa directly to the plaintiffs and other Class Members by means of so-called "reminder advertising", in which the name of a product, its strength, dosage, form and price are revealed, but not the product's indication or effectiveness. The defendants also advertised, promoted and marketed Pradaxa directly to the plaintiffs and other Class Members by means of cross-over

advertising, promotion, and marketing that was, or may have been, targeted to patients outside of Canada, but that was nonetheless consumed by Canadians; and

c. There was a high degree of consumer involvement regarding the prescription of Pradaxa given that Pradaxa was the first new anti-coagulant approved for sale in Canada in over 50 years.

48. In January and then again in April of 2012, the defendants modified the U.S. labeling and prescribing information for Pradaxa. Despite being aware of: (i) serious, and sometimes fatal, irreversible bleeding events associated with the use of Pradaxa; (ii) a July 25, 2011 article in the Archives of Internal Medicine concluding that the risk of harm in elderly populations is much increased and that there exists no antidote to excessive bleeding; (iii) the addition of a boxed warning to Pradaxa in Japan; (iv) questions being raised by physicians and the regulator in New Zealand about serious bleeding events associated with Pradaxa; and (v) a Drug Safety Communication published by the FDA in December, 2011 announcing that it was undertaking a "Drug Safety Review" of post-marketing reports of serious bleeding events with Pradaxa, the defendants nonetheless failed to provide adequate disclosures or warnings in their label regarding the risks associated with Pradaxa as detailed above.

49. At all times, the defendants' warnings to Canadians with respect to Pradaxa lagged behind the defendants' state of knowledge regarding the drug's risks, and lagged both in their timing and comprehensiveness behind the defendants' warnings in relation to Pradaxa abroad.

50. At all times relevant to this suit, the dangerous propensities of Pradaxa were known to the defendants, or were reasonably and scientifically knowable to them, through appropriate research and testing by known methods, at the time they distributed, supplied, or sold their respective product, and not known to ordinary physicians who would be expected to prescribe the drug for their patients.

51. Despite the fact that the defendants knew or should have known that Pradaxa posed a serious risk of bodily harm to consumers and/or did not provide any additional benefits, the defendants continued to manufacture and market Pradaxa for use by consumers.

52. It was as a direct and proximate result of the defendants' failure to exercise reasonable care in the design, research, development, testing, manufacture, marketing, packaging promotion, distribution, licensing, inspecting, labelling, advertising, supplying and sale of Pradaxa, that the plaintiffs and other Class Members were exposed to Pradaxa and thereby suffered personal injuries, economic and non-economic damages including pain and suffering. The defendants' failure to exercise reasonable care in the design, dosing, information, marketing, warnings, labeling, and/or manufacturing of Pradaxa was a proximate cause of the plaintiffs’ and Class Members' injuries and damages. More particularly:

a. It was as a result of the defendants' claims regarding the effectiveness, safety, and benefits of Pradaxa, and the defendants' failure to warn about the risks of serious injury associated with Pradaxa, that the plaintiffs, other Class Members, and the plaintiffs physicians healthcare professionals, and Health Canada, were unaware, and could not reasonably have known or have learned through reasonable diligence that the plaintiffs would be exposed to the risk of excessive and/or uncontrollable bleeding and the other risks and injuries described herein;

b. It was as a result of the defendants' failure to warn about the risks of serious injury associated with Pradaxa, as aforesaid, that the plaintiffs and Class Members were unaware of the increased risk for developing life-threatening injuries as compared to warfarin. Had the plaintiffs, the other and Class Members, healthcare providers, and Health Canada known of the risks and dangers associated with Pradaxa, as well as the lack of additional benefits, and had the defendants provided adequate warnings that there

is no agent to reverse the anticoagulation effects of Pradaxa, the plaintiff and Class Members would not have used Pradaxa, and

c. As a direct and proximate result of using Pradaxa, the plaintiffs and Class Members have suffered severe personal injuries, physical pain and mental anguish.

DAMAGES AND OTHER SUBROGATED CLAIMS

a. General and Special Damages

82. As a result of the defendants' negligence and other actionable conduct as set out above, the plaintiffs and the other Class Members have suffered and will continue to suffer damages and loss including:

(a) Personal injury;

(b) Out of pocket expenses including those connected with medical care and treatment, medications, the cost of Pradaxa as paid for by Class Members and by OHIP, and other provincial health insurers and drug benefit plans, and private third party payors as set out above;

(c) Cost of past care and services;

(d) Cost of future care and services; and

(e) Past loss of income and future loss of income.

83. As a result of the defendants' negligence and other actionable conduct as set out above, the resulting injuries to the plaintiff and other Class Members, members of the family class have suffered loss and damage. They have incurred out-of-pocket expenses for the benefit of plaintiffs and other Class Members. They have suffered and will continue to suffer loss of income. They have paid for or provided nursing, housekeeping and other services. They have suffered a loss of support, guidance, care and companionship that they might reasonably have expected to receive if the injuries to the plaintiffs and other Class Members had not occurred.

b. Subrogated Claims

e. Punitive and Aggravated Damages

92. At all material times, the defendants knew or should have known that Pradaxa was inherently dangerous.

93. Despite their knowledge, the defendants continued aggressively to market Pradaxa so consumers, including the plaintiffs and other Class Members, without disclosing its dangerous side effects when there existed safer alternative products. By way of example, the defendants knew that there existed an optimal range within which the blood concentration of Pradaxa needed to fall and that the anticoagulant effect of Pradaxa varied widely among patients or even in the same patient; accordingly, the defendants knew it was imperative that patients taking Pradaxa have their blood regularly monitored; however, they willfully failed to alert the plaintiffs, other Class Members, healthcare professionals, and Health Canada about this fact. They deleted reference to Pradaxa's optimal range of blood concentration from a draft report entitled, "The Relationship between the Plasma Concentration of Dabigatran, Ischemic Stroke and Major Bleeding in Atrial Fibrillation Patients - a subgroup analysis of the RE-LY trial", because they were marketing the drug as superior to the existing anti-coagulant warfarin on the strength of the representation that, unlike warfarin, Pradaxa supposedly required no monitoring; accordingly, any suggestion that patients would have to have their blood monitored to ascertain whether the Pradaxa in their bodies was present within an optimal range would potentially have a serious negative impact on the drug's sales.

