Tag: off-label drug marketing

12/11/18

A Reason to Cry Uncontrollably

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Danny Glover did a “public awareness” ad for pseudobulbar affect (PBA) in 2015. In the ad, he said if you have PBA, choosing to laugh or cry may not be your decision. The ad went on to note PBA is a neurological, not psychological condition that is treatable; by Avanir’s Nuedexta. You were given information to “get the facts” about PBA. But one of the facts you wouldn’t get is that almost half of Nuedexta claims filed with Medicare in 2015 “were filed by doctors who had received perks (financial or otherwise) from Avanir.”

The above quote was from an article on Nuedexta from the website Nursing Home Abuse Center that highlighted a CNN investigation into Avanir and Nuedexta. While experts say that PBA effects less than 5 % of elderly patients, CNN found that “more than half of all Nuedexta pills manufactured since 2012 have gone to nursing homes.” While Avanir claims in its ads that PBS can occur with patients having Alzheimer’s or dementia, it admits Nuedexta has not been extensively studied among elderly patients.

One study among Alzheimer’s patients found those taking Nuedexta were twice as likely to suffer a fall, not something you want to see with the elderly. “Fall risk has been a huge concern among Nuedexta users since 2013 when nursing home inspectors first started questioning use of the drug in dozens of nursing homes across the United States.”  The CNN investigation found over 80 cases through 19 states where nursing homes were cited for inappropriate use and monitoring of Nuedexta. Sometimes it was given to patients without a formal prescription or doctor approval. “Many of the cases were based on the fact that patients exhibited no signs of PBA.”

The original CNN investigation reported in October of 2017 stirred up concerns and significant interest in Avanir and its marketing tactics with Nuedexta. The same two reporters have written a series of articles on CNN since then noting how Los Angeles opened an investigation into Avanir following the CNN report; how a leading advocacy group for Alzheimer’s stopped accepting contributions from Avanir after the report; and that the US government warned insurance companies to look for suspicious prescriptions of Nuedexta. And there were several doctors with problem records, at least three had criminal convictions for illegal prescribing, promoting Nuedexta.

The Los Angeles City Attorney confirmed his office was seeking information and tips from the public to help assess whether state or federal laws were violated in the sale, marketing or prescribing of Nuedexta. The people receiving Nuedexta are vulnerable and rely on others to make decisions for them. “If there is a possibility they are being administered a medication not because it is in their best interest, but because it is in the financial interest of, say, the drug manufacturer, then it is important for us to intervene.” He said he would look for potential illegal activity including kickbacks to doctors and off-label marketing of Nuedexta, that is suggesting it as a treatment for any purpose not approved by the federal government.

This would include using it as a “chemical restraint” to sedate or control behavior problems. “State regulators … have found cases of doctors inappropriately diagnosing nursing home residents with PBA to justify using Nuedexta to treat patients whose confusion, agitation and unruly behavior make them difficult to manage.” In one LA nursing home, regulators found that 28% of its residents (46 of 162) had been placed on Nuedexta. A facility psychiatrist, a paid speaker for Avanir, had given a talk about the drug to employees.

At another facility, also in Southern California, an employee admitted to inspectors that a resident had been given a diagnosis of PBA to “somehow justify the use” of Nuedexta, even though its intended purpose was to control the resident’s “mood disturbances” and yelling out.

In order to line up prescriptions, sales people identified doctors, nurses and pharmacists who could be advocates for the drug. Then they worked closely with these advocates to identify potential patients. One salesperson worked with a doctor’s office manager to pull patient’s charts and identify those who should be screened for PBA. “CNN’s investigation also found that the sales force coached doctors and facility employees on how to fight for Medicare coverage of the drug if it was initially refused.”

Another CNN article noted that after the original CNN article on Avanir and Nuedexta, the Alzheimer’s Association said it would not accept any further funding from Avanir, pending the results of the LA City Attorney. Avanir gave the group almost $200,000 in 2017. In a statement, the association said: “We are committed to people living with the disease, and we encourage vigorous review and oversight of companies and prescribers to ensure best practices are followed for those impacted by Alzheimer’s disease.” It added the contribution by Avanir was only .056% of its annual revenue.

