Xarelto Media Report 9/28/16

U.S. Coverage - Trade Outlets

1. Johnson & Johnson hid faulty device concerns during key Xarelto study: BMJ

   Sep 29, 2016 | FiercePharma

   By Carly Helfand
   
   
   Last year, results from a key trial of Johnson & Johnson and Bayer’s Xarelto came into question, as investigators had used a later-recalled monitoring device. But now, the British Medical Journal says the companies knew about the device concerns while the trial was ongoing and did not notify trial monitors or regulators.
2. More Blasts Of Concern Over ROCKET-AF

   Sep 28, 2016 | Cardio Brief

   By Larry Husten
   
   
   A new investigation published in the BMJ raises more troubling questions about the ROCKET-AF trial, which compared the novel oral anticoagulant rivaroxaban (Xarelto, Johnson & Johnson) to warfarin in patients with atrial fibrillation. The controversy about the trial first unfolded last fall when it became known that the portable Alere devices used to monitor and calibrate warfarin usage in the trial were seriously defective. Since then investigators, industry, regulators, and critics have been trying to assess whether the defective devices compromised the findings of the trial.
3. Were Problems With the Point-of-Care Device Used in ROCKET AF Kept From the FDA? BMJ Says Yes

   Sep 28, 2016 | TCTMD

   By Todd Neale
   
   
   Soon after the ROCKET AF trial evaluating rivaroxaban began enrolling patients, study investigators started expressing concerns about the accuracy of the device that was being used to measure international normalized ratio (INR) values, eventually leading drug maker Janssen to initiate a safety program to check the readings, according to an investigation by the BMJ.
4. ROCKET AF Trial of Rivaroxaban Again Called into Question

   Sep 28, 2016 | Journal Watch

   By Amy Orciari Herman
   
   
   Janssen, the pharmaceutical branch of Johnson and Johnson, knew that a point-of-care device used for measuring international normalized ratio was giving falsely low readings during the ROCKET AF trial, aBMJ investigation finds. In ROCKET AF, published in the New England Journal of Medicine in 2011, the oral anticoagulant rivaroxaban was associated with less intracranial and fatal bleeding compared with warfarin in patients with atrial fibrillation. The trial's findings, which led to rivaroxaban's approval, have since come under scrutiny — in part because the INRatio device was later recalled over its poor accuracy. (INRatio's misleading results, some say, may have made rivaroxaban seem safer than warfarin.)

International Coverage - Trade Outlets

5. Johnson & Johnson failed to inform FDA over faulty blood testing device in Phase III trial

   Sep 29, 2016 | PharmaFile

   By Ben Hargreaves
   
   
   The British Medical Journal, after its own investigation, found that Janssen knew early into the Phase III trial, known as the ROCKET AF trial, that the blood testing device used to test an anti-clotting drug was not working correctly. The trial was for the blockbuster drug Xarelto (rivaroxaban), which was pitted in the trial against warfarin.
6. Manufacturer failed to disclose faulty device in rivaroxaban trial

   Sep 28, 2016 | BMJ

   By Deborah Cohen
   
   
   A drug manufacturer knew about problems with a blood testing device but did not share data before the crucial approval process, an investigation by The BMJ has found. Janssen, the pharmaceutical arm of Johnson and Johnson, withheld data from the Food and Drug Administration about problems with the INRatio device, which was used in the phase III trial (ROCKET AF) of the blockbuster anticoagulant.
7. Novel oral anticoagulants for atrial fibrillation

   Sep 28, 2016 | BMJ

   By Kamal R. Mahtani and Carl Heneghan
   
   
   Warfarin reduces the risk of stroke in patients with non-valvular atrial fibrillation but has limitations: a narrow therapeutic window, the need for regular monitoring, and risks of bleeding and drug-drug interactions. Partly because of these limitations, novel oral anticoagulants (NOACs or non-vitamin K antagonists) have emerged, including direct thrombin inhibitors, such as dabigatran, and factor Xa inhibitors, such as rivaroxaban. These drugs do not need routine monitoring and are subject to fewer drug-drug interactions. Both have evidence of cost effectiveness in stroke prevention,1 and in 2014, the UK’s National Institute for Health and Care Excellence (NICE) recommended that dabigatran and rivaroxaban should be considered as an “option for the prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation.”2
8. Commentary: Diagnostic devices in clinical trials have high stakes for patient care

   Sep 28, 2016 | BMJ

   By Vinay K Rathi and Karlan M Krumholz
   
   
   The widely used anticoagulant rivaroxaban (Xarelto) has become the centre of considerable scientific and regulatory dispute. A key clinical trial supporting US Food and Drug Administration (FDA) approval was recently found to have used faulty point-of-care devices for monitoring international normalised ratio (INR).1 2 This ongoing episode provides important insights into regulation challenges for diagnostic devices and the far reaching effects these devices have on clinical research and patient care.
9. BMJ accuses pharmaceutical firm Janssen of withholding drug trial data

   Sep 28, 2016 | Press Association

   A pharmaceutical giant has been accused of withholding trial data from a medical regulator. The British Medical Journal (BMJ) alleged that Janssen, the pharmaceutical arm of Johnson and Johnson, "withheld" data from the US Food and Drug Administration (FDA) about a faulty blood testing device used during a trial for anti-clotting drug rivaroxaban, also known as Xarelto.
10. Pharma withheld faulty device info in rivaroxaban trial

    Sep 28, 2016 | OnMedica

    By Louise Prime
    
    
    Janssen withheld data from the US Food and Drug Administration (FDA) about a faulty device used during one of the crucial trials into using rivaroxaban (Xarelto) to prevent stroke in people with non-valvular atrial fibrillation, a BMJ investigation* has revealed this morning. It found that some trial investigators had raised concerns early on about the faulty international normalised ratio (INR) measuring device – and the BMJ is now asking whether the evidence can be trusted at all.
11. Drug company failed to disclose faulty blood testing device in trial of popular medicine

    Sep 28, 2016 | iNews

    By Paul Gallagher
    
    
    The pharmaceutical arm of Johnson and Johnson, one of the world’s biggest drug companies, withheld information about a faulty blood testing device used in a key trial of a best selling anti-clotting drug. Executives at Janssen knew early on in the trial of concerns about device malfunction and launched a safety programme, called Covance recheck, to check the accuracy and reliability of blood test readings against laboratory results.
12. BMJ accuses pharmaceutical firm Janssen of withholding drug trial data

    Sep 28, 2016 | Jersey Evening Post

    The British Medical Journal (BMJ) alleged that Janssen, the pharmaceutical arm of Johnson and Johnson, "withheld" data from the US Food and Drug Administration (FDA) about a faulty blood testing device used during a trial for anti-clotting drug rivaroxaban, also known as Xarelto.

Full Text of Stories Below

U.S. Coverage - Trade Outlets

1. Johnson & Johnson hid faulty device concerns during key Xarelto study: BMJ

   Sep 29, 2016 | FiercePharma

   By Carly Helfand

   Janssen, J&J’s pharma branch, set up a safety recheck program in 2008 after investigators grew worried about accuracy and reliability with the INRatio device they were using to track blood clotting in trial participants, the BMJ reports.

   But the company didn’t share the data generated by that recheck program with the trial’s safety monitoring board or with the FDA ahead of the Xarelto approval process, the journal says.

   Janssen used the INRatio device to monitor patients in the warfarin arm of the Phase III ROCKET AF trial, a cornerstone of Xarelto's FDA approval filing. That trial compared Xarelto's performance with that of warfarin, the standard of care at the time.

   J&J's partner Bayer, which markets Xarelto overseas, knew about the device concerns as the trial progressed, but it didn’t know about the recheck program until earlier this year, the BMJ notes. One Bayer official testified in a lawsuit that Janssen, which conducted and managed the trial, kept the program from the German drugmaker.

   U.S. patients are suing both companies, claiming they misled users about Xarelto’s safety and efficacy.

   Janssen and Bayer, though, each countered “the central premise of BMJ’s report” in separate statements to FiercePharma. 

   A Janssen spokeswoman pointed out that “the data in question represent fewer than one twentieth of 1% of the 366,000 measurements taken during the ROCKET AF trial and they could not have had any impact on the conclusions of the trial.”

   Bayer added that the report includes “misleading statements which may unnecessarily alarm patients.”

   J&J and Bayer will “continue to ensure that health authorities receive all required and accurate information regarding past and ongoing clinical trials,” the J&J spokeswoman noted.

   The European Medicines Agency, for one, may agree with J&J. After launching a probe last December, the regulatory body announced in February that the device had not distorted the main findings of the study, which established Xarelto's superiority over warfarin as a treatment for atrial fibrillation.

   "Xarelto can continue to be used as before, in line with the current prescribing information," the agency said on its website.