94. Despite the defendants' knowledge of Pradaxa's defective and unreasonably dangerous nature, the defendants continued to test, design, develop, manufacture, label, package, promote, market, sell and distribute it so as to maximize sales and profits at the expense of the health and safety of the public, including the plaintiff and other Class Members, in conscious disregard of the foreseeable harm caused by Pradaxa.

95. The defendants' conduct was high-handed, outrageous, reckless, egregious, deliberate, disgraceful, wilful, callous, and in wanton disregard of the rights and safety of the Plaintiffs and of the other members of the class. The defendants' conduct was indifferent to the consequences and motivated by economic considerations such as the maintaining of profits and market share. Such conduct renders the defendants liable to pay punitive damages to the plaintiffs and other members of the class.

96. The defendants' conduct as described above, including, but not limited to, their failure to adequately test their product, to provide adequate warnings, and their continued manufacture, sale, and marketing or their products when they knew or should have known of the serious health risks created, evidences a flagrant disregard of human life as to warrant the imposition of punitive damages as the acts or omissions were committed with knowing, conscious and deliberate disregard for the rights and safety of consumers, including the plaintiffs and other Class Members.

97. The defendants' conduct, as aforesaid, was injurious to the feelings of pride, dignity and self-respect of the plaintiffs and the other Class Members. The defendants are therefore liable to the plaintiffs and other Class Members for aggravated damages.

Schedule “B”

PRODUCT MONOGRAPH

PRADAXA™

Dabigatran Etexilate Capsules

Capsules 75 mg, 110 mg and 150 mg Dabigatran Etexilate, (as Dabigatran Etexilate Mesilate)

PART 1: HEALTH PROFESSIONAL INFORMATION

INDICATIONS AND CLINICAL USE

PRADAXA (dabigatran etexilate) is indicated for the:

• prevention of venous thromboembolic events (VTE) in patients who have undergone elective total hip replacement or total knee replacement surgery

• prevention of stroke and systemic embolism in patients with atrial fibrillation, in whom anticoagulation is appropriate

Geriatrics: Clinical studies have been conducted in patients with a mean age> 65 years. Safety and efficacy data are available (see CLINICAL TRIALS).

Pharmacokinetic studies in older subjects demonstrate an increase in exposure to dabigatran in most of those patients, usually in association with age-related decline of renal function (see WARNINGS AND PRECAUTIONS, Renal, and DOSAGE AND ADMINISTRATION, Renal Impairment).

Pediatrics: The safety and efficacy of PRADAXA have not been established in children less than 18 years of age. Therefore, PRADAXA is not recommended in this patient population.

CONTRAINDICATIONS

• Severe renal impairment (CrCl < 30mL/min)

• Haemorrhagic manifestations, bleeding diathesis, or patients with spontaneous or pharmacological impairment of haemostasis

• Lesions at risk of clinically significant bleeding, e.g. extensive cerebral infarction hemorrhagic or ischemic) within the last 6 months, active peptic ulcer disease with recent bleeding ·

• Concomitant treatment with strong P-glycoprotein (P-gp) inhibitors, i.e. oral ketoconazole (see WARNINGS AND PRECAUTIONS, Interaction with P-glycoprotein, and DRUG INTERACTIONS)

• Concomitant treatment of PRADAXA (dabigatran etexilate) with any other anticoagulant, including:

o unfractionated heparin (UFH), except at doses used to maintain a patent central venous or arterial catheter,

o low molecular heparins (LMWH), such as enoxaparin and dalteparin,

o heparin derivatives, such as fondaparinux,

o anti-thrombin agents, such as bivalirudin, and

o oral anticoagulants, such as warfarin, rivaroxaban, apixaban, except under circumstances of switching therapy to or from PRADAXA

• Presence of prosthetic heart valve(s) requiring anticoagulation due to valvular status itself (see WARNINGS AND PRECAUTIONS, Patients with Valvular Disease).

• Known hypersensitivity to dabigatran or dabigatran etexilate or to any ingredient in the formulation or component of the container. For a complete listing, see DOSAGE FORMS, COMPOSITION AND PACKAGING.

WARNINGS AND PRECAUTIONS

The following Warnings and Precautions are listed in alphabetical order.

Bleeding

As with all anticoagulants, PRADAXA (dabigatran etexilate) should be used with caution in circumstances associated with an increased risk of bleeding. Bleeding can occur at any site during therapy with PRADAXA. The possibility of a hemorrhage should be considered in evaluating the condition of any anticoagulated patient. An unexplained fall in hemoglobin and/or hematocrit or blood pressure should lead to a search for a bleeding site.

Patients at high risk of bleeding should not be prescribed PRADAXA (see CONTRAINDICATIONS).

Should severe bleeding occur, treatment with PRADAXA must be discontinued and the source of bleeding investigated promptly.

Close clinical surveillance is recommended throughout the treatment period, i.e., looking for signs of bleeding or anemia, by testing for occult blood in the stool or ruling out a significant drop in serum hemoglobin, especially if risk factors are combined, see Table 1, below.

Table 1: Factors which increase hemorrhagic risk, as identified in clinical studies

Factors increasing dabgatatran plasma levels

Moderate renal impairment (30-50 ml/min CrCl)

P-glycoprotein inhibitor co-medication

Pharmacodynamic interactions

NSAID

Anti-platelet agents, including ASA, clopidogrel

Diseases/procedures with special haemorrhagic risks

Congenital or acquired coagulation disorders

Thrombocytopenia or functional platelet defects

Active ulcerative gastrointestinal disease

Recent gastro-intestinal bleeding

Recent biopsy or major trauma

Recent intracranial hamorrhage

Brain, spinal or ophthalmic surgery

Comment: Is there a title missing here?