Another nonprofit, the Alzheimer’s Foundation of America, said it received $60,000 from Avanir in 2016-2017. The organization declined to comment on the findings of CNN’s report, adding that it stood by its educational programs and that Nuedexta is not mentioned in Avanir presentations. Nuedexta is the only FDA approved treatment for PBA. One of its medical advisory board members said the AFA’s Educational Conferences provide caregivers an opportunity to understand and recognize PBA, “which afflicts a certain percentage of those with dementia.”

“Between 2013 and 2016, he received nearly $50,000 from Avanir, in the form of consulting and royalty or licensing fees, as well as travel and meals, according to government data.” He was also the lead author on the Avanir-funded study on Nuedexta that found patients on Nuedexta were more than twice as likely to fall (8.6% versus 3.9%) than those on a placebo. A research professor who studies the marketing tactics of pharmaceutical companies said Avanir’s ties with nonprofit dementia advocacy groups was “deeply troubling” and a conflict of interest. This was a particular concern for him “because Nuedexta has not been approved specifically for Alzheimer’s or dementia.

Between 2013 and 2016 Avanir Pharmaceuticals paid almost 500 doctors to speak or consult on Nuedexta. After reviewing the top prescribers of Nuedexta, CNN noted 12 who had been disciplined by state medical boards. Former Avanir employees said the company’s speaker program sought out doctors and pharmacists to present the drug to medical colleagues and nursing home employees. “Avanir and its parent company, Otsuka, paid doctors nearly $14 million for Nuedexta-related consulting, promotional speaking and other services.” In effect, these doctors are being used as a sales force, according to Michel Santoro, an expert in pharmaceutical industry ethics at Santa Clara University.

Many of the doctors with medical board issues identified by CNN involved other medications such as opioids. But one case centered on the use of Nuedexta. An Oregon doctor had already been banned by the state board from providing mental health treatment to inmates. Then he was summoned for his treatment of four nursing home patients. For one of his patients he attempted to prescribe Nuedexta “when there was no support for a PBA diagnosis.” The others were cases of inappropriately prescribing medications, changing doses or discontinuing drugs without explanation. Despite all these allegations, he was being paid by Avanir to speak publically about Nuedexta.

Then in June of 2018 CNN reported they had received documents through a public records request that indicated there have been complaints filed with the FDA about Avanir’s marketing and advertising dating back to 2012. BlueCross BlueShield of Arizona said Avanir was misrepresenting Nuedexta as “safe and effective” in populations it had not been approved for or adequately studied. “We believe that the manufacturer appears to be marketing Nuedexta far beyond the scope of the clinical evidence.” An individual complaint in 2016 said they had overheard a salesperson promote the drug for unapproved uses. “Specifically they are targeting [sic] residents with Dementia with Behavioral Disturbances.”

In March of 2018 CMS (Centers for Medicare & Medicaid Services) issued a memo asking Medicare insurance providers to monitor prescriptions for Nuedexta in order to ensure it was being appropriately given to patients. The memo reminded plan sponsors that Nuedexta was only approved to treat PBA and that insurers were legally required to ensure it was only being used for medically accepted uses. The agency said the memo was provided to “inform plan sponsors about increases in utilization that may not be readily discerned or may relate to potential fraud.”

Sadly, Avanir seems to have placed profits ahead of ethical medical care with the elderly. They have encouraged the use of Nuedexta in nursing facilities as a kind of chemical restraint. This seems to have partly occurred in response to the FDA tightening regulations on the use of antipsychotics for the same reason. There is a reason to cry uncontrollably, but it’s for how Neudexta has been mis-marketed and mis-prescribed. For more on Nuedexta and the use of antipsychotics in nursing homes, see “Conjuring Diagnoses for the Elderly” and “Nursing Homes Want Docile.”

05/11/18

Safety with Seroquel

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In 2013 a primary-care doctor suggested to a 43-year old man that he take Seroquel (quetiapine) to help him sleep. He was told that at low doses, Seroquel works like an antihistamine with mild sedation. He thought it was a good idea, as he had suffered from insomnia since his childhood. Despite working out, he gained 40 pounds. He also became pre-diabetic, started on blood-pressure medication and was seeing a cardiologist for an irregular heart beat. After a few years went by, he said: “I knew I had to get off of this drug.”