   Xarelto has been a key product for both companies since it stormed out of the gate, and it currently leads a next-gen anticoagulant market that also comprises Boehringer Ingelheim’s Pradaxa, Pfizer and Bristol-Myers Squibb’s Eliquis and Daiichi Sankyo’s Savaysa. Just last week, new Bayer CEO Werner Baumann raised peak sales potential for the drug, taking the company estimate to more than €5 billion from €3.5 billion.

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2. More Blasts Of Concern Over ROCKET-AF

   Sep 28, 2016 | Cardio Brief

   By Larry Husten

   A new investigation published in the BMJ raises more troubling questions about the ROCKET-AF trial, which compared the novel oral anticoagulant rivaroxaban (Xarelto, Johnson & Johnson) to warfarin in patients with atrial fibrillation. The controversy about the trial first unfolded last fall when it became known that the portable Alere devices used to monitor and calibrate warfarin usage in the trial were seriously defective. Since then investigators, industry, regulators, and critics have been trying to assess whether the defective devices compromised the findings of the trial.

   The new development in the story is that shortly after the trial started J&J employees became aware that questions were being raised about the monitoring device in a small number of cases. The company launched a program to investigate these concerns but, according to BMJassociate editor Deborah Cohen, failed to inform either regulators or the trial’s data and safety monitoring board (DSMB) about the findings of the program.

   The BMJ reports that 149 samples were sent to the company by trial investigators who had questions about the accuracy and reliability of the INR readings. 71 of the samples were from patients randomized to warfarin. (Fake INR readings were generated for patients who were randomized to rivaroxaban.) According to the company there were “16 instances where the value from the point of care device and lab were… inconsistent.” Thus in this small, nonrepresentative sample nearly one quarter of the portable readings used in the trial did not match standard laboratory readings.

   The BMJ quotes a member of the trial’s DSMB, Peter Rothwell (Oxford University), who said he had “no memory of the board being told” about the findings. “Clearly, if the sponsor of the trial had concerns about the validity of the point-of-care testing of INR that would have been important for the board to be made aware of [them],” he told the BMJ. Neither did the company inform either the FDA or the EMA about the findings.

   One ROCKET-AF investigator, Markku Kaste (Helskini University General Hospital) agreed that the findings should have been shared. “I now have some doubts about the validity of ROCKET AF trial. It possibly skews the data in favour of rivaroxaban,” he said.

   Defending ROCKET-AF

   J&J responded that the company behaved properly because there was no good reason for it to report this data. I spoke with Pete DiBattiste, the head of development for cardiovascular drugs Janssen (the pharmaceutical arm of J&J), who told me that the company “took great care and are highly confident that we submitted all relevant information not only to the FDA but to all health authorities around the globe.” He pointed out that the 149 samples submitted by investigators to the program represented less than one-twentieth of 1% of the approximately 366,000 INR measurements obtained in the trial.

   The small number of samples sent by investigators “is itself a sign of reassurance,” said DiBattiste. The program “was put in place as a safety check” but “ended up yielding no meaningful issue” and so there was no reason to report the findings to either the DSMB or regulators, he said. He also pointed out that a certain amount of discordance would be expected, and that the FDA standard for approval of devices does not require perfect accordance.

   J&J has also defended ROCKET-AF on the basis of analyses performed by Janssen and its European partner, Bayer, as well as separate analyses performed by the ROCKET-AF investigators. But these analyses have also been subject to criticism. In her article Cohen cites numerous questions that have been raised about these analyses.

   “We need to find ways to reduce uncertainty and increase clarity about the balance of benefit to harm,” write Kamal Mahtani and Carl Heneghan in an accompanying BMJeditorial. Ideally they would like to see independent trials to replicate the results but they acknowledge that “this may take several years. In the mean time, making the data available for independent scrutiny should be a mandatory regulatory requirement, particularly when there are questions about trial rigour.” For now, however, “patients and clinicians must… live with the uncertainty left by the evidence currently available.”

   In a second accompanying commentary, Vinay Rathi, Harlan Krumholz, and Joseph Ross discuss the larger regulatory issues involving diagnostic devices raised by this case. They note that diagnostic devices “rarely require prospective clinical studies for clearance” and that devices that have been recalled can be used as predicates for the approval of new devices. Even the FDA acknowledges that “there are few performance standards… based on clearly defined scientific parameters.”

   Perspective From Sanjay Kaul

   Sanjay Kaul (Cedars Sinai) was a member of the FDA panel that reviewed ROCKET-AF He told me that he thinks Janssen should have disclosed the data to either the DSMB or the regulators. “It was a mistake that continues to fuel the controversy and perpetuate the perception of malfeasance.” Kaul does not find strong evidence in the available data suggesting that the ROCKET-AF results are invalid, but he does support “an reassessment of benefit-risk by independent academics” to perhaps “dispel any residual doubt or adjudicate remaining uncertainties.”

   Here is Kaul’s full statement:

   “The saga continues!

   “I find it unacceptable that Janssen did not disclose the results of the Covance recheck program to the DSMB or the regulators. It was a mistake that continues to fuel the controversy and perpetuate the perception of malfeasance.

   “I am all for data transparency and independent replication as suggested by the editorialists. However, the key question here is whether there is sufficient evidence that the benefit-risk balance of rivaroxaban was materially impacted by the faulty INR readings to revoke the approved indication. The EMA conducted an ‘independent’ investigation and concluded the benefit-risk balance remained unchanged. The FDA is also conducting its own investigation and so far has not made any major pronouncements. I don’t want to second guess the FDA, but if there was an obvious ‘fatal flaw’ to render the trial data invalid, they would have acted sooner in the interest of public safety.

   “Here is my own personal perspective.

   Of the 767 values where lab INR>4, 172 (22%) device INR values were between 2 and 3 and 47 (6%) device INR values were less than 2. A device INR of <2 (a 2-INR category discordance) is likely to lead to dose adjustment (escalation). It is important to keep in mind that dose adjustments are seldom based on single INR values. Please note that the difference in bleeding in those with vs without discrepancy is 1.5/100 patient years to 2.0/100 patient years. This is a marginal difference in a relatively small subset (6% of cohort) which is not likely to result in a MATERIAL difference in the benefit-risk balance. Even if this discrepancy was observed in 100% of the cohort (worst-case scenario), I am not convinced this would result in an undesirable benefit-risk balance. It is reassuring to learn that in data sets external to ROCKET-AF trial (where the defective INR device was not utilized), warfarin-related bleeding rates were consistent with those observed in ROCKET-AF.

   “What compounds the issue is that dose adjustment resulting from a clinically meaningful discrepancy in INR values would have expected to result in lower efficacy event rates (stroke and systemic embolism) and higher safety event rates (bleeding) with warfarin. While observed bleeding rates were aligned with the expected rates, observed stroke rates were the opposite of expected (higher rates). In addition, why would rivaroxaban (fixed doses were used) bleeding outcomes also be affected in a directionally similar manner as with warfarin by INR discrepancy but not stroke? These data appear to suggest that observed differences in warfarin event rates cannot be primarily attributed to the adjustments made in warfarin dose based on discrepancy-related device INRs.

   “Bottom line, short of conducting a new trial, perhaps, an reassessment of benefit-risk by independent academics might be able to dispel any residual doubt or adjudicate remaining uncertainties amongst the skeptics.”

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3. Were Problems With the Point-of-Care Device Used in ROCKET AF Kept From the FDA? BMJ Says Yes

   Sep 28, 2016 | TCTMD

   By Todd Neale

   Soon after the ROCKET AF trial evaluating rivaroxaban began enrolling patients, study investigators started expressing concerns about the accuracy of the device that was being used to measure international normalized ratio (INR) values, eventually leading drug maker Janssen to initiate a safety program to check the readings, according to an investigation by the BMJ.

   The problem is that Janssen did not reveal the existence of or results from that program—called the Covance recheck program—to the trial’s data and safety monitoring board, Bayer (co-developer of rivaroxaban), or the US Food and Drug Administration (FDA) before rivaroxaban was approved in July 2011, reports Deborah Cohen, associate editor of the BMJ. The European Medicines Agency (EMA) and Bayer didn’t know about the program until this year, she says, claiming, however, that Bayer knew about the concerns with the device.

   Cohen notes that patients in the United States are now suing Janssen and Bayer for misleading consumers regarding the safety and efficacy of rivaroxaban and that “in legal testimony, a Bayer official has alleged that Janssen, which had responsibility for conducting and managing the trial, withheld the program from the company.”

   When asked for comment by TCTMD, Bayer deferred to Janssen. In an emailed statement, a Janssen spokesperson said: “It is always our intent to provide all data that are relevant to analyzing the results of our clinical trials to health authorities, including the US FDA.  Janssen and our development partner Bayer will continue to ensure that health authorities receive all required and accurate information regarding past and ongoing clinical trials. The companies have disclosed safety data to regulators and the safety monitoring board of the ROCKET AF trial and deny the central premise of BMJ’s report.”

