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.”


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.