11/6/18

Nursing Homes Want Docile

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The US population is aging. Between 2005 and 2015, the percentage of the population over 65 increased by 30%. “Older people now account for one in seven Americans: almost 50 million people, over 26 million women and over 21 million men.” As our population ages, the number of individuals with debilitating conditions like dementia is also increasing. By 2050, it has been estimated that as many as 15 million Americans could have Alzheimer’s. And in an average week, nursing facilities in the U.S. currently administer antipsychotic medications to over 179,000 people “who do not have diagnoses for which the drugs are approved.”

An extensive Human Rights Watch report, “They Want Docile,” described the inappropriate use of antipsychotics in older people with dementia in U.S. nursing facilities. The report found these dangerous medications were used without valid medical reasons, for the convenience of the staff, and without informed consent. Their use was often inconsistent with federal regulator requirements for the nursing facility industry. “They Want Docile” quoted a state inspector with a long career in long-term care as saying: “I see way too many people overmedicated. The doctor signs off and the nurse fills the prescription. They see it as a cost-effective way to control behaviors.”

Older people receive long-term care in various settings ranging from at home to institutional facilities. In-between settings like assisted living facilities, senior housing and retirement communities also exist. “The proportion of people living in institutional settings increases with age because care needs become more intensive.” Of the 6 million older people who receive long-term care around 4 million receive that care at home. Another 1.2 million live in nursing facilities and around 780,000 people live in other residential care communities.

The nursing facility industry is big business and Medicare and Medicaid is the financial foundation that supports it. “In 2015, the nursing facility industry, assisted living, and other types of long-term care recorded annual revenues of $156.8 billion, 41 percent of which came from Medicaid and 21 percent from Medicare.”  The Nursing Home Reform Act of 1987 requires the nursing facility industry to meet certain standards, including certification of the care facility, to be paid by Medicare and Medicaid. CMS, the Centers for Medicare & Medicaid Services, contracts with state agencies to certify facilities and to guarantee “substantial compliance.”

With the growth in older populations and the increases in debilitating conditions such as dementia, the need for long-term care and support services will grow rapidly. Although some forms of dementia have earlier onset, the disease is associated with older age: increasing age is the “greatest known risk factor” for Alzheimer’s disease. Experts estimate that approximately 70 percent of people aged 65 and over will require long-term services and support, ranging from limited support in their own homes and communities to around-the-clock care in institutional settings.

The American Psychiatric Association (APA) has “Practice Guidelines” for the use of antipsychotics to treat agitation or psychosis in patients with dementia that indicated they should only be used as a last resort to minimize the risk of violence, patient distress and care giver burden. The APA then referenced two studies finding  “the benefits of antipsychotic medications are at best small.” Contrary to these guidelines, nursing facility staff, individuals living in facilities, their families and others told Human Rights Watch “antipsychotic drugs are used sometimes almost by default for the convenience of the facility, including to control people who are difficult to manage.”

One facility social worker said that one of the most common “behaviors” leading to antipsychotic drug prescriptions was someone constantly crying out, “help me, help me, help me.” An 87-year-old woman reflected that at her prior facility, which gave her antipsychotic drugs against her will, “they just wanted you to do things just the way they wanted.” A social worker who used to work in a nursing facility said the underlying issue is that “the nursing homes don’t want behaviors.”

Among the people living in nursing homes interviewed by Human Rights Watch, a 62-year-old woman reported she had been given Seroquel without her knowledge or consent. She said it knocked her out; leading her to sleep all the time. She claimed the facility would crush and mix it in her food so she would refuse to eat food she suspected of having the drug. “Ms. D continued to object as well as she could to being administered antipsychotic drugs until her discharge from the nursing facility the day after Human Rights Watch interviewed her.”

Madeline C., an 87-year-old woman in a facility in Illinois, described the effect of antipsychotic medications administered in a prior nursing facility. She had been placed in a dementia unit. The woman said that when she “just about went crazy” from being in a locked unit with no activities, she “started speaking out, saying things were not right.” After that, she said, “suddenly I was very sleepy,” adding, “you feel like you’re going to die there.” She said she later learned that the facility had given her an antipsychotic drug. At the time of the interview, the woman was in a different facility that had discontinued the drug. “The fog lifted…. There’s the old Madeline again.” Being at the prior facility was “a very traumatic time.”Alma G., the sister and power of attorney of Mariela O., an 84-year-old woman with dementia who died in 2017, said that her sister’s nursing facility gave her an antipsychotic drug to ease the burden of bathing her. She said, “They give my sister medication to sedate her on the days of her shower: Monday, Wednesday, Friday—an antipsychotic. They give her so much she sleeps through the lunch hour and supper.”

