The FDA Center for Drug Evaluation and ResearchCardiovascular and Renal Drug Advisory Committee Meeting:Dabigatran for the prevention of stroke and thromboembolism

in patients with atrial fibrillation (NDA 22-512)1

September 20, 2010, The Washington Hilton Hotel, Silver Spring, Maryland

ABSTRACT

In a traditional NDA, the German firm Boehringer Ingelheim applied for marketing privileges for its anticoagulant, dabigatran etexilate, after a large, randomized, partially-blinded, prospective Phase III trial of 18,113 patients with atrial fibrillation at risk for stroke or other thromboembolic events (TE) in 951 centers in 44 countries, called the “RE-LY” trial, demonstrated the drug’s noninferiority to warfarin at preventing stroke and TE at one dose (110mg BID) and superiority to warfarin at another (150mg BID). The drug’s safety profile showed the risk of major bleeding at the lower dose to be smaller than for warfarin and at the higher dose to be comparable to warfarin, whose need for weekly, in-office prothrombin time monitoring and poor compliance have long raised hopes for a better anticoagulant. During its meeting, the Cardiovascular and Renal Drugs Advisory Committee of the FDA’s CDER raised doubts about the objectivity of RE-LY’s randomization process and questioned the unambiguous and first-time-anywhere association of dabigatran with higher rates of myocardial infarction, but in the end voted unanimously to endorse the drug for wider FDA approval at its October 19, 2010 meeting. Aspects of the NDA that were praised by FDA at the meeting included the clinical basis study’s focus on two effective doses of the study drug, on its comparatively long followup period of four years, and on the study’s consistently “robust” results that demonstrated dabigatran’s unprecedented prevention of stroke and TE in patients with atrial fibrillation with comparatively minimal side effects. The drug’s association with MI will be reflected in a statement in the drug’s package insert summarizing RE-LY’s findings with respect to MI and a sponsor pledge to conduct further studies of that association as well as to monitor existing patients for adverse ischemic events.

INTRODUCTION

General background. Cardiology history was made Monday, September 20, 2010, when the FDA’s Center for Drug Evaluation and Research (CDER) Cardiovascular and Renal Drug Advisory Committee met at the Washington Hilton in Silver Spring, Maryland, and unanimously endorsed 2 new drug application (NDA) 22-512, submitted by Boehringer Ingelheim Pharmaceuticals, Inc., of Ingelheim, Germany, for its anticoagulant (“blood thinner”) medication, dabigatran etexilate (DE)(formerly BIBR 1048)3 (trade name: Pradaxa), indicated for those with atrial fibrillation at risk for either stroke (cardiovascular accident, CVA, caused by blockage of an artery in the brain by a clotted blood particle [a thromboembolism] and subsequent hemorrhage or ischemia)4 or venous thromboembolism (TE, tossing of thromboembolism(s) into the cardiovascular system’s veins, where blood moves slowly back to the heart, and causing blockage and subsequent bleeding or ischemia), designed to improve upon one of the world’s most widely prescribed medications, warfarin (trade names Coumadin, Jantoven, Marevan, Lawarin,

and Waran),5 a vitamin K antagonist (vitamin K is required for the body’s coagulation cascade) now more than fifty years old and saddled with difficulties relating to its side effects (major bleeding), mandatory monitoring for prothrombin time, undesirable interactions with vitamin K-containing foods, and more than 45% non-compliance/non-efficacy due to these and other factors.

Clinical basis of the NDA. The clinical basis of the NDA was a study of more than 18,000 patients suffering from atrial fibrillation and at risk for stroke (cardiovascular accident, CVA) or thromboembolism (TE) called “Randomized Evaluation of Long-Term Anticoagulant Therapy” or “RE-LY” for short.6 This study was financed by Boehringer Ingelheim, Inc., a family-owned firm, but managed by members of the faculty at McMaster School of Medicine belonging to the Population Health Research Institute (PHRI) of Hamilton, Ontario, which independently managed the database and performed statistical analysis of study results.

REGULATORY CONSIDERATIONS: ADVISORY COMMITTEE MEETINGS

The meeting and its format. Federal authority and guidance for the meeting and its format is found in the Food, Drug, and Cosmetics Act of 1938 (FD&C) that stipulates that drugs must be cleared for safety before they are approved for marketing; the Durham-Humphrey Amendment of 1951 to FD&C that requires certain types of drugs to be sold to an individual only by prescription; the Kefauver-Harris Drug Amendments to FD&C of 1962, which require that drugs approved by the FDA are both effective and safe; in the DESI Review and Fair Packaging and Labeling Act of 1966, which requires that drugs are accurately, honestly, and informatively labeled; and, finally, to the Prescripton Drug User Fee Act of 1992, which by requiring drugmakers to pay fees for FDA services enabled the FDA to hire more consultants and speed drugs through the development and approval process.7

Scheduling. Authority for scheduling the meeting between the FDA and sponsor and guidelines for planning its format rest with the drug sponsor and are described in 21 CFR 312.47a, in which is stated:

Meetings between a sponsor and the agency are frequently useful in resolving questions and issues raised during the course of a clinical investigation. FDA encourages such meetings to the extent that they aid in the evaluation of the drug and in the solution of scientific problems concerning the drug, to the extent that FDA’s resources permit. The general principle underlying the conduct of such meetings is that there should befree, full, and open communication about any scientific or medical question that may arise during the clinical investigation.8

NDA applications. An NDA is an application requesting FDA approval to market a new drug in interstate commerce.9 The NDA document for non-antibiotic drugs has five sections—clinical, chemistry, statistics, biopharmaceutics, and nonclinical.10

Applications to the FDA from drug manufacturers requesting permission to market a new drug (NDA) are described in 21 CFR 314 as stipulated by FD&C section 505; more