Bacterial endocarditis

Others

Age ≥ 75 years

The measurement of dabigatran-related anticoagulation may be helpful to avoid excessive high exposure to dabigatran in the presence of additional risk factors (see Monitoring and Laboratory Tests, and ACTION AND CLINICAL PHARMACOLOGY, Pharmacodynamics).

Concomitant use of drugs affecting hemostasis increases the risk of bleeding (see CONTRAINDICATIONS). Care should be taken if patients are treated concomitantly with drugs affecting hemostasis such as non-steroidal anti-inflammatory drugs (NSAID), acetylsalicylic acid (ASA) or clopidogrel.

In patients with atrial fibrillation and having another cardiovascular condition that warrants single or dual antiplatelet therapy, a careful assessment of the potential risks against potential benefits should be made before combining this therapy with PRADAXA.

Specifically, with concomitant use of antiplatelet drugs, such as aspirin or clopidogrel, or P-gp inhibitors (see DRUG INTERACTIONS, P-glycoprotein inhibitors) in patients aged ≥75 years, the risk of major bleeding, including gastrointestinal bleeding, increases about twofold (see ADVERSE REACTIONS, Bleeding, Table 6).

In patients with atrial fibrillation treated for the prevention of stroke and systemic embolism, the co-administration of oral anti-platelet (including aspirin or clopidogrel) or NSAID therapies increases the risk of bleeding, by about two-fold (see ACTION AND CLINICAL PHARMACOLOGY, Pharmacokinetic Interactions). If necessary, co-administration of low dose ASA, i.e. ≤100 mg daily with PRADAXA may be considered for other indications than stroke prevention in atrial fibrillation. Note that in the RE-LY trial, there is no evidence that the addition of ASA or clopidogrel to dabigatran, or its comparator warfarin, improved outcomes in respect of stroke (see CLINICAL TRIALS, Stroke Prevention in Atrial Fibrillation).

The antiplatelet agents, prasugrel and ticagrelor, have not been studied with PRADAXA in the prevention of stroke in patients with atrial fibrillation, and are not recommended as concomitant therapy. Note that the concomitant use of ticagrelor increases exposure to dabigatran (see DRUG INTERACTIONS, Table 10, Ticagrelor, and ACTION AND CLINICAL PHARMACOLOGY, Phannacokinetic Interactions, Ticagrelor) and, further, may be expected to show pharmacodynamic interaction, leading to increased risk of bleeding.

Since there is very limited experience with the use of thrombolytic agents in conjunction with PRADAXA, a careful risk-benefit assessment is required before instituting thrombolytics due to potential increased risk of major bleeding. Thrombolytic agents for treatment of acute myocardial infarction or acute ischemic stroke in conjunction with PRADAXA may be considered, if thrombin time (TT), ecarin clotting time (ECT), or activated partial thromboplastin time (aPTT), not exceeding the upper limit of normal (ULN) have been obtained (see also, Monitoring and Laboratory Tests).

The concomitant use of the P-gp inhibitor, dronedarone, increases exposure of PRADAXA and is not recommended (see DRUG INTERACTIONS, and ACTION AND CLINICAL PHARMACOLOGY, Pharmacokinetic Interactions).

Bleeding risk may be increased in patients concomitantly treated with selective serotonin reuptake inhibitors (SSRI) or selective serotonin norepinephrine reuptake inhibitors (SNRI) (see DRUG INTERACTIONS, and ACTION AND CLINICAL PHARMACOLOGY, Pharmacodynamics).

ADVERSE REACTIONS

The safety of PRADAXA (dabigatran etexilate) has been evaluated overall in 18,726 patients who were treated with PRADAXA in seven clinical trials.

In six clinical trials conducted to evaluate the safety and effectiveness of dabigatran etexilate in the prevention of venous thromboembolic events (VTE) following major elective orthopedic surgery, 6,684 patients were treated with 150 mg or 220 mg once daily of PRADAXA.

In the RE-LY trial, investigating the prevention of stroke and systemic embolism in patients with atrial fibrillation, a total of 12,042 patients were exposed to PRADAXA. Of these 6,059 were

treated with 150 mg twice daily of dabigatran etexilate, while 5,983 received doses of 110 mg twice daily.

Nine percent of patients treated with dabigatran and about 10% of patients treated with enoxaparin for VTE prevention after elective hip or knee surgery (short-term treatment up to 42 days) experienced adverse reactions. About 21% of patients with atrial fibrillation treated with dabigatran and about 16% of patients treated with warfarin for the prevention of stroke and systemic embolism (long-term treatment for up to 3 years) experienced adverse events considered related to treatment.

Bleeding

Bleeding is the most relevant side effect of PRADAXA. Bleeding of any type or severity occurred in approximately 14% of patients treated short-term for elective hip or knee replacement surgery and in long-term treatment in 16.5% of patients with atrial fibrillation treated for the prevention of stroke and systemic embolism.

Although rare in frequency in clinical trials, major or severe bleeding may occur and, regardless of location, may lead to disabling, life-threatening or even fatal outcomes.

Since the patient populations treated with PRADAXA for different indications are not interchangeable, a summary description of major and total bleeding is provided by indication in Tables 3, 4, and 5, below.

Table 3: Number (%) of patients experiencing bleeding events during the treatment period for VTE prevention in the REMODEL and RENOVATE trials, according to dose.

