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FDA Nominee Califf Gave Questionable Answers to Senate
Feb 5, 2016 | POGO
By David Hilzenrath

As President Obama’s nominee for FDA Commissioner, former Duke University researcher Robert Califf has faced questions about the independence of clinical trials he conducted for drug companies.
Investigation questions Xarelto trial data accuracy
Feb 4, 2016 | Pharmafile
By Lilian Anekwe

An investigation in the BMJ alleges that the results, drawn from analysis of data from blood testing devices that measured the effectiveness of Xarelto (rivaroxaban), could be invalid. The testing device that was used during the trial was recalled in December 2014, after being found to give falsely low test results. The BMJ says the makers of the device admit that the fault dates back to 2002, but no action was taken.
Validity of Pivotal ROCKET AF Rivaroxaban Trial Questioned
Feb 5, 2016 | Medscape
By Deborah Brauser

The key ROCKET AF trial used a faulty point-of-care device to measure INR in its comparator arm of patients taking warfarin, which may have made warfarin results look worse than they otherwise would seem, alleges a new report released this week in the BMJ.
ROCKET AF Investigators: Problems With Warfarin Monitoring Device Did Not Skew Results
Feb 4, 2016 | TCTMD
By Todd Neale

Potential problems with the point-of-care device used to monitor warfarin in ROCKET AF did not appear to have a meaningful impact on the trial results, an analysis by study investigators shows. The findings come in response to questions about the validity of the trial’s main results, an issue that has also been connected to Robert Califf, MD, the nominee for FDA commissioner
EMA: Faulty device didn't distort study findings for Bayer's Xarelto
Feb 5, 2016 | FiercePharma
By Carly Helfand

Last December, European regulators said they were no longer sure whether results from a trial of Bayer's new-age clot-buster Xarelto were accurate thanks to a defect in a blood-clotting testing device used in the study. But the German pharma can breathe easy now.
BMJ questions trial evidence for rivaroxaban
Feb 4, 2016 | OnMedica
By Louise Prime

The evidence supporting the safety of rivaroxaban – now the best-selling anticlotting drug – is based on outcomes of a ‘pivotal’ drugs trial in which defective clotting test devices were used and whose validity is now in question, according to a BMJ article* published online today. Its author, BMJ associate editor Deborah Cohen, has reported calls for an independent investigation and release of trial data, to clarify the drug’s benefits.
(UPDATE-1) Xarelto trial results reaffirmed despite faulty device
Feb 5, 2016 | Reuters

Europe's drug regulator said on Friday the defective blood clotting test device used in a key trial for the approval of Bayer's top-selling anti-clotting drug Xarelto did not distort the study's main findings.
Anti-clotting drug ‘may be unsafe to take’
Feb 4, 2016 | The Telegraph

A blood clot-busting drug taken by thousands of people in the UK may be unsafe, scientists have warned. Xarelto, also known as rivaroxaban, was hailed for its ability to prevent strokes in 2011 after good trial results.
EMA Says Defective Device in Xarelto Study Has No Safety Impact
Feb 5, 2016 | Bloomberg
By Chiara Remondini

EMA has concluded that a defect with the international normalized ratio (INR) device used in the ROCKET study doesn’t change its conclusions on the overall safety or benefit-risk balance of Bayer’s Xarelto.
EMA concludes defective device in ROCKET study does not impact Xarelto’s safety
Feb 5, 2016 | European Medicines Agency

The European Medicines Agency (EMA) has concluded that a defect with the international normalised ratio (INR) device used in the ROCKET study does not change its conclusions on the overall safety or benefit-risk balance of Xarelto (rivaroxaban). The ROCKET study was the main clinical trial underpinning the use of this anti-clotting medicine in patients with non-valvular atrial fibrillation (irregular heartbeat).
Stroke Drug Fear
Feb 4, 2016 | The Sun

Stroke prevention drug taken by tens of thousands of Brits may be unsafe, a report warns.
Questions raised about pivotal rivaroxaban trial
Feb 4, 2016 | Australian Doctor
By Alice Klein

Doctors are calling for further inquiry into a key trial supporting the safety of rivaroxaban following reports its results may have been skewed by a faulty measurement device.
Concerns raised about trial supporting top selling anticoagulant drug
Feb 5, 2016 | The Pharmaceutical Journal

The validity of data produced by a pivotal trial to gain approval for direct oral anticoagulant rivaroxaban (Xarelto) from US and European regulators has been called into question by an investigation published by The BMJ.
Pivotal NOAC trial may have been compromised: BMJ
Feb 4, 2016 | Medical Observer
By Anna Evangeli and Rada Rouse

Results from a pivotal trial on the NOAC rivaroxaban may have been compromised as a device used to measure international normalised ratio (INR) in the warfarin arm was later found defective, the BMJ has charged.
Point-of-Care Warfarin Monitoring in the ROCKET AF Trial
Feb 3, 2016 | New England Journal of Medicine
By Manesh R. Patel, M.D. and Anne S. Hellkamp, M.S.

In the Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF), investigators found that rivaroxaban was noninferior to warfarin in the prevention of stroke and systemic embolism in patients with atrial fibrillation. In December 2014, four years after completion of the trial, the Food and Drug Administration (FDA) issued a recall notice for a medical device correction of the Alere INRatio Monitor System (formally known as the Hemosense INRatio device). The recall correction notice was issued because the FDA-approved and European Conformity (CE)–marked whole-blood, point-of-care device may provide an international normalized ratio (INR) result that is lower than an automated, plasma-based laboratory INR in patients with certain specific medical conditions.
Rivaroxaban: can we trust the evidence?
Feb 3, 2016 | BMJ
By Deborah Cohen

An investigation by The BMJ has uncovered the use of a faulty device in a regulatory drug trial, potentially putting patients at unnecessary risk, Deborah Cohen reports
Questions raised about clinical trial of popular heart drug
Feb 3, 2016 | CBS News
By Mary Brophy Marcus

New questions are being raised about the clinical trial of a widely used heart drug, and critics are calling for an independent investigation, after a medical device used during the study was later found to be faulty and recalled.
New Studies Seek To Allay Concerns Over The ROCKET-AF Trial
Feb 3, 2016 | Cardiobrief
By Larry Husten

New post-hoc analyses of ROCKET-AF confirm the main results of the controversial trial, according to a paper published in the New England Journal of Medicine. The papers are a response to disturbing questions about the trial raised last fall. But the new analyses will not fully satisfy some critics of the trial who are calling for independent analysis of the trial.
Scientists Calling For Independent Investigation Of Blood-Thinning Drug Rivaroxaban After Clinical Trial Snafu
Feb 3, 2016 | Medical Daily
By Ed Cara

A new special report released Wednesday by The BMJ is renewing calls for an independent investigation of a blood thinner, rivaroxaban, that has quickly become the most popular drug of its kind.
(UPDATE) BMJ Investigation Casts Doubt on Validity of Rivaroxaban Trial
Feb 3, 2016 | Drug Discovery and Development
By Stephanie Guzowski

New questions have been raised about the validity and reliability of data in the ROCKET-AF trial, which serves as the backbone for the approval of rivaroxaban (Xarelto), according to an investigation published Wednesday by The BMJ. Rivaroxaban is a blockbuster drug for stroke prevention in atrial fibrillation (AF) that gained approval from both U.S. and European regulators.
(UPDATE) Concerns Raised Over Approval Process for Top-Selling Blood Clotting Prevention Medication
Feb 3, 2016 | Healthline
By David Mills

Questions are reportedly being raised about a clinical drug trial that was part of the approval process for a top-selling blood clotting prevention drug.
Rivaroxaban Trial Threatened by Possibly Flawed INR Measurements
Feb 3, 2016 | NEJM Journal Watch
By Joe Elia

A faulty device used in the trial leading to approval of rivaroxaban — a direct-acting oral anticoagulant — has called those results into question, according to an investigation reported in The BMJ. The trial's authors, however, refute the concern.

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Traditional and Online

FDA Nominee Califf Gave Questionable Answers to Senate

Feb 5, 2016 | POGO

By David Hilzenrath

As President Obama’s nominee for FDA Commissioner, former Duke University researcher Robert Califf has faced questions about the independence of clinical trials he conducted for drug companies.
At a confirmation hearing in November and in a written response to later questions from Senator Elizabeth Warren (D-MA), Califf offered comforting answers. He said that plans for clinical trials are subject to FDA review.
But those answers omitted some history that might be less reassuring: a clinical trial Califf had co-chaired was conducted in defiance of FDA guidance.
At least one member of an FDA advisory committee looked back on that history at a 2011 committee meeting and worried that the clinical trial put commercial considerations ahead of health and safety. Minutes of the meeting say that, within the committee, “There was concern about . . . a marketing ploy.”
The issue Warren asked Califf to address as part of his confirmation review essentially boiled down to this: How much confidence can the public and the FDA have in clinical trials that are sponsored by the very companies whose drugs are being tested? At Duke, Califf led an institute that tests drugs for pharmaceutical companies. The companies use the test results when petitioning the FDA to approve their products, and the FDA bases decisions on that data.
The financial support Califf and his research have received from drug companies “naturally raises questions about your relationship with the drug industry,” Warren told Califf during his confirmation hearing. “And one particular concern with industry funding of academic work is that drug companies may be able to exert influence over the conduct of those studies,” Warren said.
Warren asked Califf to detail, among other things, what input the sponsors of the clinical trials had in the design of trials he conducted or oversaw at Duke.
Califf said that, though the drug companies participate in the design process, the academic leaders of the trial have the final say. He also highlighted the FDA’s involvement.
“When industry funds a clinical trial, whether it’s devices or drugs, done through our institute, the design of the trial is something that’s done jointly and done very publicly, because typically it’s done to try to get an indication from the FDA,” Califf said.
The plan or “protocol” for the trial “has to be submitted” to the FDA “before the trial starts,” Califf said.
Warren followed up with written questions, and, in his answers, Califf offered similar reassurance.
“All aspects of the design are included in the protocol, which is subject to review and approval by the FDA,” Califf wrote.
Califf’s comments might leave the impression that, because the FDA gets to review the protocols, there’s no reason to worry.
But the people running manufacturer-sponsored clinical trials don’t necessarily have to do what the FDA says, and a clinical trial that Califf helped lead illustrated that fact by disregarding the FDA’s wishes.
That history is reflected in FDA records, including a review of the clinical trial by FDA staff, an FDA memo explaining the agency’s decision to approve the drug, the minutes of the 2011 FDA advisory committee meeting, and the transcript of that meeting.
The clinical trial, known as ROCKET AF, studied the safety and effectiveness of the blood thinner Xarelto. In 2011, based on that trial, the FDA approved the drug to prevent blood clots and strokes in patients with a heart condition called atrial fibrillation. Califf co-chaired the ROCKET AF executive committee, which “designed the trial and was responsible for oversight of study conduct.”
The FDA was consulted before the trial began, but that wasn’t the whole story, FDA records show.
Because Xarelto has a half-life in the body of about half a day, FDA staff wanted the trial to use a regimen in which patients took the drug twice a day. Instead, in ROCKET AF, patients were given only one dose per day.
Taking one dose per day is more convenient than taking two, so once-a-day dosing had potential marketing advantages. However, given Xarelto’s half life, FDA reviewers worried that, if patients were taking only one dose per day, the concentration of the drug in their bodies would plunge between doses and fluctuate sharply over each 24-hour period.
For patients who need blood thinners, there are dangers if their blood gets either too thick or too thin. If the blood is too thin, they are at heightened risk of bleeding, including strokes caused by bleeding the brain. If the blood is too thick, they are at heightened risk of developing clots, which can travel through the body and block blood circulation, potentially causing a different type of stroke.
In an FDA memo, the agency’s Stephen M. Grant recounted that, before the Xarelto trial began, drug company Janssen Pharmaceuticals asked the FDA if it agreed with the planned once-a-day dosing regimen.
“[W]e said that we did not concur,” Grant wrote. “[W]e suggested that administering XARELTO twice a day might result in better outcomes.”
ROCKET used the once-a-day regimen anyway.
A report by FDA reviewers literally underlined the difference of opinion between the people behind the clinical trial and the regulators at the FDA. As that review put it:
“Agreement was not prospectively achieved on the dose(s) to be tested prior to the execution of the ROCKET trial.” [Emphasis in original]
Califf’s responses to Warren are not his only dubious statements on the subject.
After the Xarelto trial was completed, he co-authored an article that presented the results in the New England Journal of Medicine. The article included this statement:
“Pertinent national regulatory authorities . . . approved the protocol” for the ROCKET AF trial.
POGO asked FDA spokeswoman Sandy Walsh if it would be accurate to say the FDA approved the protocol for ROCKET AF.
“No, we say that we allowed it to proceed,” she answered.
Apparently, the FDA refrained from blocking the trial, which is not the same as explicitly approving the protocol. The agency allowed the trial to proceed because, based solely on “inadequate dose selection,” it lacked the authority to do otherwise, the FDA’s Grant wrote in his memo.
The statement in Califf’s New England Journal of Medicine article glossed over the FDA’s objections to the dosing regimen and made it appear that the FDA blessed the protocol when it merely capitulated.
Califf did not respond to questions sent by email for this article. His nomination, which is awaiting a vote by the full Senate, won the endorsement last month of the Senate Committee on Health, Education, Labor and Pensions.
In the committee, Warren voted for Califf. “I am satisfied that he has conducted himself with integrity as an academic researcher,” she said in a statement.
She did express broader concerns.
“My examination of the Califf nomination has raised serious questions about our current clinical trials system,” Warren said. “I am particularly concerned with a lack of overall transparency, numerous opportunities for conflicts of interest, and a marked shortage of trials that are designed to determine which products to treat a given condition are the most effective—as well as cost-effective—for various patient populations.”
“My examination has also raised concerns about the FDA’s willingness to stand up to industry preferences in the design and conduct of clinical trials,” Warren said.
Califf has committed to address those issues, Warren added.

