Preview Newsletter
Xarelto Coverage
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Did heart drug makers withhold data from leading medical journal?
Mar 2, 2016 | CBS News
By Mary Brophy Marcus
Lawyers for patients who are suing two big drug makers who market a popular blood-clotting drug say the companies withheld important information from a letter published recently in a major medical journal. -
Lawsuit alleges Johnson & Johnson, Bayer misled New England Journal of Medicine editors
Mar 2, 2016 | Cardiovascular Business
By Tim Casey
Lawyers for patients suing Johnson & Johnson and Bayer allege that the companies misled editors at The New England Journal of Medicine about the safety of rivaroxaban (Xarelto), the New York Times reports. -
Documents Accuse Bayer, Johnson & Johnson of Deceiving The New England Journal of Medicine
Mar 2, 2016 | BioSpace
By Alex Keown
In the ongoing legal concerns surrounding the anticlotting drug Xarelto developed by Janssen Pharmaceuticals, a Johnson & Johnson (JNJ) company, and marketed by Bayer (BAYZF), a new wrinkle surfaced in a legal brief filed last week in federal court in New Orleans claiming the two companies mislead editors at the New England Journal of Medicine over the safety of the drug, the New York Times reported this morning. -
Legal Brief Claims Pharma Companies Misled Medical Journal
Mar 2, 2016 | Drug Discovery and Development
By Stephanie Guzowski
Details surrounding the approval of cardiovascular drug rivaroxaban (Xarelto) are questionable, but new events revealed Tuesday have further muddied the waters. -
Major drugmakers are being accused of hiding information about some potentially critical health risks — and people are furious
Mar 2, 2016 | Business Insider
By Lydia Ramsey
A controversy is brewing after a document claimed that two major pharmaceutical companies may have misled a medical journal by leaving out some critical data on their drug. -
Morning Break: Was NEJM Snookered? Zika in Cuba; Gray Hair Gene
Mar 2, 2016 | MedPage Today
Was NEJM duped by the makers of Xarelto (rivaroxaban)? And what did researchers at Duke know about the deception? The New York Times takes another look at the dust-up over missing lab data. Here is some coverage from MedPage Today. -
Pharmalot, Pharmalittle: Drug makers accused of misleading medical journal on blood thinner
Mar 2, 2016 | STAT News
By Ed Silverman
Lawyers for patients who are suing Bayer and Johnson & Johnson over the safety of the Xarelto blood thinner say the drug makers misled editors at the New England Journal of Medicine, The New York Times says. They claim that a letter published in the journal about a review of trial data and written primarily by Duke University researchers omitted important lab data, but the companies were aware of the omission and remain silent. -
Missing Data from Rivaroxaban Letter Draws Speculation, Criticism
Mar 3, 2016 | NEJM Journal Watch
By Amy Orciari Herman
A letter published in the New England Journal of Medicine in February — asserting that a faulty device did not influence the safety and efficacy outcomes for the anticoagulant rivaroxaban (Xarelto) in the ROCKET AF trial — did not include laboratory data that could have been used to evaluate the device's accuracy, the New York Times reports. -
Health Brief: Trump Offers Some Health Plan Details
Mar 3, 2016 | Morning Consult
By Mary Ellen Mcintire
Document Claims Drug Makers Deceived a Top Medical Journal Katie Thomas, The New York Times -
What’s Wrong with Our Prescription Drug Trials
Mar 3, 2016 | Healthline
By Brian Krans
For 12 years, Roy A. Teel Jr. was involved in human research trials at the University of California, Los Angeles, but he didn’t don a lab coat. As a research subject with progressive multiple sclerosis, he was involved in five medical trials. -
Court document accuses J&J, Bayer of keeping mum about Xarelto lab data
Mar 3, 2016 | FiercePharma
By Tracy Staton
Lawyers suing Johnson & Johnson ($JNJ) and Bayer over alleged injuries from their anti-clotting drug Xarelto say that the companies misled editors at The New England Journal of Medicine by failing to speak up about possible discrepancies in patient data from a key trial.
Traditional and Online Media Coverage
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Did heart drug makers withhold data from leading medical journal?
Mar 2, 2016 | CBS News
By Mary Brophy Marcus
Lawyers for patients who are suing two big drug makers who market a popular blood-clotting drug say the companies withheld important information from a letter published recently in a major medical journal.