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specifically, applications from these same entities to market an existing drug for a new indication are described in 21 CFR 314.54. Since DE had not yet been approved for marketing in the US, this particular NDA was governed more generally by 21 CFR 314.11

Information made available at meetings. A guidance document published in February, 2000, by the agency, spelling out the particulars requested of sponsors prior to formal meetings with the FDA, specifies that the type of meeting be categorized as A, B, or C, and that information regarding the purpose of the meeting, proposed topics to be discussed, and a list of those to be in attendance be included in briefing documents provided all attendees and available at least two days prior to the meeting. This meeting fell into neither category A nor B and therefore must be classified as a type C meeting 12

associated not with a drug that has stalled in the approval process (A) or as a pre-NDA request for guidance (B) but in association of a potential blockbuster drug with the NDA for an indication other than one that had been previously approved around the world13—anticoagulation treatment for those with atrial fibrillation at risk for stroke and thromboembolic events, rather than association with orthopedic surgery. Draft documents pertaining to the meeting were, indeed, published exactly two days prior to the meeting at www.fda.gov, and extensive final briefing documents summarizing the major clinical trials on which the NDA was based, as well as competing issues and arguments relevant to the NDA, had been photocopied and were available on tables as attendees entered the hotel ballroom.

Personal considerations. This was my first visit to a federal meeting other than sessions of the House and Senate. I arrived a half hour after presentations had begun because of bumper to bumper traffic caused by construction in the Washington, DC, sections of Interstates 95 and 495, but since all of the presentations planned for the session were available on paper for attendees as they entered the ballroom, I missed nothing substantive in the meeting. I am also a former University of Pennsylvania School of Medicine clinical cardiac electrophysiology research coordinator, well versed in the issues that were taken up in the meeting relating to dabigatran.

(The only drawback of the meeting for me was that in trying to save money by staying overnight the night before the meeting at the Baltimore Hostel, I failed to sleep a minute of the night and felt hung over throughout the next day and evening, unable to cheerfully greet two cardiologists at the meeting I knew well from my years at Penn. I was alert during the meetings and took careful notes, but physically felt by no means healthy.)

Logistics. The moderator and acting chair of the FDA committee, A. Michael Lincoff, MD, and a patient representative, Thomas Simon, faced the audience in the middle of the bottom segment of an inverted U; the sponsor’s representatives, Dr. Salim Yusuf, sat to the moderator’s left, and the FDA and its representatives, psychometrician Kevin Krudys and physicians Drs. Aliza Thompson, Steven Nissen, Sanjay Kaul, and Robert Temple sat to his right.14 Two microphones stationed on the far right and left sides of the room were shared by FDA and sponsor representatives alike. All on-the-record discussions were videotaped by two manned cameras posted at the midway point between the speakers’ platform and the last row in the audience.

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Agenda. After introductions of the main presenters, presentations by BI representatives proceeded. An introduction was provided by Dr. Christopher Corsico, medical director of BI. Corsico’s introduction was followed by McMaster Medical School professor Stuart Connolly’s description of the clinical trial design of RE-LY and BI cardiologist Dr. Paul Reilly’s outline of DE safety findings obtained through Phase I, II, and III studies.15 The longest morning presentation (90 minutes) belonged to Dr. Salim Yusuf, another McMaster professor, PHRI associate, and DE proponent, who summarized RE-LY exhaustively and afterwards answered questions from the FDA and patient advocate Thomas Simon, sitting next to the moderator.

After a twenty minute coffee break, Drs. Aliza Thompson and Robert Temple, FDA cardiologist and medical director, respectively, summarized RE-LY’s efficacy and net clinical benefit findings and remained near the microphone for the rest of the morning, occasionally answering questions. The morning session began at approximately 8:25 am and lasted with one twenty-minute break until after a half-hour period of questions for the presenters in a lunch break that began at 12:20 pm. Since no one from the public had asked to address the meeting, the FDA’s reply presentations, led by pharmacometrician Kevin Krudys and Dr. Thompson, began immediately after lunch at 1:40 pm and lasted until after another half-hour period of questions at 5:00 pm, at which time a vote was taken regarding the committee’s endorsement of dabigatran’s NDA for patients with AF.16

The meeting’s discussion was spirited, perhaps because in the comparison under discussion, the patient couldn’t lose; warfarin has been considered an effective drug, albeit with its problems, since before most of the people in the room had been born. The study drug’s proponents, both with PHRI and the FDA, were openly enthusiastic about dabigatran and its NDA, mainly because it is widely acknowledged that RE-LY, the clinical trial basis of the NDA, had been unusually well conceived, designed, and executed. DE was approved in 2008 in 75 countries, including Europe and Canada, on the basis of Phase III trials of the drug for prevention of TE events following orthopedic surgery,17 and RE-LY results on more than 18,000 patients were published on September 17, 2009, in the widely respected New England Journal of Medicine.18 Yet the meeting touched upon every possible aspect of the drug’s pharmacodynamics and –kinetics, and the committee’s final verdict, 9-0 endorsing the drug,19 was both well deserved and comprehensively grounded in scientifically tested clinical success.