It is unclear if or when Califf’s nomination will be voted on by the full Senate. Citing a variety of concerns, including his ties to the pharmaceutical industry, several Senators have placed holds on the nomination or said they will try to block it by other means.

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Investigation questions Xarelto trial data accuracy

Feb 4, 2016 | Pharmafile

By Lilian Anekwe

An investigation in the BMJ alleges that the results, drawn from analysis of data from blood testing devices that measured the effectiveness of Xarelto (rivaroxaban), could be invalid. The testing device that was used during the trial was recalled in December 2014, after being found to give falsely low test results. The BMJ says the makers of the device admit that the fault dates back to 2002, but no action was taken.
In November 2015, the EMA told The BMJ they were investigating the fault, while the FDA said they were “aware of concerns regarding the INRatio device and its use in the ROCKET-AF trial and is reviewing relevant data.”
In December Duke University’s Clinical Research Institute carried out a trial on behalf of Johnson & Johnson, the owner of Janssen which markets Xarelto in the US. The sponsored analyses found finding that Duke said “are consistent with the results from the original trial and do not alter the conclusions of ROCKET-AF.”
The BMJ, and several clinicians approached by the journal, are calling for an independent investigation and access to the original trial data to clarify the drug’s benefits and harms. But the journal says that “previous attempts to do this have been thwarted by Bayer who... have only signed up to sharing information on 'study reports for new medicines approved in the US and the EU after January 1, 2014.'”
And Harlan Krumholz, professor of medicine at Yale University, says the New England Journal of Medicine (NEJM), the journal that published the ROCKET-AF trial, should flag up concerns about the paper to the medical community. There should be “an investigation by an independent group of experts to quickly determine if there are grounds for retraction,” he adds.
This week the ROCKET AF executive committee have published their re-analysis of the study in the NEJM. Their research letter states that “these results are consistent with those of the overall trial population in showing the non-inferiority of rivaroxaban versus warfarin for preventing stroke and systemic embolism, with similar rates of overall bleeding and lower rates of fatal and intracranial bleeding among patients treated with rivaroxaban but a higher rate of gastrointestinal bleeding.”
They conclude that “these results are consistent with the overall trial findings and indicate that possible malfunction of the point-of-care device used for INR measurement in the ROCKET AF trial that potentially led to lower INR values than would be obtained by laboratory testing did not have any significant clinical effect on the primary efficacy and safety outcomes in the trial.”
Dr Michael Devoy, head of medical affairs and pharmacovigilance and Bayer’s chief medical officer, says in a statement: “Thoroughly investigating whether the use of this device had any impact on the ROCKET AF study results has been our priority since we learnt about the potential malfunctioning of the INR device and it is very reassuring to us that the analyses confirm the results of the ROCKET AF study.

“What was reassuring from the start is that the results originally seen in ROCKET AF are in line with the post-marketing studies with Xarelto in stroke prevention in patients with atrial fibrillation. Xarelto is the most studied of all of the NOACs and its positive benefit-risk profile has been repeatedly demonstrated across its approved indications."

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Validity of Pivotal ROCKET AF Rivaroxaban Trial Questioned

Feb 5, 2016 | Medscape

By Deborah Brauser

The key ROCKET AF trial used a faulty point-of-care device to measure INR in its comparator arm of patients taking warfarin, which may have made warfarin results look worse than they otherwise would seem, alleges a new report released this week in the BMJ[1].
The findings from ROCKET AF, which were first published in the New England Journal of Medicine in August 2011, showed that the novel oral anticoagulant (NOAC) rivaroxaban (Xarelto, Bayer/Johnson & Johnson) was noninferior to dose-adjusted warfarin for the prevention of stroke or major embolism in more than 14,000 patients with atrial fibrillation (AF). Three months later, the FDA approved rivaroxaban for the treatment of AF based solely on these results.
But as described in the BMJ, the warfarin arm used an INR-measuring device that was included in a December 2014 recall because of the possibility of delivering "clinically significantly lower" results than those delivered from a plasma-based laboratory reading.
"A falsely low reading could mean that patients had their warfarin dose unnecessarily increased, leading to a greater risk of bleeding," writes BMJ associate editor Deborah Cohen. "It could [also] make rivaroxaban seem better than it was at reducing the risk of bleeding and throws doubt onto outcomes used to support the use" of rivaroxaban.
However, in a research letter in the NEJM[2], also published this week, ROCKET AF lead investigator Dr Manesh R Patel (Duke Clinical Research Institute [DCRI], Durham, NC) and other executive committee members report that, after conducting a series of post hoc analyses, new results "are consistent with the overall trial findings" and any possible malfunctions in the device "did not have any significant clinical effect on the primary efficacy and safety outcomes in the trial."
"We recognize that there are people who may have concerns with these findings. We hope that the diligent, thorough analysis we've done will answer a lot of those concerns," Patel told heartwire from Medscape.
In the BMJ report, Dr Harlan Krumholz (Yale University, New Haven, CT) noted that the NEJM should place "an immediate expression of concern" on the original ROCKET AF paper—and that the study "should be considered of uncertain validity until a more thorough review can be done."
Do the new data released by Patel et al alleviate his worries? Krumholz told heartwire "no." Although he noted that the DCRI provided a "nice analysis to prove their trial valid," he wished they had done further analyses; he stressed that all data should be made public. "Why not share the data and let others take a look?" he asked.
On the other hand, Dr Lars Wallentin (Uppsala Clinical Research Center, Sweden) told heartwire by email that although the time in therapeutic range (TTR) was lower than targeted in the warfarin arm of ROCKET AF, the standards of warfarin care still seemed "rather similar" to real-life situations.
"Based on the totality of available knowledge, there are no compelling reasons to change the current treatment recommendations concerning any of the new oral anticoagulants for stroke prevention in atrial fibrillation."
Class I Recall
The FDA issued a class I recall notice in December 2014 for the Alere INRatio Monitor System and announced that the manufacturer had received 924 reports of device malfunctions. But Patel said the ROCKET AF executive committee did not receive notice that the device used in their warfarin arm was part of this recall until the fall of 2015.
Cohen writes that the BMJ did not receive any response from the DCRI, but the drug manufacturers told the journal they were taking the concerns seriously. After she contacted the European Medicines Agency (EMA), the EMA responded in November 2015 that it was investigating and that "the INR device may have impacted the clotting results" in some of the warfarin-treated patients.
In addition, the FDA told the BMJ that it was "reviewing relevant data" in regard to the defective device's possible effect on ROCKET AF's results.
Patel said the investigators began their new analyses in October and finished in December. A short summary statement was released by Bayer/Johnson & Johnson soon after, reporting that the results confirmed the ROCKET AF findings and the positive benefit/risk profile of rivaroxaban in the treatment of nonvalvular AF.
At that time, there was a clamor for more details to be released immediately instead of waiting for publication. But Patel notes that there were concerns about making a statement without having all of the data ready.
"We spent a lot of time with two independent statisticians, a group of individuals reviewing the data in a blinded fashion, doing the reanalysis, and then we wanted it to go through peer review," he said. "We tried to act as fast as possible, with substantial analysis now in press 4 months after we first received notice."
He added that it's important to note that the reanalysis by the ROCKET executive committee is independent from the one done by the sponsors, which was provided to both US and European regulatory agencies.
Reexamining Subgroups
In their research letter, the investigators point out that the FDA's recall said the device INR readings may be lower in patients "with certain specific medical conditions," including abnormal hematocrit levels, bleeding or unusual bruising, or conditions linked to higher fibrinogen levels.
So for their new analyses, they identified study participants with any of the listed "recall conditions" and then compared outcomes in the treatment subgroups. A total of 37% of the patient population had at least one of the recall conditions, which were distributed almost equally between those receiving each treatment.
When they looked at the entire patient population (primary results), those with no recall condition, and those with any recall condition, there were no differences in rates of stroke or embolism.
The subgroup with no recall condition also had safety end points consistent with the primary results, with similar rates of overall bleeding and lower rates of fatal and intracranial bleeding among patients treated with rivaroxaban but a higher rate of gastrointestinal bleeding (hazard ratio [HR] 1.47, 95% CI 1.04–2.06).
Bleeding rates were higher in both treatment arms for those with any recall condition, "with a trend toward a higher relative risk of major bleeding with rivaroxaban than with warfarin" (5.53 vs 4.79 events per 100 person-years, respectively)—something that wasn't found in those without any recall condition (2.34 vs 2.68 events, respectively).
"This result runs counter to the concern that a potentially malfunctioning INR device in patients with relevant conditions would have led to incorrect low reading and inappropriate increase in warfarin dose, resulting in a higher warfarin bleeding risk in these patients," said Patel
Given the totality of the findings, we concluded that we do not find a statistically significant interaction between the device in patients who may have had a condition and the outcomes of those patients," he summarized. "Therefore, we think the original trial conclusions are still held."
Still, Patel added that the investigators are doing further analyses "to make sure no other concerns remain." A statement sent to heartwire from Duke added that the trial's executive committee "will continue to discuss options for additional analysis of the data, including review and replication by other groups."
Debate Continues
"Although I congratulate Duke for starting in this direction, I don't think they settled the questions. They took one approach to try to test whether this defective device disadvantaged the warfarin arm; but I think there are many other ways you may want to look at this," said Krumholz.
"This is just a start. And I was a little surprised that they felt that this confirmed the results."
He added that he's skeptical as to whether the device was mismeasuring only certain groups of patients and "would like to see the data on that." Also, "I'd like for someone to really explain why this device is defective. What is the mechanism?"
In addition, the BMJ report quotes former FDA clinical pharmacologist Bob Powell as saying "a comparison should be made between the defective point-of-care readings and the two sets of 'gold-standard' central lab readings" that the investigators conducted at 12 and 24 weeks.
"This is information that the investigators have," said Krumholz. "I just don't know why they didn't share it. My hope is that the data show that there's no difference [in the two types of readings] and then we're all set. I would like to not be uncertain about this drug."
Also in the BMJ, Krumholz noted that further investigation into the trial is needed "by an independent group of experts to quickly determine whether there are grounds for retraction."
Even with the new release of data, he still thinks an independent investigation is needed. "These questions cannot be easily answered by a single analysis. And there should be a public dialogue as to whether the findings are truly valid."
And he reiterated his call for the release of more data, noting that Johnson & Johnson told him it would allow access to all trial information. However, Bayer refused. The BMJ reports that a Bayer spokesperson said the company shares data only on studies for new medications approved after January 2014.
Device Transparency Needed?
"Currently, there is little public information about which . . . devices are used in any of the direct oral anticoagulant trials," writes Cohen. "They are not named in the published phase 3 trials." She reports that it was only after examining European regulatory documents that she discovered that ROCKET AF used one of the faulty devices and adds that Alere told her the faults date back to 2002.
Cohen notes that questions that remain unanswered include whether there were any investigator complaints about mismatched readings and whether the device had been validated any time before or during the trial.
As the new debate continues about the rivaroxaban trial, what changes (if any) should clinicians make in the meantime to the way they prescribe the drug?

