August was a rough month for the Food and Drug Administration. On August 7, a federal judge in New York entered a preliminary injunction in Amarin Pharma, Inc.’s lawsuit against the FDA, holding that the FDA could not prevent a drug manufacturer from marketing its drug for uses that haven’t been approved by the FDA, so long as the marketing was “truthful,” a loaded word we’ll get to in a moment. Then, on August 20, Forbes published an analysis that concluded the FDA approves 96% of new drugs or; in essence, “the FDA is basically approving everything.”

 

Let’s start first with the Amarin lawsuit. The primary weapon in the FDA’s legal arsenal is the “misbranding” statute, which allows the FDA to prosecute anyone who markets a drug or medical device “if its labeling is false or misleading in any particular.” For decades, the FDA has attempted to keep pharmaceutical companies in line by telling them that, if they market a drug for uses that were not approved by the FDA, so-called “off-label marketing,” the FDA will prosecute them. However, the pharmaceutical industry, emboldened by Citizens United, has tried to make this into a free speech issue in recent years.

 

On the one hand, the pharmaceutical companies have a point: why shouldn’t drug companies be allowed to “truthfully” market their drugs?

 

On the other hand, this argument about the “truth” falls apart when we consider the complexity of drug efficacy and safety, and when we recognize the billions of dollars that drug companies will use to push their “truth” on unwitting doctors and patients.

 

Amarin makes a prescription drug called “Vascepa,” which is essentially an expensive version of fish oil. The FDA approved Vascepa for use in patients with severe hypertriglyceridemia based on the results of a single clinical trial. The FDA did not, however, approve Vascepa’s use in patients with very high triglycerides for the rather straight-forward reason that it doesn’t work. Read for yourself the FDA’s 94-page Advisory Committee Brief. Vascepa lowers triglyceride levels, but it hasn’t been shown to actually reduce the risk of cardiovascular disease. This isn’t some sort of attack on Amarin or Vascepa particularly; medical science as a whole has come to realize that, apart from severe hypertriglyceridemia, omega-3 supplementation doesn’t do anything to reduce patients’ risk of “all-cause mortality, cardiac death, sudden death, myocardial infarction, or stroke.” As a matter of medicine, unless a person has truly severe hypertriglyceridemia, omega-3 supplementation isn’t going to make much of a difference.

 

From the FDA’s standpoint, this was a no-brainer: Amarin failed to show that Vascepa was effective. I doubt anyone at the FDA figured they would lose in court over this one.
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Can you guess the best-selling class of drugs? It may be that a fifth of Americans suffer gastroesophageal reflux disease at least once a week, over 30% have hypertension, and over a third of U.S. adults have high LDL cholesterol, but the best-selling class of drugs isn’t proton-pump inhibitors for reflux, or angiotensin II receptor antagonists for blood pressure, or statins. It’s anti-psychotics.

The best-selling drug in America is Abilify, the prescribing information for which says it is only approved for:

  • Use as an add-on treatment to an antidepressant for adults with Major Depressive Disorder who have had an inadequate response to antidepressant therapy
  • Treatment of manic or mixed episodes associated with Bipolar I Disorder in adults and in pediatric patients 10 to 17 years of age
  • Treatment of Schizophrenia in adults and in adolescents 13 to 17 years of age
  • Treatment of irritability associated with Autistic Disorder in pediatric patients 6 to 17 years of age

It’s commonplace for people to refer to themselves or others as “depressed” or “bipolar,” but that’s a far cry from a diagnosis. The NIH has a handy page with the statistics on mental illness. At the most generous estimate, 5-8% of the adult population can be diagnosed with Major Depressive Disorder, and Abilify isn’t even indicated for them — it’s indicated only for those who haven’t responded to typical antidepressants, which is half or less. Bipolar Disorder affects 2.6% of the popular, but Bipolar I, the more severe version defined by a week or more of mania or mania so severe it requires hospitalization, is only a small fraction of that. Schizophrenia affects 1% of the population. Finally, depending on your definition, between 0.8% and 1.2% of children have autism.