SCIENTIFIC BACKGROUND: DABIGATRAN AND ATRIAL FIBRILLATION

Atrial fibrillation. Atrial fibrillation (AF)—the non-regular (arrhythmic) beating of the upper chambers of the heart in an inefficient means of forcing blood from the vena cavae and pulmonary veins into the right and left ventricles for expulsion and subsequent oxygenation into the lungs20—is the most common cardiac arrhythmia, found in one-third of all patients presenting for hospitalization with cardiac arrhythmias. More than two million people in North America and 4.5 million in Europe have AF. The incidence of the arrhythmia increases with age, and 10% of all people between 80 and 90 years of age,

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according to the well-known Framingham Study,21,22 have AF. Patients with atrial fibrillation are five times as likely as those without AF to suffer stroke, and 15% of all strokes are due to AF, with such strokes being more severe than in those without AF. Patients with AF are also more likely to suffer other types of thromboembolic events in the absence of anticoagulation.23

Comparator drug. Warfarin, a vitamin K antagonist (vitamin K is required in the body’s coagulation cascade), the current drug of choice to prevent CVA and TE in patients with AF, is awkward to use, not only because it interacts harmfully with metabolism of high-K foods and therefore requires severe dietary modification but because it requires weekly monitoring of the prothrombin time (a measure that correlates inversely with blood clotting tendency) to guard against over- or under-anticoagulation, greatly heightens the risk of fatal cerebral hemorrhage, and only achieves optimal therapeutic efficacy less than two-thirds of the time due to non-compliance or inadequate therapeutic blood levels.24

Aspirin (ASA) is sometimes used in AF patients but is less effective at preventing CVA and therefore is recommended only for those AF patients at low risk for CVA.25 A better alternative to warfarin has long been sought by cardiologists for these reasons.

Dabigatran. Boehringer Ingelheim Pharmaceuticals, Inc.(BI), developed dabigatran etexilate (DE) as an oral prodrug—a molecule that precedes a drug metabolically—that is rapidly metabolized in the liver by serum esterases into dabigatran, a molecule that preferentially binds to thrombin (it is a “competitive inhibitor” of thrombin)--the coagulation cascade’s central component--that after its conversion from prothrombin breaks down soluble fibrinogen into insoluble fibrin, preventing thromboembolic events including CVA. Eighty percent of the given DE dose is excreted without causing local toxicity by the kidneys (except in the instance of pronounced kidney failure, when the drug accumulates in the tissues and is potentiated) (the remainder in the feces), and its serum half-life is 12 to 17 hours, meaning that it can safely and effectively be administered once or twice daily.26

Earlier clinical trials. According to the sponsor, BI, in its briefing document,27

“numerous” Phase I trials explored the pharmacokinetics of DE on healthy volunteers, and seven Phase II and III trials on more than 10,000 patients elucidated the drug’s ability to prevent thromboembolic events in patients undergoing major orthopedic surgery. Six thousand of these patients were administered DE and were followed from 5 to 35 days.

Another Phase III trial of 2500 subjects randomized half to double-blind, double-dummy warfarin or to DE,28 and a Phase II study of 1800 victims of acute coronary syndrome, 1400 of which took DE--the RE-DEEM trial--showed promising results at 4 different doses of DE combined with clopidogrel (trade name Plavix, a platelet-adherence antagonist).29

Other Phase III randomized, double-blind trials measured DE’s ability to prevent thromboembolic events following orthopedic surgery at doses of 150mg and 220mg or at 220mg with enoxaparin, achieving results that won the drug worldwide approval for use

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in conjunction with total hip and knee replacement operations.30 Further Phase III studies are planned to win NDA approval for this indication in the US.

RE-LY. RE-LY, a huge Phase III clinical trial (20% larger than initially conceived), was begun at the end of December, 2005, to settle the drug’s claim to safety and efficacy at BID (twice daily) doses of 110mg and 150mg among more than 18,000 (18,113) AF patients.31

When in a previous Phase III trial the drug was administered once a day in a double dose, the frequency of major bleeding increased sixfold, leading the sponsor to drop plans for a once-a-day version.32

RE-LY is a “non-inferiority” trial (long term followup continues), as both the sponsor and FDA emphasized at the outset of the meeting and throughout its course.33 That is, the drug’s superior safety and compliance profile established by Phase I-II studies in comparison to the incumbent medication, warfarin, required the Phase III RE-LY study only to demonstrate that the new molecule is at least as effective at preventing stroke and TE as warfarin and not that it is superior or more effective to warfarin for these purposes.

THE CLINICAL BASIS OF NDA 22-512: RE-LY 34

Clinical trial design of RE-LY.18,113 patients recruited from 951 clinical centers in 44 countries who had both atrial fibrillation and a heightened risk of suffering stroke were randomized in single-blinded fashion (without the patient knowing which arm of the study he was participating in) to 110mg or 150mg BID of dabigatran etexilate or, in unblinded fashion (because caregivers were required to monitor every patients prothrombin time) to patient-adjusted doses of warfarin to achieve a therapeutic international normalized ratio (INR) (an index of the blood’s clotting tendency) of 2.0 to 3.0, with an intent-to-treat (patients were only included in the study’s statistical analysis to the extent that they received the treatment to which they had been randomized; otherwise they were omitted). The median duration of followup was 2.0 years, and the primary endpoints (outcomes undergoing primary statistical analysis) of the study were either stroke or systemic thromboembolism. Complete followup was achieved in 99.9% of patients, and only twenty were lost to followup. The study drug was discontinued by 10.2% of those on warfarin, 14.5% of those on 110mg dabigatran BID, and 15.5% of those taking 150mg dabigatran BID. The mean percentage of the study period during which those patients on warfarin were within the INR was 64%, a rate very comparable to typical daily practice.

Results. Rates of the primary outcome (combined CVA and TE) were 1.69% in the warfarin group and 1.53% (110mg BID)(p<0.001 for noninferiority) and 1.11% (150mg BID)(p<0.001 for superiority) in the dabigatran group, respectively.