"Patients shouldn't immediately stop using this drug. There's no imminent danger that's been raised. But I'm not sure what clinicians should do," said Krumholz. "It's hard to say we know for sure it doesn't work as well as the trial said. But we're certainly less certain of the results than we were before we heard this news."

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ROCKET AF Investigators: Problems With Warfarin Monitoring Device Did Not Skew Results

Feb 4, 2016 | TCTMD

By Todd Neale

Potential problems with the point-of-care device used to monitor warfarin in ROCKET AF did not appear to have a meaningful impact on the trial results, an analysis by study investigators shows. The findings come in response to questions about the validity of the trial’s main results, an issue that has also been connected to Robert Califf, MD, the nominee for FDA commissioner.
Califf, then at Duke University, was co-chair of the executive steering committee for ROCKET AF, which showed that rivaroxaban (Xarelto; Bayer/Janssen Pharmaceuticals) was noninferior to warfarin for preventing stroke or systemic embolism in patients with nonvalvular A-fib.
In December 2014, roughly 4 years after the main trial results were reported and 3 years after rivaroxaban was approved for stroke prevention, testing device manufacturer Alere issued an alert about its INRatio and INRatio2 PT/INR Monitor System, which was used to monitor anticoagulation levels in warfarin-treated patients in ROCKET AF.
The company informed users in its medical device correction that patients with certain conditions—including anemia with a hematocrit less than 30%, unusual bleeding or bruising, and conditions associated with elevated fibrinogen levels—should not be tested with the system because of the possibility of obtaining INR results lower than would be expected with an automated, plasma-based laboratory INR test. The announcement, which came in the form of an FDA recall notice, also noted that the instructions for optimal use recommend using the test in patients with a hematocrit of 30% to 55%.
The concern is that a low INR reading could prompt an inappropriately high warfarin dose and, in turn, induce excess bleeding. This would inadvertently lead to rivaroxaban appearing safer than warfarin in the ROCKET AF study.
The possibility of skewed INR findings has focused attention on whether the trial results can still be considered valid and has put heat on the ROCKET AF leaders, who say they were made aware of the issue in October 2015. Califf, in particular, has been affected by the nagging questions as he moves through the nomination process. Both the FDA and the European Medicines Agency have said that they are reviewing data related to the potential impact of the device issues on the ROCKET AF results.
After members of the trial’s executive committee learned about the potential problem, they initiated a series of post hoc analyses, the results of which were published online this week in a research letter in the New England Journal of Medicine.
Results Match Those of Overall Trial
Manesh Patel, MD, of the Duke Clinical Research Institute (Durham, NC), and colleagues performed efficacy and safety analyses in subgroups of patients with and without any of the conditions listed in the device recall notice. Also included in the recall group were patients with hematocrit values outside of the recommended range. Of the 14,236 patients in ROCKET AF, 63% did not have any recall condition and 37% had at least 1.
In the subgroup without recall conditions, results were consistent with the overall trial findings. Rivaroxaban was noninferior to warfarin for preventing stroke or systemic embolism, with similar rates of overall bleeding in both groups. Rivaroxaban carried lower risks of fatal and intracranial bleeding but a higher risk of GI bleeding.
Results also were generally consistent in the patients with recall conditions, although there was a nonsignificant trend toward a higher major bleeding risk with rivaroxaban vs warfarin; this trend was not seen in patients without recall conditions (P = .04 for interaction).
Patel told TCTMD that the finding is likely due to chance considering the number of tests that were performed. “But nevertheless,” he added, “that finding goes against the hypothesis that the device was leading to a bleeding risk.”
Other analyses are ongoing, but these initial ones most directly address the concerns that have been raised, Patel said.
“We take the integrity of the trial and the findings very seriously and as soon as we learned about [the issue] we were able to at least do this first wave of analyses, which have comforted us and give us at least some support to tell our investigators, our patients, and our colleagues that we think the trial results remain consistent,” he said.
In a separate prepared statement, the members of the executive committee concluded that “the re-analysis found that any possible malfunction of the device that could have led to lower INR measures than laboratory testing did not have any significant clinical effect on the primary efficacy and safety outcome measures recorded in the ROCKET AF trial.”

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EMA: Faulty device didn't distort study findings for Bayer's Xarelto

Feb 5, 2016 | FiercePharma

By Carly Helfand

Last December, European regulators said they were no longer sure whether results from a trial of Bayer's new-age clot-buster Xarelto were accurate thanks to a defect in a blood-clotting testing device used in the study. But the German pharma can breathe easy now.
Friday, the European Medicines Agency said that the device--an INR product from Alere ($ALR), recalled in December--did not distort the main findings of the study, which established Xarelto's superiority over old-guard therapy warfarin as a treatment for atrial fibrillation.
"Xarelto can continue to be used as before, in line with the current prescribing information," the agency said on its website.
It's good news for Bayer, which counts Xarelto among 5 new products slated to bring in the bulk of its growth going forward. At the end of October, the med boasted a 34% market share around the world, Reuters reports, and it raked in €1.6 billion for the German pharma--which shares it with Johnson & Johnson ($JNJ)--through the first 9 months of last year.
And while Xarelto's makers are hard at work on clinical trials that could bring in new indications, atrial fibrillation is currently its largest market--and there, it competes with Boehringer Ingelheim's Pradaxa and Pfizer ($PFE) and Bristol-Myers Squibb's ($BMY) Eliquis.
So far in its lifespan, Xarelto hasn't had any problem climbing its way to the top of its class--and staying there. But new developments for its rivals could mean more serious competition. Last October, the FDA approved Praxbind, a reversal agent for Boehringer's med, making it the only next-gen anticoagulant whose effects can be reversed in the event of profuse bleeding.

And last week, Bristol-Myers execs told shareholders that Eliquis is now No.1 in new-to-brand patient share in cardiology in 12 markets around the world, predicting that the therapy was "well on our way" to becoming the top dog worldwide.

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BMJ questions trial evidence for rivaroxaban

Feb 4, 2016 | OnMedica

By Louise Prime

The evidence supporting the safety of rivaroxaban – now the best-selling anticlotting drug – is based on outcomes of a ‘pivotal’ drugs trial in which defective clotting test devices were used and whose validity is now in question, according to a BMJ article* published online today. Its author, BMJ associate editor Deborah Cohen, has reported calls for an independent investigation and release of trial data, to clarify the drug’s benefits.
In 2011 the New England Journal of Medicine published the ROCKET-AF trial,** in which the ability of the direct oral anticoagulant rivaroxaban (Xarelto) and warfarin to prevent ischaemic stroke and systemic embolism were compared in 14,264 people with non-valvular atrial fibrillation, as well as the drugs’ safety. Data from this trial, supporting the non-inferiority of rivaroxaban – and showing there was no significant difference between groups in the risk of major bleeding (although intracranial and fatal bleeding occurred less often in the rivaroxaban group) – were used to gain approval for the drug from both US and European regulators. The BMJ said it is marketed as “a better alternative to warfarin because patients don’t need regular tests to check if they have the right amount of drug in their bloodstream”.
However, the BMJ has discovered that the device used in the ROCKET-AF trial to measure international normalised ratio (INR) – the INRatio device – was recalled in December 2014 after it was found to give false-low test results. INRatio’s manufacturer, Alere, had received 925 reports of malfunctions including 14 serious injuries; it told the BMJ that the fault predated the beginning of the ROCKET-AF trial.
Dr Cohen wrote: “In terms of the trial results, it could make rivaroxaban seem safer than it was with respect to the risk of bleeding and throws doubt onto outcomes used to support the use of the world’s best-selling new oral anticoagulant.” She said there are now concerns about the validity of the trial results underpinning rivaroxaban’s safety. The European Medicines Agency (EMA) and US Food and Drug Administration (FDA) said they were aware of such concerns, and reviewing relevant data.
Although there are now demands from doctors and scientists for an independent investigation, and for manufacturer Bayer to allow access to the original trial data, to clarify its drug’s benefits and harms, Dr Cohen said it looked unlikely that Bayer would sanction this data release “any time soon”, as a spokesperson told the BMJ that it had only agreed to share information on “study reports for new medicines approved in the US and the EU after 1 January 2014”.
Yale University professor of medicine (cardiology) Harlan Krumholz called on the NEJM, which published the original research paper, to place on it an “immediate expression of concern” to alert the medical community that it should be considered of uncertain validity, and said that there should be “an investigation by an independent group of experts to quickly determine if there are grounds for retraction”.