   Likewise, in her story, Cohen quotes Bayer stating that it “expressly [disagrees] with the allegation that Bayer would have withheld safety data from drug regulators and the safety monitoring board of the ROCKET AF trial.”

   Issue Precedes ROCKET AF

   The device in question—the INRatio and INRatio2 PT/INR Monitoring System—was on the FDA’s radar as early as October 2005, when the agency told then-manufacturer HemoSense (Alere is the current manufacturer) that it had determined that the company knew about problems with the device giving incorrect values, a problem that could lead to inappropriate doses of warfarin and excess bleeding risks. That was followed by another warning letter in November 2006 that listed violations revealed during an FDA inspection.

   The first patient was enrolled in ROCKET AF in December 2006. Cohen reports that just a few months later, in February 2007, several investigators, including members of the trial’s executive committee, expressed concerns about the accuracy of the device. Janssen eventually launched the recheck program in early 2008.

   Results of the trial—showing rivaroxaban to be noninferior to warfarin at preventing stroke or systemic embolism in patients with nonvalvular A-fib without an increase in major or nonmajor clinically relevant bleeding—were presented at the American Heart Association Scientific Sessions in November 2010.

   In March 2011, the FDA was reviewing rivaroxaban for approval when it asked Janssen for information about the performance of the INRatio device. The company responded but did not include data from the recheck program or tell the agency about investigators’ concerns, Cohen reports. Later that year, rivaroxaban was approved in both the United States and Europe.

   Issues with the device came to the forefront again in December 2014, when Alere issued a medical device correction—through an FDA recall notice—for the INRatio and INRatio2 PT/INR Monitor System, warning that it should not be used in patients with certain conditions because of the possibility of getting INR results lower than would be expected with laboratory testing.

   ROCKET AF trial leaders, who said that they only became aware of the recall in October 2015, have since performed multiple analyses—one published in February 2016 and another in July 2016—that show any issues with the device would not have influenced the results of the trial.

   The FDA continues to review the issue, but the EMA conducted its own review and concluded that the benefit-risk balance with rivaroxaban remains unchanged.

   The device, meanwhile, has been withdrawn from the market by Alere after discussions with the FDA.

   Uncertainty Remains

   Not everybody is convinced that the issue settled and that device issues did not skew the results of ROCKET AF, however.

   Referring to Thomas Marciniak, MD, a former reviewer for the FDA, Cohen writes, “Marciniak described EMA’s review as a ‘whitewash,’ alleging that the regulator has ignored ‘the serious device inaccuracies that those analyses reveal.’”

   Cohen says the investigation raises questions about the EMA’s review and the analyses published by the ROCKET AF investigators to address concerns.

   In an accompanying editorial, Kamal Mahtani, MBBS, PhD, and Carl Heneghan, BMBCh, DPhil (University of Oxford’s Centre for Evidence-Based Medicine, England), call for a reevaluation of rivaroxaban, as well as dabigatran, citing uncertainty about the reliability of the pivotal trials of those two drugs.

   “Although independent replication of trials, data transparency, and detailed analysis of clinical study reports will be arduous and costly, the concerns highlighted by recent investigations have shown how essential these approaches are to increase our confidence in new oral anticoagulants,” they say. “Meanwhile, patients and clinicians must, for now, live with the uncertainty left by the evidence currently available.”

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4. ROCKET AF Trial of Rivaroxaban Again Called into Question

   Sep 28, 2016 | Journal Watch

   By Amy Orciari Herman

   Janssen, the pharmaceutical branch of Johnson and Johnson, knew that a point-of-care device used for measuring international normalized ratio was giving falsely low readings during the ROCKET AF trial, aBMJ investigation finds.

   In ROCKET AF, published in the New England Journal of Medicine in 2011, the oral anticoagulant rivaroxaban was associated with less intracranial and fatal bleeding compared with warfarin in patients with atrial fibrillation. The trial's findings, which led to rivaroxaban's approval, have since come under scrutiny — in part because the INRatio device was later recalled over its poor accuracy. (INRatio's misleading results, some say, may have made rivaroxaban seem safer than warfarin.)

   Now The BMJ reports that Janssen withheld its knowledge of the device's poor performance from the trial's data safety monitoring board and from the FDA prior to rivaroxaban's approval.

   For now, the jury is out on whether ROCKET AF's results can be trusted, the report says. The FDA is conducting its own safety investigation, which includes using electronic health records to compare rivaroxaban and warfarin.

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International Coverage - Trade Outlets

5. Johnson & Johnson failed to inform FDA over faulty blood testing device in Phase III trial

   Sep 29, 2016 | PharmaFile

   By Ben Hargreaves

   The British Medical Journal, after its own investigation, found that Janssen knew early into the Phase III trial, known as the ROCKET AF trial, that the blood testing device used to test an anti-clotting drug was not working correctly. The trial was for the blockbuster drug Xarelto (rivaroxaban), which was pitted in the trial against warfarin.

   It was known early into the trial that concerns had been raised about the reliability of the device used to monitor patients who were taking warfarin. Janssen reacted by initiating a safety programme, called Covance recheck, to monitor the accuracy and reliability of blood test readings against laboratory results.

   Carl Heneghan is quoted by The British Medical Journal as saying that the INR device errors “are worrying” as there is “a near exponential increase in bleeding risk with increasing INR.” The suggestion being that the patients who were monitored by the fault device were potentially put at risk of harm during the trial. The journal states that the information was not passed onto the trial's data safety monitoring board, the co-developer of rivaroxaban, Bayer, and the FDA prior to drug approval.

   Both Bayer and Janssen have since launched a robust defence of the clinical trial. A Janssen spokeswoman said: "Janssen and our development partner Bayer will continue to ensure that health authorities receive all required and accurate information regarding past and ongoing clinical trials.

   "The companies have disclosed safety data to regulators and the safety monitoring board of the ROCKET AF trial and deny the central premise of BMJ's report.

   "The data in question represent fewer than one-twentieth of one percent of the 366,000 measurements taken during the ROCKET AF trial and they could not have had any impact on the conclusions of the trial.”

   A spokewoman for Bayer also commented that "Janssen and Bayer have ensured and will continue to ensure that health authorities receive all required and accurate information regarding past and ongoing clinical trials.”

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6. Manufacturer failed to disclose faulty device in rivaroxaban trial

   Sep 28, 2016 | BMJ

   By Deborah Cohen

   A drug manufacturer knew about problems with a blood testing device but did not share data before the crucial approval process, an investigation by The BMJ has found.

   Janssen, the pharmaceutical arm of Johnson and Johnson, withheld data from the Food and Drug Administration about problems with the INRatio device, which was used in the phase III trial (ROCKET AF) of the blockbuster anticoagulant.

   Janssen, the pharmaceutical arm of Johnson and Johnson, withheld data from the Food and Drug Administration about problems with the INRatio device, which was used in the phase III trial (ROCKET AF) of the blockbuster anticoagulant.

   The company generated these data in a safety programme (called the Covance recheck programme) set up after trial investigators became concerned, shortly after the study began, about the accuracy and reliability of the point-of-care device used to monitor patients receiving warfarin.

   Janssen also failed to share these data with the safety monitoring board of the trial.

   Executives from Bayer—which codeveloped rivaroxaban and markets it outside the United States—were also aware about concerns about the device used in the trial. However, the German company did not know about the existence of the recheck programme until this year.

   Patients in the US are suing Janssen and Bayer for allegedly misleading users about the safety and efficacy of rivaroxaban (Xarelto).

   In legal testimony, a Bayer official has alleged that Janssen, which had responsibility for conducting and managing the trial, withheld the programme from the company.

   When asked by The BMJ, Bayer stated that it “Expressly contradicts with the allegation that Bayer would have withheld safety data from drug regulators and the safety monitoring board of the ROCKET AF trial.”

   Pivotal trial comes under scrutiny

   Published in the New England Journal of Medicine (NEJM) in 2011, the trial included over 14 000 patients and concluded that rivaroxaban was “similar to warfarin in its ability to prevent” ischaemic stroke or systemic embolism in people with non-valvular atrial fibrillation.1

   The authors reported there was no significant difference between groups in major bleeding risk—although intracranial and fatal bleeding occurred less often in the rivaroxaban group.

   The point-of-care device INRatio—initially marketed by HemoSense and later by Alere—was used to measure international normalised ratio (INR) values in the 7133 participants in the warfarin arm of the study. However, the FDA recalled the device in December 2014 because INR results it generated could be “clinically significantly lower” than those found by a laboratory method.2

   However, Janssen and Bayer did not tell the authorities that the device used in the ROCKET trial had subsequently been recalled until The BMJ probed them in September 2015, the New York Times reported.3

   Global regulators have subsequently launched inquiries; Bayer and Janssen have reanalysed the trial data; the study’s executive committee has published two letters in NEJM containing its “independent” reanalyses of the data45; and the US Department of Justice has issued Alere with a subpoena seeking “various documents related to the accuracy, reliability and performance of the INRatio system.”6

   Only the European Medicines Agency has published its full conclusion stating, “Any incorrect measurements obtained with the defective device would have had only a marginal effect on the study results, and the safety of Xarelto remains unchanged.”7

   A spokesperson for the FDA told The BMJ that it is “continuing to review relevant data,” but said that it has “not changed its recommendations regarding the use of Xarelto.”