The rate of major bleeding (AE) in the warfarin group was 3.36%, 2.71% in the dabigatran 110mg BID group (p=0.003), and 3.11% in the dabigatran 150mg BID group (p=0.31). The rate of hemorrhagic stroke (AE) was 0.38% per year in the warfarin group,

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0.12% per year in the dabigatran 110mg BID group (P<0.001), and 0.10% per year for the dabigatran 1502mg BID group (p<0.001).

The rate of myocardial infarction was 0.53% per year (0.6% overall) among those on warfarin and higher among those on dabigatran: 0.72% on 110mg BID (1.2% overall)(p=0.07, marginally significant) and 0.74% on 150mg BID dabigatran (1.8% overall)(p=0.048, significant).

Mortality was 4.13% per year in the warfarin group, 3.75% with dabigatran 110mg BID (p=0.13), and 3.64% per year with dabigatran 150mg BID (p=0.051).At 95% confidence intervals, these statistics indicated that the lower dosage of DE was as effective as warfarin in preventing stroke and thromboembolism (noninferior) and that the higher dose was clearly superior to the incumbent medication at achieving these parameters.

The lower dose of DE was significantly less frequently associated with major bleeding (2.71% vs. 3.36%) and the higher dose was noninferior to warfarin in this respect (3.11% vs. 3.36%), while both doses of DE offered significantly better protection against hemorrhagic stroke than warfarin (0.12 and 0.10% vs. 0.38%).

There were increases in the risk of myocardial infarction (heart attack) on DE that neither the study’s sponsors nor the FDA could explain—36% at 110mg BID (marginally significant) and 40% at 150mg BID (significant).

The lower dose of DE was noninferior to warfarin with respect to mortality, while the higher dose was superior to warfarin in this respect (results of 0.051 rounded to two decimal places).

In net clinical benefit—an overall measure of the drug’s effectiveness at preventing major vascular events, major bleeding, and death—the study drug was significantly superior to warfarin at the higher dose—6.91% per year versus 7.64% per year (p=0.04)—and noninferior to warfarin at the lower dose (7.09% per year; p=0.10).

REGULATORY CONSIDERATIONS : RE-LY

Size of patient population. While the FDA suggests that patient populations of 1500 are sufficient for many and perhaps most Phase II trials,35,36 certain circumstances justify much larger studies and in some cases make larger studies preferable to smaller ones. An International Conference on Harmonisation’s (ICH) guidance states that when the indication under study is not life-threatening, or when an “active, positive control” that is already available and effective at preventing that life-threatening disease, condition, or event, as warfarin is in the present study, larger databases may be useful in elucidating aspects of a drug’s effect on diverse medical conditions and its interactions with concomitant drugs to an extent only possible with very large populations. The use of warfarin as an active positive control enabled RE-LY “to show the efficacy of the test treatment is as good as the known treatment” (noninferior at preventing stroke and TE) at

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the lower dose of dabigatran as well as to show “the superiority of the test treatment over the active control” (at preventing stroke/TE events) at the higher dose of the medication.37

RE-LY’s large patient population also confers another advantage on the study, touched upon by the ICH’s E1A guidance.38 There are certain situations in which the incidence of a particular adverse event or endpoint in the trial is so small, such as stroke or thromboembolism in RE-LY when the active control is as effective a drug as warfarin, that only large population studies will result in frequencies of the study’s endpoints on the control medication that are statistically significant enough to measure.

The study also illustrated another aspect of studies the ICH mentions in E1A that was not expected: the unmistakable association of dabigatran administration with higher incidences of myocardial infarction over long-term followup may only have been observable in such a large, diverse, and statistically typical patient population over a comparatively generous term of followup (four years) because the disease’s progression is slow and associated with so few patients taking either warfarin or dabigatran on a chronic or long-term basis.39

Clinical study design. RE-LY is accurately classified as a Phase 3 study according to the ICH.40 Its primary objectives were to “demonstrate or confirm therapeutic benefit” of the study medication “for its intended indication and patient population”, confirming the preliminary evidence made available in Phase 2. Such studies “may also further explore the dose-response relationship (or) its use in a broader patient population.” By concomitantly studying dabigatran at two different doses and in its broadest patient population to date, RE-LY met these two criteria for large clinical trials as well.

RE-LY also meets the ICH and FDA standards for “pivotal” single clinical trial studies (SCT) because of its patient population size, the large number of study centers and cooperating principal investigators, its consistency across study subsets, the large number of primary and secondary endpoints evaluated, and its statistically powerful findings.41

Such SCT’s have in recent years become the norm among large pharmaceutical company-sponsored clinical trials,42 perhaps because a well planned SCT can save the sponsor valuable time and money by expediting the drug approval process.

Pivotal studies. Higher standards must be met by “pivotal” trials than by other studies, and RE-LY more than meets the FDA’s four main criteria for such studies.43

(1) In meeting the criteria for PROBE44 studies, RE-LY was well controlled . Since an effective active control, warfarin, was both cheap and readily available, the study could exclude all patients not at risk for stroke or thromboembolism and focus exclusively on the patient population targeted by the incumbent medication. Use of this population obviated the need to further control the study through use of a placebo, which in any case had been studied in Phase I and II trials.45

(2) RE-LY was blinded, but only to the extent that it could be blinded and, argued FDA statistician Emerson, medical director Temple, and BI proponent Yusuf,

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only to the extent that it could be optimally blinded. Because administration of warfarin requires weekly prothrombin time tests and dabigatran does not, only the dabigatran arm of the study was blinded to the clinicians, while both sets of patients were blinded to the medication they were taking. Such a study is called a “single-blinded” study and in this case also a “hybrid” study (because one arm was clinician-blinded and the other was not) whose design was questioned by members of the committee (see below) without actually causing these members to deny the strength, applicability, or generalizability of the study’s findings or deny dabigatran’s approval.46

(3) Although Dr. Steven Nissen repeated his doubts about the validity of the study’s randomization (see below), RE-LY appears to have been rigorously randomized to one of three arms—treatment with 110mg BID of dabigatran; treatment with 150mg BID of dabigatran, or treatment with patient-adjusted doses of the control drug, warfarin. Nissen’s allegations were hypothetical and it is impossible to confirm or deny whether the known effectiveness and safety profiles of either drug allowed clinicians to handpick what patients would belong to each arm. Certainly, those experienced at participating in clinical trials should have known that any such expressed bias would invalidate the study and waste large sums of time, money, and patient compliance, so we should hope that such bias was absent from RE-LY.