Adding all of those up gets us to 5% or so of the population that could even qualify for Abilify, less than a quarter of the people with GERD, hypertension, or high cholesterol. So who is taking all of this Abilify, and why? As the Wall Street Journal reported last week, “Federal health officials have launched a probe into the use of antipsychotic drugs on children in the Medicaid system, amid concern that the medications are being prescribed too often to treat behavioral problems in the very young.” The quote Mark Duggan, a health-policy expert at the University of Pennsylvania’s Wharton School, saying that more than 70% of the cost of the five leading antipsychotics was paid for by Medicaid and other government programs.

While the public school system in many urban areas is in collapse — a problem we feel quite acutely here in Philadelphia — and there’s still no interest in putting tax dollars into early childhood education or after-school problems, and even the upper-middle-class can’t afford childcare so both parents can work, it seems Medicaid has $3.6 billion to spend on antipsychotic medications like Abilify, Zyprexa, Geodon, and Seroquel. (That’s just as of 2008 — the number is likely double or higher now given how rapidly prescriptions have grown.)

So what happened? Maybe it has something to do with this
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It’s déjà vu all over again. Remember how, three years ago, Pfizer paid $2.3 billion to the Department of Justice to settle off-label claims relating to Bextra and other drugs, and Eli Lilly paid $1.4 billion for Zyprexa marketing?

If so, then last week was no surprise: GlaxoSmithKline agreed to pay a whopping $3 billion to settle criminal and civil charges brought against it by the Department of Justice. Quoting from the DOJ press release, GlaxoSmithKline was accused of:

  • distributing a misleading medical journal article that misreported that a clinical trial of Paxil demonstrated efficacy in the treatment of depression in patients under age 18,
  • GSK did not make available data from two other studies in which Paxil also failed to demonstrate efficacy in treating depression in patients under 18.
  • GSK sponsored dinner programs, lunch programs, spa programs and similar activities to promote the use of Paxil in children and adolescents.
  • GSK paid millions of dollars to doctors to speak at and attend meetings, sometimes at lavish resorts, at which the off-label uses of Wellbutrin were routinely promoted and also used sales representatives, sham advisory boards, and supposedly independent Continuing Medical Education (CME) programs to promote Wellbutrin for these unapproved uses.
  • GSK failed to include certain safety data about Avandia, a diabetes drug, in reports to the FDA that are meant to allow the FDA to determine if a drug continues to be safe for its approved indications and to spot drug safety trends.   The missing information included data regarding certain post-marketing studies, as well as data regarding two studies undertaken in response to European regulators’ concerns about the cardiovascular safety of Avandia.
  • GSK promoted Avandia to physicians and other health care providers with false and misleading representations about Avandia’s safety profile … GSK stated that Avandia had a positive cholesterol profile despite having no well-controlled studies to support that message. The United States also alleges that the company sponsored programs suggesting cardiovascular benefits from Avandia therapy despite warnings on the FDA-approved label regarding cardiovascular risks.
  • GSK paid kickbacks to health care professionals to induce them to promote and prescribe these drugs [Paxil, Wellbutrin, Avandia, Advair, Lamictal, and Zofran] as well as the drugs Imitrex, Lotronex, Flovent and Valtrex.

Let’s call GlaxoSmithKline what it is: a criminal enterprise. GSK didn’t miss the finer points of a couple red-tape regulations: the DOJ alleged they tampered with scientific studies, concealed safety data, then lied to doctors and patients and, if that didn’t work, outright bribed the doctors. Why?
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Have you ever seen a commercial on TV, or heard a commercial on the radio, or read an advertisement in a magazine, or saw a commercial on a website, for a prescription drug?

Of course you have, if you’re in the United States (or New Zealand — the rest of the modern world bans the practice). You see them all the time. Why? Because, as io9 profiled extensively, “For every dollar spent on ads for drugs, over four dollars in retail sales are garnered. A May 2011 study showed that new drugs that feature direct-to-consumer advertising are prescribed nine times more than their new counterparts that lack consumer advertising.” Billions of dollars are spent on ads to patients to convince them (1) to “ask your doctor about” whatever medication is most profitable and lobby for it based on the advertising and (2) to choose the medication over other available options.