When he tried to slowly taper his dosage, his symptoms periodically seemed to worsen. “They say it’s not addictive, but your whole body gets used to it.” He said he was back and forth to the hospital 25-30 times with anxiety and heart palpitations. It took him a year to taper down from 200 milligrams to 25. His insomnia returned and if he took a pill to help him sleep, he’d wake up with his heart pounding. He was throwing up; he had cold sweats and itching all over his body. “Coming off, you’re seriously worse. I was struggling through, day by day.” This person’s experience was described in an article in The Washington Post, highlighting the issues with the off-label use of Seroquel (quetiapine).

Back in 2006, the FDA informed AstraZeneca, the parent company for Seroquel, that its marketing information false and misleading “because it minimizes the risk of hyperglycemia and diabetes mellitus and fails to communicate important information regarding neuroleptic malignant syndrome, tardive dyskinesia, and the bolded cataracts precaution.”

What followed was an onslaught of litigation by state attorneys general, who charged AstraZeneca with fraudulently promoting Seroquel for unapproved uses, and by individual patients, who claimed that it had failed to alert consumers about some of the drug’s most pernicious side effects. Although the company never admitted wrongdoing, by the end of 2011 it had paid out more than $1 billion to settle many of the cases.

Within the Justice Department’s announcement of its 2010 settlement with AstraZeneca was the following:

According to the settlement agreement, AstraZeneca targeted its illegal marketing of the antipsychotic Seroquel towards doctors who do not typically treat schizophrenia or bipolar disorder, such as physicians who treat the elderly, primary care physicians, pediatric and adolescent physicians, and in long-term care facilities and prisons.

Despite the lawsuits, some of which are still ongoing, AstraZeneca annual reports showed $3.6 billion in Seroquel sales from 2014 to 2016. Beside insomnia, Seroquel has been prescribed off-label for PTSD and agitation with dementia patients. Medical experts have expressed concern that many of the doctors prescribing it off-label have minimal training in psychiatry and little knowledge of its adverse effects. British psychiatrist David Healy said: “The range of problems it causes in terms of deteriorating quality of life makes it not worth it.”

Recent court rulings have said pharmaceutical companies have a First Amendment right to commercial free speech, raising questions about the extent the FDA can regulate the off-label marketing of medications. The FDA remains silent about its review process of its policies and regulations for “manufacturer communications” about unapproved, off-label uses of medical products. The review has been ongoing since the Obama administration. The current FDA Commissioner has previously advocated for allowing manufacturers to promote their products for off-label uses. An FDA spokesperson said: “The FDA continues to examine our rules and policies . . . as part of our efforts to make sure our authorities and policies best protect and promote the public health and are informed by ongoing scientific and legal developments.”

The Washington Post did an analysis of data from the FDA’s Adverse Event Reporting System through the first quarter of 2017. They found that “about 20,000 cases where Seroquel or its generic equivalent, quetiapine, was listed as the primary or secondary suspect in an adverse event.” That included 1,754 reported deaths where Seroquel or quetiapine was listed as the primary and 2,309 reported deaths where they were a secondary suspect. “Overall, 93 percent were apparently the result of off-label prescribing of the drug.”

Earlier data, analyzed by the nonprofit Institute for Safe Medication Practices, looked at adverse events by category of quetiapine use and found that off-label prescribing accounted for more than a quarter of 5,657 cases from 2004 through September 2010. More than half of the off-label cases were for insomnia and sleep disorders.

The Chicago Tribune wrote about an ongoing whistleblower lawsuit against AstraZeneca. In 2009 one of its sales representatives was told by a doctor in New York City outpatient clinic that a methadone patient died while taking Seroquel. Soon afterwards two other doctors told her that as many as 10 patients at New York methadone clinics had died while taking Seroquel and methadone together. She reported the deaths to her company, “but that it continued to aggressively market the blockbuster drug, even to methadone clinics.” Alarmed at the company’s failure to take action, she quit AstraZeneca and filed a whistleblower lawsuit, alleging the company “concealed the true cardiac risks of Seroquel when taken with certain other medications.”

Her lawsuit, which seems to be still in talks regarding a settlement, charged the company withheld safety information from two FDA advisory panels and failed to alert patients, doctors and pharmacists about Seroquel’s heart risks. She claims AstraZeneca “directs and incentivized” its sales representatives to sell to doctors “whom it knew prescribed Seroquel with methadone and other drugs that might trigger a dangerous reaction.” According to court filings, in 2010 AstraZeneca made revised prescribing information to advise “caution” when using the drug with certain medications. Then in 2011 the FDA requested the language be strengthened to say Seroquel “should be avoided” with those drugs.

