12/2/16

Pharma and Advertising

© Maksim Kabakou | 123rf.com

© Maksim Kabakou | 123rf.com

The FDA recently held public hearings on the off-label advertising of approved medications and medical devices on November 9 and 10, 2016. “FDA is engaged in a comprehensive review of its regulations and policies governing firms’ communications about unapproved uses of approved/cleared medical products, and the input from this meeting will inform FDA’s policy development in this area.” There were specific questions asked at the hearing, but the FDA was also interested in “any other pertinent information participants would like to share.” If you weren’t able to be in Maryland for the hearing, electronic or written comments will be accepted until January 9, 2017. A videotape of the hearing will be available for one year afterwards.

Your initial reaction may be one of “Boring!” That is unless you are aware of the crossroads we are approaching with regard to the off-label advertising of medications and medical devices. On March 8, 2016, the FDA made a settlement agreement with the pharmaceutical company Amarin that allows the company to promote its drug Vascepa for off-label use. What is this important breakthrough medication? Vascepa is prescription strength fish oil. This action was the outcome of a struggle between Amarin and the FDA going back several years.

Amarin wanted to widen the population for whom they could recommend Vascepa to include patients with different cardiovascular diseases—patients other than what Vascepa was initially approved to treat. But the FDA ruled against their request. Amarin’s stock price took a nosedive. Concerned with how their investors were reacting, the company fought back by suing the FDA. Then in August of 2015, a judge ruled that Amarin could market its drug to the 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.

Amarin successfully 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 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 by a pharmaceutical company for their product were truthful and not misleading.

Amarin argued that this system is unconstitutional, and that companies should instead be allowed to market their products in any way that a judge would consider to be neither false nor misleading.

Commenting on the FDA settlement agreement in Amrain Pharma v. U.S. Food & Drug Administration, 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.

So if this is the supposed future for off-label drug advertising unless there is some radical change by Congress, let’s now take a look at the past—what has been taking place under the existing FDA rules. In his book Saving Normal, Allen Frances published a chart that he called the drug company “hall of shame.” Prepared by Melissa Raven, PhD, it listed the fines and settlements by Pharma companies for off-label promotion, marketing and fraudulent misbranding of 20 well know pharmaceuticals.

Here is a sampling of the companies and their total fines and settlements between 2004 and 2012 recorded in the Saving Normal chart. The fines and settlements listed below combine both civil and criminal cases. Johnson & Johnson ($1.44 billion); GlaxoSmithKline ($3 billion); Abbott ($1.5 billion); Novartis ($422.5 million); Forrest ($313 million); AstraZeneca ($520 million); Pfizer ($2.3 billion); Eli Lily ($1.415 billion); Bristol-Myers Squibb ($515 million); Purdue (almost $635 million). I think it’s clear why Pharma is going after the FDA. The sum total in fines and settlements from the chart was $12.06 billion in fines and settlements between 2004 and 2012.

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. It seems these fines were simply the cost of doing business.

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.

Since the U.S. approved direct-to-consumer advertising of prescription drugs in 1997, there has been a dramatic increase in spending on pharmaceuticals. A New England Journal of Medicine study by Donohue, Cevasco and Rosenthal in 2007 found that spending on pharmaceutical promotions increased from $11.4 billion in 1996 to $29.9 billion in 2005. This was a 330% increase. Promotion to physicians was still the primary marketing strategy, but spending on direct-to-consumer advertising increased both in absolute terms and as a percentage of pharmaceutical sales.

Becker and Midoun recently published an article that investigated the effects of direct-to-consumer advertising (DTCA) on patient prescription requests in the Journal of Clinical Psychiatry. Of the 989 articles they initially identified, they read full-text reviews of 69 articles, but only found four that met their inclusion criteria for investigating the consequences of these ads on prescription rates and treatment quality. They conclusion was: “Findings suggest that DTCA requests are typically accommodated, promote higher prescribing volume, and have competing effects on treatment quality.” They called for methodlogically stronger studies to increase the confidence in their conclusions.

Reporting for Mad in America on the study, Justin Karter noted where the U.S. is only one of three countries globally that allows DTCA. He said the pharmaceutical industry spent $3.83 billion on DTCA in 2013 and $4.53 billion in 2014. He also noted that the American Medical Association (here) and the American Society of Health-System Pharmacists (ASHP) (here) have called for a ban on DTCA. The AMA Board Chair, Patrice Harris, commented that physicians were concerned with the negative impact of DTCA and the role marketing costs play in fueling escalating drug prices. “Direct-to-consumer advertising also inflates demand for new and more expensive drugs, even when these drugs may not be appropriate.” The ASHP approved a new policy at their 2016 meeting that would advocated for Congress to ban DTCA for prescription drugs and medication-containing devices.

Pharmaceutical companies have whittled away at existing FDA regulations that restrict direct-to-consumer advertising. And they seem to be poised to begin an era of DTCA that will massively overshadow what has already taken place under the existing rules. Healthcare organizations representing physicians and pharmacists in the U.S. have publically voiced their opposition to DTCA. Individuals and organizations have an opportunity to voice their concern for this practice, which is implicated in the rising cost of healthcare and medications. Congress also has an opportunity to enact new legislation that would eliminate this predatory marketing practice. But it will have to overcome the horde of lobbyists—more than there are members of Congress—and the $272,000 in campaign donations Pharma spent per member of Congress in 2015.

08/2/16

Not Everything Is As It Appears

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© vlue | 123rf.com

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.”