Doctors in the Dark With Only Half of Drug Research

Only half of all clinical trial results are published. Favorable results are twice as likely to be released.

Your doctor only knows half of the research on the medication they just prescribed to you. Scary, right? That’s not all: Governments, regulators, and scientists are similarly left with limited data.

A study published in the New England Journal of Medicine estimates that only half of all clinical trial results are published. Results that are published are twice as likely to favor the medical treatment.

Similarly, a PLOS Medicine study found that half of the research on new medical treatments under reports adverse events. Though 95% of research contains adverse effects, only 46% of published documents include them.

So, what does this mean? It means that drugs are approved, regulated, and prescribed based on skewed data. It means that taxpayer dollars are wasted by scientists unknowingly repeating the same clinical trials over and over again. And it means that patients receive medications that may do them more harm than good.

A “Cancer” at the Heart of Medical Research

Credit: AllTrials.net
Credit: AllTrials.net

It’s easy to understand why drug companies are more likely to hide negative clinical trial results. But universities and non-industry sponsored researchers are even more susceptible to leaving out data.

Starting in 2007, the FDA required that all clinical trials are registered and their results published within one year of completion on ClinicalTrials.gov

However, the New England Journal of Medicine study discovered that of the clinical trials registered, only 13.4% of trials reported their results within the one-year time frame. While 17% of industry trials were published, only 8.1% of NIH-funded trials were, and a mere 5.7% of university and other government-sponsored trials were released. Five years on, still less than half of clinical trial results were published.

“If I conducted one study and I withheld half of the data points from that one study, you would rightly accuse me, essentially, of research fraud,” said Ben Goldacre, creator of the AllTrials campaign, in his popular TED Talk. “And yet, for some reason, if somebody conducts 10 studies but only publishes the five that give the result that they want, we don’t consider that to be research misconduct.”

The problem is more complex than protecting profits. Medical journals have to change their publishing incentives, Goldacre says. Studies that flop rarely get accepted for publication.

Doctors Rely on Distorted Information 

With only half of the information, doctors can’t know all the possible side effects of a medication, if its benefits outweigh the risks, or whether or not it is better than cheaper alternatives.

You want to do the best for the patient, but if you can access only half the information, then a decision on choosing a particular drug or device might not be as reliable as you’d like,” said Yoon Loke, one of the PLOS Medicine study researchers.

Even with the journal results they do have access to, psychiatrist Erick Turner told LiveScience that most physicians lack the statistical knowledge to understand how reports can distort results.

“If the average physician believes that every trial done on a drug is positive, they’re going to have a very rosy impression and perhaps pooh-pooh [other] treatments that might also be effective,” said Turner.

An Unpublished Study Costs 100,000 Lives

If researchers had released the results earlier, they “might have provided an early warning of trouble ahead.”

Lorcainide offers a classic example of the importance of publishing failed trials. Created in the 1960s, it was an antiarrhythmic medication that helped restore regular heartbeats in patients.

Its 1980 clinical trial was a failure: Nine of the 49 participants on Lorcainide died, while only one of the 46 who received a placebo died. The company didn’t release the results.

Without knowing the outcomes of the trial and its deadly consequences, other manufacturers pursued their own antiarrhythmic medications. It’s estimated that more than 100,000 people died because of it.

The researchers finally published Lorcainide’s clinical trial results in 1993, and wrote that if they had released them earlier, they “might have provided an early warning of trouble ahead.”

Billions of Government Money Wasted on Tamiflu

After five years, Roche released the results of all 70 clinical trials, showing that Tamiflu was largely ineffective.

Even if a drug is relatively harmless, withholding results can result in a waste of money if a medication isn’t as effective as its data claims it is.

Tamiflu, an anti-influenza drug made by Roche, didn’t publish the results of 70 clinical trials.  The results they did release presented Tamiflu as more effective than comparable drugs for preventing flu complications and reducing symptoms.