The Chicago Tribune said according to the whistleblower lawsuit, when Seroquel came to market in 1997, it failed to warn against taking the drug with medications known to lengthen the QT interval (a measure of the time between when the heart starts squeezing to when it finishes relaxing and prepares to beat again) “even though there were such warnings on Seroquel’s label in the United Kingdom.”  After a 2000 study by Pfizer found evidence that Seroquel did indeed increase the QT interval, an internal AstraZeneca document described a plan to “defend against potential FDA label lawsuits” related to QT prolongation. The heart problem referred to here, QT prolongation, can trigger a potentially fatal arrhythmia.

Dozens of medications, including methadone, have been shown to cause a long QT interval and the dangerous arrhythmia, but no one knows how many people have died. Unless a person is connected to an EKG monitor at the time of death, it is difficult to prove that an abnormal heart rhythm was the culprit. Perhaps even more difficult to determine is whether a drug combination caused the death.

The company was privately concerned about the drug’s heart risks and addressed the issue in an internal safety meeting in April of 2009. The lawsuit states AstraZeneca decided to strengthen Seroquel’s “core data sheet,” to use caution when prescribing Seroquel with QT-prolonging medications. This should have dictated changes to the prescribing information worldwide. But AstraZeneca delayed that action. A week after the internal safety meeting reached its decision, AstraZeneca officials went before an FDA advisory panel that was considering the company’s requests to expand the use of the drug. “According to the suit, the drugmaker said there were no cardiac safety issues associated with Seroquel, and the company did not disclose it had changed the core data sheet.”

In June of 2009 the FDA advisory panel convened to consider AstraZeneca’s applications. Again, AstraZeneca failed to disclose its decision to toughen Seroquel’s label. In December of 2009 the FDA approved three of the five requests to broaden the use of Seroquel; one of those applications was to use Seroquel with children. “According to the suit, a month later, in January 2010, AstraZeneca amended Seroquel’s warning label, advising ‘caution’ when the drug is used with QT-prolonging medications.” The financial incentive of the company for delaying its notification of the FDA is seen the company reportedly made $28 billion in Seroquel sales between 2007 and 2013.

The Canadian newspaper, the National Post, published an article documenting the concerns some Canadian physicians have with the off-label use of Seroquel. It began by relating the tweet of Dr. David Juurlink lamenting the patients prescribed Seroquel for sleep in his hospital. Despite drug safety experts growing concerns of its use to treat insomnia, there was a ten-fold increase of quetiapine (Seroquel) prescription for sleep problems in Canada between 2005 and 2012. Juurlink noted his experience with seeing several patients over a ten-year period who “had had quetiapine as part of, or one of the contributing causes to NMS [neuroleptic malignant syndrome].”

He went on to say he’s seen people diagnosed with Parkinson’s disease that he was confident was caused by quetiapine. “It’s getting to the point now where, when I admit a patient with Parkinson’s, I reflexively look at their other medications to see, ‘are they on quetiapine?’” According to a drug research firm, 25% of the 33 million prescriptions dispensed by Canadian retail drug stores for “tranquilizers” were for quetiapine. Low doses of the drug are used for sleep—25 mg tablets instead of the 150 to 800 mg per day recommended dose range for approved disorders. Dr. Ian Mitchell said: It’s popping up as a patient’s typical medication for insomnia all the time.”

AstraZeneca seems to have been illegally and immorally marketing Seroquel off-label for insomnia despite having knowledge of its serious, potential adverse effects. The company also appears to have withheld that information in order to maximize its chances of FDA approval for broader uses of Seroquel. It stragetically follows the time-honored drug- company method of trying to settle lawsuits out of court whenever it can, so there is no court record of corporate wrongdoing. And the profits from drug sales appears to make such an approach worthwhile. But for consumers, the off-label use of Seroquel as a sleep aide is simply not worth the risk.