Dr Cohen ends her report with criticism from a former FDA clinical pharmacologist of the regulators’ lack of a mandate to act without a safety signal, once a drug is on the market. Bob Powell concluded: “It is this lack of safety signal that appears to be hindering the FDA in their desire to pursue tailored dosing for DOACs. If it turns out that the issue with the INRatio device changes the safety profile of rivaroxaban, this very well may constitute the safety signal necessary for the FDA to act in this regard.”

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(UPDATE-1) Xarelto trial results reaffirmed despite faulty device

Feb 5, 2016 | Reuters

Europe's drug regulator said on Friday the defective blood clotting test device used in a key trial for the approval of Bayer's top-selling anti-clotting drug Xarelto did not distort the study's main findings.
"Xarelto can continue to be used as before, in line with the current prescribing information," the European Medicines Agency (EMA) said on its website.
The study known as ROCKET compared Xarelto with older drug warfarin for preventing strokes in patients with a type of irregular heartbeat common among the elderly.
That is by far the biggest market for the drug, which Bayer jointly developed with Johnson & Johnson, and which competes with Bristol Myers-Squibb and Pfizer's Eliquis.
A so-called INR device by Alere, which measures how quickly blood starts clotting and which was used in the trial, was recalled in December 2014 after giving falsely low test results.
"A defect with the international normalized ratio (INR) device used in the ROCKET study does not change its conclusions on the overall safety or benefit-risk balance of Xarelto," EMA said in the statement. Bayer said at the end of October that Xarelto has a 34 percent market share globally. Bayer chalked up 1.68 billion euros ($1.8 billion) in revenue from Xarelto in 2014 and 1.60 billion in the first nine months of 2015, up 38 percent from a year earlier, making it Bayer's best-selling drug.

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Anti-clotting drug ‘may be unsafe to take’

Feb 4, 2016 | The Telegraph

A blood clot-busting drug taken by thousands of people in the UK may be unsafe, scientists have warned. Xarelto, also known as rivaroxaban, was hailed for its ability to prevent strokes in 2011 after good trial results.
But an investigation published in the BMJ has question the trial's validity, claiming to used a blood clot test device recalled in December 2014 for giving falsely low test results.
The BMJ wrote: "It could make rivaroxaban seem safer than it was with respect to the risk of bleeding."
Bayer, Xarelto's manufacturer, has said the faulty device did not have an effect on the overall trial results.

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EMA Says Defective Device in Xarelto Study Has No Safety Impact

Feb 5, 2016 | Bloomberg

By Chiara Remondini

EMA has concluded that a defect with the international normalized ratio (INR) device used in the ROCKET study doesn’t change its conclusions on the overall safety or benefit-risk balance of Bayer’s Xarelto.
* EMA says Xarelto can continue to be used as before, in line with the current prescribing information
* ROCKET study was main clinical trial underpinning use of this anti-clotting drug in patients with non-valvular atrial fibrillation (irregular heartbeat)
* NOTE Dec. 9: Bayer Confirms Positive Benefit-Risk Profile of Xarelto
* NOTE Dec. 9: Bayer anticoagulant investigated by EMA
* Statement
To contact the reporter on this story:
Chiara Remondini in Milan at cremondini@bloomberg.net
To contact the editors responsible for this story:

Gaurav Panchal at gpanchal2@bloomberg.net

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EMA concludes defective device in ROCKET study does not impact Xarelto’s safety

Feb 5, 2016 | European Medicines Agency

The European Medicines Agency (EMA) has concluded that a defect with the international normalised ratio (INR) device used in the ROCKET study does not change its conclusions on the overall safety or benefit-risk balance of Xarelto (rivaroxaban). The ROCKET study was the main clinical trial underpinning the use of this anti-clotting medicine in patients with non-valvular atrial fibrillation (irregular heartbeat).
This means that Xarelto can continue to be used as before, in line with the current prescribing information.
In the study, which compared Xarelto with warfarin, the INR device was used to measure blood clotting in patients taking warfarin. Because of the defect, there were concerns that the INR device could have provided lower INR values in some patients in the warfarin group. The lower values could in turn have led investigators to give too high a dose in the warfarin group, increasing their risk of bleeding and so giving a false impression of the comparative safety of Xarelto.
After further analyses of the ROCKET study data taking into account the defect in the INR device, EMA’s Committee for Medicinal Products for Human Use (CHMP) concluded 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. In addition, data from other large studies confirmed the comparative safety of the medicine and showed similar rates of bleeding in their warfarin groups.
The CHMP therefore considered that the benefit-risk balance of Xarelto in patients with non‑valvular atrial fibrillation remains unchanged.
EMA started investigating this issue as soon as it was informed of the defect in the INR device by the marketing authorisation holder of Xarelto, Bayer Pharma AG, in September 2015.
The CHMP assessment report with detailed information on the analyses performed will be published shortly on EMA’s website.
Note
An INR device is a device used to monitor the effects of warfarin and similar anticoagulants (anti-clotting medicines). It measures how long it takes for blood to clot. The higher the INR, the longer it will take for the blood to clot (and the higher the risk of bleeding)

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Stroke Drug Fear

Feb 4, 2016 | The Sun

Stroke prevention drug taken by tens of thousands of Brits may be unsafe, a report warns.
Experts fear blood thinning pill Xarelto, also called Rivaroxaban, could trigger life-threatening bleeding.
A British Medical Journal investigation has revealed a blood-testing device gave false readings in some patients in trials. There were 830,000 prescriptions for it last year, the Health and Social Care Information Centre says.
Alere Inc recalled its INratio device in December 2014. Drug maker Bayer said it notified health authorities when alerted but tests confirmed it was safe.

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Questions raised about pivotal rivaroxaban trial

Feb 4, 2016 | Australian Doctor

By Alice Klein

Doctors are calling for further inquiry into a key trial supporting the safety of rivaroxaban following reports its results may have been skewed by a faulty measurement device.
The ROCKETAF trial, which involved more than 14,000 patients with nonvalvular atrial fibrillation, found that rivaroxaban (Xarelto) was as effective as warfarin at preventing stroke and had a similar risk of major bleeds.
The results were published in the New England Journal of Medicine in 2011 and earned the drug approval in Australia, Europe and the US soon afterwards.
However, a BMJ investigation has revealed that the pointofcare devices used to measure INR in the warfarin arm of the trial were recalled in 2014 because they gave falsely low readings.
According to the journal's Associate Editor Deborah Cohen, this may have led warfarin patients to receive inappropriately high doses, which could have increased their risk of haemorrhage.
Higher bleeding risk in the warfarin group would make rivaroxaban look relatively safe in comparison, she noted.
"[This] could make rivaroxaban seem safer than it was in terms of the risk of bleeding and throws doubt on outcomes used to support the use of the world's bestselling new oral anticoagulant," she wrote.
Since learning of the recall, Bayer, the manufacturer of rivaroxaban, said it had undertaken thorough analyses to assess whether the potential malfunctioning of the INR device had any impact on the trial results.
"These analyses confirm the results of the ROCKETAF study and the positive benefitrisk profile of Xarelto in patients with nonvalvular atrial fibrillation," the company said in a statement.
PBS data shows that almost one million scripts for rivaroxaban are written each year in
Australia.
The TGA confirmed on Thursday that it is looking into the matter.
A spokesperson said that the regulator was reviewing the information to determine what action was required.
Professor Alexander Gallus, a professor of haematology at Flinders University, said it was too early to say whether the faulty pointofcare devices in the ROCKETAF trial represented a "fatal flaw".
"Remember that warfarin dosing is a very inexact science," he told Australian Doctor. "Until we know just how wide the systematic error in the trial was, we don't know how much of a concern it is.
"It is a question that needs to be addressed and it needs to be addressed quickly, but I don't think this is something we should exaggerate at this stage."
The US Food and Drug Administration and the European Medicines Agency (EMA) also confirmed they were carrying out investigations into rivaroxaban and seeking further information from manufacturers.

Professor Guido Rasi, the executive director of the EMA told the BMJ: “It would be nice to have some independent study carried out to give confidence in the use of this medicine.”

Dr Bob Powell, a former FDA clinical pharmacologist, added that a key question would be whether INR results obtained with the pointofcare devices matched those obtained by ‘gold standard' central lab tests in the trial.

Last year, an investigation by US journalist Charles Seife revealed that an earlier trial of rivaroxaban — the RECORD trial — received warnings in eight out of 16 FDA inspections. The warnings were based on evidence of falsification, deliberate unblinding, and systemic discarding of medical records, Mr Seife wrote in JAMA Internal Medicine.

Professor Gallus has received honoraria from Bayer in the past but declared no immediate conflicts of interest.

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Concerns raised about trial supporting top selling anticoagulant drug

Feb 5, 2016 | The Pharmaceutical Journal

The validity of data produced by a pivotal trial to gain approval for direct oral anticoagulant rivaroxaban (Xarelto) from US and European regulators has been called into question by an investigation published by The BMJ.
The ROCKET-AF trial – published in the New England Journal of Medicine (NEJM) in 2011[1] – used a point of care device to measure international normalised (INR) ratio in patients taking warfarin, which The BMJ discovered had been recalled in December 2014 after giving falsely low test results, raising concerns about the accuracy of data on rivaroxaban’s safety profile. Rivaroxaban is manufactured by Bayer and is marketed in the US by Janssen, part of Johnson and Johnson.
The makers of the INRatio device told The BMJ that the device’s fault dated back to 2002. The US Food and Drug Administration (FDA) told The BMJ that it was “aware of concerns regarding the INRatio device and its use in the ROCKET-AF trial and is reviewing relevant data”. The European Medicines Agency (EMA) has also said it is investigating.
Harlan Krumholz, former FDA reviewer and professor of medicine at Yale University in Connecticut, said the NEJM should place an “immediate expression of concern” on the ROCKET-AF paper to notify the medical community, and that there should be “an investigation by an independent group of experts to quickly determine if there are grounds for retraction”.

However, attempts to access the original data have so far been thwarted. Bayer told The BMJ that it has only signed up to sharing information on “study reports for new medicines approved in the US and the EU after January 1, 2014”.