There’s nothing novel or even disputable about that, but try pointing out the purpose and effect of prescription drug advertising to the Supreme Courts of the three dozen or so states — including most of the large population states like California, New York, Florida, Illinois, Pennsylvania, Ohio, Michigan, and so on — that have followed some version of the “learned intermediary doctrine.” (Only one court, West Virginia, has expressly rejected the doctrine, in State ex rel. Johnson & Johnson Corp. v. Karl, 647 S.E.2d 899, 913–14 (W. Va. 2007)). Texas formally joined the ranks of learned intermediary courts about two weeks ago. LexisNexis summarizes here, there’s some defense oriented coverage here and here and here, and I haven’t seen any plaintiff’s comment (but feel free to email me).

Under the most basic version of the learned intermediary doctrine, prescription drug users are considered by law to be lab rats who have no say in what their doctor prescribes and have no ability to turn the medication down. More formally, the doctrine provides:

 (1) that manufacturers of prescription drugs and medical devices discharge their duty to of care to patients by providing adequate warnings to prescribing physicians, and (2) that any failure to warn cannot be considered a proximate cause of a subsequent injury if the physician was fully aware of the dangers that would have been included in an alternative warning.

Greaves v. Eli Lilly, 2011 U.S. Dist. LEXIS 129443 (E.D.N.Y. Nov. 8, 2011). In Greaves, a man developed diabetes as a result of 9 years of Zyprexa use. Six years into his Zyprexa use, the doctor learned Zyprexa could cause diabetes, and continued prescribing it. When the doctor was later asked if knowing Zyprexa could cause diabetes would have changed anything about his interactions with the patient or his prescription, the doctor said no, he would have prescribed it just the same, regardless of the warning and regardless of how his patient felt about that, even though Abilify — which the patient was eventually moved to once he was diagnosed with diabetes — would have worked just as well. That’s when the learned intermediary rule came into play: because the doctor said he wouldn’t have done anything different if the doctor had known about the risk of diabetes, the plaintiff’s testimony was irrelevant, and so the plaintiff’s claim was dismissed.

There are thousands of cases like Greaves. Consider Wendell v. Johnson & Johnson,  2011 U.S. Dist. LEXIS 144437 (N.D. Cal. Dec. 15, 2011), where a young man developed hepatosplenic T-cell lymphoma (and died from it) as a result of irritable bowl syndrome medications. When the young man was diagnosed with lymphome, his treating doctor didn’t even suspect the medications — but not long after the man’s death, the doctor stopped giving that therapy to patients. Under the learned intermediary doctrine, it didn’t matter: the doctor didn’t emphatically state that he would have changed everything in response to an adequate warning, and so “Plaintiffs lack evidence that any further warning regarding the use of 6-MP, such as a warning about its use in combination with Humira, would have changed the manner in which Dr. Rich treated Maxx.”

It’s a bad rule, a sleight of hand that allows the prescription drug company to avoid liability for misleading prescription drug users by pointing the finger at their doctors. All a doctor has to say — and we’ll get to why they would say this in a moment — is, “a better warning wouldn’t have changed my prescribing decision” and, poof!, the plaintiff’s case vanishes. The whole case is decided without even considering whether the defendant drug company had warned the patient — the one who, at all times, had the final say on whether or not they actually took the medicine — about the real risks. 
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A few days ago I reviewed the list of “worst” pharmaceutical and medical device liability court opinions of the last year as chosen by the defense lawyers at Drug & Device Law, so I feel obligated to follow-up on their post on the “best” prescription drug and medical device decisions.

The short version is quite simple: drug and device companies really like activist judges legislating from the bench or overruling juries’ factual findings. How else to explain the love for PLIVA, Inc. v. Mensing, in which the United States Supreme Court couldn’t find a federal statute or regulation in support of granting generic drug manufacturers legal immunity and so contrived an argument the Court admitted “makes little sense,” or Garza v. Merck & Co., in which the Texas Supreme Court held that it was unreasonable for a jury to agree with two cardiologists that Vioxx caused a heart attack?