08/2/16

Not Everything Is As It Appears

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On the Food and Drugs Administration (FDA) website is an article on: “The Impact of Direct-to-Consumer Advertising.” It stated that doctors, for the most part, believe that direct-to-consumer advertising for drugs has both positive and negative effects.  This conclusion was based on a survey of physicians released by the FDA in 2004. Most physicians thought direct-to-consumer (DTC) advertising stimulated their patients to ask thoughtful questions and become more aware of possible treatments. “Many physicians thought that DTC ads made their patients more involved in their treatment.” As I was reading this article, I had the distinct feeling that Rod Serling was giving his commentary over the opening music for his show and then he said: “Your next stop, the Twilight Zone.”

Although the above FDA page was last updated on 10/23/2015, the American Medical Association (AMA) publically called for a ban on direct-to-consumer advertising for prescription drugs and medical devices on November 17, 2015. The AMA news release said: “Today’s vote in support of an advertising ban reflects concerns among physicians about the negative impact of commercially-driven promotions, and the role that marketing costs play in fueling escalating drug prices.” Writing for STAT, Ed Silverman said he thought the chances of an advertising ban happening were negligible. Lawmakers have attempted to ban drug ads before without success; and court rulings recognizing the free speech rights of pharmaceutical companies could thwart any new attempts.

A public opinion poll done by the Kaiser Family Foundation was cited by Silverman as finding that about half of its respondents thought prescription drug advertising did a good job describing the potential benefits and side effects; and was mostly a good thing. Based on the Kaiser poll, Silverman concluded that most Americans believe drug ads allow patients to have greater involvement in their health care decisions. A spokesperson for the Pharmaceutical Research and Manufacturers of America (PhRMA) agreed: ““It’s not a bad thing for patients to bring questions to the doctor’s office.”

This Kaiser poll echoed a 2011 article in Pharmacy and Therapeutics, by C. Lee Ventola, “Direct-to-Consumer Pharmaceutical Advertising.”  Ventola concluded the available evidence indicated there were both positive and negative effects on consumers from DTC advertising. He thought a ban or severe curtailment was unlikely. But remedies that maximized the benefits and minimized the risks of DTC advertising with prescription drugs were possible. “It is hoped that these measures will allow this controversial, but powerful, medium to be better utilized for the improvement of public health.”

However, STAT seems to have developed doubts about the validity of those findings. In conjunction with The Harvard T.H. Chan School of Public Health, they recently published the results of a poll on American’s attitudes towards changing regulations about prescription drugs.

The STAT-Harvard poll found that 57% of adults in the U.S. supported removing prescription drug advertising from television. Almost the same percentage (58%) opposed changing government standards to speed up the process of developing new prescription drugs and medical devices. Only 7% said they considered taking a drug they saw advertised on TV and 14% said they had experienced a serious side effect from taking prescription drugs in the past five years. Robert Blendon, a professor of health policy at Harvard who oversaw the poll, said: “There is a cautiousness about safety and efficacy here that people hadn’t realized before.”

The World Health Organization (WHO) noted that attempts to establish DTC advertising for drugs in Europe were “doomed to failure.” Back in 2009, 22 of the 27 European Union member states opposed the “information to patients” strand of a proposal for new pharmaceutical legislation. “This despite the fact that the legislation would have limited pharmaceutical companies to using the internet and specialist health publications to disseminate information.” According to Dr. Dee Mangin, an associate professor at the Christchurch School of Medicine and Health Sciences in New Zealand: “The truth is direct-to-consumer advertising is used to drive choice rather than inform it.”

However, the situation is different in the U.S. The STAT-Harvard poll comes just as lawmakers begin to grapple with whether to approve legislation to change government regulations, ones that are blamed by Pharma for slowing the approval process for new drugs and medical devices. The House passed H.R.6-the 21st Century Cures Act, in July of 2015. Among other things, H.R.6 seeks to revise government safety and effectiveness standards to speed up the approval process for new prescription drugs. It also includes more than $8 billion of additional funding for the NIH. However, disagreement between Democrats and Republicans in the Senate over how to pay for H.R.6 led to an impasse. So the House bill was broken up into several smaller ones.

Dr. Robert Califf, the newly appointed FDA commissioner, expressed concern that if the pending legislation was not carefully crafted, it could pose significant risks for the FDA and American patients. “Innovative therapies are not helpful to patients if they don’t work, or worse, cause harm.” But there is a concurrent series of judicial actions that could make the regulatory situation even more chaotic.