	Dabigatran etexilate 150mg N(%)	Dabigatran etexilate 220mg (N%)	Dabigatran etexilate 40mg QD (N%)
Treated	1,866 (100.0)	1,825 (100.0)	1,848 (100.0)
Major Bleeding	24 (1.3)	33 (1.8)	27 (1.5)
Any Bleeding*	258 (13.8)	251 (13.8)	247 (13.4)

Table 4: Number (%) of patients experiencing bleeding events during the treatment period for VTE prevention in the REMOBILIZE trial, according to dose.

	Dabigatran etexilate 150mg N(%)	Dabigatran etexilate 220mg (N%)	Dabigatran etexilate 40mg QD (N%)
Treated	871 (100.0)	857 (100.0)	868 (100.0)
Major Bleeding*	5 (0.6)	5 (0.6)	12 (1.4)
Any Bleeding	72 (8.3)	74 (8.6)	84 (9.7)

• Major Bleeding: Major bleeding was defined as clinically overt bleeding associated with 20g/LL fall hemoglobin; clinically overt bleeding leading to transfusion of ≥ 2 units packed cells or whole blood; fatal, retroperitoneal, intracranial, intraocular or intraspinal bleeding; bleeding warranting treatment cessation or leading to reoperation. Major bleeding included those events occurring at the surgical site.

Table 5 shows the number of patients experiencing major and total bleeding event rates during the treatment period in the RE-LY study, conducted in patients with atrial fibrillation. In Table 5, the category of major bleeds includes both life-threatening and non-life threatening bleeds. Within life-threatening, intracranial bleeds is a subcategory of life-threatening bleeds. Intracranial bleeds include intracerebral (hemorrhagic stroke), subarachnoid and subdural bleeds. For this reason, these events may be counted in multiple categories.

Table 5: Frequency and annualized event rate (%) of bleeding events from the RE-LY trial

	Dabigatran etexilate 110mg N(%)	Dabigatran etexilate 150mg (N%)	warfarin** (N%)
Patients randomized	6,015	6,075	6,022
Patient-years	11,899	12,033	11,794
Major bleeding events (MBE)*	342 (2.9)	399 (3.3)	421 (3.6)
Hazard ratio v. warfarin (95% CI)	0.80 (0.70, 0.93)	0.93 (9.81, 1.07)
p-value	0.0026	0.3146
Life-threatening MBE	147 (1.2)	179 (1.5)	218 (1.9)
Hazard ratio v. warfarin (95 % CI)	0.67 (0.54, 0.82)	0.80 (0.66, 0.98)
p-value	< 0.0001	< 0.0001
Fatal bleeding	23 (0.19)	28 (0.23)	39 (0.330
Hazard ratio v. warfarin (95 % CI)	0.58 (0.35, j0.98)	0.70 (0.43, 1.14)
p-value	0.0400	0.1535
Any bleeding event*	1,754 (14.7)	1,993 (16.6)	2,166 (18.4)
Hazard ratio v. warfarin (95 % CI)	0.78 (0.73, 0.83)	0.91 (0.85, 0.96)
p-value	< 0.0001	0.0016

• Adjudicated Bleeds ** Dose-adjusted warfarin to an INR of 2.0- 3.0 +ICH consists of adjudicated hemorrhagic stroke and subdural and/or subarachnoid hemorrhage. Investigator-reported bleeding events

Major bleeding fulfilled one or more of the following criteria:

• Bleeding associated with a reduction in hemoglobin of at least 20 grams per litre or leading to a transfusion of at least 2 units of blood or packed cells;

• Symptomatic bleeding in a critical area or organ: intraocular, intracranial, intraspinal or intramuscular with compartment syndrome, retroperitoneal bleeding, intra-articular bleeding or pericardial bleeding.

Major bleeds were classified as life-threatening if they fulfilled one or more of the following criteria:

• Fatal bleed; symptomatic intracranial bleed; reduction in hemoglobin of at least 50 grams per litre; transfusion of at least 4 units of blood or packed cells; a bleed associated with hypotension requiring the use of intravenous inotropic agents; a bleed that necessitated surgical intervention.

Patients with atrial fibrillation over the age of 75 years taking an anticoagulant are known to be at increased risk of having a stroke, serious and non-serious bleeding events and death compared to those less than 75 years of age. Patients over the age of 75 years who are also receiving concomitant ASA or an antiplatelet agent are at further increased risk of stroke, bleeding, and death compared to those over the age of 75 years not receiving ASA or an antiplatelet agent, see Table 6, below.

Table 6: Annualized rates of key safety outcomes in the RE-LY trial in patients > 75 years with or without antiplatelets (AP) or P-glycoprotein inhibitors (Pgp-inh.):

Group	Treatment	No. of patients	Major Bleed (%/y)	Life- Threat Bleed (%/y)	Major GI- bleed (%/y)	ICH (%/y)	Stroke /SEE (%/y)	Ischemic Stroke (%/y)	Any Death (%/y)
>75 years with AP or Pgp- inh.	DE 110* DE 150** warfarin+	1356 1446 1422	5.65 6.52 5.16	2.30 2.71 2.67	2.42 3.21 1.57	0.31 0.50 1.13	2.11 1.89 2.53	1.81 1.57 1.72	6.11 5.85 5.53
>75 years without APor Pgp-inh.	DE 110* DE 150** warfarin+	993 1020 1001	2.86 3.15 3.57	1.40 1.50 1.85	1.10 1.35 1.06	0.45 0.25 0.76	1.61 0.8 1.71	1.25 0.45 1.14	4.06 4.09 4.13

• Dabigatran etexilate 110 mg bid ** Dabigatran etexilate 150 mg bid

• dose adjusted, INR 2.0 – 3.0

Stroke/SEE and Ischemic Stroke outcomes are provided for comparative purposes only.

Clinical Trial Adverse Drug Reactions

Because clinical trials are conducted under very specific conditions the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates.