Governments around the world stocked up on the drug in preparation for the next flu outbreak. Britain spent £473 million and the U.S. spent $1.3 billion on Tamiflu and other anti-viral medications.

After five years, the Cochrane Collaboration, a nonprofit in Britain, was able to persuade Roche to release all 70 trials. They discovered that Tamiflu didn’t prevent hospitalizations or flu complications. At best, it just reduced symptoms by one day.

These weak benefits didn’t outweigh the risks for many patients. At least 70 people committed suicide while on Tamiflu, and many others suffered from temporary bipolar disorder, schizophrenia, and other psychotic episodes.

New Rules Ignore Problems From the Past

“Selective reporting…leads to an incomplete and potentially biased view of the trial and its results.”

Regulators and companies like Roche have committed to greater transparency, offering some hope for the future. In 2015, the World Health Organization (WHO) warned that, “Selective reporting, regardless of the reason for it, leads to an incomplete and potentially biased view of the trial and its results.”

Perhaps recognizing that the FDA’s existing rule is ineffective, the U.S. Department of Human Health and Services published a final rule on clinical trial reporting in September 2016, which goes into effect later this month. The rule has been expanded to include trials that have yet to be regulated by the FDA, ensuring that all resultsregardless of whether a medication is eventually soldare released.

However, even if every trial is published going forward, we’re still saddled with erroneous decisions from the past. In order for doctors and scientists to get a complete understanding of every medication that is currently prescribed, we have to publish historic data.

Are You Suffering From Adverse Effects?

With this pervasive cover-up culture, it’s no wonder that we frequently hear of harmful medical treatments. If you are suffering from complications caused by your medications, you may be entitled to compensation. Contact ClassAction.com today for a free, no-obligation legal review.

FDA Chief’s Conflicts of Interest and the “Revolving Door” Problem

When a government official holds or has held a professional position in the same industry that he or she is charged with regulating, it raises questions about whether public or private interests are being served.

The “revolving door” between the public and private sectors is a major impediment to responsible democratic governance.

The current U.S. Food and Drug Administration (FDA) commissioner, Dr. Robert M. Califf, has extensive pharmaceutical industry ties and has been accused of undermining public health and safety.

With President-elect Donald Trump set to choose a new FDA chief, ClassAction.com looks at how an official’s non-government experience can muddy the regulatory waters.

What Is the Revolving Door?

The revolving door refers to the practice of switching back and forth between public and private employment.

This phenomenon is commonly observed among members of Congress who leave the federal government and become lobbyists, although it can occur whenever someone with government experience gains employment in a private sector job where they can influence public policy decisions, or vice versa.

Lobbying’s return on investment bears out its effectiveness.

Although generally seen as negative, the revolving door has a practical upside. Namely, corporate experience gives regulators and policymakers a deeper understanding of complex issues that, in a capitalist system, cannot be divorced entirely from private interests.

However, the opposite also holds true: once a public official leaves office, he or she can leverage knowledge about the workings of government into lucrative private sector compensation.

Lobbying’s return on investment bears out its effectiveness. Research conducted by the Sunlight Foundation found that from 2007-2012, 200 corporations spent $5.8 billion on federal lobbying and campaign contributions and got back $4.4 trillion in federal business and support.

In other words, for every dollar these corporations spent on influencing politics, they received $760 from the government.

Lobbying-ROI-1024x461
Credit: UnitedRepublic.org/Represent.us

Robert Califf, Big Pharma, and the FDA

Current FDA commissioner Robert Califf, a cardiologist and clinical researcher tapped by President Obama to run the nation’s drug regulatory agency, was criticized at the time of his nomination for his drug company connections.

The New York Times reported that Dr. Califf “has deeper ties to the pharmaceutical industry than any FDA commissioner in recent memory, and some public health advocates question whether his background could tilt him in the direction of an industry he would be in charge of supervising.”