   The FDA also said that because the INRatio devices were used only to monitor blood clotting rates and adjust the dose of warfarin in the trial, they are “confident that the rates of stroke, bleeding, and other clinical outcomes” in patients taking rivaroxaban are correct.

   However, the relative risk of stroke and bleeding of rivaroxaban compared with warfarin “could be affected” by the performance of these devices.

   Could the regulatory investigations have been avoided?

   Markku Kaste, one of the trial investigators and former head of the Clinical Stroke Research Group at Helsinki University Central Hospital, was worried about the use of the INRatio device and one of the earliest to ask questions.

   Kaste told The BMJ that he warned a study monitor from Parexel, which had responsibility for overseeing investigational sites outside North America, that INRatio’s performance should first be validated. According to Kaste, the monitor reassured him that there was “nothing to worry about.”

   The BMJ asked Parexel what it knew about the malfunctioning device and the Covance recheck programme.

   A spokesperson said: “I cannot discuss the specifics of a study due to Parexel’s confidentiality obligations to our clients.”

   Yet several physicians raised concerns that the devices were providing inaccurate results.

   Shortly after the trial started in February 2007, members of the trial’s executive committee emailed Janssen questioning the accuracy and reliability of the INRatio. Following complaints from other trial investigators about the device, Janssen launched the Covance recheck programme in early 2008.

   In a letter from Janssen to investigators dated 21 February 2008, the company described a new kit for collecting “special blinded INRs … designed to assist investigators who believe that a subject’s INR values obtained with HemoSense point of care (POC) device [INRatio] are greatly different from what was expected.”

   Janssen’s letter did not describe the concerns that led the company to send the special kits. Nor was the new recheck programme ever added to the trial protocol (although EMA disputed this point, after confirming that the first it heard of the recheck programme was when The BMJ notified the agency in May 2016). Bayer has told The BMJthat: “This support program was in addition to the use of an unblinded INR monitor which was described in the protocol for the trial.”

   Yet in March 2016, Janssen’s lawyers described the recheck programme as a “component” of the ROCKET trial.

   Both Bayer and Janssen have told The BMJ that investigators submitted 149 samples to the recheck programme (rivaroxaban 78; warfarin 71). In Janssen’s legal pleading, it stated that there were “16 instances where the value from the point of care device and lab were recorded as inconsistent.”

   Since the rivaroxaban arm used a sham device, this means that 23% of warfarin participants in the programme had mismatching laboratory and point-of-care INR values.

   However, it is unclear how Janssen defined “inconsistent” readings, and the company did not explain when asked byThe BMJ.

   Perhaps most alarming, Janssen did not tell the FDA about the recheck programme or trial investigators’ concerns about the device during the approval process in 2011.

   Who was informed?

   Despite the safety of trial participants potentially being compromised, The BMJ’s investigation shows that Janssen did not give the data generated by the recheck programme to the trial’s data and safety monitoring board.

   Peter Rothwell, professor of clinical neurology at Oxford University, was a member of the board. He told The BMJthat he has “no memory of the board being told about the programme.

   “Clearly, if the sponsor of the trial had concerns about the validity of the point-of-care testing of INR that would have been important for the board to be made aware of [them],” Rothwell said.

   Kaste told The BMJ that the data from the Covance recheck programme should have also been shared with investigators as “it’s vital for the ongoing ethical approval for the trial.”

   “In my institution I have to renew ethical approval annually and it is questionable if they would have given their approval if they knew about the problems with the device,” he said, adding: “I now have some doubts about the validity of ROCKET AF trial. It possibly skews the data in favour of rivaroxaban.”

   Hiding in plain sight

   There may be reason to believe regulators could have caught the problem themselves.

   As part of the ROCKET trial design—which is online at NEJM.org—a split sample was taken from participants at weeks 12 and 24 of the trial. One sample was analysed by the point-of-care device and the other by a central laboratory. The samples were taken for pharmacodynamic studies and the results were kept blinded until the trial was completed.

   The 12 and 24 week paired sample data were not used to ascertain the accuracy of the device before the drug was approved, but since questions have been raised, they are central to the current debate over the device’s accuracy and its implications for the validity and generalisability of the trial.

   Reviews submitted to the EMA by Bayer and Janssen “each determined that the potential issue with Alere’s monitoring device did not impact the conclusions of the ROCKET-AF trial,” a spokesperson from Janssen told The BMJ in a statement adding: “The benefit-risk profile of Xarelto remains positive and unchanged for reducing the risk of stroke in patients with non-valvular atrial fibrillation.”

   However, these analyses did not include all the patients. When the device was recalled in December 2014, the recall notice listed specific patient populations that were purportedly more likely to have faulty readings. The companies focused their analyses on these subgroups.

   Thomas Marciniak, a former FDA official who was a drug reviewer on Janssen’s application to use rivaroxaban in acute coronary syndrome, told The BMJ that these analyses are “worthless” because the “inaccuracies are not limited to the recall patients.”

   And EMA’s review—published in February 2016—seems to corroborate Marciniak’s concern. Its analysis of the week 12 and 24 paired samples found “discrepancies of potential clinical relevance” in about 35% of the estimations.

   The target INR range during the trial for people taking warfarin was 2-3. However, EMA’s report shows at week 12, for more than 28% of laboratory INR readings above 4 the corresponding INRatio readings were below 3 three (and some were below 2). Documents obtained under freedom of information by The BMJ show that this rose to 33% at week 24.

   EMA’s report further states that warfarin may have been improperly dosed in participants whose INRatio readings were lower than the corresponding laboratory value.

   It’s a point with which the FDA concurs. A spokesperson told The BMJ: “The information that has been developed to date indicates that some patients may have received higher warfarin doses than needed because of the use of INRatio devices in this trial.”

   To estimate the effect of the misreading, EMA asked Bayer to compare event rates between those participants whose laboratory results fell within range of the INRatio reading and those whose results were out of range, by different degrees. These analyses found that the larger the difference between the INRatio and laboratory readings, the higher the rate of major bleeding. People whose readings were more than 2 units apart were over 40% more likely to have a major bleed than those whose readings were the same.

   Carl Heneghan, professor of evidence based medicine at Oxford University and an author on a forthcoming Cochrane review of direct thrombin inhibitors and factor Xa inhibitors for atrial fibrillation, believes patients in the trial may have been put at undue risk of harm.

   He told The BMJ that the INR device errors “are worrying” as there is “a near exponential increase in bleeding risk with increasing INR.

   “With INRs above 4, dose adjustment is required. INRs above 5 require investigation and doses to be withheld, and because of the defective readings this will not have happened. More worrying is some of the normal results were actually INRs above 8, which require active intervention to reduce the risk of bleeding.”

   Despite all this, the EMA report stated “that there was sufficient evidence to conclude that the benefit/risk balance remains unchanged and favourable for treatment with rivaroxaban in the prevention of thromboembolism in non-valvular atrial fibrillation.”7

   Marciniak described EMA’s review as a “whitewash,” alleging that the regulator has ignored “the serious device inaccuracies that those analyses reveal.”

   Former FDA clinical pharmacologist, Bob Powell, who has also worked with industry and academia, told The BMJ that he is “disappointed” with EMA’s conclusion. “The decision not to change the label [of rivaroxaban] does not accurately describe the uncertainty around the trial results.”

   The FDA says it is still investigating.

   FDA’s concerns before approval

   Marciniak says that the FDA should have identified the problems with the 12 and 24 week data. The division of FDA responsible for reviewing the ROCKET AF data had concerns about the performance of INRatio.

   In March 2011, while the drug was under review, the FDA asked Janssen for information about the accuracy of the device. But according to plaintiffs’ legal filings, the company did not provide the evidence from the Covance recheck programme nor the thousands of paired laboratory samples.

   Janssen did not respond to The BMJ’s questions about this. The company instead sent a statement saying: “We have acted with urgency, diligence and in the best interests of patients and prescribers, sharing data with health authorities and the safety monitoring board of the ROCKET-AF trial.”

   NEJM reanalysis

   Bayer and Janssen have highlighted the “independent reanalysis” performed by the ROCKET AF executive committee in conjunction with the Duke Clinical Research Institute to support their conclusions that the device malfunction did not affect trial outcomes. This was published as a letter in the NEJM in February 2016.4

   But this letter did not include an analysis of the paired week 12 and 24 data—despite a peer reviewer of the letter asking, “What percentage of major bleeds in the warfarin arm had an elevated INR as measured by a lab-based plasma INR?”