Table 7: Common Adverse Reactions observed in ≥ 1% of dabigatran-treated patients in active-controlled VTE prevention trials

	Dabigatran etexilate 150 mg N(%) 2M737 (100)	Dabigatran etexilate 220 mg N (%) 2,682 (100)	Enoxaparinb (N%) 3,108 (100)
Blood and lymphatic system
Anemia	110 (4.0)	117 (4.4)	141 (4.5)
Gastrointestinal hemorrhage	33 (1.2)	17 (0.6)	20 (0.6)
Hematoma	38 (1.4)	37 (1.4)	55 (1.8)
Hematuria	34 (1.2)	31 (1.2)	25 (0.8)
Wound hemorrhage	35 (1.3)	28 (1.0)	31 (1.0)
Procedural Complications
Wound secretion	130 (4.7)	130 (4.8)	93 (3.0)
Post-procedural hematoma	66 (2.4)	45 (1.7)	78 (2.5)
Anemia post-operative	37 (1.4)	54 (1.5)	56 (1.8)
Traumatic hematoma	37 (1.4)	54 (2.0)	56 (1.8)
Traumatic hematoma	37 (1.4)	41 (1.5)	51 (1.6)
Post-procedural discharge	31 (1.1)	34 (1.3)	31 (1.0)
Laboratory investigations
ALT ≥ 3xULN	68 (2.5)	58 (2.2)	93 (3.5)a
Hemoglobin decreased	45 (1.6)	35 (1.3)	74 (2.4)

a. Based on N=2,716 b. Enoxaparin 40mg QD or 30 mg BID

Table 8: Common Adverse Reactions observed in ≥ 1% of dabigatran patients with atrial fibrillation in the active-controlled trial, RE-LY

	Dabigatran etexilate 110mg N (%) 5,983 (100)	Dabigatran etexilate 150mg N (%) 6,059 (100)	warfarin N (%) 5,998 (100)
Bleeding and anemia*	599 (10.0)	747 (12.3)	825 (13.8)
Anemia	73 (1.2)	97 (1.6)	74 (1.2)
Epistaxis	66 (1.1)	67 (1.1)	74 (1.2)
Gastointestinal hemorrhage	186 (3.3)	277 (4.6)	155 (2.6)
Urogenital hemorrhage	66 (1.1)	84 (1.4)	96 (1.6)
Gastrointestinal disorders*	735 (12.3)	772 (12.7)	220 (3.7)
Abdominal pain	135 (2.3)	134 (2.2)	15 (0.3)
Diarrhoea	75 (1.3)	71 (1.2)	11 (j0.2)
Dyspepsia	250 (4.2)	234 (3.9)	13 (0.2)
Nausea	58 (1.0)	73 (1.2)	12 (0.2)

*Aggregate incidence presented for all adverse reactions within the body system, including those reactions occurring < 1% and not listed in the Table 8 above.

Gastrointestinal adverse reactions occurred more often with dabigatran etexilate than warfarin. These were related to dyspepsia (including upper abdominal pain, abdominal pain, abdominal discomfort, epigastric discomfort), or gastritis-like symptoms (including GERD, esophagitis, erosive gastritis, gastric hemorrhage, hemorrhagic gastritis, hemorrhagic erosive gastritis, gastrointestinal ulcer).

Gastrointestinal (GI) hemorrhage occurred at a higher frequency with PRADAXA 150 mg bid, compared to warfarin (see Table 8 above). GI-adjudicated major bleeds were reported at 1.1 %, 1.6%, and 1.1% (annualized rates) in the DE 110 mg, DE 150 mg and warfarin groups, respectively. GI life-threatening bleeds occurred with a frequency of 0.6%, 0.8% and 0.5% in the DE 110 mg, DE 150 mg and warfarin groups, respectively. Any GI bleeds occurred with frequency of 5.4%, 6.1% and 4.0% in the DE 110 mg, DE 150 mg and warfarin groups, respectively. The underlying mechanism of the increased rate of GI bleeding has not been established (see CLINICAL TRIALS, Prevention of stoke and systemic embolism in patients with atrial fibrillation).

Allergic reactions or drug hypersensitivity including angioedema, urticaria, bronchospasm, rash and pruritus have been reported in patients who received dabigatran etexilate. Rare cases of anaphylactic reactions have also been reported.

Less Common Clinical Trial Adverse Drug Reactions (<1 %)

• Observed with exposure to dabigatran 150 mg and 220 mg /day during active-controlled venous thromboembolic prevention trials in the context of major orthopedic surgery:

Blood and lymphatic system: thrombocytopenia

Gastrointestinal disorders: hemorrhoidal hemorrhage, rectal hemorrhage

General: bloody discharge, catheter site hemorrhage

Hepatobiliary disorders: alanine aminotransferase increased, aspartate aminotransferase increased, hepatic enzyme increased, hepatic function abnormal/liver function test abnormal, transaminases increased.

Injury, poisoning and procedural complications: incision site hemorrhage

Laboratory Investigations: occult blood positive, blood urine present, hematocrit decrease

Musculoskeletal and cumulative tissue disorders: hemarthrosis

Respiratory and thoracic system: epistaxis

Skin and subcutaneous tissue: ecchymosis

Surgical and medical procedures: post-procedural drainage, wound drainage

Vascular disorders: hemorrhage

• Observed with exposure to dabigatran 110 mg bid and 150 mg bid during the RE-LY trial, an active-controlled clinical trial for the prevention of stroke and systemic embolism in patients with atrial fibrillation:

Blood and lymphatic system disorders: thrombocytopenia

Vascular disorders: haematoma, hemorrhage

Gastrointestinal disorders: gastrointestinal ulcer (including esophageal ulcer), gastroesophagitis,

gastro-esophageal reflux disease, vomiting, dysphagia

Hepatobiliary disorders: hepatic function abnormal I liver function test abnormal, hepatic enzyme increased

Skin and subcutaneous tissue disorder: skin hemorrhage, urticaria, rash, pruritus

Musculoskeletal and connective tissue and bone disorders: hemarthrosis

Renal and urinary disorders: urogenital hemorrhage

General disorders and administration site conditions: injection site hemorrhage, catheter site hemorrhage

Injury, poisoning and procedural complications: incision site hematoma, traumatic hemorrhage, traumatic hematoma, incision site hemorrhage

Immune system disorder: drug hypersensitivity, anaphylaxis

Respiratory disorders: hemoptysis, bronchospasm

Nervous system disorders: intracranial hemorrhage

DOSAGE AND ADMINISTRATION

PRADAXA (dabigatran etexilate) should be taken orally, with the entire capsule to be swallowed whole. The capsule should not be chewed, broken, or opened.