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Pivotal NOAC trial may have been compromised: BMJ

Feb 4, 2016 | Medical Observer

By Anna Evangeli and Rada Rouse

Results from a pivotal trial on the NOAC rivaroxaban may have been compromised as a device
used to measure international normalised ratio (INR) in the warfarin arm was later found
defective, the BMJ has charged.
The journal is calling for an independent investigation into the 2011 ROCKET AF trial of
rivaroxaban (Xarelto, Bayer) as the point-of-care testing device it used has since been withdrawn
from the market.
“It could make rivaroxaban seem better than it was at reducing the risk of bleeding and throws
doubt onto outcomes used to support the use of the world’s best-selling new anticoagulant,”
writes BMJ associate editor Deborah Cohen.
However rivaroxaban’s manufacturer and the trial’s investigators say the results, which underpin
approvals for the agent, still stand.
In a research letter published today, the researchers say they have reanalysed their data taking
into account the possible malfunction of the device leading to lower INR values and shown it “did
not have any significant clinical effect on the primary efficacy and safety outcomes” of the trial.
The device at the centre of the dispute was used in one arm of a 14,200-person study to compare
rivaroxaban (20mg daily) with dose-adjusted warfarin for patients with non-valvular AF at
moderate-to-high risk of stroke.
According to the results rivaroxaban was non-inferior to warfarin in preventing a stroke or systemic
embolism.
There was no significant difference in major and non-major clinically relevant bleeding between
the newer and older anticoagulants. The study did, however, find that intracranial and fatal
bleeding was less common with the newer drug.
The BMJ says it had been told by the European Medicines Agency (EMA) last November that the
INR device may have affected the clotting results in some patients in the warfarin group.
The EMA’s executive director, Guido Rasi, also backed an independent study “to give confidence
in the use of this medicine”.
The Food and Drug Administration told the BMJ it was aware of concerns about the INR device. It
subsequently announced a public workshop about safety and effectiveness of such devices, to be
held next month.
The BMJ quotes a Yale professor of cardiology saying that where there is uncertainty about
validity of evidence the journal should notify the medical community.
Brisbane academic Dr Virginia Barbour, chair of the international Committee on Publication Ethics,
says if there’s good evidence that something that has come to light after publication that could
affect the paper’s conclusions, especially as in this case if there are potential clinical

consequences, “it is important that readers are alerted”.

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Point-of-Care Warfarin Monitoring in the ROCKET AF Trial

Feb 3, 2016 | New England Journal of Medicine

By Manesh R. Patel, M.D. and Anne S. Hellkamp, M.S.

To the Editor:
In the Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF), investigators found that rivaroxaban was noninferior to warfarin in the prevention of stroke and systemic embolism in patients with atrial fibrillation. In December 2014, four years after completion of the trial, the Food and Drug Administration (FDA) issued a recall notice for a medical device correction of the Alere INRatio Monitor System (formally known as the Hemosense INRatio device). The recall correction notice was issued because the FDA-approved and European Conformity (CE)–marked whole-blood, point-of-care device may provide an international normalized ratio (INR) result that is lower than an automated, plasma-based laboratory INR in patients with certain specific medical conditions. These conditions include abnormal hematocrit levels, conditions associated with raised fibrinogen levels, and bleeding or unusual bruising (see a description of conditions and Table S1 in the Supplementary Appendix, available with the full text of this letter at NEJM.org). In October 2015, the ROCKET AF executive committee was notified that the device that was used in the trial was included in this FDA recall correction notice. To understand the effect of possible device malfunction leading to lower INR values and inappropriately high doses of warfarin and bleeding, we conducted a series of post hoc analyses of the ROCKET AF data.
Two physicians who were unaware of study-group assignments reviewed baseline medical history and adverse events identified during trial follow-up for all patients enrolled in the trial for any of the conditions cited in the recall (Table S2 in the Supplementary Appendix). Patients with central laboratory evidence of hematocrit values of less than 30% or more than 55% were also identified. We categorized the entire trial population according to whether patients had any recall condition or no recall condition and then compared efficacy and safety outcomes of patients receiving rivaroxaban with those receiving warfarin within these subgroups. Details regarding the study methods are provided in the Supplementary Appendix.
In the primary analysis, we compared the relative effect of rivaroxaban versus warfarin on major efficacy and safety outcomes in the overall trial population (as-treated population) and in patients with no recall conditions. In a subsequent analysis, we compared the relative effect of rivaroxaban versus warfarin on major efficacy and safety outcomes in patients with any recall condition (Figure 1). We also performed a sensitivity analysis in which patients with possible acute-onset recall conditions (e.g., an acute infection) were included in the subgroup of patients with no recall condition until the time of onset of the acute condition (Table S1 in the Supplementary Appendix). In addition, we evaluated the primary efficacy end point in the intention-to-treat and per-protocol populations to present results consistent with those in the primary trial report.
Of the total safety population of 14,236 patients, 8942 (63%) had no recall condition and 5294 (37%) had a recall condition. Both types of patients were equally distributed between the warfarin and rivaroxaban groups (Table S2 in the Supplementary Appendix). Patients without recall conditions were younger than those with recall conditions (72 years vs. 74 years) and were more likely to have a history of stroke or transient ischemic attack (57% vs. 51%), less likely to have diabetes (39% vs. 42%), and less likely to have been treated with a vitamin K antagonist before study entry (60% vs. 66%) (Table S3 in the Supplementary Appendix). The characteristics of the patients were similar in the rivaroxaban group and the warfarin group in the subgroups with and without recall conditions (Tables S4 and S5 in the Supplementary Appendix).
The main trial results for the primary efficacy and safety end points of the overall ROCKET AF trial population have been reported previously and are provided in Table S6 in the Supplementary Appendix. The results of the primary analysis of efficacy and safety outcomes in the subgroup of patients with no recall conditions are shown in Table S7 in the Supplementary Appendix. These results are consistent with those of the overall trial population in showing the noninferiority of rivaroxaban versus warfarin for preventing stroke and systemic embolism, with similar rates of overall bleeding and lower rates of fatal and intracranial bleeding among patients treated with rivaroxaban but a higher rate of gastrointestinal bleeding.
The primary efficacy and safety findings in patients with any recall condition are also consistent with the reported results of the overall trial (Table S8 in the Supplementary Appendix). Among patients with any recall condition, the bleeding rate was higher in both the rivaroxaban and warfarin groups. Furthermore, among patients with any recall condition, there was a trend toward a higher relative risk of major bleeding with rivaroxaban than with warfarin, a trend that was not seen among patients with no recall condition (P=0.04 for interaction) (Figure 1). This finding does not support the hypothesis that device malfunction led to an increased risk of bleeding in the warfarin group of the trial. The results of the additional sensitivity analyses are consistent with those already reported for the primary efficacy and safety end points in patients with or without recall conditions (Tables S9 and S10 in the Supplementary Appendix) and for key secondary efficacy and safety end points (Fig. S1 in the Supplementary Appendix).

These results are consistent with the overall trial findings and indicate that possible malfunction of the point-of-care device used for INR measurement in the ROCKET AF trial that potentially led to lower INR values than would be obtained by laboratory testing did not have any significant clinical effect on the primary efficacy and safety outcomes in the trial.

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Rivaroxaban: can we trust the evidence?