   Manesh Patel, associate professor of medicine at Duke Clinical Research Institute and lead author of the published trial and letter, told the NEJM editors that they “are unable to do this analysis as we do not have systematic measurement of both point-of-care and laboratory values throughout the course of the study.”

   However, in court filings from earlier this year, Janssen’s lawyers seemed to contradict this position, stating that the paired laboratory and INRatio data were available to the authors.

   Neither Patel nor Fox responded to The BMJ’s questions about this.

   After a letter of complaint by Powell to the NEJM in July,8 stressing the laboratory data at 12 and 24 weeks should be compared with the point-of-care data from the split samples, Patel and colleagues reanalysed the data again. They calculated that 13% of warfarin patients had discordant results at 12 or 24 weeks and 4% at both, and concluded that the new results were “consistent” with their original trial report.5

   But much of the debate hinges on what degree of inaccuracy is considered acceptable. In the case of INR point-of-care devices, the FDA has required at least 90% agreement with laboratory INR results, but there are signs the agency may soon tighten its rules (box).

   Current point-of-care device standards not stringent enough, says FDA

   Current international standards set a level of acceptable mismatch between the point-of-care device and laboratory results.

   According to 2007 ISO guidance, a point-of-care device should report INRs within 0.5 of laboratory value (for INRs <2) or within 30% (for INRs between 2 and 4.5), at least 90% of the time.

   Following a “high number” of medical device reports of malfunction, serious adverse events, and patient deaths, the FDA has said it will review current standards.

   At a meeting in March, Rong Rong, medical officer in the haematology branch in the FDA’s Division of Immunology and Hematology Devices, said that accurate INR measurement was critical to the safety and effectiveness of warfarin. Over the past two years, the FDA received reports of 3231 malfunctions, 384 serious injuries, and 18 deaths for INR point-of-care devices. Rong is concerned: “Inaccuracy in INR measurement can have serious consequences and can cause patient death.”

   Point-of-care INR devices are currently classified as a moderate risk class II device cleared through the FDA’s 510(k) process. This means that they do not require clinical studies to prove their safety and effectiveness.

   Rachel Goehe, also from the FDA, told the March meeting that some manufacturers want the FDA to continue to recognise the ISO standard. However, she said: “The FDA does not recognise the standard for need of professional use nor patient self-testing, because the allowable bias limits are too large and may impact management of patient care.”

   She added the agency had proposed to tighten the standard to reduce the allowable bias and add recommendations when to monitor the devices performance against laboratory tests.

   Goehe stressed the FDA’s need “to obtain postmarket surveillance data for adverse events while using a wide variety of sources and methods” in case of device malfunction.

   However, Jay Ronquillo a physician and engineer speaking on behalf of the National Center for Health Research, argued that the ROCKET AF trial “has raised questions about the comparative safety of Xarelto. This shows how device malfunctions no longer affect just single users but directly influence approval decisions for any new drug being compared to warfarin.”

   He urged the FDA to consider putting point of care PT/INR devices through the agency’s more rigorous premarket approval process.

   “[These devices] represent an increasingly important part of the healthcare landscape. Transparent and robust design, performance studies and clear data supporting safety and effectiveness are required to avoid device problems that could have wide reaching consequences for patients and public health,” he said.

   Patel and his coauthors also reported that in warfarin treated participants with discrepant INRatio and laboratory results, both ischaemic stroke and bleeding rates were higher than in those with non-discrepant results. They argued that the rise in both types of events—not just bleeding—countered the hypothesis that device malfunction would have led to increased clinical events.

   However, Powell told The BMJ that some of the ROCKET team’s assumptions were wrong: “The incidence of both ischaemic stroke and bleeding increase with warfarin treatment as the INR goes above 4.”

   He added that the discrepancies in the INR readings from INRatio did not occur in the same patients at 12 and 24 weeks, and this variation would have occurred throughout the study.

   Some are also questioning how “independent” these analyses actually are, particularly since employees of both Janssen and Bayer are members of the executive committee that did the reanalysis.

   Both Janssen and Bayer may have known the extent to which INRatio malfunctioned before the letter was submitted for publication. US plaintiffs’ lawyers allege that on 21 September 2015, Janssen and Bayer held an internal meeting that showed 32% of the paired laboratory and point-of-care device samples obtained by the INRatio were off by 0.5 units or more.

   A spokesperson for Bayer said it and Janssen “did not attempt to influence the ROCKET AF executive committee re-analysis data submission to the NEJM.” However, in correspondence with the editors of the NEJM, Patel said that “the entire executive committee and team on the letter helped revise and work on the data response.”

   Patel and Keith Fox, professor of cardiology at Edinburgh University and chair of ROCKET AF, provided a statement on behalf of the trial’s executive steering committee.

   “The ROCKET AF Executive Committee (EC) stands behind the conduct and rigor of the study, the trial findings, and the recently published research letter,” they said.

   Can we trust ROCKET at all?

   The problems with INRatio are not the first ROCKET has faced, and people are now questioning if regulators can salvage the trial. During the drug’s assessment, two FDA clinical reviewers recommended rivaroxaban not be approved because of inadequate warfarin control in the trial. The mean time in therapeutic range was 55%—lower than in any of the phase III trials of other direct oral anticoagulants.

   Steven Nissen, a cardiologist at the Cleveland Clinic who served on the FDA advisory panel and voted against approving rivaroxaban in 2011, told the New York Times that: “Given the fact that the device was inaccurate, there is no way anybody can tell you what would have happened in the trial.”

   While the FDA continues its investigation, which will include a surveillance study using electronic health records to compare rivaroxaban with warfarin, it told The BMJ that the device malfunction didn’t have a “significant impact”—but it’s as yet unclear just what this means.

   Heneghan remains unsure. “It is impossible to create subgroups that had ‘accurate results' based on just two external quality control measures. In addition, the measures of TTR [time in therapeutic range] quoted in the trial results would be worse if the results were based on a lab INR results,” he said.

   “The implications are we still do not know whether this is a safe drug. We need a trial to assess the safety and efficacy of rivaroxaban. Just one caveat—it should be run independently.”

   “What The BMJ reported in February 20169 INRatio, the point-of-care device used to monitor warfarin in the control arm of the key pivotal trial underpinning rivaroxaban’s approval to prevent ischaemic stroke in non-valvular atrial fibrillation, was faulty and later subject to a class 1 FDA recall The BMJ alerted regulators and the authors of the trial that was published in the NEJM. Janssen said it was the first it had heard of the device recall Janssen and Bayer told The BMJ their own analyses show the device had not affected trial outcomes; EMA and FDA said they were still investigating Doctors and academics called for the data to be released and independently evaluated

   What this story adds Janssen executives were aware, early on in the trial, of concerns about device malfunction Bayer executives also knew of concerns about the device in the trial Janssen, which had primary responsibility for the trial, launched an unpublicised safety programme. This involved an “unblinded monitor” who would check INRatio readings against laboratory (Covance) results if an investigator had concerns Janssen continued to use INRatio throughout the trial and did not disclose the presence of, nor the data from, the Covance recheck programme to the trial’s data and safety monitoring board, Bayer, or the FDA before drug approval EMA only learnt about the recheck programme after The BMJ alerted it to it in May 2016 Patients in the US are suing both Janssen and Bayer for allegedly misleading users about the safety and efficacy of rivaroxaban. The first trial is scheduled to start next year

   Timeline

   2002 FDA 510(k) clearance of HemoSense INRatio point-of-care INR device

   October 2004 Paper published showing that of 8 people with hypertherapeutic INR values were misclassified as normotherpeutic by INRatio10

   October 2005 FDA sends warning letter to HemoSense stating: “Our review indicates that your firm had information indicating that INRatio devices were generating clinically significant erroneous values”

   September 2006 Johnson & Johnson submitted the final protocol, case report forms, and other study documents for regulatory approval of rivaroxaban to the FDA

   November 2006 FDA sends warning letter to HemoSense stating: “These violations include, but are not limited to, the following: Failure to investigate complaints involving the possible failure of a device … For example: … The complaint involved discrepant results between the INRatio INR device and the Lab INR.” (In Janssen’s possession as of January 2007)

   December 2006 First patient enrolled in ROCKET AF

   February 2007 Numerous people, including members of the ROCKET AF executive committee, are said to have expressed concern over the accuracy and reliability of the INRatio device and called on Janssen to validate the device or implement study-wide routine quality control procedures, plaintiffs’ lawyers allege

   July 2007 Bluestein et al publish paper published with the conclusion: “POC devices may not be appropriate for commercial laboratory test substitutions without prior performance evaluation”11 February 2008 ROCKET AF investigators told in letter from Janssen to contact the medical monitor, Parexel or Duke Clinical Research Institute helpline if they have concerns about the INRatio device

   September 2010 Last patient contact in ROCKET AF

   October 2010 Database lock of ROCKET AF

   14 March 2011 FDA issues Janssen information request relating to performance of INRatio device in ROCKET AF

   17 March 2011 Janssen’s response to information request submitted, which it is claimed does not include Covance recheck programme data nor week 12/24 paired data

   8 September 2011 ROCKET AF published in NEJM

   8 September 2011 FDA advisory committee meeting to discuss approving rivaroxaban for non-valvular atrial fibrillation. Clinical reviewers express concern about warfarin’s time in therapeutic range

   22 September 2011 EMA grants marketing authorisation for rivaroxaban for the prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation

   November 2011 FDA grants market authorisation for rivaroxaban to Janssen for the prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation.