On March 8, 2016, the FDA agreed that Amarin could promote its drug Vascepa for off-label use. This was the end result of an August 2015 ruling by a judge that Amarin could market its product to a broader patient population than the FDA had originally approved. The heart of the company’s argument was that it had a first Amendment right of  “commercial free speech” to market Vascepa off-label to a broader patient group. See “Opening the Off-Label Floodgates” for more on this issue. Given the recent court rulings in favor of the commercial free speech of pharmaceutical companies, the FDA needs to revise its regulations regarding off-label marketing. But it seems that some members of Congress are getting impatient with the time the agency is taking.

STAT indicated that two members of Congress have accused the Department of Health and Human Services (HHS) of delaying guidelines for off-label marketing of drugs and medical devices. They wrote they were “perplexed” the FDA had not yet issued new guidelines and thought a disagreement between HHS and FDA leadership was the reason for the delay. “They also attached a draft bill that would allow companies to market products for unapproved uses.” Michael Carone of the Public Citizen Health Research Group said: “The threat to patient health posed by the draft bill attached to their letter is tremendous.” According to STAT, one source said:

HHS leadership doesn’t trust industry to do the right thing … HHS leadership believes off-label speech will lead to more aggressive marketing of new products that will raise costs to [Medicare and Medicaid]. They are allowing both their prejudices [industry as the bad guy] and priorities [keeping spending down] to get in the way … The White House shares these fears, and as a result the FDA’s desire to issue guidance is stymied.

Not surprisingly, three of the interest groups contributing heavily to the reelection campaigns of these Congressmen were related to healthcare, according to MapLight. From April 1, 2013 to March 31, 2015 Joe Pitt’s reelection campaign received $256,150 from Health Professionals, $178,500 from Pharmaceuticals/Health Products, and $69,600 from Health Services/HMOs, for a total of $504,250. Fred Upton, who is chair of the House Committee on Energy and Commerce, received $304,700 from Pharmaceuticals/Health Products, $301,051 from Health Professionals, and $94,350 from Health Services/HMOs—for a total of $701,101.

The 21st Century Cures Act has a carrot-and-stick approach for health care reform embedded into it. The ‘carrot’ is a $9 billion increase of funding to the National Institutes of Health budget over the next five years. But the funding is attached to the ‘stick’ of faster approval of prescription drugs and medical devices. Ed Silverman said the House bill would allow the FDA to approve added uses for a drug WITHOUT relying on a randomized clinical trial. Daniel Carpenter, a Harvard political scientist who studies the FDA called the 21st Century Cures Act “the 19th Century Fraud Act” because of this provision. “This is a part of the bill that threatens to take us back more than a century.”

Instead of requiring a randomized clinical trial, the agency could base their decision on “clinical experience,” which essentially means anecdotal observations from physicians and patients.  The unreliability of basing judgments of drug effectiveness on anecdotal observations was why randomized double blind placebo-controlled method became the “gold standard” for clinical drug trials in the first place. Removing this requirement would be like returning to the time of patent medicines or stepping into the Twilight Zone of drug approvals. As he did when narrating the original show, Rod Serling has some words of wisdom we need to remember: “It may be said with a degree of assurance that not everything that meets the eye is as it appears.”

05/10/16

Opening the Off-Label Floodgates

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© Christa Eder | 123rf.con

On March 8, 2016 the FDA made a settlement agreement with the pharmaceutical company Amarin that allows Amarin to promote its drug Vascepa for off-label use to treat patients with hypertriglycerdemia, persistently high triglycerides. That is, as long as its promotion is truthful and not misleading. Amarin wanted to widen the population for whom they could recommend Vascepa to include other patients with different cardiovascular diseases, but the FDA initially ruled against this. Amarin’s stock price took a nosedive. Concerned with how their investors were reacting, the company fought back by suing the FDA. So what was this breakthrough medication worth taking on the FDA? Fish oil; Vascepa is prescription strength fish oil.

Amarin argued that it had a First Amendment right to market its drug for a broader patient group, “despite the lack of regulatory approval and the lack of evidence of an outcomes benefit for patients.” Justin Karter of Mad in America noted how the FDA settlement strikes at the heart of the drug regulatory system in the U.S. Amarin argued that companies should have the right to market their products consistent with what “a judge would consider to be neither false or misleading.” Be clear on what Amarin was saying. A judge, not the FDA, should rule on whether or not the marketing claims for their product were truthful and not misleading.