Feb 3, 2016 | BMJ

By Deborah Cohen

An investigation by The BMJ has uncovered the use of a faulty device in a regulatory drug trial, potentially putting patients at unnecessary risk, Deborah Cohen reports
Doctors and scientists are calling for an independent investigation into the key trial underpinning use of rivaroxaban to prevent ischaemic stroke in non-valvular atrial fibrillation after The BMJ found that a defective point of care device was used in the warfarin arm of the trial.
Doctors and scientists have also told The BMJ that the validity of the trial—called ROCKET-AF and published in the New England Journal of Medicine in 20111—is in question until such independent analysis is done.
The drug was manufactured by Bayer and marketed in the United States by Janssen, part of Johnson and Johnson, and the companies relied on a single trial–ROCKET-AF—to gain approval from the US and European regulators. The trial included over 14 000 patients and found that rivaroxaban was non-inferior to warfarin for preventing ischaemic stroke or systemic embolism. There was no significant difference between groups in the risk of major bleeding—although intracranial and fatal bleeding occurred less often in the rivaroxaban group.
But there are now concerns about these outcomes. In a letter submitted to the NEJM (as yet unpublished) and shown to The BMJ, former FDA cardiovascular and renal drug reviewer, Thomas Marcinicak, says: “The care for the warfarin control arm patients [in ROCKET-AF] appears to have been compromised.”
Earlier last year, The BMJ found that the point of care device used to measure international normalised ratio (INR) in patients taking warfarin in ROCKET-AF had been recalled in December 2014. An FDA class I recall notice (the most serious kind) said that certain INR devices could deliver results that were “clinically significantly lower” than a laboratory method. It added that Alere—the device manufacturer—had received 18 924 reports of malfunctions, including 14 serious injuries. The company confirmed to The BMJ that the fault went back to 2002, before the ROCKET-AF trial started.
A falsely low reading could mean that patients had their warfarin dose unnecessarily increased, leading to a greater risk of bleeding. In terms of the trial results, it could make rivaroxaban seem safer than it was in terms of the risk of bleeding and throws doubt on outcomes used to support the use of the world’s best selling new oral anticoagulant.2
Direct oral anticoagulants
Rivaroxaban is a factor Xa inhibitor and belongs to a class of medicines known as the direct oral anticoagulants (DOAC), which also includes dabigatran, apixaban, and edoxaban. They have gained popularity in place of warfarin for the prevention of ischaemic stroke in non-valvular atrial fibrillation because routine blood monitoring is not required.3
Back in September 2015, The BMJ asked the investigators named in the NEJM paper about the recall. They included researchers from Bayer, Johnson and Johnson, and the Duke Clinical Research Institute, which carried out the trial on behalf of the drug companies.
None of the authors responded, but a spokesperson for Johnson and Johnson contacted The BMJ to say that they were “unaware of this recall” and they took the journal’s concerns “seriously.” But it took months of probing by The BMJ before the companies, world drug regulators, and Duke began to investigate the problem in earnest.
Joining the dots
As for the regulators, when The BMJ contacted the European Medicines Agency in April 2015 and subsequently the Food and Drug Administration, both said they did not know that the recalled device had been used in ROCKET-AF. It’s new territory for the regulators. What happens to a pivotal drug trial when a device used is found to be defective?
In November the EMA told The BMJ it was investigating, and the agency subsequently told journalists: “Due to the defect it is now thought that the INR device may have impacted the clotting results in some patients in the warfarin group.”4
Executive director of EMA, Guido Rasi, also called for further independent investigation into direct oral anticoagulants. “It would be nice to have some independent study carried out to give confidence in the use of this medicine,” he said.
The FDA also told The BMJ that it is “aware of concerns regarding the INR device and its use in the ROCKET-AF trial and is reviewing relevant data.” It subsequently announced that it will hold a public workshop about the safety and effectiveness” of point of care INR devices in March “to seek and identify potential solutions” to what it said were “scientific and regulatory challenges.”
However, in the meantime spokespeople for Johnson and Johnson and Bayer issued identical statements in December 2015: “We have conducted a number of sensitivity analyses. These sensitivity analyses confirm the results of the ROCKET-AF study and the positive benefit-risk profile of Xarelto (rivaroxaban) in patients with non valvular atrial fibrillation.”
But what should happen amid the uncertainty?
Harlan Krumholz, professor of medicine (cardiology) at Yale University, says that the NEJM should place an “immediate expression of concern” on the paper to notify the medical community.
“The study should be considered of uncertain validity until a more thorough review can be done,” he says, adding that there should be “an investigation by an independent group of experts to quickly determine if there are grounds for retraction.”
Concerns about warfarin control
Even before rivaroxaban was approved in Europe and the US in 2011 for use in non-valvular atrial fibrillation, regulatory officials raised concerns about the warfarin control in the ROCKET-AF trial. Two primary clinical FDA reviewers of the drug recommended that it should not be approved for the US market.
“ROCKET provides inadequate information to assess the relative safety and efficacy of Xarelto in patients whose warfarin administration can be well-controlled,” they wrote in an FDA decisional memo—which outlines clinical reviewers’ view on whether a drug should be approved.5
However, they were seemingly unaware that there are other reasons to be concerned about the adequacy of the warfarin control in the ROCKET-AF trial that have since emerged.
Lack of transparency over devices in trials
Currently, there is little public information about which diagnostic point of care devices are used in any of the direct oral anticoagulant trials (box). They are not named in the published phase III trials. The BMJ became aware that the problematic device was used in the ROCKET-AF trial only by reviewing European regulatory documents in April last year.
Devices used in other trials
Given the lack of publicly available information about the point of care testing devices used in the other direct oral anticoagulant trials, The BMJ sought to find out what they are.
Lars Wallentin, corresponding author of the phase III ARISTOTLE trial (Apixaban versus Warfarin in Patients with Atrial Fibrillation)6 said that the trials used the ProTime POC device made by International Technidyne Corporation, Edison, NJ, USA.
Daiichi-Sankyo, the manufacturers of edoxaban, also said that the ProTime POC device was supplied to all study sites in the Edoxaban versus Warfarin in Patients with Atrial Fibrillation Trial (ENGAGE AF)7 and in its venous thromboembolism trial.
Marciniak says that the NEJM, which published the trials for three of the direct oral anticoagulants, should rectify that.
“You should require that the devices used in trials are clearly and specifically identified in your publications,” he wrote in his letter.
How has this come to happen?
In tracking the faulty recall and its potential effect on the outcomes of a global clinical trial, The BMJ has once again come across flaws in device regulation. A series of journal investigations have highlighted the lack of clinical data required by US and Europe regulators for high risk implants, such as metal on metal hips, before they are put on the market.8 They have also shown how slow regulators can be to act when problems do emerge and shown how oversight can be lacking on the performance diagnostic tests.9 10
In 2005, a warning letter from the FDA to HemoSense—the company that marketed the faulty device before Alere bought it—reprimanded them for failing to investigate “clinically significant erroneous” high and low INR results generated by the point of care device.
“Both high and low test [INR] results have the potential to cause or contribute to a death or serious injury, because: they may result in erroneous dosing and thus improper control of coagulation,” the letter said.11
Despite these warning letters, the FDA cleared subsequent iterations of the device through its 510(k) regulatory system. This system requires makers of such devices to show only that the new version is “substantially equivalent,” or similar, to one already on the market. It has been criticised by the likes of the Institute of Medicine for not providing enough evidence that a device is safe and effective.12
Johnson and Johnson, however, has lobbied against tightening up this aspect of device regulation and the need to provide more evidence.13 But the lack of a regulatory requirement for the diagnostic accuracy of the device to be checked before it came on to the market has allowed the fault to creep through the system.
Alere has confirmed to The BMJ that the fault dates back to 2002 and it may occur in all devices and not just one batch. However, neither it nor the FDA responded to questions about why nothing had been done about the problem earlier.
Were the companies aware of any problems during the trial?
The BMJ asked Johnson and Johnson, Bayer, and Duke if any investigator complained to them about mismatched point of care and laboratory INR readings if someone had a bleed in the trial. The BMJ also asked if they had validated the device at any point before or during the trial. None responded to the questions.
According to former FDA clinical pharmacologist, Bob Powell, who has also worked with industry and academia, the specificity and reproducibility of a diagnostic test or assay is vital to the performance of a trial.
“The fact that this was apparently not previously done nor reported in the primary publication is concerning as this is a basic principle in drug development,” he says.
What next?
The EMA has told The BMJ that it has asked the companies for analyses and would consider any analyses by Duke too. During the trial INR at 12 and 24 weeks was measured at a central laboratory as well as with the point of care device. Powell says that “a comparison should be made between the defective point of care readings and the two sets of ‘gold standard’ central lab readings” as this would “determine whether this defective device undermined the integrity of the trial results.”
It is not clear that this has happened. In December last year, Duke issued a press release with a summary report of the results of their “secondary analysis of the trial findings.”
“The findings from the analysis are consistent with the results from the original trial and do not alter the conclusions of ROCKET-AF—rivaroxaban is a reasonable alternative to warfarin and is non-inferior for the prevention of stroke and systemic embolism with less intracranial hemorrhage and fatal bleeding” it said.
But Powell says this statement is “misleading” because of the lack of information.
Krumholz also thinks that this statement did not give enough information about what Duke found in terms of the major safety endpoint—major bleeds.
“The DCRI is among the most respected research institutions, but this statement suggests that they know important information that relates to the ROCKET-AF trial but are delaying in disseminating the information until it can be published,” he says.
Hugo ten Cate, medical director of the Maastricht thrombosis anticoagulation clinic and coeditor in chief of Thrombosis Journal, says that major bleeds have serious consequences.
“Large bleeds mostly occur in the gastrointestinal tract and can be lethal if substantial blood loss occurs, especially in elderly subjects with comorbidity; this can be a devastating complication,” he says.
Any changes to the ROCKET-AF trial will have a broader effect on the literature.
Carl Heneghan is an author on a forthcoming Cochrane Collaboration review of “direct thrombin inhibitors and factor Xa inhibitors for atrial fibrillation,” which includes the ROCKET trial.
He has written to Duke to ask if the results for the main outcome measures in the reanalysis are the same as in the original published paper and, if not, what the differences are after the reanalysis.
A spokesperson for Duke did not answer the question but said that the ROCKET-AF executive committee “intends to publish a full description of its analysis as rapidly as possible.”
Independent oversight
But given the lack of clarity over the outcomes and the methods used, is a reanalysis by Duke enough?
Marciniak is unequivocal. He says that he would not rely on any reanalyses done by Duke, Johnson and Johnson, or the FDA.
“Because they already missed the problems both in the trial and with the public marketing, I would not trust them to publish anything that is accurate—or that provides any details,” he told The BMJ.
He added that the datasets need to be released as “the only solution that would lead to unbiased analyses.”
But previous attempts to do this have been thwarted.
Krumholz has approached Johnson and Johnson for access to the trial data. His Yale University Open Data Access (YODA) project has an agreement with Johnson and Johnson to make all of the clinical trial data available for its approved products. However, although the company agreed to allow access to the data, Bayer refused.
“This is an ideal situation for data sharing. The evaluation of the data in this trial should not go on behind the curtain. And it seems imprudent to allow those who conducted the trial to be the only ones who can touch the data,” Krumholz says.
But it doesn’t look like the data release is going to be sanctioned by Bayer any time soon. A spokesperson for the company told The BMJ that this is because they have signed up to sharing information only on “study reports for new medicines approved in the US and the EU after January 1, 2014.”
The request does not fit in their “current scope of clinical trial data sharing.”
Good outcome for patients?
But in the end might this series of errors lead to a favourable outcome for the regulators—and perhaps patients?
At the end of 2015, both the EMA and the FDA held meetings to discuss the need to measure blood levels of direct oral anticoagulants and adjust the dose accordingly to maximise benefit and minimise harm—despite all the manufacturers claiming that this is not necessary. The meetings were held after The BMJ revealed that Boerhinger Ingelheim, manufacturers of dabigatran, withheld analyses from the regulators that showed how many major bleeds could be prevented by monitoring anticoagulant activity and adjusting the dose.14
A presentation to EMA last year by Robert Temple, deputy director for clinical science at the FDA’s Center for Drug Evaluation and Research, suggests that the FDA believes there is a scientific argument for measuring the blood levels of these drugs and adjusting the dose.
“Being too low leads to a stroke, a very bad outcome, and being too high leads to major bleeds, also bad, so that early optimization [of the dose] seems worthwhile,” he said adding that direct oral anticoagulants are “very good, but could probably be better.”
But once a drug is on the market, regulators lack a mandate to act unless there are safety concerns. However, according to Powell, depending on the outcomes of any reanalysis of the ROCKET-AF trial, this might allow them to take action.
“After a drug is approved, it usually takes a safety signal to prompt significant action on the part of the FDA. It is this lack of safety signal that appears to be hindering the FDA in their desire to pursue tailored dosing for DOACs. If it turns out that the issue with the [INR] device changes the safety profile of rivaroxaban, this may constitute the safety signal necessary for the FDA to act in this regard,” h

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Questions raised about clinical trial of popular heart drug