An article in The New York Times today says lawyers suing Johnson & Johnson and Bayer over the safety of the blood thinning drug Xarelto are calling out an analysis by Duke researchers published in The New England Journal of Medicine. Their analysis showed that problems with a device used in clinical trials of the drug, to test blood for clotting, did not change the drug trial's results.
But according to The Times, the lawyers said the Duke researchers left out key research information that might have affected clinical trial results that compared Xarelto (rivaroxaban) to warfarin, another, older blood thinner.
The original concern with the Xarelto clinical trial was that a device used to test the effectiveness of the drugs on blood clotting was faulty and made Xarelto look better compared to warfarin. The device was later recalled.
The Duke Clinical Research Institute ran the three-year clinical trial, which included more than 14,000 patients and led to Xarelto's FDA approval. It reanalyzed the results after questions were raised about the faulty device and whether the study's findings held up.
But now, it appears, according to The Times, other information might have been withheld that should have been published in the follow-up analysis.
During the course of the trial, about 5,000 blood samples were taken from a small number of the study patients and sent off to a central laboratory.
"I think it was done so the trial investigators would be confident the test results being produced locally were pretty accurate. I believe that's why they took random samples and sent them out," said Dr. Kirk Garratt, associate director for the Center for Heart and Vascular Health at Christiana Care Health System, in Wilmington, Delaware, who was not involved in the Xarelto clinical trials.
During later hearings, the drug companies did not offer up the additional information, even though it was available, the lawyers are suggesting.
"It doesn't say it was hidden, and no one denied it, but no one stepped up," Garratt told CBS News.
The Duke researchers said in a previous statement that they had conducted research separately from the drug companies.
The medical journal editors who published the analysis told The Times that they did not know about the lab data until last Tuesday, when a reporter asked them about it.
"At the time we published the letter, we didn't know that it existed," Dr. Jeffrey M. Drazen, editor in chief of The New England Journal of Medicine, told the paper.
Although the missing data raises questions, Garratt says he remains confident in the overall safety and effectiveness of the drugs.
"I tend to believe that these drugs, rivaroxaban and other drugs like it, are very good medicines. We've already had several years experience with them and they're very good," said Garratt. "No drug is perfect but there's nothing that's come up with these in clinical practice that makes me believe these trial results were misleading."
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.
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Lawsuit alleges Johnson & Johnson, Bayer misled New England Journal of Medicine editors
Mar 2, 2016 | Cardiovascular Business
By Tim Casey
Lawyers for patients suing Johnson & Johnson and Bayer allege that the companies misled editors at The New England Journal of Medicine about the safety of rivaroxaban (Xarelto), the New York Times reports.
The attorneys allege that Duke University researchers left out critical laboratory data. Johnson & Johnson and Duke said they worked independently, while Bayer declined to comment. Sales of rivaroxaban, an oral anticoagulant, were nearly $2 billion in the U.S. last year.
Click below for the full story:
Document Claims Drug Makers Deceived a Top Medical Journal
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Documents Accuse Bayer, Johnson & Johnson of Deceiving The New England Journal of Medicine
Mar 2, 2016 | BioSpace
By Alex Keown
In the ongoing legal concerns surrounding the anticlotting drug Xarelto developed by Janssen Pharmaceuticals, a Johnson & Johnson (JNJ) company, and marketed by Bayer (BAYZF), a new wrinkle surfaced in a legal brief filed last week in federal court in New Orleans claiming the two companies mislead editors at the New England Journal of Medicine over the safety of the drug, the New York Times reported this morning.
Lawsuits filed against Janssen, the maker of Xarelto, and Bayer, the drug’s co-marketer, claim the companies failed to warn patients and physicians of increased risks of fatal internal bleeding when using the drug. In the latest legal maneuver, the Times said plaintiffs argue that researchers at Duke University left out “critical laboratory data” about the drug in an article they published in the prestigious medical journal. They also claim the two pharmaceutical companies were complicit by remaining silent during the regulatory process in the United States and Europe, the Times said.
Xarelto, a popular drug being used in place of the older blood-thinner, warfarin, earned $2 billion in the United States alone last year. Xarelto was approved by the U.S. Food and Drug Administration in 2011.