Dr. Califf’s disclosed industry ties include financial support from Johnson & Johnson, Lilly, Merck, Bayer, Boehringer Ingelheim, GlaxoSmithKline, Medtronic, and Bayer. He also has financial links to Gambro, Regeneron, Gilead, AstraZeneca, Roche, Genetech, Medscape LLC, Portola Pharmaceuticals, and other companies.

Dr. Califf first joined the FDA as deputy commissioner for medical products and tobacco. Before his government tenure, he ran a multimillion-dollar clinical research center at Duke University that was a major contractor to the pharmaceutical industry. The center was more than 60% industry-funded.

Califf Ran Troubled Xarelto Trial

While at Duke, Johnson & Johnson paid Dr. Califf to conduct an important clinical study of the blood-thinner Xarelto. That study was criticized for being biased in the drug’s favor.

Although the FDA approved the anticoagulant Xarelto, FDA scientists expressed misgivings about its safety and effectiveness, warning that it could pose greater stroke and/or bleeding risks than its predecessor, warfarin.

Xarelto is a blockbuster drug for Johnson & Johnson but it has also been the target of thousands of lawsuits alleging the drug caused serious bleeding events and deaths. Unlike warfarin, Xarelto does not have an antidote to stop internal bleeding.

Some Question Califf’s Involvement in 21st Century Cures Act

Congress recently passed the 21st Century Cures Act, a sweeping health bill some say is too friendly to drug and device companies.

“It should be unimaginable that the most senior [FDA] officials would collude with the lead medical device trade association.”

Leading the legislation’s criticism was Ralph Nader’s Public Citizen. In 2015, when an earlier version of the bill was being considered and Dr. Califf was awaiting confirmation as FDA chief, Public Citizen criticized him for participating in at least one high-level strategy meeting with the industry about the bill.

“It should be unimaginable that the most senior Food and Drug Administration officials would collude with the lead medical device trade association to write legislation to weaken the agency’s regulatory oversight and approval standards for medical devices. But that is exactly what appears to have happened,” said Public Citizen’s Dr. Michael Carmone in a statement.

New Nomination, New Questions

The incoming Trump administration hasn’t officially nominated an FDA commissioner, but rumored picks are drawing scrutiny.

Leading candidates to run Trump’s FDA include Jim O’Neill and Dr. Scott Gottlieb.

Potential nominee Jim O’Neill, a self-described libertarian, served as principal associate secretary of health and human services under George W. Bush and is a managing director at Peter Thiel’s Mithril Capital Management.

While Mr. O’Neill doesn’t have a medical background, perhaps more worrying is his endorsement of what he calls “progressive approval,” which would allow drugs proven safe—but not necessarily effective—by the FDA to be marketed.

Another potential Trump FDA pick, Dr. Scott Gottlieb, has medical credentials as well as government experience, having served as a senior adviser to the FDA commissioner in 2003-2004, senior adviser to the Centers for Medicare and Medicaid Services in 2004, and FDA deputy commissioner for medical and scientific affairs from 2005-2007. But Dr. Gottlieb also has deep pharmaceutical industry ties, reports Reuters.

Trump’s eventual nominee requires Senate approval. But despite a divided government, the revolving door between government and industry has bipartisan support: after all, Robert Califf was confirmed in an 89-4 vote.

Clinical Trials Likely to Be Focal Point in Xarelto Lawsuits

Although the legal strategy of Xarelto plaintiff attorneys won’t become clear until the first trials begin in early 2017, it appears that the quality—or seeming lack thereof—of clinical trials used to approve Xarelto (rivaroxaban) will be a key issue. One particular point of emphasis could be a lack of quality data supporting once-daily Xarelto dosing, something drugmakers Bayer/Janssen claim makes Xarelto more convenient but could cause life-threatening side effects.

Xarelto’s once-daily dosing makes the blood thinner more convenient, but could also make it more dangerous.