(4) Finally, RE-LY was even larger in size than its designers might have hoped for.47

Originally estimated to include 15,000 patients, the study’s statisticians advised the number be raised to 18,000 to enhance the value of the study’s findings relating to its endpoints of low incidence, stroke and thromboembolism, on an effective control medication.48

Additional useful characteristics of the study. Other aspects noted by the FDA in its regulations to be characteristic of “adequate and well-controlled studies” enhanced RE-LY’s reputation, underscored the significance of its findings, and sped the committee’s endorsement of dabigatran:49

(1) The study was published in The New England Journal of Medicine which (say what one wants to say about it) continues to be one of the most respected, widely-read, and effectively edited medical periodicals in the world, whose standards of writing clarity are among medicine’s highest.

(2) The study’s three-arm design and large number of patients in each group “permits a valid comparison” with “a quantitative assessment” between the study drug and the control regarding both efficacy and safety.

(3) Patients were selected according to inclusion and exclusion criteria that ensured study patients possessed the condition(s) being studied (AF, risk for CVA and TE events).

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(4) RE-LY’s authors insisted repeatedly that their “method of randomization minimized bias and assured the comparability of groups with respect to variables pertinent to the endpoints of the study (age, sex, severity of disease, duration of disease, and concomitant medications)”, and, indeed, statistical analysis summoned during the meeting pointed to no significant differences among the three trial arms in any of these variables.

(5) “Adequate and reliable methods for objectively assessing subjects’ responses” during followup were available throughout the study, which was notable for the exceedingly small percentage of patients completely lost to followup (0.1%). While small numbers of patients were evaluated for outcomes based only on telephone followup, the vast majority continued to be followed in regular patient visits to the investigating doctor’s office.

DISCUSSION

Randomization. The most persistent critic of RE-LY at the meeting was Dr. Steven Nissen, a committee member, who persisted during the meeting’s first two hours (very probably playing devil’s advocate in light of the meeting’s outcome) in casting doubts on the study’s validity by citing the possibility of ascertainment bias--the likelihood that patients were not really randomly assigned to either warfarin or dabigatran but classified by study physicians, either consciously or subconsciously, on the basis of their relative risk of major bleeding or stroke. Nissen, a temporary voting member, repeatedly returned to the superiority of truly randomized and double-blinded studies over RE-LY, which had a “hybrid” or “probe” (prospective, randomized, open, blinded endpoint”) design 50,51—i.e., it was randomized but only single-blinded due to the need for periodic monitoring of all warfarin arm patients. For reasons of ascertainment bias, said Nissen early on, he could only agree with the study drug’s noninferiority claim at the higher dose, stating that its superiority claim could not confidently be established by the results. Yet at the meeting’s conclusion, Nissen voted with the other eight voting members in unanimously endorsing NDA 22-512, based on RE-LY’s “robust” results,52 and leaving the issue of the two doses up to the manufacturer.

“Optimal” hybrid randomization. Drs. Robert Temple, CDER medical policy director, and Scott Emerson, the committee’s leading biostatistician, key proponents of DE, offered another interpretation of the study’s blindedness, one that was immediately taken up by others and eventually seemed to be shared by virtually everyone: that true blinding of the study would have required prothrombin time monitoring of both dabigatran and warfarin, leading to resentment by staff members of the difficulties of both drugs and introducing an element of bias (against DE efficacy and compliance) never actually present in reality. Instead, said Temple, the study’s actual design mirrored real-life therapeutic conditions, with the incumbent drug requiring all of the effort and causing all of the resentment and difficulties that it normally does and with the study drug completely free of them. The study, in other words, was a far better test of both medications, and in particular of the efficacy of both medications, than a truly double-blinded study would have been. Committee member Sanjay Kaul voiced his agreement

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immediately. Then, in a statement near the end of the day-long session, acting chair Lincoff allied himself with this position and surprised everyone (or at least me) by giving his unambiguous assent to the drug’s superiority claim even before the committee had come to a vote, making the meeting’s outcome all but certain.

Validation. Just to make sure the blinding mechanism used did not, in fact, bias adjudication (clinical classification) of events, in what is called a “validation procedure”53

the study did pair two smaller, double-blinded groups on dabigatran and warfarin and observed no significant differences in outcome or characteristics between the double-blinded and larger, single-blinded groups. Revelation of this precaution by Dr. Yusuf during his morning presentation mollified Dr. Nissen and caused the meeting to veer sharply away from considering his claim of ascertainment bias after the meeting’s first two hours.

Multiple dose arms. The fact that RE-LY was organized around the evaluation of two dosages of the study medication rather than one was also praised by the committee. The earlier Phase I-II studies had established good safety and efficacy at 150mg BID but higher risk profiles for major bleeding at 220mg BID, causing the sponsor to decline further study of the highest dosage. Committee members agreed that when they first read the RE-LY protocol, they doubted the value of studying two dose regimens so close in number of milligrams to each other, but said that the results clearly vindicated the choice of the two regimens and made the job of understanding the therapeutic value and pharmacodynamics of the medication that much easier.