The Duke researchers were hired to run a three-year clinical trial that involved more than 14,000 patients. The trial results lead to regulatory approval of the drug. However, there have been concerns over a possible defective blood-clotting test device affected the trial. The study compared Xarelto with warfarin for the prevention of stroke and systemic embolisms in patients with a type of irregular heartbeat that is common among the elderly. The malfunctioning device may have caused doctors to administer the wrong dose of warfarin, causing favorability for Xarelto. In February, Duke researchers published a letter in the New England Journal of Medicine arguing that issues with the device did not impact the results of the trial, the Times reported. That letter failed to mention lab data, which the editors of the New England Journal of Medicine claimed they did not know existed until the New York Times reached out to them.
The Duke study was done independently of Janssen and Bayer, however, the Times noted Bayer’s regulatory filing with the European Medicines Agency was nearly identical to the Duke research.
Although the medical journal’s editorial staff have disputed claims they were misled by the Duke researchers, Dr. Jeffrey Drazen, editor in chief of The New England Journal of Medicine, told the Times that the Duke researchers have agreed to conduct an analysis of the lab data.
Critics have suggested the lack of the lab data in the report are “reminiscent of other instances in which drug companies concealed or altered drug-trial data in medical journals,” the Times reported.
There have been more than 5,000 lawsuits filed by patients and their families claiming harm from taking Xarelto. Of those lawsuits, 500 involved patient deaths, the Times said.
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Legal Brief Claims Pharma Companies Misled Medical Journal
Mar 2, 2016 | Drug Discovery and Development
By Stephanie Guzowski
Details surrounding the approval of cardiovascular drug rivaroxaban (Xarelto) are questionable, but new events revealed Tuesday have further muddied the waters.
Last month, an investigation published by the British Medical Journal, questioned the results of data in the ROCKET-AF trial, which served as the backbone for rivaroxaban’s approval. A major concern is the portable device used to monitor and calibrate medication usage in the trial may have been seriously defective.
Now, in a report published first by The New York Times, lawyers for patients suing Johnson & Johnson and Bayer over the safety of rivaroxaban claim that a letter published in The New England Journal of Medicine omitted “critical laboratory data.”
The companies may have been “complicit by staying silent, helping deceive the editors while the companies were in the midst of providing the very same data to regulators in the U.S. and Europe,” reported The New York Times.
Duke University’s Clinical Research Institute, who did the study on behalf of Bayer, published a letter in February in the New England Journal of Medicine stating that it had 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 Pharmaceuticals (part of Johnson & Johnson), 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 February.
Duke University and Johnson & Johnson contend they worked independently. Top editors at The New England Journal of Medicine told The New York Times they did know that separate laboratory data existed until a reported contacted them last week, “but they dismissed its relevance and said they stood by the article’s analysis.”
The ROCKET-AF trial compared the number of strokes and bleeding events experienced by patients taking rivaroxaban with those taking the older anticoagulant drug warfarin. A concern is that faulty results (potentially caused by a defective device) may have led doctors to give patients the incorrect dose of warfarin, which could have favored rivaroxaban.
Rivaroxaban (Xarelto) is a blockbuster drug for stroke prevention in atrial fibrillation that gained approval from both U.S. and European regulators. The drug had nearly $2 billion in U.S. sales last year.
Bayer and Johnson & Johnson hired Duke University’s Clinical Research Institute to run a three-year clinical trial involving more than 14,000 patients, which led to rivaroxaban’s approval. The trial’s results have come under scrutiny since September, when the companies notified regulators that a device used in the trial — the Alere INRatio and INRatio2 PT/INR Monitor System — had malfunctioned.
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Mar 2, 2016 | Business Insider
By Lydia Ramsey
A controversy is brewing after a document claimed that two major pharmaceutical companies may have misled a medical journal by leaving out some critical data on their drug.
The drug in question is Xarelto, a blood thinner used to treat and prevent blood clots approved in 2011. In 2015, Xarelto made about $1.8 billion in US sales. But it's also the subject of more than 5,000 lawsuits, 500 of which involve patient deaths.
The New York Times' Katie Thomas found in a footnote in a federal legal briefing that there might be some evidence that the drug's developers, Johnson & Johnson and Bayer, may have left out some critical data when a peer reviewer (a researcher who is independent of the study who goes through and vets the findings) at the New England Journal of Medicine asked for it. Peer reviewers are responsible for evaluating the design and data that comes out of studies, to make sure that what the study concludes is accurate. That data could have given the reviewer an idea of how the blood readings from one device compare to another.