   December 2014 FDA initiates class I recall of the INRatio and INRatio 2 stating: “Device may provide INR results that are clinically significantly lower than results obtained using a reference INR system (laboratory method)”

   February 2015The BMJ contacts the EMA about the recalled device used in ROCKET AF

   March 2015 Alere confirms to The BMJ that the devices affected by the recall include those used in the ROCKET AF trial

   September 2015The BMJ asks investigators named in the NEJM paper about the recall

   September 2015 According to the plaintiffs’ legal documents ROCKET AF Task Force held a meeting where data were discussed indicating that INRatio results were off by 0.5 INR units or more 32% of the time as compared with central lab at two points during the trial (week 12 and 24)

   24 September 2015 Alere confirmed to Janssen/Bayer that recall applied to INRatio devices used in ROCKET AF

   December 2015 Letter containing the “independent” reanalysis of ROCKET AF submitted to the NEJM by the executive steering committee

   December 2015 Janssen provides the FDA a comparison of the week 12 and 24 paired samples, plaintiffs’ lawyers state

   11 January 2016 Duke Clinical Research Institute omits paired INRs from response to NEJM despite being specifically asked by peer reviewers

   3 February 2016 Patel and colleagues reanalysis published in NEJM4

   3 February 2016The BMJ  publishes “Rivaroxaban: Can we trust the evidence?”9

   5 February 2016 EMA assessment report states that: “any incorrect measurements obtained with the defective device would have had only a marginal effect on the study results, and the safety of Xarelto remains unchanged”7

   7 March 2016 Janssen provides FDA “documents, which consist primarily of email chains, that demonstrate on numerous occasions physicians involved in ROCKET AF trial raised concerns that the devices were providing inaccurate results,” plaintiffs’ lawyers allege

   8 March 2016 Janssen lawyers acknowledge the existence of the Covance recheck programme in the US courts

   April 2016 FDA confirms it had previously been unaware of the recheck programme. It asks Janssen for a detailed description of its purpose, operational details, data generated by the programme, and information on who knew what and when they knew it.

   May 2016The BMJ contacts the EMA to ask about the recheck programme. The agency later confirms it’s the first it had heard about it

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7. Novel oral anticoagulants for atrial fibrillation

   Sep 28, 2016 | BMJ

   By Kamal R. Mahtani and Carl Heneghan

   Despite this, use of new anticoagulants has proved to be highly variable in patients most at risk, ranging from 4% to 70% in different areas in England.3 This may partly be attributable to higher perceived costs , clinical uncertainty about the balance of benefit to harm, and the lack of routinely available antidotes in cases of overdose (although this looks likely to change in the future).

   Questions remain about the key drivers of this uncertainty. NICE technology appraisals for both dabigatran 4 and rivaroxaban 5 were primarily based on two large, multinational, industry sponsored clinical trials, RE-LY and ROCKET AF.6 7 RE-LY compared warfarin and dabigatran in 18 113 participants with non-valvular atrial fibrillation; rates of stroke, systemic embolism, and major haemorrhage were (depending on the dose of dabigatran) either the same as or lower than in those taking warfarin. ROCKET randomised 14 264 participants to either rivaroxaban or warfarin; rivaroxaban was non-inferior to warfarin and was associated with fewer fatal bleeding events and fewer intracranial haemorrhages.

   However, there were early concerns that the conduct of the RE-LY trial and the quality of the data may be compromised. Specifically, the manufacturer had not fully disclosed information about the potential benefits of monitoring anticoagulation in people taking dabigatran—one of the key selling points is lack of monitoring.8 The US Food and Drug Administration therefore initially refused to file an approval of the drug for non-valvular atrial fibrillation because of these concerns and requested a review of RE-LY data. This revealed inconsistencies for 3054 participants and identified previously unreported adverse events (32 myocardial infarctions and 69 major haemorrhages).9

   The validity of the ROCKET AF trial of rivaroxaban has also been questioned.10 It has transpired that participants randomised to warfarin were monitored using a defective point-of-care device that was subsequently recalled.11 It is therefore unclear whether participants in the warfarin arm were managed appropriately, giving a possible unfair advantage to rivaroxaban. Cohen’s latest investigation highlights that some of the ROCKET investigators raised concerns about the faulty device and that the data and monitoring safety board may not have been fully informed about a safety investigation instigated by Janssen, which was running the trial.12

   Published trials suggest that novel oral anticoagulants, such as dabigatran and rivaroxaban, are non-inferior to warfarin,13 a finding replicated in routine data collected from observational cohorts.14 Yet uncertainty remains about the reliability of the evidence underpinning the pivotal trials. Part of this uncertainty can be traced back to the rapid review approval process, which aims to accelerate the approval of drugs with the potential for significant clinical benefit. However, when a trial’s validity is then called into question this may hinder translation, and in some cases, delay wider uptake.15 Furthermore, oral anticoagulants are one of the highest risk drugs used in outpatient settings, and valid questions have been asked about why ease of use has been a greater focus than the need to improve the safety profile of anticoagulants.16

   We need to find ways to reduce uncertainty and increase clarity about the balance of benefit to harm. Replication of the results from RE-LY and ROCKET in independent trials would be one approach, but this may take several years. In the mean time, making the data available for independent scrutiny should be a mandatory regulatory requirement, particularly when there are questions about trial rigour. Finally, a detailed independent analysis of unpublished data from clinical study reports, similar to previous analyses of neuraminidase inhibitors,17 would also help. We have requested the relevant clinical study reports from the European Medicines Agency, and it has become clear that there are likely to be challenges for the trial sponsors in condensing large reports into digestible publications.

   Although independent replication of trials, data transparency, and detailed analysis of clinical study reports will be arduous and costly, the concerns highlighted by recent investigations have shown how essential these approaches are to increase our confidence in new oral anticoagulants. Meanwhile patients and clinicians must, for now, live with the uncertainty left by the evidence currently available.

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8. Commentary: Diagnostic devices in clinical trials have high stakes for patient care

   Sep 28, 2016 | BMJ

   By Vinay K Rathi and Karlan M Krumholz

   The widely used anticoagulant rivaroxaban (Xarelto) has become the centre of considerable scientific and regulatory dispute. A key clinical trial supporting US Food and Drug Administration (FDA) approval was recently found to have used faulty point-of-care devices for monitoring international normalised ratio (INR).1 2 This ongoing episode provides important insights into regulation challenges for diagnostic devices and the far reaching effects these devices have on clinical research and patient care.

   Regulatory history

   The FDA defines in vitro devices as devices using human specimens to guide the treatment or prevention of disease, and clears the large majority for use through the 510(k) process for moderate risk devices, which requires only that a device be “substantially equivalent” to another previously cleared device.3

   In 2002, the FDA cleared the INRatio model used in the ROCKET trial4 based on substantial equivalence to the CoaguChek S point-of-care monitor. This approval shows several critical challenges that the FDA faces with clearing diagnostic devices:

   Predicates—Analytical and clinical validity of predicate devices may be inherently limited. The CoaguChek S was found to underestimate INR compared with laboratory reference methods, with >40% of measurements deviating by ≥15%,5 and in 2006 was subject to a class II (moderate risk) FDA recall because defective testing strips produced falsely raised results. Currently, no restrictions prohibit using voluntarily recalled devices as predicates, and devices with malfunctioning predicates cannot be readily identified for further testing after clearance.

   Clinical testing—Diagnostic devices rarely require prospective clinical studies for clearance, and these studies may not be generalisable when conducted.3 While details of premarket studies examining the INRatio model used in ROCKET are absent from FDA documents, the previous model, INRatio 2, was cleared for patient self testing based on evidence from a single benchmarking study (8 weeks, 105 patients, 4 sites, laboratory reference method). A small study such as this would be expected to have limited relevance to the diverse population of real world users.