Adverse events I: dyspepsia. Since the drug only acts at lower pH, it is manufactured around an acidic core that causes dyspepsia and leads to medication discontinuation in a higher proportion of patients than that seen with warfarin (11.8% on DE 110, 11.3% on DE 150 vs. 5.8% on warfarin; p<0.001). No one disputed these results and, surprisingly to my mind, no one either offered to reject the medication on their basis or proposed a solution to the clinical problem. Dr. Yusuf suggested in his presentation that many discontinuations very likely took place because the comparator drug, warfarin, was so well known and commanded such confidence that clinicians were quicker to discontinue dabigatran than they would have been with a lesser comparator medication.54 I myself wondered if concomitant antacid therapy later in the twelve-hour therapeutic period might somehow be combined with successful administration of the drug but came to no conclusion, not knowing how long the drug remains in the gut before being metabolized and/or passing to the duodenum, nor quite clear on whether the drug’s efficacy requires an acid gut medium throughout its duration of action or not.

Adverse events II: myocardial infarction. Clearly the most damning and potentially transforming result of RE-LY was dabigatran’s statistically significant and physiologically inexplicable association with higher rates of myocardial infarction in comparison to warfarin. Three times as many patients suffered MI on the higher doses of DE as on patient-adjusted levels of warfarin. Whether this was due to the effect of DE on MI, on the protective effect of warfarin against MI, or of chance could not be determined. Many studies of warfarin, including the large WARIS II trial,55 established the drug’s

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tendency to prevent MI, which would explain the lower rates of MI in comparison to DE if the latter confers no such advantages. But other studies of DE, such as RE-COVER56

and RE-DEEM,57 suggested the drug neither increased risk of MI nor promoted acute coronary syndrome.58

In studies of a drug different from but chemically similar to DE—ximelagatran (XG), also an oral, direct thrombin inhibitor--more coronary artery disease-related (CAD) adverse events were observed in short-term studies of TE prevention than with warfarin, but longer-term studies of XG—notably SPORTIF III59 AND SPORTIF V60--were inconclusive with respect to CAD. One Phase II study of XG actually suggested that the drug prevents CAD-related AE.61

If the finding of higher risk for MI is in fact related to DE, two more patients out of every thousand treated each year with DE for AF will suffer MI compared to warfarin. The committee and its presenters were convinced that the clear superiority of the drug over warfarin in achieving its therapeutic aims, also achieving significantly lower rates of major bleeding—warfarin’s main danger—outweighed the drug’s still-unproven association with MI. It advises clinicians and future investigators to keep a watchful eye on patients at risk for MI, and require the higher rate of MI achieved in RE-LY to be included in the drug’s new label.62 Yet if I were a cardiologist treating an AF patient with demonstrated CAD who is therefore at considerable risk for suffering MI--especially if he exhibited reduced risk of stroke or major bleeding due to well controlled blood pressure--I would take the additional precaution and undergo the additional trouble to keep him on warfarin due to its demonstrated prevention of MI. This opinion was not volunteered by anyone during the meeting.

Patient considerations. In a question and answer session following the sponsor’s morning presentation, patient advocate Thomas Simon grilled Dr. Yusuf on matters relating to the administration of the drug in clinical practice. “How exactly should the drug be administered in a BID manner?” Simon asked. “The drug can be taken with either water or food,” Yusuf replied. “What if the patient misses a dose?” “With only a 12-17 hour half life, such an event could have an impact on the drug’s ability to prevent stroke and TE,” replied Dr. Yusuf, “so the dose should probably be taken as soon as possible, subject to circumstances.” “Do we know anything about the drug’s potential for long-term toxicity?” asked Simon. “Only up to our study’s four-year followup period,” was the answer. “How could a clinician seeking to monitor the drug’s effect on his patient do so, even though such action is not required?” “None of the patients in RE-LY were monitored,” said Dr. Yusuf, “but the APTT (activated partial thromboplastin time) and thrombin time tests would be the most sensitive means of measuring the drug’s pharmacokinetics and pharmacodynamics on an individual patient, while the measurement of INR would be less sensitive with this drug.”

Questions for the sponsor. A member of the FDA told Yusuf he wanted “Kaplan-Meier curves comparing ‘time to MI’, ‘time to MI-stroke-or cardiovascular death’, ‘time until drug discontinuation’, and ‘time until first gastrointestinal (GI) bleed’” in order to better measure the totality of the drug’s benefit to its risk. “We don’t have such curves,” replied Dr. Yusuf, and everyone laughed. (Myocardial infarction was only a “secondary outcome” in RE-LY. When I myself was studying the comparative value of

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subendocardial resection (an operation that surgically removes an arrhythmia substrate of ventricular tachycardia) versus non-surgical pharmaceutical treatment for ventricular tachycardia between 1985 and 1990, I did calculate “time until MI”, “time until first recurrence of VT”, and “time until first cardiac arrest”, and a cardiology fellow I worked with exclaimed how useful my database therefore could be. But pharmaceutical companies must meet stockholder demands that studies save money and time as well as be effective, and thus such data luxury items such as were asked of Dr. Yusuf had to be omitted in favor of studying DE’s preventive effect on thromboembolic events, its therapeutic purpose in patients with AF.)

Another FDA representative asked the study’s proponents what the clinician should do if he finds bleeding, swelling, or hyptertension associated with administration of DE. “Discontinue the medication or try a lower dose, since it is known that GI bleeding is dose-related with dabigatran,” answered Dr. Yusuf, alluding to the Phase III study noted above (see page 5) in which higher doses and once-a-day administration were each associated with higher incidences of major bleeding. “Both aspirin and proton pump inhibitors [gastric reflux inhibitors such as Prevacid and Prilosec] have also been shown to raise the incidence of GI bleeding, while occurrences of dyspepsia [in association with DE] are not associated with such bleeding.”