This complication comes after months of concern about the design of a trial to test how safe and effective Xarelto was. The goal was to figure out if Xarelto worked better than Warfarin, an older blood thinning drug that has been associated with some serious complications. But the study, it was later revealed, used a blood-testing device that had been recalled.
The study has been contentious, especially with regard to its ties to the recently-approved FDA boss Dr. Robert Califf, who led the trial. Califf has been critiqued because of his connections to the drug industry, which he is now in charge of regulating. And late last month, researchers from Duke University, which led the original study, took another look at their work and concluded that the recalled device didn't impact the study's results anyway.
Still, even if the results would not have changed as a result of the comparative data that was reportedly left out, that doesn't mean leaving them out in the first place wouldn't be a problem. As Thomas writes:
"But the claim — that industry influence led to the concealing of data — carries echoes, some experts said, of an earlier era of drug marketing, when crucial clinical data went missing from journal articles, leading to high-profile corrections and a wave of ethics policies to limit the influence of drug companies on medical literature."
The FDA and the European Medicine Agency are both looking into whether the faulty blood-testing device could have led to the drug's approval.
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Morning Break: Was NEJM Snookered? Zika in Cuba; Gray Hair Gene
Mar 2, 2016 | MedPage Today
Was NEJM duped by the makers of Xarelto (rivaroxaban)? And what did researchers at Duke know about the deception? The New York Times takes another look at the dust-up over missing lab data. Here is some coverage from MedPage Today.
Device maker Olympus said it would pay $646 million to settle charges of bribery and kickbacks. (Kaiser Health News)
Nearly $3 billion goes down the drain every year. The culprit: cancer drug packaging? (Washington Post)
LAPD says 37% of the people shot by its officers last year had documented signs of mental illness (Los Angeles Times)
FDA issues new guidance on preventing Zika transmission through donated cells and tissues. And Cuba announces the country's first case of Zika. (AP)
The Incidental Economist looks at the ethics of assisted suicide in lucid and vulnerable psychiatric patients.
About 750 people were asked several questions about their use of nootropics, and it turns out that people really like Adderall. (Slate Star Codex)
Is it possible? Physicians, hospitals, and insurers coming together to end "surprise billing" -- when patients are socked with huge out-of-network charges for services they thought were covered by their plans. (Pittsburgh Post-Gazette)
A new target for gene therapy? A study of 6,000 people in Latin America identified the first gene associated with gray hair, CNN reported.
Another USPSTF punt: insufficient evidence to recommend for or against visual acuity screening in older adults without specific complaints.
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Pharmalot, Pharmalittle: Drug makers accused of misleading medical journal on blood thinner
Mar 2, 2016 | STAT News
By Ed Silverman
Hello, everyone, and how are you this morning? We are just fine, thank you, especially since we have made it to the middle of the week. This is always something of a milestone, in our view, given the hectic daily routine. To celebrate, yes, we are quaffing cups of stimulation and hope you will join us. Neurons need nurturing, too. Meanwhile, here are some tidbits. Have a lovely day and do drop us a line if you hear anything interesting …
The US Securities and Exchange Commission probe into Valeant Pharmaceuticals is focused on the relationship between the drug maker and Philidor Rx Services, the specialty pharmacy, but was sparked by Valeant’s own request that regulators investigate allegations made by a short seller that company accounting was fraudulent, Reuters reports. Valeant, meanwhile, called analysts to try to restore confidence in the company, The Wall Street Journal writes, and also challenged Hillary Clinton for her ads slamming its pricing practices.
The Canadian Medical Association is being accused of compromising the independence of its medical journal after firing its editor-in-chief and disbanding the editorial oversight committee, The Globe and Mail tells us. “It’s slightly Orwellian to remove the editor, disband the [oversight committee], which is charged with maintaining editorial independence, and then suggest you’re enhancing editorial independence,” one former committee member says.
Lawyers for patients who are suing Bayer and Johnson & Johnson over the safety of the Xarelto blood thinner say the drug makers misled editors at the New England Journal of Medicine, The New York Times says. They claim that a letter published in the journal about a review of trial data and written primarily by Duke University researchers omitted important lab data, but the companies were aware of the omission and remain silent.