Feb 3, 2016 | CBS News

By Mary Brophy Marcus

New questions are being raised about the clinical trial of a widely used heart drug, and critics are calling for an independent investigation, after a medical device used during the study was later found to be faulty and recalled.
The clinical trial tested a blood-thinning medication called rivaroxaban, which is now marketed under the brand name Xarelto. More than 13 million Xarelto prescriptions have been written in the U.S., making it the most prescribed blood thinner in its class in the country.
Editors at The BMJ, a medical journal based in the UK, have published a paper that raises concerns about the clinical trial -- known as the ROCKET-AF study -- whose findings were published in 2011 in the New England Journal of Medicine. The study compared rivaroxaban (Xarelto) to an older drug, warfarin (Coumadin). The study helped convince U.S. and European regulators to approve rivaroxaban for use in patients with atrial fibrillation (a type of heart rhythm problem) who are at a higher risk for stroke. Warfarin is an older anti-clotting medicine used to prevent heart attacks, strokes, and blood clots in veins and arteries.
The BMJ associate editor Dr. Deborah Cohen wrote that the device used to test for blood clotting during the trial was recalled in December 2014 for giving falsely low results. The device maker confirmed to The BMJ that the problem dated back to 2002.
The study included over 14,000 patients and found that rivaroxaban and warfarin both prevented ischemic stroke or systemic embolism, an obstruction in a blood vessel due to a blood clot. The study results showed there was no significant difference between the two drugs in the risk of major bleeding -- but bleeding in the brain and fatal bleeding occurred less often in the rivaroxaban group.
Cohen wrote that the device flaw could have skewed those study results, making rivaroxaban seem safer than warfarin with respect to the risk of bleeding.
Rivaroxaban is manufactured by Bayer and marketed in the U.S. by Janssen Pharmaceuticals, part of Johnson & Johnson.
Duke University's Clinical Research Institute, where the trial was carried out on behalf of the manufacturer, published a letter today in the New England Journal of Medicine stating that it has re-analyzed the results of the trial and stands by its conclusions. Issues with the medical testing devices "did not have any significant clinical effect on the primary efficacy and safety outcomes in the trial," the researchers wrote.
In a statement to CBS News, Janssen Pharmaceuticals said the re-analysis "confirm the conclusions of the ROCKET-AF study and the positive benefit-risk profile of XARELTO® (rivaroxaban) in patients with non-valvular atrial fibrillation."
Impact of the study
Dr. Ravi Dave, a cardiologist at UCLA Medical Center, in Santa Monica, California, who's been in practice for 18 years, told CBS News that direct oral anticoagulants (DOACs), including rivaroxaban, have changed the way cardiologists are able to treat patients with atrial fibrillation, or AFib, an irregular and often rapid heart rate that can increase a person's chances of suffering a stroke, heart failure and other cardiac-related complications.
"I treat a lot of patients with AFib and when the DOAC agents came out, it was really exciting," said Dave.
Warfarin is a higher maintenance medication, he explained. Patients need to be tested every month to be sure their blood is clotting at the safest level - too much and a stroke can happen, not enough clotting and bleeding risks go up. Diet also has to be controlled when someone is taking warfarin because certain foods, such as leafy greens with vitamin K, combined with the drug can influence how it works in the body, he said.
Patients can also experience interactions with other commonly used medications, including antibiotics.
"If a patient with AFib needed antibiotics for a sore throat or something like that, the Coumadin level would jump up really high," said Dave.
He said the frequent monitoring and adjustments make warfarin difficult for patients who want to travel for a prolonged time.
"It was always a challenge. Our patients would end up going to hospitals in foreign countries and it was a difficult process for them to be checked since the level of the drug had to be maintained very closely. If the level went low, their risk for stroke went up, but too high and their risk for bleeding went up," Dave said.
Another rivaroxaban perk: it's a one-dose-a-day drug, without the need for constant adjustments.
"The best thing is you don't have to get your blood checked. Patients really like that freedom," Dave said.
The BMJ's Cohen wrote that during the drug trial, the use of the faulty device led participants and their doctors to think that their warfarin levels were lower than they really were, and so the patients were given more of the drug. That may explain why warfarin ended up causing more bleeding than rivaroxaban in the study.
"In terms of the trial results, it throws doubt onto outcomes used to support the use of the world's best selling new oral anticoagulant," Cohen said.
These issues are uncharted territory for regulators. When The BMJ first contacted the European Medicines Agency and the U.S. Food and Drug Administration, both said they did not know that the recalled device had been used in the ROCKET-AF trial -- the rivaroxaban and warfarin study.
"What happens to a pivotal drug trial when a device used is found to be defective?" Cohen asked.
She said doctors and scientists would like to see an independent investigation and full transparency of the 2011 trial data. The European Medicines Agency told The BMJ it is now reviewing the data, and its executive director Guido Rasi called for further independent investigation into direct oral anticoagulants.
"It would be nice to have some independent study carried out to give confidence in the use of this medicine," Rasi said.
The FDA now says it is "aware of concerns regarding the INR device and its use in the ROCKET-AF trial and is reviewing relevant data," The BMJ reported.
The BMJ said Bayer and Johnson & Johnson issued a statement in December saying they stand behind the 2011 drug trial results: "We have conducted a number of sensitivity analyses. These sensitivity analyses confirm the results of the ROCKET-AF study and the positive benefit-risk profile of Xarelto (rivaroxaban) in patients with non-valvular atrial fibrillation," the companies said.
What should doctors and patients do?
Dr. Chip Lavie, medical director of cardiac rehabilitation and prevention at John Ochsner Heart and Vascular Institute, in New Orleans, said it won't change the way he prescribes medication to his patients.
For transparency, Lavie shared that he is a spokesperson for the heart drugs dabigatran (Pradaxa) and apixaban (Eliquis), but not for rivaroxaban (Xarelto). He told CBS News, "Although I personally use more dabigatran, and especially apixaban in my older patients (more so in the older patients with highest bleeding risks), I believe that rivaroxaban is a very good and safe agent and would not change anything based on the BMJ article, which seems a bit 'over the top' to me."
He said he also trusted the Duke statements.
Dave said he'll keep prescribing rivaroxaban, too.
"When this news comes out, we're going to get a lot of phone calls from patients concerned that they're getting a faulty drug. What I'd like to communicate is that these medications are used for lowering the risk for stroke, and I don't think there's any question about how well they work," said Dave.
"It was compared to this historic medication Coumadin, which may have had a higher incidence of bleeding because of the faulty machine. Comparing bleeding risk in the two drugs is what is being called into question and what needs to be further evaluated. Not the efficacy of this drug. Rivaroxaban is not being called into question," he explained. "I will not change clinical practice."
Dave's UCLA colleagues, Dr. Sheila Sahni, chief fellow in cardiovascular disease at the David Geffen School of Medicine, and Dr. Karol Watson, professor of medicine and cardiology director of the UCLA Barbra Streisand Women's Heart Health Program and co-director of the UCLA Program in Preventive Cardiology, told CBS News that the new BMJ investigation is "very important."
Sahni said it highlights the fact that devices used in studies to track blood clotting factors are often not regulated.
Watson added, "After ROCKET [the 2011 study] came out, we would counsel patients regarding the decreased fatalities and intracranial bleeding." But until further investigation is conducted, as The BMJ article calls for, the patient-doctor dialogue will change.
As Sahni put it: "We can say with confidence that rivaroxaban works. However you can't say it's better than Coumadin."

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New Studies Seek To Allay Concerns Over The ROCKET-AF Trial

Feb 3, 2016 | Cardiobrief

By Larry Husten

New post-hoc analyses of ROCKET-AF confirm the main results of the controversial trial, according to a paper published in the New England Journal of Medicine. The papers are a response to disturbing questions about the trial raised last fall. But the new analyses will not fully satisfy some critics of the trial who are calling for independent analysis of the trial.
ROCKET AF was the pivotal trial that compared rivaroxaban (Xarelto, Johnson & Johnson) to warfarin in patients with atrial fibrillation. Last year it became known that the portable device used to monitor and calibrate warfarin usage in the trial had been seriously defective. The device– the Alere INRatio and INRatio2 PT/INR Monitor System– was the subject of a broad class 1 FDA recall. The FDA said that the devices “may provide an INR result that is lower than the expected result obtained using a laboratory INR method” in patients with certain conditions, including abnormal hematocrit levels, conditions associated with raised fibrinogen levels, and bleeding or unusual bruising.
In an interview last fall, Duke’s Manesh Patel, a member of the ROCKET AF executive committee, said that the ROCKET AF investigators first became aware of the problem in October and immediately began a series of analyses to assess the impact of the problem. They said that the results were “consistent with the results from the original trial and do not alter the conclusions of ROCKET AF” but they did not then release the details of their study.
Now the details of their analyses have been published in the New England Journal of Medicine. In their studies the investigators identified patients who had conditions linked to the recall of the INR device and asked whether the results of the trial were any different in this group, and specifically whether rivaroxaban appeared to do better because warfarin was not used properly.
“These results are consistent with the overall trial findings and indicate that possible malfunction of the point-of-care device used for INR measurement in the ROCKET AF trial that potentially led to lower iNR values than would be obtained by laboratory testing did not have any significant clinical effect on the primary efficacy and safety outcomes in the trial,” the investigators concluded.
In an interview today Patel said the new results are broadly consistent with a separate analysis conducted by the drug’s sponsors and presented to the FDA. In a statement, the drug’s sponsors said that the “findings are in line with the sensitivity analyses conducted by Bayer and Janssen, which also affirm the results of the ROCKET AF study and the positive benefit-risk profile of” rivaroxaban.
One expert, Sanjay Kaul (Cedars-Sinai), who served on the FDA advisory committee that reviewed ROCKET AF, said that the “investigators have done the appropriate due diligence.” He noted that “the observation of a higher relative risk of major bleeding with rivaroxaban in those with recalled conditions (HR of 1.18) contradicts the claim that underestimation of INR by the recalled device could have amplified warfarin bleeding thereby enhancing the safety of rivaroxaban.”
Lingering Concerns
But in a separate paper published in BMJ, associate editor Deborah Cohen quotes several leading experts who say that the trial data should be made available for independent analysis by outside investigators not involved with the trial.
One of these experts, Harlan Krumholz (Yale Open Data Access project) praised the analysis of the trial but said this is “the perfect case” to support the recent ICMJE proposal that would mandate sharing of trial data. Krumholz said that there are still remaining questions about the trial. “I think the question of whether the study is valid is still unanswered. There should be a note associated with this study that explains to readers that one arm was managed with measures from a device that was subsequently recalled.” Krumholz told the BMJ that although Johnson & Johnson has agreed to make trial data available, its partner on the drug, Bayer, has refused.
Cohen also called for an independent analysis of the trial data. Both Cohen and Krumholz also want to know why the investigators did not perform a comparison of the point of care tests with blood samples stored in the core lab. In an email Cohen told me:
Their reanalysis has a fundamental flaw. It assumes the the defect in INRatio only affects certain subgroups of patients. The investigators could have and should have evaluated this assumption. They have a huge dataset to evaluate the performance of the device. They took split samples at 12 and 24 weeks and tested those with both INRatio and lab tests. The investigators should not only compare the point of care measurements with lab results in those patients in the recall notice, but also include evaluate those without a recall related condition.
I asked Patel about this question. He said the trial investigators did not perform this analysis because their studies were designed to address the problems identified in the specific patient population identified in the FDA recall. But, he said, the INR data from the core lab is available for analysis and may be the subject of future studies
Patel expressed frustration at some of the criticism directed at the ROCKET AF investigators. He noted that it only took four months from the first notification of the problem with the device to the publication of the paper in the New England Journal of Medicine.

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Scientists Calling For Independent Investigation Of Blood-Thinning Drug Rivaroxaban After Clinical Trial Snafu

Feb 3, 2016 | Medical Daily

By Ed Cara

A new special report released Wednesday by The BMJ is renewing calls for an independent investigation of a blood thinner, rivaroxaban, that has quickly become the most popular drug of its kind.
As Dr. Deborah Cohen, associate editor of The BMJ, details, the kerfuffle over rivaroxaban is mostly over the large clinical trial (ROCKET-AF) that convinced regulatory agencies such as the Food and Drug Administration (FDA) and the European Medicines Agency (EMA) to approve the drug as a treatment for non-valvular atrial fibrillation in 2011.
At the time, rivaroxaban was pitted against, and declared equally effective and safe as warfarin, a long-established anticoagulant. In 2015, however, The BMJ discovered that a since-recalled device that measured a person’s level of blood clotting, (via their International Normalized Ratio, or INR), was exclusively used in the warfarin portion of the trial. It’s possible the device may have provided inaccurately low INR readings for an untold number of patients, starting a chain reaction where these patients were unknowingly given too much warfarin, which then raised their risk of inadvertent bleeding, and ultimately made rivaroxaban appear safer by comparison.
The mechanical fault found in the device was confirmed to have existed since 2002 by its current manufacturer, Alere, long before it was used in the Rocket-AF trial.
“The study should be considered of uncertain validity until a more thorough review can be done,” Harlan Krumholz, professor of medicine at Yale University, told The BMJ, before going on to voice the need for “an investigation by an independent group of experts to quickly determine if there are grounds for retraction.” Krumholz has also advocated that the New England Journal of Medicine, which published the Rocket-AF trial, place an “immediate expression of concern” on the paper to inform other researchers and the public of the potential mistake.
Pharmaceutical company Bayer, rivaroxaban’s manufacturer, and Johnson and Johnson, its marketer in the United States (as Xarelto), have thus far refused any pressure to submit to such an independent testing. Last winter. they told Stat News their own analyses hadn’t shown any substantial differences in outcome when accounting for the possible device flaw. The Duke Clinical Research Institute (DCRI), which conducted the trial on behalf of Bayer, similarly stated in a summary report last December that its secondary analysis failed to find any difference.
None of these analyses have been released to the public, though the DCRI said it intends to as soon as possible. The EMA told The BMJ it has requested data from both companies, and the FDA is purportedly reviewing the trial data as well.
Given the failures by everyone involved in finding the initial snafu and their hesitance to aggressively investigate the matter, however, Thomas Marcinicak, a former cardiovascular and renal drug reviewer for the FDA, believes it would be foolhardy to have faith in either drug regulators or rivaroxaban’s masters. Only by having the raw data released can there be a “solution that would lead to unbiased analyses,” Marcinicak told The BMJ. Bayer has similarly refused to do that either, claiming that its earlier pledge to always share clinical trial data with independent researchers only applies to new drugs licensed for approval after January 1, 2014.
Meantime, rivaroxaban, part of a more modern class of blood thinners known as direct oral anticoagulants (DOACs), continues to be the best-selling new DOAC on the market, having eclipsed $3.5 billion in worldwide sales in 2014, according to PMLiVE. Despite its resounding popularity, there are people who have sued the company because they claim the drug led to the deaths of their loved ones.