After the main FDA speakers had spoken, a laundry list of questions written down for the FDA prior to the meeting were flipped through in a few minutes by moderator Lincoff, as all of the questions had already been taken up and answered exhaustively in the day’s preceding discussion.

Dose-response analysis at multiple doses. With dabigatran’s stroke-preventive efficacy established as superior to the incumbent comparator medication and indications the drug was superior in safety (risk of bleeding) only at the lower dose of 110mg BID and only noninferior in safety at 150mg BID, the main question in the afternoon sessions concerned the comparative utility of the two doses and specifically, whether the lower risk of major bleeding to be found at 110mg BID and the higher dose’s superior prevention of stroke/TE and inferior AE profile make it advisable to prescribe the lower dose in the elderly, who are at greater risk of major bleeding. To answer this question, net benefit analysis was summoned by Aliza Thompson and exposure-response analysis described by psychometrician Kevin Krudys to prove that the 29% better protection against life-threatening stroke at the higher dose (150mg BID) compared to the lower dose and the negligible difference in tendency to life-threatening major bleeding between the doses means that “there is no clear advantage to administering dabigatran at 110mg BID in the elderly despite their higher risk for bleeding because of the drug’s superior stroke/TE prevention, which would be compromised at the lower dose without accompanying reductions in risk of major bleeding.” 63

Availability. How soon dabigatran etexilate will become available for prescription by physicians, and what it will cost consumers, are both unknowns at this time. The FDA is set to vote on the drug’s approval on October 19, 2010.64 The possible $4-8 price per pill mentioned in the presentation was said by Dr. Lincoff to be “the elephant in the room” to

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which no one wanted to draw attention, and no dates of planned manufacture or release were made available at the meeting. What is known is that other companies have also been conducting clinical trials on potential replacements for warfarin, and that these medications--Pfizer’s apixaban, JnJ’s rivaroxaban, Daiichi-Sankyo’s edoxaban, and Merck’s betrixaban--will also soon result in NDA’s, potentially preventing BI’s dabigatran from having a monopoly on the AF indication very long.65

Final thoughts: process. Certainly one takes away from this meeting the impression that the drug evaluation process as currently conducted by the U. S. Food and Drug Administration is at least as painstaking as the clinical development process that the pharmaceutical companies themselves conduct; that representatives of the FDA are at least as skillful at raising important questions and answering them as representatives from industry, and very probably better; that the friendly, adversarial relationship between sponsor and FDA ultimately works to each’s benefit; that some of medicine’s best minds are now employed both by pharmaceutical companies and the federal government’s watchdog agencies, assuring that suitable new compounds are swiftly and accurately funneled through the drug development and clinical evaluation pipeline so that patients benefit from them as rapidly as practicable; and, perhaps most importantly, that working in the clinical research industry or for the FDA is potentially one of the most profound, useful, and far-reaching ways a good mind inclined to medicine, law, or statistics can be employed to benefit humanity, searching for new ways to alleviate suffering and helping improve and prolong life worldwide.

NOTES

1. Center for Drug Evaluation and Research, Food and Drug Administration. Briefing Document. Cardiovascular and Renal Drugs Advisory Committee Meeting, Dabigatran (NDA 22-512), September 20, 2010.

2. Stiles, Steve. “Warfarin, Move Over: Dabigatran Gets Unanimous Thumbs-Up From FDA Advisory Panel.” Heartwire, September 21, 2010. Internet, http://www.medscape.com/viewarticle/729002.

3. “A dose response study of dabigatran etexilate (BIBR 1048) in pharmacodynamics and safety in patients with non-valvular atrial fibrillation in comparison to warfarin.” Clinical Trial #NCT01136408. http://clinicaltrials.gov/ct2/show/NCT01136408.

4. Kasper DL et al. Harrison’s Principles of Internal Medicine, 16th edition. New York: McGraw-Hill Medical Publishing, 2005, 1301-1494. The standard text and reference source of internal medicine and the source of medical principles and terminology for succeeding references in this paper.

5. “Warfarin.” The Physician’s Desk Reference, 64th edition, 2010.

6. Connolly SJ et al. “Dabigatran versus warfarin in patients with atrial fibrillation (RE-LY).” The New England Journal of Medicine 2009; 361:1139-51.

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7. Brown-Tuttle, Meredith, ed. Fundamentals of US Regulatory Affairs, 5th edition. Rockville: The Regulatory Affairs Professionals Society (RAPS), 2007, 2-6.

8. The U. S. Code of Federal Regulations 21 CFR 312.47a. Internet, http://www.edocket.access.gov/cfrac.

9. RAPS, 99.

10. RAPS, 100.

11. 21 CFR 314.

12. RAPS, 28.

13. Boehringer Ingelheim Pharmaceuticals, Inc. “Dabigatran etexilate vs enoxaparin in prevention of VTE post total knee replacement.” Clinical Trial # NCT00152971, 2005. Internet, http://clinicaltrials.gov/ct2/show/nct00152971. In briefing document.

14. Center for Drug Evaluation and Research, Food and Ddrug Administration. Draft Meeting Roster. Cardiovascular and Renal Drugs Advisory Committee Meeting, Dabigatran (NDA 22-512), September 20, 2010.

15. Center for Drug Evaluation and Research, Food and Drug Administration. Draft Agenda. Cardiovascular and Renal Drugs Advisory Committee Meeting, Dabigatran (NDA 22-512), September 20, 2010.

16. Drahl, Carmen. “Boehringer’s Blood Thinner Dabigatran (Pradaxa) Unanimously Endorsed.” Central Science, September 21, 2010. Internet, http://cenblog.org/the-haystack/2010/09.