AstraZeneca and Novo Nordisk are looking for a lift in coming weeks from a pair of closely watched trial results, according to Reuters. Novo hopes to demonstrate the cardiovascular benefits of its Victoza diabetes treatment, while AstraZeneca looks to prove that its Brilinta blood thinner can help stroke patients, not just those people with heart problems.
Gilead Sciences added a new product to its HIV franchise after the Food and Drug Administration approved Odefsey, a three-drug regimen taken as a single, once-daily tablet, PMLive writes.
The FDA’s Science Board met Tuesday, and Dr. Robert Califf, the newly confirmed commissioner, outlined plans to tackle pain management and opioid abuse, Regulatory Focus informs us.
The UK’s National Institute for Health and Care Excellence rejected Johnson & Johnson’s Imbruvica for patients with chronic lymphocytic leukemia over cost concerns, Pharma Times says.
An Indian health ministry committee recommended that licenses of at least 10 drug makers to make a generic version of a life-saving drug be suspended over quality concerns, The Economic Times reports.
Ipsen bought an oncology drug from Exelixis in a deal worth up to $855 million, plus potential royalties, according to Pharma Times.
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Missing Data from Rivaroxaban Letter Draws Speculation, Criticism
Mar 3, 2016 | NEJM Journal Watch
By Amy Orciari Herman
A letter published in the New England Journal of Medicine in February — asserting that a faulty device did not influence the safety and efficacy outcomes for the anticoagulant rivaroxaban (Xarelto) in the ROCKET AF trial — did not include laboratory data that could have been used to evaluate the device's accuracy, the New York Times reports.
The letter in question was written mainly by researchers from Duke University, who'd been hired by Johnson & Johnson and Bayer to run ROCKET AF.
The lab data in question are comparisons between patients' international normalized ratios as measured by the point-of-care device and results of tests performed at a central laboratory. The device was later recalled by the FDA because it often gave falsely low INR readings.
Asked to comment, a spokesperson for the New England Journal of Medicine said, "During the editing process ... the editors told the authors that they would like to see a systematic evaluation of routinely obtained central laboratory INR data but assumed that such data did not exist. This was affirmed by the authors and was the case. Only two data points existed for a subset of the study population. Without a substantial majority of paired values, a comparison between the two methods would not be clinically directive."
Lawyers representing patients suing the drug makers over rivaroxaban's safety say the companies intentionally stayed silent about the data while "in the midst of providing the very same data to regulators in the United States and Europe," the Times reports.
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Health Brief: Trump Offers Some Health Plan Details
Mar 3, 2016 | Morning Consult
By Mary Ellen Mcintire
Document Claims Drug Makers Deceived a Top Medical Journal
Katie Thomas, The New York TimesIt is a startling accusation, buried in a footnote in a legal briefing filed recently in federal court: Did two major pharmaceutical companies, in an effort to protect their blockbuster drug, mislead editors at one of the world’s most prestigious medical journals?
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What’s Wrong with Our Prescription Drug Trials
Mar 3, 2016 | Healthline
By Brian Krans
For 12 years, Roy A. Teel Jr. was involved in human research trials at the University of California, Los Angeles, but he didn’t don a lab coat.
As a research subject with progressive multiple sclerosis, he was involved in five medical trials.
When his condition didn’t improve, he retired on disability in 2011. The whole ordeal left a sour taste in his mouth.
“As long as there is a profit to be made, it is very, very unlikely that you are going to see any significant changes in how trials work,” Teel, now an author, told Healthline. “For those patients who are injured or lose their lives in clinical trials they are nothing more than collateral damage or the cost of doing business. There is no direct harm to the researcher, institution, or the drug company.”
The old analogy of breaking a few eggs to make an omelet seems fitting.
In searching for new and potentially life-saving drugs, mistakes and adverse events —including deaths — are seemingly inevitable.
The U.S. Food and Drug Administration (FDA) is the gatekeeper in ensuring the science is sound and the drugs brought to market are relatively safe and used appropriately.
Getting there is an often long, expensive, and complicated journey for drug makers.
According to the Tufts Center for the Study of Drug Development, the cost of bringing a new prescription drug to market comes in at an estimated $2.6 billion.