Where does a judge get the expertise to discern whether or not a company has made misleading, untruthful medical claims about their product? Pharmaceutical companies have paid millions of dollars for violating off-label promotion of their medications. One example is the blockbuster drug Neurontin, which has cost its parent drug companies millions of dollars in fines for “illegal and fraudulent promotion of unapproved uses.” An internal company email referred to Neurontin as “the ‘snake oil’ of the twentieth century.” This is but one example of the violations from multiple drug companies under the more restrictive FDA guidelines forbidding all off-label marketing.

In August of 2015, a judge in the district court of Manhattan ruled that Amarin could market its drug to the desired broader population. He also ruled the company could claim that Vascepa “may reduce the risk of coronary heart disease.” This was despite the fact that the FDA had called the claim misleading, as there was “supportive but not conclusive research” to that effect. The Amarin ruling, according to attorney Amy Kapczynski, “has the potential to unleash a flood of misleading marketing to physcians.” She believes that at some point, the FDA will have to take the issue to the Supreme Court.

Writing for FDA Law Blog, David Gibbons gave a detailed description of the legal aspects of the case. While Amarin was attempting to gain FDA approval for its off-label promotion of Vespacia, data from several high-profile cardiovascular outcomes trials cast doubt on the clinical benefit of triglyceride lowering. After reviewing the data, the FDA then asked an Advisory Committee to express its opinion on whether or not “Vascepa’s triglyceride lowering effect was sufficient to approve the drug for use in patients with persistently high triglycerides. The Advisory Committee voted 9 to 2 against approval for that indication.” So Amarin sued the FDA.

In a bold move, Amarin filed a civil complaint against FDA claiming that FDA’s threat of prosecution for misbranding Vascepa had a chilling effect on Amarin’s commercial speech that was otherwise protected by the First Amendment.  For that reason, Amarin sought declaratory and injunctive relief that would prevent FDA from prosecuting the Company for truthful, non-misleading speech concerning Vascepa, going so far as to detail, in its complaint, certain off-label promotional content regarding Vascepa that the Company proposed to disseminate.  Early in the litigation proceedings, Amarin filed a motion for preliminary injunction and the court heard oral arguments on the motion on July 7, 2015, and, on August 7, the court handed down a 71-page opinion in which it granted Amarin’s requests.

Commenting on the FDA settlement agreement in Amrain Pharma v. U.S. Food & Drug Administration for Mad in America, lawyer and mental health advocate Jim Gottstein said he thought that for all practical purposes, the FDA ban against off-label promotion of drug companies was dead. He noted that the ruling in the Amarin case was based upon a 2012 decision in Unites States v. Caronia that reversed a criminal conviction for off-label promotion.

In light of the settlement I think it is fair to ask where things stand with the FDA’s enforcement of its ban against off-label promotion and Department of Justice prosecutions of drug companies for off-label promotion leading to false claims.  I think the ban against off-label promotion is dead for all practical purposes.  The FDA could try and get a different ruling in another circuit and, if successful, ask the Supreme Court to rule, but since it didn’t ask the Supreme Court to take the case in Caronia, it doesn’t seem likely that it has any intention of trying to overturn Caronia.  This will give the drug companies free rein for off-label promotion.  Of course, anything that is false or misleading is still grounds for charges, but that is a far harder case to make.

Eric Palmer, writing for FiercePharma, noted that the free speech argument has been closely monitored by the pharmaceutical industry to see just how much leeway they might expect from the FDA in their ability to market for off-label use of their products. Another pharmaceutical company, Pacira, filed suit against the FDA after the August 2015 ruling in favor of Amarin.

Tracy Staton noted on FiercePharma that the FDA agreed to remove its limits on Pacira’s marketing of Exparel, which is now approved for pain treatment at any surgical site. She said that by making a deal with Pacira, the FDA avoided another court ruling on the free-speech issue, as it seeks to adjust its marketing rules. In an attempt to limit any broader application of the Amarin ruling, the FDA has said its Vascepa promotions would not have broken FDA rules in any case. As it did with Amarin, the FDA said regarding its agreement with Pacira: “It’s important to note that this resolution is specific to the parties involved in this matter.”