PRADAXA should be taken regularly, as prescribed, to ensure optimal effectiveness. All temporary discontinuations should be avoided, unless medically indicated.

Recommended Dose and Dosage Adjustment

• VTE prevention following elective knee replacement surgery: The recommended dose of PRADAXA is 220 mg daily, taken orally as two (2) capsules of 110 mg once a day in patients with intact renal function. Treatment should normally be initiated within 1-4 hours of completed surgery once hemostasis is secured. Start with a single capsule of 110 mg, and continue with two (2) capsules once daily thereafter for a total of 10 days. If hemostasis is not secured, initiation of

• VTE prevention following elective hip replacement surgery: The recommended dose of PRADAXA is 220 mg daily, taken orally as two (2) capsules of 110 mg once a day in patients with intact renal function. Treatment should normally be initiated within 1-4 hours of completed surgery once hemostasis is secured. Start with a single capsule of 110 mg, and continue with 2 capsules once daily thereafter for a total of 28-35 days. If hemostasis is not secured, initiation of treatment should be delayed. If treatment is not started on the day of surgery for whatever reason, then treatment should be initiated with 2 capsules at once.

• Prevention of stroke and systemic embolism in patients with atrial fibrillation: The recommended dose of PRADAXA is 300 mg daily, taken orally as one 150 mg capsule twice a day.

Elderly:

• VTE prevention following orthopedic surgery: In patients treated for prevention of VTE after hip- or knee-replacement surgery and > 75 years of age, PRADAXA should be used with caution. A dose of 150 mg daily should be considered, taken as two (2) capsules of 75 mg daily, since age-related compromise of renal function is frequently encountered (see WARNINGS AND PRECAUTIONS, Geriatrics, and Renal). As with all patients, treatment should normally be initiated within 1-4 hours of completed surgery once hemostasis is secured. Start with a single capsule, and continue with two (2) capsules once daily thereafter for the duration of the treatment.

• Prevention of stroke and systemic embolism in patients with atrial fibrillation: Patients aged 80 years and above should be treated with a dose of 220 mg of PRADAXA daily, taken orally as one 110 mg capsule twice a day (see WARNINGS AND PRECAUTIONS, Geriatrics, and CLINICAL TRIALS, Prevention of Stroke and Systemic Embolism in Patients with Atrial Fibrillation, Tables 25-26).

The usual recommended dose for most geriatric patients under the age of 80 years is 300 mg daily, taken orally as one 150 mg capsule twice a day (see CLINICAL TRIALS, Prevention of Stroke and Systemic Embolism in Patients with Atrial Fibrillation, Tables 25 and 26). However, in geriatric patients, especially those over the age of 75 with at least one other risk factor for bleeding (see WARNINGS AND PRECAUTIONS, Bleeding, Table 1), the administration of a dose of 220 mg of PRADAXA daily, taken orally as one 110 mg capsule twice a day, may be considered, including for patients taking concomitant anti-platelet agents or P-gp inhibitors (see ADVERSE REACTIONS, Bleeding, Table 6, and DRUG INTERACTIONS, P-glycoprotein inhibitors). It should be noted, however, that the effectiveness of stroke prevention may be expected to be lessened with this dosage regimen, compared to that of the usual one of 300 mg of PRADAXA daily (see CLINICAL TRIALS, Tables 25 and 26). As with any anticoagulant, caution is required when prescribing PRADAXA to the elderly (see CONTRAINDICATIONS, and WARNINGS AND PRECAUTIONS, Bleeding).

As renal impairment may be frequent in the elderly (≥75 years), renal function should be assessed by calculating the estimated creatinine clearance (eCrCl) prior to initiation of treatment with PRADAXA to exclude patients for treatment with severe renal impairment (i.e. eCrCl < 30ml/min). Renal function should also be assessed routinely at least once a year in patients treated with PRADAXA, or more frequently as needed in clinical situations when it is suspected that renal function could decline or deteriorate rapidly, such as hypovoemia, dehydration, and with certain co-medications, etc. (see DOSAGE AND ADMINISTRATION, Renal impairment).

Patients at risk of bleeding:

Prevention of stroke and systemic embolism in patients with atrial fibrillation: Patients with an increased risk of bleeding (see WARNINGS AND PRECAUTIONS, Bleeding, Table 1), should be closely monitored clinically (looking for signs of bleeding or anaemia). The presence of the following factors may increase the risk of bleeding: e.g. age: ≥ 75 years, moderate renal impairment (30-50 ml eCrCl/min), concomitant treatment with strong P-gp inhibitors (see

WARNINGS AND PRECAUTIONS, Bleeding), antiplatelets or previous gastro-intestinal bleed. In such patients, a dose of 220 mg, given as 110 mg twice daily may be considered at the discretion of the physician.

A coagulation test, such as a PTT (see WARNINGS AND PRECAUTIONS, Monitoring and Laboratory Tests), may help to identify patients with an increased bleeding risk caused by excessive dabigatran exposure.

As for any anticoagulant, PRADAXA is NOT indicated in patients at excessive risk of bleeding (see CONTRAINDICATIONS).

OVERDOSAGE

For management of a suspected drug overdose, contact your regional Poison Control Centre.