Almost half of that estimate accounts for revenues a drug company doesn’t receive while a new drug is in development. Still, almost $1.4 billion is listed as “out of pocket costs,” including $312 million for research and development.
“Companies learn a lot by failure,” Peter Pitts, president of the Center for Medicine in the Public Interest and former FDA associate commissioner for external relations, told Healthline. “That’s how science works.”How One Detail Can Skew Results
The latest study under fire involves rivaroxaban (Xarelto), the blood-thinning medication manufactured by Bayer, marketed by Janssen, a Johnson & Johnson company, and endorsed by celebrities like Arnold Palmer and Kevin Nealon.
In an investigation published in the British Medical Journal, researchers pointed out faults in the single trial used to gain approval in the United States and Europe.
The trial — ROCKET-AF — pitted Xarelto against warfarin, the most widely prescribed oral blood thinner drug in North America. The trial was overseen by the Duke Clinical Research Institute (DCRI).
Before ROCKET-AF began in 2002, a device that measured international normalized ratio (INR), important numbers when testing blood thinners, were found to be delivering lower results.
The FDA later recalled the device. A warning letter issued in 2005 detailed erroneous high and low results, which can lead to death or serious injury such as major bleeding. Too much of the drug can cause uncontrolled bleeding while too little can lead to a stroke.
The device’s use wasn’t published in phase III trials, so the potentially faulty numbers went unnoticed for years. The FDA did, however, warn Xarelto manufacturers about false or misleading ads for downplaying the risks of the drug. It also rejected wider use of the drug in early 2014 when the medicine was already bringing in $1.5 billion a year.
In September, Bayer and Johnson & Johnson announced findings from a 45,000-patient trial — including data from the ROCKET-AF study — that rates of major bleeding in patients with atrial fibrillation remained low.
“Bayer is committed to supporting physicians and patients in the safe and responsible use of Xarelto,” Dr. Michael Devoy, chief medical officer of Bayer HealthCare, said in a press release.
Read More: Emergency Rooms Facing Shortages of Important Drugs »Study Sponsors Influence Outcomes
While doctors and scientists are calling for an independent investigation into the ROCKET-AF trial, a review of the data released in October found Xarelto was similar in safety and efficacy to warfarin.
Of the 16 researchers listed on the study, all but three received consulting fees from, were on advisory boards for, or were employees of Bayer, Janssen, or Johnson & Johnson, according to the disclosure statements.
Overall, nine companies have spent $25 million on 88,548 doctors related to Xarelto, according to ProPublica’s “Dollars for Docs” project.
While these potential conflicts of interest may seem alarming to some people, for those familiar with pharmaceutical research, it’s just another day at the office.
According to a recent review of meta-analyses of antidepressant drugs, when a drug company employee authors research on one of their drugs, it’s 22 times less likely to contain negative statements. Nearly a third of 185 analyzed studies had authors that were drug company employees and 79 percent had some conflict of interest, the review stated.
Read More: Drugs Used in Jimmy Carter’s Treatment Among a New Generation of Immune Therapies »How Drug Trials Work
Drug companies front the money to develop a drug and bring it to market; it’s their research and they hold the keys to the data.
But, in order to receive approval by the FDA, they have to follow certain steps in the clinical process.
First, a potential drug is tested on animals — typically rodents, dogs, and primates — to determine toxicity.
Ira S. Pastor, CEO of Bioquark Inc., said it’s widely acknowledged animal models remain poorly predictive for humans, yet remain a mandatory cornerstone behind years and millions of dollars of early drug development activities.
“Penicillin kills guinea pigs and produces birth defects in rats. Aspirin is poisonous to cats. Cancer has been ‘cured in mice’ thousands of times and dozens of drugs found safe in animals are later withdrawn from market due to adverse drug events in humans,” Pastor told Healthline.
From there, a drug moves to a Phase I study — or first-in-human trials — which often has a small sample size of healthy adults.
Here, again, the focus is to determine toxicology. Should it be deemed safe to a certain extent then a Phase II trial, with a few dozen to a few hundred of potential patients to determine the drugs’ efficacy at treating a certain disease or condition, is launched.
On Feb. 29, AstraZeneca announced that a Phase IIb trial for tremelimumab to treat mesothelioma, a rare and deadly cancer of the lining of the lungs or abdomen, didn’t “meet its primary endpoint of overall survival,” meaning it will not proceed to a Phase II trial or be considered by the FDA.