   Performance standards—Acceptance criteria for diagnostic devices and their supporting rationale are not consistently publicly available within FDA documents. In general, the FDA acknowledges, “There are few performance standards … based on clearly defined scientific parameters.”3 Even widely accepted performance standards may be inadequate to assure analytical (that is, the ability to detect target analyte) and clinical (accuracy in assessing clinical conditions) validity. INRatio 2 was evaluated using 2007 International Organization for Standardization criteria, which the European Medicines Agency noted are, “somewhat arbitrary and cannot be easily interpreted in terms of relevance for clinical decisions on dosing.”6

   Stakes for patient care

   The INRatio episode highlights the regulatory challenges for diagnostic devices, but the clinical challenges are perhaps greater. About 3300 devices were cleared through the 510(k) process in the past decade, during which time manufacturers issued nearly 190 highest risk and 1800 moderate risk recalls, including for troponin assays, antibiotic susceptibility tests, and glucometers. These malfunctions can have serious consequences—even severe injury and death1—for the millions of patients whose clinical diagnosis or management depends on the devices.

   Faulty devices may further affect patient care when they are used in clinical research, especially studies intended to inform regulatory approval. The INRatio is but one example. For instance, the Medtronic MiniMed continuous glucose monitor was approved on the basis of a pivotal clinical study that benchmarked performance against the Accu-Chek Advantage glucometer,7 which was subsequently recalled because only 30% of glucose measurements fell within 10% of laboratory reference values.8 However, it is currently not possible to determine how many studies have been conducted, regardless of their use as part of regulatory approval, that may have relied on faulty devices. Diagnostic devices are rarely identified by name in FDA documents, published study protocols, or ClinicalTrials.gov, and manufacturers may have limited ability to track faulty devices.1 For instance, Alere became aware that the INRatio units used in ROCKET were defective only when Johnson & Johnson requested an investigation roughly 10 months after the initial recall.6

   The potential for compromised clinical research and patient care is even greater among laboratory developed tests, which are currently not regulated by the FDA and often operate using new and unfamiliar technologies. The FDA is already aware of several oncology trials enrolling and allocating potentially inappropriate chemotherapy to patients based on the results of insufficiently validated laboratory tests.9 Despite these concerns, the FDA has encountered resistance to regulating these tests in the same way as point-of-care devices.

   Better regulation

   The FDA is implementing measures to strengthen the 510(k) process, such as disclosing premarket study data within publicly available documents, curtailing clearances based on inappropriate predicates, and improving performance criteria for a broad array of devices.10 11 As part of these efforts, the FDA should develop informational capabilities allowing patients, physicians, and the agency to track the regulatory lineage of devices cleared via the 510(k) process and ensure that unproved or underperforming predicates can be easily linked to currently marketed devices, similar to existing resources for high risk devices approved through the premarket approval pathway. Such information would show if the original device received FDA clearance decades ago, perhaps indicating a need for renewed scrutiny.

   To improve performance criteria for point-of-care devices using well established technology, the FDA could consider requiring that analytical validity be determined using the highest established standards. Furthermore, sensitivity and specificity could be evaluated against established reference methods under real world conditions of use. In March 2016, the FDA convened a public workshop to discuss the challenges of regulating point-of-care INR monitors and expressed willingness to work towards such higher standards. The agency is now considering adopting more stringent performance criteria and requiring data from various clinical settings as a condition of clearance for these devices.12 The US Congress should give the FDA adequate authority to ensure that the highest evidentiary standards are adopted for regulation of both diagnostic devices and laboratory assays.

   In addition, the FDA should work to promote greater transparency in clinical research relying on diagnostic devices. For premarket clinical studies, the FDA should be authorized to request external validation measures and an evidence based rationale for the specific device(s) used; the FDA could then link approval pages to existing total product life cycle performance reports. Investigators should be required to identify diagnostics by name and lot number in trial protocols, peer reviewed publications, and on ClinicalTrials.gov, which would enable rapid identification of potentially affected clinical studies in the event of device malfunction.

   Widespread adoption of unique device identifiers may enable the FDA to provide enhanced oversight of real world use that leverages its expertise in risk management, ensuring that devices with critically unsafe and poorly understood defects are removed from the market, while allowing flexibility to implement tailored recall strategies for less harmful device malfunctions. To this end, the FDA is considering using postmarket surveillance studies to improve understanding of factors limiting real world performance (eg, user errors) and design quality control measures capable of safeguarding diverse patient populations.10 13 Although much work remains to be done, the FDA serves as an exemplar for regulators across the world; after approving a number of unsafe and ineffective devices rejected by the FDA,14 the European Union has recently proposed more stringent evidentiary standards for diagnostic and therapeutic devices.15

   Although the ROCKET controversy remains unsettled, the potential for faulty diagnostic devices to compromise clinical research and patient care has become increasingly clear. This eye-opening episode may encourage patients, physicians, manufacturers, and regulators to re-examine performance expectations for these devices and work towards a better framework to support their use in clinical diagnosis, management, and research.

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9. BMJ accuses pharmaceutical firm Janssen of withholding drug trial data

   Sep 28, 2016 | Press Association

   A pharmaceutical giant has been accused of withholding trial data from a medical regulator.

   The British Medical Journal (BMJ) alleged that Janssen, the pharmaceutical arm of Johnson and Johnson, "withheld" data from the US Food and Drug Administration (FDA) about a faulty blood testing device used during a trial for anti-clotting drug rivaroxaban, also known as Xarelto.

   During the trial to assess the effectiveness of rivaroxaban for preventing strokes in patients with irregular heartbeat, some participants took anti-clotting drug warfarin and others took rivaroxaban.

   Concerns were later raised those taking warfarin were monitored using a faulty device.

   The BMJ has reported that Janssen knew of concerns about potential device malfunction and launched a "safety programme" to check the accuracy and reliability of blood test readings against laboratory results.

   The journal said Janssen did not share these data with the trial's data safety monitoring board, the co-developer of rivaroxaban Bayer and the FDA prior to drug approval.

   "Drug manufacturers knew about problems with a blood testing device but did not share data before the crucial approval process," the feature by BMJ associate editor Deborah Cohen states.

   "Janssen withheld data from the Food and Drug Administration about problems with the INRatio device, which was used in the phase III trial (ROCKET AF) of the blockbuster anticoagulant.

   "The company generated these data in a safety programme (called the Covance recheck programme) set up after trial investigators became concerned, shortly after the study began, about the accuracy and reliability of the point-of-care device used to monitor patients receiving warfarin."
   

   Figures from NHS Digital show that in 2015, there were 1.5 million prescription items of rivaroxaban dispensed in England.

   Bayer and Janssen said they had undertaken "thorough analyses" to assess whether the potential malfunctioning of the monitoring device had any impact on the study results.

   "These analyses confirm the results of the ROCKET AF study and the positive benefit-risk profile of Xarelto in patients with non-valvular atrial fibrillation," a Bayer spokeswoman said.

   On the Covance recheck programme, the Bayer spokeswoman continued: "Janssen and Bayer have ensured and will continue to ensure that health authorities receive all required and accurate information regarding past and ongoing clinical trials.

   "Early in the conduct of the ROCKET AF trial, a support programme was offered to investigators that would provide non-random checks of the point-of-care device values via a central laboratory (Covance).

   "This support programme was in addition to the use of an unblinded INR monitor which was described in the protocol for the trial.

   "The aim of this process was twofold: first, to provide clinical assurance to the investigators, and second, to have a mechanism to return a lab-based INR value to the investigator.

   "Importantly, this had to be accomplished while maintaining the integrity of the study blind.

   "Investigators used this option only infrequently. Of the more than 366,000 INR measurements taken over the three-year ROCKET AF clinical trial, investigators submitted 149 cases to Covance.

   "These data were not part of the database evaluated to obtain the study results. Bayer and Janssen have provided these data to health authorities.

   "The European Medicines Agency assessed these additional data and published its conclusion in September 2016 that the benefit/risk balance remains unchanged and favourable for treatment with rivaroxaban in the prevention of thromboembolism in non-valvular atrial fibrillation."

   A Janssen spokeswoman said: "It is always our intent to provide all data that are relevant to analysing the results of our clinical trials to health authorities, including the US FDA.

   "Janssen and our development partner Bayer will continue to ensure that health authorities receive all required and accurate information regarding past and ongoing clinical trials.

   "The companies have disclosed safety data to regulators and the safety monitoring board of the ROCKET AF trial and deny the central premise of BMJ's report.

   "The data in question represent fewer than one-twentieth of one percent of the 366,000 measurements taken during the ROCKET AF trial and they could not have had any impact on the conclusions of the trial.

   "With more than 23 million patients prescribed Xarelto (rivaroxaban) worldwide, real world evidence continues to confirm the positive benefit-risk profile of Xarelto.

   "Xarelto has been thoroughly evaluated across its approved indications in real world research following the medicine's approval and study after study confirm that Xarelto is performing as expected."