Xarelto and other so-called “novel anticoagulants” are vying to replace the older blood thinner Coumadin (warfarin) largely on the grounds that they are easier to use than warfarin. Blood thinners are prescribed to patients at risk for developing blood clots and suffering related complications such as stroke and deep vein thrombosis.

Xarelto does not require medical monitoring to ensure patient safety, whereas warfarin patients must be monitored once or twice per month for blood clot risks and have their dosage adjusted accordingly. Another purported benefit of Xarelto over warfarin is its once-daily dosing, something that makes Xarelto more user-friendly—and thus more marketable—but according to some critics makes the drug more dangerous.

Xarelto’s Short Half-Life

The dosing problem has to do with Xarelto’s relatively short half-life of 5-9 hours. Other new coagulants such as Pradaxa and Eliquis have a half-life of 12-17 hours, while warfarin has a half-life of 20-60 hours.

A short half-life means that a drug’s concentration in the body diminishes rather quickly. This leads to drug “peaks” (high drug concentrations) and “troughs” (low drug concentrations). Fluctuations in drug concentration present a twofold risk: of bleeding (when concentrations are high), and of lower blood clot prevention efficacy (when concentrations are low).

According to one study, at its peak the amount of Xarelto measured in the blood was 16.9 times higher than at its trough. For Eliquis (abixaban), which is administered twice per day, the peak was 4.7 times higher than the trough.

FDA staff clearly identified this issue during the approval process but decided to clear Xarelto for sale because clinical trial data indicated it had a safety profile that was no worse than warfarin.

But while the overall safety of the drugs was comparable in premarketing studies, postmarketing adverse event data shows what would be expected of a drug with a short half-life and once-daily dosing. According to data provided by the Institute for Safe Medication Practices (ISMP), compared to other blood thinners, Xarelto has a significantly higher frequency of treatment failure events (embolic-thrombotic events, or blood clot events), an apparent outcome of a “trough.”

Potential side effects of rivaroxaban “peaks,” which may lead to excessive levels of the drug in some patients’ bodies,  are especially concerning when considered alongside Xarelto’s lack of a reversal agent. Plaintiffs in Xarelto lawsuits commonly claim that they were not properly warned about the lack of a Xarelto bleeding antidote. If serious bleeding occurs with warfarin, the drug’s effect is easily reversible.

Bad Dosing Data

FDA reviewers noted that the “the clinical relevance was uncertain” in regards to the safety profile of Xarelto 10 mg twice daily versus Xarelto 20 mg once daily. The reason for their uncertainty? In the pivotal trial (ROCKET AF study) used to support Xarelto’s approval, only the once-a-day regimen was tested.

One study did compare once daily dosing with twice daily dosing, but according to an attorney representing Xarelto lawsuit plaintiffs, the study was on par with “an elementary school science fair project” due to numerous shortcomings, including missing data.

One attorney compared Xarelto clinical trials to “an elementary school science fair project.”

An article published in the Journal of the American College of Cardiology reviewed the trial-in-question (the ATLAS ACS 2–TIMI 51 Trial) and found that “an unanticipated high rate of missing data, particularly the vital status of patients, precludes reliable and valid information.” The article also found that “there was a lack of an expected dose response—the 5-mg dose did not have greater efficacy compared with the 2.5-mg dose of rivaroxaban.”

So why, in spite of inadequate safety and efficacy data, is Xarelto recommended for once-daily dosing? It could simply be a marketing ploy. Once-a-day dosing helps to sell the idea that Xarelto is more convenient than competitors.

If plaintiff attorneys are able to poke holes in Xarelto clinical trials and show that Bayer/Janssen should have provided stronger warnings about the potential side effects associated with once-daily dosing, they may have success in the initial Xarelto trials that are scheduled for February and March 2017.

Questions about Xarelto litigation? Interested in filing a claim? Get in touch with ClassAction.com and learn your legal options.

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(Sources: ISMP Quarter Watch; FDA; JACC; PennRecord)