“They Want Docile” described many additional examples of the misuse of antipsychotic medications at nursing facilities. The authors said many of their interviews supported the statement that antipsychotic medications were often given to nursing home residents for no valid reason. Some nursing home staff told Human Rights Watch antipsychotics were prescribed for screaming or calling out. A long-term care pharmacist said he regularly sees medication requests without an appropriate diagnosis—things like “‘Seroquel for dementia,’ or ‘Seroquel for anxiety,’ or ‘Seroquel for behavior dysfunction.’”

The report is disturbing and I’ve only scratched the surface of what it describes. It also had several recommendations to federal and state legislatures, and agencies. Here are just a couple. The CMS (Centers for Medicare & Medicaid Services) should strengthen the enforcement of existing regulatory requirements to end all inappropriate use of antipsychotics in nursing facilities, including when their use would amount to being used as a “chemical restraint.” It should also strengthen enforcement of existing regulatory requirements for informed consent and appropriate medication administration. Care planning should include the right of patients to refuse treatment; to be involved in their care planning; to be free from unnecessary drugs and chemical restraints. Medicaid fraud units should be required to investigate and prosecute abuse, including the use of chemical restraints, and neglect in nursing facilities.”

The Washington Post published an article, Why are nursing homes drugging dementia patients without their consent?, that was written by an individual who was part of the Human Rights Watch research. She noted how the use of antipsychotics as chemical restraints in nursing homes has a long history. A 1975 Senate report documented some of the same issues occurring today. While there are federal regulations stating residents have the right to be fully informed of their treatment and even to refuse treatment, nursing homes regularly ignore the rules because they are rarely held accountable.

Human Rights Watch found that in 97 percent of citations for violations related to antipsychotic drugs, the incidents were determined to have caused “no actual harm” to residents. As a result, in almost no cases did the government impose financial penalties, which correspond to the severity of harm caused by the noncompliance. The prospect of enforcement actions, and the rare sanctions issued, unsurprisingly had little deterrent effect, our analysis found. Nursing homes cited for antipsychotic-drug-related issues did not reduce their rates of drug use any more than facilities not cited.

Further limitations on holding nursing facilities accountable have ironically come as a result of the Trump administration’s Patient’s Over Paperwork deregulatory efforts. In response to an industry request, the instances in which inspectors can assess the heaviest fines was limited. That guidance now favors one-time sanctions rather than per-day sanctions, leading in many cases for facilities to face less significant consequences. And since November of 2016, “CMS imposed an 18-month moratorium on Obama-era revisions to some regulations — not updated since 1991 — intended in part to protect residents whose psychotropic medications are prescribed on an “as needed” basis.”

A JAMA Psychiatry study showed how a peer comparison letter could reduce off-label prescribing of an antipsychotic in older adults. The researchers found that “a peer comparison letter randomized across the 5055 highest Medicare prescribers of the antipsychotic quetiapine fumarate [Seroquel] reduced prescribing for at least 2 years.” The effects were larger than those found with large-scale behavioral interventions, possibly because the content of the peer letter “mentioned the potential for a review of prescribing activity.” Writing for Mad in America about the study, Bernalyn Ruiz said:

This study provides some hopeful evidence that a simple intervention that can reach a large group of prescribers effectively. Given the high rates of overprescribing, especially within this vulnerable population, effective ways of addressing this issue are needed.

In another article reflecting on the study by Ina Jaffe for NPR, Dr. Helen Kales, the head of the University of Michigan’s Program for Positive Aging, said stopping the overmedication of dementia patients was just the beginning. She pointed out how the use of mood stabilizers with dementia patients has also accelerated. “So any kind of fixation on one [drug] — it’s maybe winning the battle, but not the war.” Dr. Kales chaired an international committee of dementia specialists who published a consensus statement on the ways to treat dementia behaviors like agitation and wandering, and said it’s better to find out what triggers the behavior or modify the patient’s environment instead of prescribing medication. “The highest ranked and endorsed treatments are all non-pharmacological approaches.”

In closing, consider the following. The graphic below by Human Rights Watch shows the proportion of nursing home residents across the U.S. on antipsychotic drugs. The more intensely red areas indicate a higher percentage of antipsychotic use, with 45% being the highest. If you or a loved one were in a nursing home somewhere in the U.S. would you want it to be using antipsychotics to chemically manage you and your behavior?

05/10/16

Opening the Off-Label Floodgates

© Christa Eder | 123rf.con

© 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.