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10. Pharma withheld faulty device info in rivaroxaban trial

    Sep 28, 2016 | OnMedica

    By Louise Prime

    Janssen withheld data from the US Food and Drug Administration (FDA) about a faulty device used during one of the crucial trials into using rivaroxaban (Xarelto) to prevent stroke in people with non-valvular atrial fibrillation, a BMJ investigation* has revealed this morning. It found that some trial investigators had raised concerns early on about the faulty international normalised ratio (INR) measuring device – and the BMJ is now asking whether the evidence can be trusted at all.

    The ROCKET AF trial comparing rivaroxaban with warfarin concluded that the newer drug was non-inferior, but the BMJ reported in February that the evidence was flawed because the trial used the INRatio device, subsequently recalled because it could give false-low test results. At that point, experts called for an independent investigation to quickly determine if there were grounds for the New England Journal of Medicine to retract the paper, which it had published in 2011.
    
    Both Janssen and Bayer said in a letter to NEJM that an “independent reanalysis” showed that problems with the device had not affected trial outcomes. Neither the European Medicines Agency (EMA) nor the FDA have changed their recommendations regarding the use of rivaroxaban.
    
    BMJ associate editor Dr Deborah Cohen has now led an investigation into the background to the trial and approval process. She has discovered that early on in the ROCKET AF trial, Janssen executives already knew about the problems with the INRatio device – and as a result launched the Covance recheck programme to check the accuracy and reliability of INR readings made with the device, against laboratory results.
    
    But Dr Cohen found that despite the potential for this problem to compromise trial participants’ safety, as well as trial outcomes, Janssen did not reveal it to either the trial’s safety monitoring board; to rivaroxaban’s co-developer Bayer; or to the FDA prior to the drug’s approval. One of the trial investigators Markku Kaste, former head of the Clinical Stroke Research Group at Helsinki University General Hospital, said the data from the Covance recheck programme should have also been shared with investigators because “it’s vital for the ongoing ethical approval for the trial”. He added: “I now have some doubts about the validity of ROCKET AF trial. It possibly skews the data in favour of rivaroxaban.”
    
    During a review by the EMA, published in February, its analysis of blood samples taken at weeks 12 and 24 revealed that in more than a third (35%) of cases, there were “discrepancies of potential clinical relevance”. And further analyses showed that the rate of major bleeding increased exponentially with the size of the difference between INRatio and laboratory test results. Yet, the EMA said in its report that “there is sufficient evidence to conclude that the benefit/risk balance remains unchanged and favourable for treatment with rivaroxaban in the prevention of thromboembolism in non-valvular atrial fibrillation” – and the FDA is still investigating.
    
    The authors of an accompanying editorial** commented: “Although independent replication of trials, data transparency, and detailed analysis of clinical study reports will be arduous and costly, the concerns highlighted by recent investigations have shown how essential these approaches are to increase our confidence in new oral anticoagulants.”
    
    They concluded: “Meanwhile patients and clinicians must, for now, live with the uncertainty left by the evidence currently available.”

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11. Drug company failed to disclose faulty blood testing device in trial of popular medicine

    Sep 28, 2016 | iNews

    By Paul Gallagher

    The pharmaceutical arm of Johnson and Johnson, one of the world’s biggest drug companies, withheld information about a faulty blood testing device used in a key trial of a best selling anti-clotting drug.

    Executives at Janssen knew early on in the trial of concerns about device malfunction and launched a safety programme, called Covance recheck, to check the accuracy and reliability of blood test readings against laboratory results.

    The company withheld data from the US Food and Drug Administration (FDA) about the faulty equipment during approval of their blockbuster anti-clotting drug, rivaroxaban, marketed as Xarelto.

    An investigation published by The BMJ reveals the firm also failed to share these data with the trial’s data safety monitoring board, Bayer, the co-developer of rivaroxaban, despite the safety of trial participants potentially being compromised.

    The trial, known as the ROCKET AF trial, was published in the New England Journal of Medicine in 2011. It compared rivaroxaban with the older anti-clotting drug warfarin for preventing strokes in patients with irregular heartbeat.

    Rivaroxaban, a new type of oral anticoagulant, works by preventing blood from clotting and is marketed as a better alternative to the popular warfarin because patients do not need regular tests to check if they have the right amount of drug in their bloodstream.

    Concerns raised

    In February 2016, The BMJ raised concerns about the ROCKET AF trial results after the blood testing device was recalled for giving falsely low readings.

    Doctors and researchers called for the data to be independently checked, but both Janssen and Bayer said an “independent reanalysis” – published as a letter to NEJM – showed the device had not affected trial outcomes.

    Both the European Medicines Agency and the FDA have not changed their recommendations regarding the use of Xarelto, although the latter said it is “investigating”.

    Carl Heneghan, professor of evidence based medicine at Oxford University, believes patients in the trial may have been put at undue risk of harm.

    He told The BMJ that the INR device errors “are worrying” as there is “a near exponential increase in bleeding risk with increasing INR.”

    A spokesperson for Bayer said: “The European Medicines Agency’s assessment reports published in February 2016 and in September 2016 determined that the potential issue with Alere’s monitoring device did not impact the conclusions of the ROCKET-AF trial… Janssen and Bayer have ensured and will continue to ensure that health authorities receive all required and accurate information regarding past and ongoing clinical trials.”

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12. BMJ accuses pharmaceutical firm Janssen of withholding drug trial data

    Sep 28, 2016 | Jersey Evening Post

    The British Medical Journal (BMJ) alleged that Janssen, the pharmaceutical arm of Johnson and Johnson, "withheld" data from the US Food and Drug Administration (FDA) about a faulty blood testing device used during a trial for anti-clotting drug rivaroxaban, also known as Xarelto.

    During the trial to assess the effectiveness of rivaroxaban for preventing strokes in patients with irregular heartbeat , some participants took anti-clotting drug warfarin and others took rivaroxaban.

    Concerns were later raised those taking warfarin were monitored using a faulty device.

    The BMJ has reported that Jan ssen knew of concerns about potential device malfunction and launched a "safety programme" to check the accuracy and reliability of blood test readings against laboratory results.

    The journal said Janssen did not share these data with the trial's data safety monitoring board, the co-developer of rivaroxaban Bayer and the FDA prior to drug approval.

    "Drug manufacturers knew about problems with a blood testing device but did not share data before the crucial approval process," the feature by BMJ associate editor Deborah Cohen states.

    " Janssen withheld data from the Food and Drug Administration about problems with the INRatio device, which was used in the phase III trial (ROCKET AF) of the blockbuster anticoagulant.

    " The company generated these data in a safety programme (called the Covance recheck programme) set up after trial investigators became concerned, shortly after the study began, about the accuracy and reliability of the point-of-care device used to monitor patients receiving warfarin."

    Bayer and Janssen said they had undertaken " thorough analyses" to assess whether the potential malfunctioning of the monitoring device had any impact on the study results.

    " These analyses confirm the results of the ROCKET AF study and the positive benefit-risk profile of Xarelto in patients with non-valvular atrial fibrillation," a Bayer spokeswoman said .

    On the Covance recheck programme, the Bayer spokeswoman continued: " Janssen and Bayer have ensured and will continue to ensure that health authorities receive all required and accurate information regarding past and ongoing clinical trials.

    "Early in the conduct of the ROCKET AF trial, a support programme was offered to investigators that would provide non-random checks of the point-of-care device values via a central laboratory (Covance).

    "This support programme was in addition to the use of an unblinded INR monitor which was described in the protocol for the trial.

    "The aim of this process was twofold: first, to provide clinical assurance to the investigators, and second, to have a mechanism to return a lab-based INR value to the investigator.

    "Importantly, this had to be accomplished while maintaining the integrity of the study blind.

    "Investigators used this option only infrequently. Of the more than 366,000 INR measurements taken over the three-year ROCKET AF clinical trial, investigators submitted 149 cases to Covance.

    "These data were not part of the database evaluated to obtain the study results. Bayer and Janssen have provided these data to health authorities.

    "The European Medicines Agency assessed these additional data and published its conclusion in September 2016 that the benefit/risk balance remains unchanged and favourable for treatment with rivaroxaban in the prevention of thromboembolism in non-valvular atrial fibrillation."

    A Janssen spokeswoman said: "It is always our intent to provide all data that are relevant to analysing the results of our clinical trials to health authorities, including the US FDA.

    "Janssen and our development partner Bayer will continue to ensure that health authorities receive all required and accurate information regarding past and ongoing clinical trials.

    "The companies have disclosed safety data to regulators and the safety monitoring board of the ROCKET AF trial and deny the central premise of BMJ's report.

    "The data in question represent fewer than one-twentieth of one percent of the 366,000 measurements taken during the ROCKET AF trial and they could not have had any impact on the conclusions of the trial.

    "With more than 23 million patients prescribed Xarelto ( rivaroxaban) worldwide, real world evidence continues to confirm the positive benefit-risk profile of Xarelto.

    "Xarelto has been thoroughly evaluated across its approved indications in real world research following the medicine's approval and study after study confirm that Xarelto is performing as expected."

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