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(UPDATE) BMJ Investigation Casts Doubt on Validity of Rivaroxaban Trial

Feb 3, 2016 | Drug Discovery and Development

By Stephanie Guzowski

New questions have been raised about the validity and reliability of data in the ROCKET-AF trial, which serves as the backbone for the approval of rivaroxaban (Xarelto), according to an investigation published Wednesday by The BMJ. Rivaroxaban is a blockbuster drug for stroke prevention in atrial fibrillation (AF) that gained approval from both U.S. and European regulators.
The ROCKET-AF trial, published in the New England Journal of Medicine (NEJM) in 2011, compared rivaroxaban with the older anticoagluant drug warfarin (marketed as Coumadin, Jantoven). The U.S. FDA recommended that year rivaroxaban not be approved because of evidence that warfarin use in the trial’s control arm was not adequately performed. Although the advisory committee meeting was highly contentious, in the end, the committee voted to recommend approval of rivaroxaban.
Now, concerns about the trial results that were used to gain approval have resurfaced, including a major new concern: the portable device used to monitor and calibrate warfarin usage in the trial appears to have been seriously defective. The device — the Alere INRatio and INRatio2 PT/INR Monitor System — was recalled in December 2014 after giving falsely low test results. The recall was listed as a Class I recall, which according to the FDA, is “the most serious type of recall. They involve situations when it is likely that use of these devices will cause serious health problems or death.”
The BMJ’s Associate Editor, Dr. Deborah Cohen, says in a special report: “In terms of the trial results, it could make rivaroxaban seem safer than it was with respect to the risk of bleeding and throws doubt onto outcomes used to support the use of the world’s best-selling new oral anticoagulant.”
Rivaroxaban, manufactured by Bayer and marketed in the U.S. by Janssen Pharmaceuticals, part of Johnson & Johnson, belongs to a class of drugs called ‘direct oral anticoagulants’ (DOACs). Unlike warfarin, rivaroxaban doesn’t require that patients undergo regular blood testing to ensure the dosage is correct.
Duke University’s Clinical Research Institute, who did the study on behalf of Bayer, published a letter Thursday in the New England Journal of Medicine stating that it has re-analyzed the trial's results and stands by its conclusions. Problems with the device "did not have any significant clinical effect on the primary efficacy and safety outcomes in the trial," the researchers wrote.
The re-analysis findings "are in line with the sensitivity analyses conducted by Bayer and Janssen, which also affirm the results of the ROCKET-AF study and the positive benefit-risk profile of rivaroxaban (Xarelto) in patients with non-valvular atrial fibrillation," said Janssen in a statement to Drug Discovery & Development.
In response to The BMJ report, doctors and scientists are calling for an independent investigation to determine if there are grounds for retraction, and access to the original data to clear up the drug’s benefits and harms.
In December, Duke University’s Clinical Research Institute said further analyses “are consistent with the results from the original trial and do not alter the conclusions of ROCKET-AF.” But a former FDA reviewer Dr. Thomas Marciniak, told The BMJ that he would not rely on re-analyses done by Duke, the affiliated pharmaceutical companies or the FDA. “The only solution that would lead to unbiased analyses” is to release the original data, he said.
The BMJ reports: The manufacturers of the INRatio device confirmed to the medical journal that problems with the device date back to 2002. Yet, they nor the FDA responded to “questions about why nothing had been done about the problem earlier.”
There have been hundreds of Xarelto lawsuits alleging the anticoagulant drug caused excessive bleeding.
Update: Duke University’s Clinical Research Institute published a letter Thursday in the New England Journal of Medicine, and Janssen Pharmaceuticals made a statement, standing by its re-analysis findings.
The BMJ reports: The manufacturers of the INRatio device confirmed to the medical journal that problems with the device date back to 2002. Yet, they nor the FDA responded to “questions about why nothing had been done about the problem earlier.”

There have been hundreds of Xarelto lawsuits alleging the anticoagulant drug caused excessive bleeding.

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(UPDATE) Concerns Raised Over Approval Process for Top-Selling Blood Clotting Prevention Medication

Feb 3, 2016 | Healthline

By David Mills

Questions are reportedly being raised about a clinical drug trial that was part of the approval process for a top-selling blood clotting prevention drug.
The 2011 trial known as ROCKET-AF helped convince the U.S. Food Drug and Administration (FDA) and the European Medicines Agency (EMA) to approve the drug rivaroxaban for use as a blood thinner in the United States and Europe.
In an investigative story published today, The BMJ reported that doctors and scientists are calling for an independent investigation into the drug trial that pitted rivaroxaban against an older blood thinner called warfarin.
Rivaroxaban is developed under the name Xarelto by Bayer and Janssen Global Services. Janssen is a part of Johnson & Johnson.
Officials from both Janssen and the DCRI said today they have conducted recent follow-up analyses that affirm the results from the drug trial.
The 2011 drug trial involved 14,000 patients and found rivaroxaban to be “non-inferior to warfarin for preventing ischemic stroke or systematic embolism,” according to The BMJ article.Officials from both the company and the DCRI said today they have conducted recent follow-up analyses that affirm the results from the drug trial.
Device Called Into Question
The trial also concluded there was no significant difference in the risk of major bleeding between the two drugs.
However, scientists told The BMJ that a defective point-of-care device was used in the warfarin portion of the trial. The device was used to measure international normalized ratio (INR) in patients.
The INR is a standardized number computed in a lab. It’s part of a test that measures the time it takes a person’s blood to clot.
The BMJ reported that this particular INF device could have produced faulty readings for patients using warfarin. That could have caused warfarin doses to be increased. That, in turn, could have produced a greater risk of bleeding in warfarin patients.
“[That] could make rivaroxaban seem safer than it was in terms of the risk of bleeding and throws doubt on outcomes used to support the use of the world’s best selling new oral anticoagulant,” The BMJ wrote.
The device, manufactured by Alere, was recalled in December 2014 by the FDA.
Attempts by Healthline to get comment from Alere officials were unsuccessful.
Company officials told The BMJ they were aware of complaints about the device’s functionality as early as 2002, before the ROCKET-AF trial began.
The BMJ said neither Alere nor the FDA would comment on why those complaints weren’t investigated more fully.
In an editorial published today in the New England Journal of Medicine, DCRI officials said their follow-up analyses show the device shortcomings did not affect the overall results of the drug trial.
“These results are consistent with the overall trial findings and indicate that possible malfunction of the point-of-care device used for INR measurement in the ROCKET AF trial that potentially led to lower INR values than would be obtained by laboratory testing did not have any significant clinical effect on the primary efficacy and safety outcomes in the trial,” the DCRI officials wrote.
In addition, officials at Janssen Global Services, another division of Johnson & Johnson, said their separate analysis concluded the same thing.
“(The DCRI) findings are in line with the sensitivity analyses conducted by Bayer and Janssen, which also affirm the results of the ROCKET AF study and the positive benefit-risk profile of Xarelto,” Kristina Chang, director of product communication at Janssen, told Healthline in an email statement.
However, an official with the EMA issued a statement that said: “Due to the defect it is now thought that the INR device may have impacted the clotting results in some patients in the warfarin group.”
What Happens Now?
The question now facing regulators is what to do when a device used in a drug trial is found to be faulty.
An official with the FDA told The BMJ it was aware of the concerns about the Alere device and was “reviewing relevant data.” The agency also announced it will hold a public workshop in March to examine the effectiveness of point-of-care INR devices.
That, however, is not alleviating the concerns of some scientists.
Harlan Krumholz, a professor of medicine at Yale University, told The BMJ that the New England Journal of Medicine should place an “immediate expression of concern” on the 2011 published study to alert the medical community.
“The study should be considered of uncertain validity until a more thorough review can be done,” Krumholz was quoted as saying. “[There should be] an investigation by an independent group of experts to quickly determine if there are grounds for retraction.”
In addition, Dr. Thomas Marciniak, a former FDA reviewer, told The BMJ he wouldn’t rely on any analyses done by the DCRI, the FDA or Johnson & Johnson. He said the data from the trial needs to be released so “unbiased analyses” can be done.
Pulling rivaroxaban from the market could be difficult, though.

Former FDA clinical pharmacologist Bob Powell told The BMJ that once a drug is on the market, regulators lack a mandate to act unless safety concerns arise.

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Rivaroxaban Trial Threatened by Possibly Flawed INR Measurements

Feb 3, 2016 | NEJM Journal Watch

By Joe Elia

A faulty device used in the trial leading to approval of rivaroxaban — a direct-acting oral anticoagulant — has called those results into question, according to an investigation reported in The BMJ. The trial's authors, however, refute the concern.
The ROCKET AF trial investigators distributed the point-of-care device to measure international normalized ratios after dosing with warfarin, the comparator drug. However, the instrument was later recalled by the FDA; it was distributed to all 1200 participating sites according to the study's protocol. The device was prone to giving falsely low INR readings.
Such readings would have prompted higher doses of warfarin — resulting in higher bleeding risks for the drug — making rivaroxaban seem comparatively safer.
In a letter to the New England Journal of Medicine, where the ROCKET AF results appeared in 2011, the trial's authors present a reanalysis of their data and conclude that use of the device "did not have any significant clinical effect on the primary efficacy and safety outcomes in the trial."

Asked to comment, NEJM Journal Watch Cardiology Editor-in-Chief Harlan Krumholz said, "If the trial data were publicly available — especially that pertaining to INR testing — it would reduce uncertainty about the trial and allow more informed choice in the use of rivaroxaban."

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Broadcast

KWTV-CBS (Oklahoma City, OK) Clip

Feb 4, 2016 | KWTV-CBS (Oklahoma City, OK)

View clip here: http://app.criticalmention.com/app/#clip/view/20429944?token=5b0bef73-722b-4500-807c-8b314bf143e1
Rough Transcript: a popular heart drug is now at the center of controversy. critics are calling for an independent investigation of the blood thinner xarelto. the drug is the most prescribed blood hinner in the countr with more than 13- million xareltoprescriptions written. lawsuits have been filed by plaintiffs claiming itaused serious internal bleeding. a new study says that americans are 10 times more likely to be killed

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