The “gold standard” of testing is the randomized, double-blind trials, where neither patient nor researcher knows if a drug or a placebo is being administered. These are typically done in Phase III trials involving several hundred to 3,000 people.
Should a drug be shown to be safe and effective, it’s sent to the FDA for approval. The FDA determines whom the drug can be given to and what the drug can be used to treat.
Some drugs can receive “accelerated approval” where they hit the market after favorable Phase II results with the caveat of doing a follow-up study while the drug is being used in real-life patients. Drugs that make their way through this process are most often for life-saving medications such as cancer and public health emergencies like HIV/AIDS.
Since 2007, drug companies have registered their trials with ClinicalTrials.gov, operated by the U.S. National Institutes of Health. As of March 1, there were 209,563 studies registered, 105,573 of which were for drug or biologic therapies.When Trials Go Wrong
In 1993, 15 people participated in a trial for the experimental hepatitis B treatment fialuridine. Five of them died and two others needed life-saving liver transplants.
In 2006, six volunteers were given an antibody — TGN1412 — 500 times lower than what had been deemed safe in animal studies. After their first dose, all were hospitalized with multiple organ failure.
In January, a French trial of 128 healthy volunteers had to be stopped. Of the 90 who received increased doses of the drug, six participants fell ill and one died. Since it’s common for pharmaceutical companies to not release the makeup of the molecules they’re testing, outsiders have been left in the dark about the substance used in the trial.
These alarming stories are indeed rare and regulatory agencies like the FDA are working to revamp the drug trial process in the wake of these adverse events, including the need for better mechanisms to safely test first-in-human studies.
In his book, Bad Pharma, Dr. Ben Goldacre examined the problems that arise in modern trials, including poor designs, faulty analysis of the data, exaggerated benefits, and downplayed harmful side effects.
While outright fraud is rare, Goldacre wrote, more trials are impacted by recruiting too few patients, stopping the trial early or late, testing drugs against something that doesn’t work, testing against relatively meaningless outcomes, ignoring patients who drop out, switching focus of the trial midway through, and spinning the results in a favorable light.
The results of these studies when bolstered, such as the case of a trial about intensive blood sugar control for diabetics, can permeate medical knowledge.
“There is a terrifying reality revealed by this study: rumours, oversimplifications, and wishful thinking can spread through the academic literature, just as easily as they do through any Internet discussion forum,” Goldacre wrote.
Another common occurrence is that when a trial doesn’t find its intended results, it often doesn’t see the light of day.
According to data from ClinicalTrials.gov, of the more than 1.2 million trials registered from 2009 to today, 90,381 — or less than 8 percent — have posted their results.
Brad Thompson, PhD, chief executive officer of Oncolytics Biotech, a startup focusing on oncology with five ongoing phase II studies, said when pharmaceutical companies pay for research the positive results are what become published in academic journals.
Journals themselves aren’t interested in studies with negative results, so getting all pertinent data available is a problem.
“No one wants to promote a negative study,” he told Healthline, “but there are checks and balances in place.”
Pitts says the FDA has an “extremely robust process” and if a company was found falsifying data it “would be out of business.”
“Could a company hide data? They could, but they’d be caught,” he told Healthline.Fixing Faulty Data Takes Time
If a drug hits the market on faulty data, it’s difficult to get it revoked as regulators can’t act unless there are safety concerns.
When this does occur, the FDA issues “black box warnings” that alert physicians to an increased risk of adverse effects.
On Monday, the FDA announced it will require a “black box” warning for Bayer’s permanent birth control device Essure as well as directing Bayer to study heightened risks for woman, including unplanned pregnancies, pain, and other complications. One review linked 303 fetal deaths to Essure, Reuters reported.
The initial studies found 97 percent of women could rely on the device, but only 25 percent of the 926 women enrolled in the program were studied for effectiveness two years after the device was implanted. Of those 926 women, 181 didn’t even undergo the procedure, according to an article in the New England Journal of Medicine.
Bayer was supposed to do two five-year follow-up studies, but neither was registered, one remains unpublished, and the other wasn’t widely circulated.