There is no antidote to PRADAXA (dabigatran etexilate), or its active moiety, dabigatran.

Doses of PRADAXA beyond those recommended expose the patient to increased risk of bleeding. Excessive anticoagulation may require discontinuation of PRADAXA.

The use of activated charcoal to reduce absorption in case of PRADAXA overdose may be considered.

Management of Bleeding

In the event of hemorrhagic complications in a patient receiving PRADAXA, treatment must be discontinued, and the source of bleeding investigated. Since dabigatran is excreted predominantly by the renal route, adequate diuresis must be maintained. Appropriate standard treatment, e.g. surgical hemostasis as indicated and blood volume replacement, should be undertaken. In addition, consideration may be given to the use of fresh whole blood or the transfusion of fresh frozen plasma.

As protein binding is low, dabigatran can be dialysed, (see below), although there is limited clinical experience in using dialysis in this setting.

In patients who are bleeding due to excess activity of dabigatran, activated partial thromboplastin time (aPTT), thrombin time (TT) and ecarin clotting time (ECT) would be expected to be elevated and may be helpful in assessing anticoagulant activity of dabigatran, if necessary (see WARNINGS AND PRECAUTIONS, Monitoring and Laboratory Tests, and ACTION AND CLINICAL PHARMACOLOGY, Pharmacodynamics). If TT or ECT are not available, the aPTT test provides an approximation of PRADAXA anticoagulant activity in these circumstances. The PT (INR) measurement is not reliable and should not be used (see WARNINGS AND PRECAUTIONS, Monitoring and Laboratory Tests).

For TT assessment in patients treated with PRADAXA, a calibrated Hemoclot® thrombin inhibitor assay (a diluted TT assay) with dabigatran standards should be used to calculate the dabigatran concentration, rather than to determine a standard TT measurement.

Protamine sulfate and vitamin K are not expected to affect the anticoagulant activity of PRADAXA.

Administration of one of the following procoagulants may be considered:

• activated prothrombin complex concentrates (APCC), e.g., FEIBA

• recombinant Factor-VIla (rFVIIa)

• prothrombin complex concentrate (PCC)

There is some experimental evidence to support the role of these procoagulant agents in reversing the anticoagulant effect of dabigatran but their usefulness in clinical settings has not yet been clearly demonstrated. Consideration should also be given to administration of platelet concentrates

in cases where thrombocytopenia is present or long acting antiplatelet drugs have been used. All symptomatic treatment should be given according to the physician's judgement.

Hemodialysis

Clearance of dabigatran by hemodialysis was investigated in patients with end-stage renal disease (ESRD), without atrial fibrillation. Dialysis was conducted with 700 ml/min dialysate flow rate, four hour duration, a blood flow rate of either 200 ml/min or 350-390 ml/min. This resulted in a removal of 50% or 60% of total dabigatran concentrations, respectively, depending on the blood-flow rate. The amount of drug cleared by dialysis is proportional to the blood flow rate. The anticoagulant activity of dabigatran decreased with decreasing plasma concentrations and the PK/PD relationship was not affected by the procedure.

ACTION AND CLINICAL PHARMACOLOGY

Mechanism of Action

PRADAXA (dabigatran etexilate) is a prodrug which does not exhibit anticoagulant activity itself. Following oral administration, dabigatran etexilate is rapidly absorbed and converted to dabigatran by esterase-catalysed hydrolysis in plasma and in the liver.

Dabigatran is a competitive, reversible direct thrombin inhibitor, and is the main active principle in plasma. Since thrombin (serine protease) enables the conversion of fibrinogen into fibrin during the coagulation cascade, its inhibition prevents the development of thrombus. Dabigatran also inhibits free thrombin, fibrin-bound thrombin and thrombin induced platelet aggregation.

In vivo and ex vivo animal studies have demonstrated antithrombotic efficacy and anticoagulant activity of dabigatran after intravenous administration and of dabigatran etexilate following oral administration in various animal models of thrombosis.

PART III: CONSUMER INFORMATION

Pradaxa™

Dabigatran Etexilate Capsules

This leaflet is part III of a three-part "Product Monograph" published when PRADAXA was approved for sale in Canada and is designed specifically for Consumers. This leaflet is a summary and will not tell you everything about PRADAXA. Contact your doctor or pharmacist if you have any questions about the drug.

ABOUT THIS MEDICATION

What the medication is used for:

PRADAXA is an anticoagulant agent (prevents blood clots from forming).

Knee or hip replacement surgery

PRADAXA is prescribed after knee or hip replacement surgery to prevent the formation of blood clots in the vein of your leg(s) or in your lung(s).

Atrial fibrillation

PRADAXA is prescribed to prevent the occurrence of stroke (damage to part of the brain caused by an interruption of its blood supply), or sudden blocking of a blood vessel by a blood clot, in people who have a heart condition called atrial fibrillation (irregular heart beat).

With atrial fibrillation, part of the heart does not beat the way it should. This can lead to formation of blood clots which increases the risk of stroke.

What it does:

PRADAXA helps prevent the formation of blood clots by blocking the activity of a protein called thrombin.

When it should not be used:

• You have body lesions at risk of bleeding, including bleeding in the brain (stroke) within the last 6 months.

• You have bleeding such as recent bleeding of a stomach ulcer.

• You have severely reduced kidney function or your kidneys do not function. Your doctor will know how to determine your kidney function.

Your kidney function should be tested before starting therapy with PRADAXA.

• While epidural or spinal catheters are in place or within the first two hours after their removal.

Your doctor will know what precautionary measures are required. PRADAXA is not recommended for patients receiving epidural pain control after surgery.

• PRADAXA should not be used during pregnancy, since its effects on pregnancy and the unborn child are not known.

• You are taking oral ketoconazole (a drug used to treat fungus infection).

• You are taking dronedarone, a medicine used to prevent repetition of your problem of irregular heartbeat.