17. Total knee replacement.

18. RE-LY.

19. Stiles.

20. Libby, Peter et al, ed. Braunwald’s Heart Disease, 9th edition. Philadelphia: Saunders, 2007. Whatever cardiology I know was made possible by reading and savoring this astonishingly well-written and inspiring text.

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21. Dawber TR et al. Epidemiological Approaches to Heart Disease: The Framingham Study. Washington, D.C.: National Heart Institute, National Institutes of Health, Public Health Service, Federal Security Agency. Presented at a Joint Session of the Epidemiology, Health Officers, Medical Care, and Statistics Sections of the American Public Health Association at their Seventy-eighth Annual Meeting, November 3, 1950, St. Louis, Missouri. In briefing document.

22. Schnabel RB et al. “Development of a risk score for atrial fibrillation (Framingham Heart Study): a community-based cohort study.” Lancet 2009, Feb 28; 373 (9665): 739-45. In briefing document.

23. RE-LY

24. RE-LY.

25. Briefing document.

26. RE-LY.

27. Briefing document.

28. Boehringer Ingelheim Pharmaceuticals, Inc. “Efficacy and safety of dabigatran compared to warfarin for 6 month treatment of acute symptomatic venous thromboembolism.” Clinical Trial #NCT00291330. Internet, http://clinicaltrials.gov/ct2/show/nct00291330. In briefing document.

29. Oldgren J et al. “Randomized dabigatran etexilate dose-finding study in patients with acute coronary syndromes (ACS), post index event, with additional risk factors for cardiovascular complications, also receiving aspirin and clopidogrel: a multi-centre, prospective, placebo-controlled, cohort dose escalation study (RE-DEEM).” #165. Presented at the American Heart Association Scientific Sessions 2009; November 14-18, 2009, Orlando, Florida. In briefing document.

30. Total knee replacement.

31. RE-LY.

32. Briefing document.

33. Boehringer Ingelheim, Inc., and the Population Institute for Health Research. Sponsor Presentation. Cardiovascular and Renal Drugs Advisory Committee Meeting, Dabigatran (NDA 22-512), September 20, 2010.

34. RE-LY.

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35. U. S. Food and Drug Administration. Plan for Accelerated Approval of Drugs to Treat Life-Threatening and Severely Debilitating Illnesses. October, 1988. In:

36. Linberg SE. Expediting Drug and Biologics Development: A Strategic Approach, 3rd edition. Waltham: Paraxel International Publishers, 2006, 139.

37. International Conference on Harmonisation’s (ICH). Choice of Control Group and Related Issues in Clinical Trials, E10, July 2000. In Linberg, 140-1.

38. International Conference on Harmonisation’s (ICH).The Extent of Population Exposure to Assess Clinical Safety: For Drugs Intended for Long-Term Treatment of Non-Life-Threatening Conditions, E1A, March 1995. In Linberg, 140.

39. ICH E1A.

40. International Conference on Harmonisation (ICH). Final Guideline on General Considerations for Clinical Trials, December 1997. In Linberg, 130.

41. Linberg, 136.

42. U. S. Food and Drug Administration. Guidance for Industry: Providing Clinical Evidence of Effectiveness for Human Drug and Biological Products. May 1998, in Linberg 136-7.

43. Linberg, 137.

44. Hensson L et al. “The prospective randomized open blinded endpoint (PROBE) study: a novel design for interventional trials.” Blood Pressure, 1992; 1:2, 113-19.

45. ICH E10.

46. International Conference on Harmonisation (ICH). Statistical Principles for Clinical Trials, E9, September 1999. In Linberg, 138.

47. U. S. Food and Drug Administration. General Considerations for the Clinical Evaluation of Drugs. In Linberg, 138-9.

48. Sponsor presentation.

49. Linberg, 139.

50. Sponsor presentation.

51. Hensson.

52. Sponsor presentation.

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53. Sponsor presentation.

54. Sponsor presentation.

55. Hurlen M et al. “Effects of warfarin, aspirin, and the two combined on mortality and thromboembolic morbidity after myocardial infarction. The WARIS-II design (Warfarin-Aspirin Reinfarction Study). Scandinavian Cardiovascular Journal 2000; 34(2): 168-71. In sponsor presentation.

56. Jo S-H et al. The RECOVER study: a randomized controlled trial. Journal of the American College of Cardiology 2006; 48:924-30. In sponsor presentation.

57. RE-DEEM.

58. Briefing document.

59. The Executive Steering Committee on behalf of the SPORTIF III Investigators. “Stroke prevention with the oral direct thrombin inhibitor ximelagatran compared with warfarin in patients with non-valvular atrial fibrillation (SPORTIF III): randomised controlled trial.” Lancet 2003; 362: 1691–98. In briefing document.

60. The Executive Steering Committee on behalf of the SPORTIF III and V Investigators. “Stroke prevention using the oral direct thrombin inhibitor ximelagatran in patients with non-valvular atrial fibrillation (SPORTIF V).” Cerebrovascular Disease 2006; 21: 279–293. In briefing document.

61. Briefing document.

62. Beasley N. Addendum to the Clinical Review for NDA 22-512. Center for Drug Evaluation and Research, Food and Drug Administration. Cardiovascular and Renal Drugs Advisory Meeting, Dabigatran (NDA 22-512), September 20, 2010.

63. Cardiovascular and Renal Drug Advisory Committee, Center for Drug Evaluation and Research, Food and Drug Administration. FDA Presentation. Cardiovascular and Renal Drugs Advisory Committee Meeting, Dabigatran (NDA 22-512), September 20, 2010.

64. Drahl.

65. Stiles.

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