Parallel to these attempts to weaken the FDA regulations against off-label marketing, there was a January 2016 article published in JAMA Internal Medicine by Eguale et al. that looked at the association between off-label drug use and the risk of adverse drug events (ADEs).  Commenting on Medscape, Eguale said to his knowledge, theirs was the first systematic evaluation of the association between off-label use of drugs and the risk for ADEs. They concluded that off-label use of prescription drugs was associated with ADEs. “Caution should be exercised in prescribing drugs for off-label uses that lack strong scientific evidence.”

The study found that the majority of prescriptions (88.2%) were for approved uses. Another 9.5% involved off-label use without strong supportive evidence; and 2.3% were off-label, but had strong evidence supporting its use off-label. The ADE rate was higher for off-label use than for on-label use, “at 19.7 per 10,000 person-months vs 12.5 per 10,000 person-months.” When analysis was done according to the strength of supporting evidence for off-label use, there was an even higher rate (at 21.7 per 10,000 person-months) for use unsupported by strong scientific evidence. “Off-label use indicated by solid scientific evidence had a rate of 13.2 per 10,000 person-months, which was virtually the same as its on-label counterpart.”

The risk for adverse events also rose with the number of prescription drugs used by individual patients. Individuals taking eight or more medications had “a more than fivefold increased risk for ADEs compared to patients who used one or two drugs.”

[P]hysicians and physician organizations should recognize the enormity of the problem and be active participants in the promotion of cautious prescribing of drugs for off-label uses lacking strong scientific evidence.

Within an invited commentary of the study, “Off-Label Drug Use and Adverse Events,” Chester Good and Walid Gellad warned that the FDA and the courts needed to carefully consider the study’s findings as they contemplate any further relaxation of regulations to permit the promotion of drugs beyond their labeled indications. “In light of these concerns, the study of off-label drug use and adverse drug events by Eguale and colleagues … is particularly timely.”

Too bad the Eguale et al. study wasn’t published earlier. Maybe it would have had some influence on the FDA settlement with Amarin. The response of pharmaceutical companies with psychiatric medications to the Amarin settlement is a serious concern. They have already demonstrated a history of flaunting the more restrictive FDA regulations to the tune of billions of dollars in fines.

On March 31, 2016, the nonprofit organization Public Citizen published an updated analysis of all major financial settlements and court judgments between pharmaceutical companies and the federal and state governments. The time period covered by their analysis ran from 1991 through 2015 and included 373 settlements for a total of $35.7 BILLION. Financial penalties have declined sharply since 2013. The most striking decrease occurred with criminal penalties. “For 2012 and 2013 combined, criminal penalties totaled $2.7 billion, but by 2014-2015, the total had fallen to $44 million, a decrease of more than 98%.”

From 1991 through 2015, GlaxoSmithKline and Pfizer reached the most settlements—with 31 each— and paid the most in penalties, $7.9 billion and $3.9 billion respectively. Six additional companies, Johnson & Johnson, Merck, Abbott, Eli Lilly, Teva, Schering-Plough, Novartis, and AstraZeneca paid more than $1 billion in financial penalties. Six of the above eight were listed in the top 14 pharmaceutical companies by global sales in 2014. Thirty-one companies entered repeat settlements. Pfizer (11), Merck (9), GlaxoSmithKline, Novartis, and Bristol-Myers Squibb (8 each) finalized the most federal settlements.

Financial penalties continued to pale in comparison to company profits, with the $35.7 billion in penalties from 1991 through 2015 amounting to only 5% of the $711 billion in net profits made by the 11 largest global drug companies during just 10 of those 25 years (2003-2012). To our knowledge, a parent company has never been excluded from participation in Medicare and Medicaid for illegal activities, which endanger the public health and deplete taxpayer-funded programs. Nor has almost any senior executive been given a jail sentence for leading companies engaged in these illegal activities. Much larger penalties and successful prosecutions of company executives that oversee systemic fraud, including jail sentences if appropriate, are necessary to deter future unlawful behavior. Otherwise, these illegal but profitable activities will continue to be part of companies’ business model.

It seems to this point, risking the fines has just been a potential cost of doing business with medications. With the FDA failing to challenge the decision in Caronia and its recent settlement with Amarin, the floodgates for off-label marketing of medications may have been opened. I hope that Jim Gottstein’s prediction that FDA opposition to off-label marketing is “dead” turns out to be wrong. If he is correct, and the FDA does not actively oppose future off-label marketing of psychiatric medications, we will be flooded with adverse events from their off-label use.