• You are already taking medicines to prevent blood clots, e.g. warfarin (COUMADIN), heparin, rivaroxaban (XARELTO), apixaban (ELIQUIS), unless your physician has decided to switch you to PRADAXA.

• You are also taking prasugrel (EFFIENT), or ticagrelor (BRILINTA).

• You are suffering from liver disease.

• You have an artificial heart valve (mechanical or biological).

• You are younger than 18 years of age.

• You are allergic to dabigatran etexilate, dabigatran, or any other ingredient of PRADAXA (see What the non-medicinal ingredients are). ·

What the medicinal ingredient is:

Dabigatran-etexilate, as dabigatran etexilate mesilate.

What the non-medicinal ingredients are:

acacia, carragenan, dimethicone, hydroxypropyl cellulose, hypromellose, indigocarmin, iron oxide black, potassium chloride, propylene glycol, shellac, sunset yellow, talc, tartaric acid, titanium dioxide.

What dosage forms it comes in:

Capsules: 75 mg, 110 mg and 150 mg.

WARNINGS AND PRECAUTIONS

Major or severe bleeding can occur in any part of your body while you are taking PRADAXA.

BEFORE you use PRADAXA talk to your doctor or pharmacist if:

• You have an increased bleeding risk or have ever had any bleeding problems, any disease known to cause an increased risk of bleeding (e.g. blood clotting disorders), recent tissue sampling (biopsy), major trauma or recent brain bleeding, stomach ulcer or a previous diagnosis of inflammation of parts of your heart (endocarditis), or if you are 75 years old or older.

• You know that you have impaired kidney function, or you are suffering from dehydration (symptoms of feeling thirsty and passing reduced amounts of dark-colored (concentrated) urine. If during treatment with PRADAXA you stop producing urine, inform your doctor immediately.

• You are pregnant or plan to become pregnant.

You should avoid pregnancy during treatment with PRADAXA.

• You are nursing. Breast-feeding should be stopped during treatment with PRADAXA.

• You have reduced liver function, life-threatening liver disease or increased liver enzymes.

• You are going to have surgery for any reason including brain, spinal or eye surgery, or other invasive medical or dental procedures. To avoid a risk of bleeding you may need to stop taking PRADAXA temporarily. It is very important to take PRADAXA before and after the surgery exactly at the times you have been told by your doctor.

• You are taking any other prescription or over-the- counter medication (see INTERACTIONS WITH THIS MEDICATION below).

INTERACTIONS WITH THIS MEDICATION

• Please be sure to tell your doctor taking PRADAXA if you are taking or have taken any medications that affect the blood clotting system, for example:

• Blood thinners and medicine used to reduce the risk of heart attacks such as warfarin, heparin or low molecular weight heparin (LMWH), fondaparinux, bivalirudin, rivaroxaban, apixaban, or clopidogrel, ticlopidine, prasugrel, and ticagrelor.

• Anti-inflammatory and pain reliever medications such as aspirin (ASA), or other medications you might take for headache, inflammation or arthritis, known as nonsteroidal anti-inflammatory drugs (NSAID), e.g. ibuprofen (MOTRIN), naproxen (NAPROSYN).

• Also be sure to tell your doctor before you start taking PRADAXA if you are taking any of the following: ….

Overdose

In case of drug overdose, contact a health care practitioner, hospital emergency department or regional Poison Control Centre immediately, even if there are no symptoms.

If you take more than the recommended dose of PRADAXA, you may have an increased risk of bleeding. Your doctor can perform a blood test to assess the risk of bleeding.

SIDE EFFECTS AND WHAT TO DO ABOUT THEM

You should be aware that prescription medicines carry some risks and that all possible risks may not be known at this stage.

As PRADAXA acts on the blood clotting system, most

side effects are related to signs of bruising or bleeding.

Although rare, major or severe bleeding may occur and regardless of its location, may become disabling, life-threatening or even lead to death.

If you fall or injure yourself during treatment with PRADAXA, especially if you hit your head, please seek urgent medical attention. You may need to be checked by a doctor, as you may be at increased risk of bleeding.

Patients treated with PRADAXA may experience the fol1owing side effects: diarrhea, nausea, bruising, rash, itching, reflux of gastric juice, vomiting, difficulty swallowing and hives.

Before starting PRADAXA and periodically after, your doctor will monitor your blood for test results such as kidney and liver function, number of platelets, and number of red blood cells (anemia).

SERIOUS SIDE EFFECTS, HOW OFTEN THEY HAPPEN AND WHAT TO DO ABOUT THEM

Symptom/Effect	Talk with your doctor or pharmacist	Stop taking drug and seek immediate emergency medical attention
	Only if severe	In all cases
Common
Bleeding from penis/vagina or urinary track
Bleeding from stomach or bowel
Upset stomach (dyspepsia), abdominal pain
Bruising or bleeding due to injury or after operation
After surgery: Severe bleeding from the surgical wound, an injury or other procedures
After surgery: Liquid oozing from the surgical wound
Uncommon
Bleeding under the skin
Nose Bleed
Blood in the urine that stains it pink or red
Allergic reaction (sudden unexplained swelling of the face or throat, red and lumpy skin, rash, itchiness, hives difficulty breathing or wheezing or possible low blood pressure)
Coughing blood or blood stained sputum
Bleeding into the rectum or from hemorrhoids
Blood in stools
Bleeding from the site of catheter entry into vein
Bleeding into the brain
Inflammation of the stomach, esophagus (food pipe), or alimentary tract (ulcer)
Rare
Blood-stained discharge from the site of entry of an injection needle or catheter into a vein, bleeding from surgical incision
Very Rare
Liver disorder- symptoms include nausea, vomiting, loss of appetite combined with itching, yellowing of the skin or eyes, dark urine

This is not a complete list of side effects. For any unexpected effects while taking PRADAXA, contact your doctor or pharmacist immediately.