“The problems of inadequately rigorous premarketing and postmarketing studies, unregistered clinical trials, and incomplete and delayed dissemination of results are not unique to Essure,” the NEJM authors wrote. “The 13-year history of Essure emphasizes the necessity for thorough examination and timely reporting of patient outcomes in well-conducted premarketing clinical trials and dedicated follow-up in postmarketing studies. Only then will we better understand the risks and benefits of various devices.”
One case of hidden unfavorable data regarded the antidepressant Paxil when maker GlaxoSmithKline deliberately hid two studies showing the drug had modest results compared with a placebo and could increase the risk of suicide in children. In 2012, GSK pleaded guilty and agreed to pay $3 billion for fraud, including failing to report safety data regarding Paxil, Wellbutrin, and Avandia.
But when pharmaceutical companies pay out fines, it’s most often for marketing their drugs for “off label” uses or those that the drugs have not been approved to treat.
Pitts, who is also the global food, drug and policy expert at YourEncore, says these kinds of cases highlight the importance of proper labeling language so physicians are aware of a drug’s risk as part of an “ongoing, imperfect system.”
“It’s complicated,” he said. “Nothing is for free and there’s no product without risk.”Trials Don’t Reflect Real-World Patients
Patients looking to enroll in a trial can check ClinicalTrials.gov, but Tom Krohn, chief development officer of TrialReach, says that’s an overly scientific and confusing process for the average patient.
For example, there are more than 1,000 different ways to say “not pregnant” in trial recruitment data.
TrialReach — a patient recruitment service for clinical trials — is one company helping to close the gap between researchers and trial participants. Those conducting the trials, typically pharmaceutical companies, dictate what specific patients they are looking to recruit.
“It’s a big challenge,” Krohn told Healthline. “From the patient’s perspective, they are looking for help for their disease and a clinical trial is one way to do it.”
Scientific discovery is beholden to imperfect human behavior, which means controlling for variables is even more difficult. People leave trials. They stop taking medication.
“You can’t force people to follow-up that don’t want to. You can’t force a patient to keep taking a drug,” Thompson said. “Those are the realities of dealing with humans.”
More than half of drugs destined for U.S. patients are tested overseas. Medically, this can create problems as they may metabolize drugs differently than Americans.
In poorer countries — India, Malawi, Thailand, etc. — where more drug trials are being conducted, patients will often lie to stay on drugs in trials because it’s the only way they can get needed medication, Thompson said.
Pastor says these trials also often exclude parts of the population who will end up taking the drugs and they affect each person differently, showing flaws in the drug-approval process.
“The more we learn, the more we realize that every patient’s disease is a rare disease,” he said. “One need only look at the sheer number of withdrawals, as well as adverse drug events (ADE) and deaths, associated with approved, marketed drugs — 2 million ADE and 100,000 fatalities annually in U.S. alone — which have gone through decades of human testing and use, to realize that something is very wrong with the current model.”
Andrea LaFountain, PhD, a cognitive psychologist with eight years of healthcare experience, says data from clinical trials vastly over-promise health benefits because on average people take half of their prescribed medications.
In trials, if a person takes less than 90 percent, “they are terminated from the trial and their data is scrubbed from the record.”
“Clinical trials do not factor in this lower consumption rate in the real world,” she told Healthline. “And even when pharmaceutical companies support patients with coupons and reminder programs, adherence rates do not lift to the levels seen in clinical trials.”
While the clinical trial process isn’t perfect, it’s currently the complicated way drugs go from the lab to the real world.
“Of course there needs to be improvements,” Thompson said. “There always needs to be improvements, but (we) can only get them with this kind of commentary.”
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Court document accuses J&J, Bayer of keeping mum about Xarelto lab data
Mar 3, 2016 | FiercePharma
By Tracy Staton
Lawyers suing Johnson & Johnson ($JNJ) and Bayer over alleged injuries from their anti-clotting drug Xarelto say that the companies misled editors at The New England Journal of Medicine by failing to speak up about possible discrepancies in patient data from a key trial. The NEJM published a letter, primarily written by Duke University researchers, about the trial, which came under scrutiny last fall because a blood-testing device used in the study had given inaccurate readings. In the letter, the researchers said that readings from the faulty device would not have changed the trial's results. They weren't aware of lab data that might have shed a different light on the device's readings, but the companies were, The New York Times reports. Report
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