As with their “worst” list, the “best” list is most interesting for what it reveals about the current state of drug and medical device company liability: heads defendant wins, tails plaintiff loses. In Mensing (#1), a plaintiff’s claim was dismissed because the Court didn’t want to speculate about what the FDA would do if a drug company proposed strengthening a warning label, while in Dobbs (#8) a plaintiff’s claim was dismissed because the Court speculated that the FDA wouldn’t accept a drug company’s proposal for a strengthened warning label. In Williams (#4), a plaintiff’s claim was dismissed because her doctors disposed of the pieces of the device in question, while in Wolicki-Gables (#6), a plaintiff’s claim was dismissed because, even though the plaintiff asked in writing for her doctors to preserve the device, a representative of the device manufacturer slipped into the surgery without the patient’s consent, took the device, lied to the patient about testing it and destroyed it, leaving the plaintiff nothing to examine or to test.

Let’s roll the tape.
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[Update: the American Medical Association recently posted an article about how “off-label” marketing is so pervasive that many doctors don’t even know what the approved purposes of the prescription drugs and medical devices are, exposing them to malpractice liability.]

The pharmaceutical defense lawyers at Drug & Device Law, one of my favorite blogs to throw rocks at (we went Jersey Shore over the Wellbutrin litigation a year ago), are at it again, this time attacking a legal theory they refer to as ‘FDA regulatory informed consent.’ Although drug companies aren’t allowed to market drugs for any purpose other than those purposes approved by the Food and Drug Administration (it’s called “off-label marketing” and it’s blatantly illegal), the FDA permits individual doctors to prescribe FDA-approved drugs for any purpose, creating a disconnect between FDA approval and actual medical practice. The FDA doesn’t do anything to regulate what doctors prescribe; the closest it comes to informed consent are its regulations for clinical trials.

Under the theory of FDA regulatory informed consent, physicians should be required to tell patients if the physician is prescribing a medication for a use not approved by the FDA. Jim Beck at Drug & Device Law thinks it’s a bad idea, and wrote his post in response to a new law review article, “The Case For Legal Regulation Of Physicians’ Off-Label Prescribing,” 86 Notre Dame L. Rev. 649 (2011)(online copy here), by Philip M. Rosoff, a professor at Duke Medical School, and Doriane Lambelet Coleman, a professor at Duke Law School. As Beck notes, most courts don’t accept the explicit version of this — i.e., the requirement that a doctor specifically say the drug or medical device isn’t FDA-approved — but, as Beck doesn’t note, some courts get awfully close. See, e.g., DeNeui v. Wellman, No. 2009 U.S. Dist. LEXIS 114853, at *11–14 (D.S.D. Dec. 9, 2009)(“a jury must determine whether a reasonable person would attach significance to the off-label use of [the medical device] before deciding whether to undergo the surgery in this case”); In re Diet Drug Litigation, 384 N.J. Super. 525, 895 A.2d 480 (Law Div. 2005)(distinguishing Blazoski v. Cook, holding “While obesity is a serious condition, phen-fen is hardly its only cure. While phen-fen may have provided real benefits for those who took it, these patients were entitled to know of its risks. And it is certainly foreseeable that, if advised of the risks, they might well have chosen alternatives.”).

I’m unsurprisingly more on Rosoff and Coleman’s side. I’ll explain.

First, a little bit of background on the subject. As I’ve discussed before, intense lobbying by drug companies — including infiltration of the supposedly neutral legal research groups like the American Law Institute, which publishes the various Restatements — has whittled away at most of the potential claims against defective drug manufacturers. The law’s so hostile to patients that even doctors think it’s too protective of drug companies. (At the same time, those same companies have lobbied for absurd laws like the Prescription Drug User Fee Act that penalize the FDA if it doesn’t approve drugs quickly enough; unsurprising, that has made drugs less safe and more likely to be withdrawn.)

If you try to sue a drug company for inadequately testing or improperly designing a drug, the drug company will cite FDA approval and shout “pre-emption,” arguing that the FDA already signed off on the drug’s safety and efficacy and that the courts aren’t allowed to second-guess that — even if neither the FDA nor Congress said they meant to foreclose tort lawsuits. Defense lawyers call that dubious argument “implied pre-emption.”

Courts will too often buy those arguments; consider the lengths to which Judge Posner jumped to deny a toxic epidermal necrolysis / Stevens-Johnson syndrome victim a $3.5 million jury award. I’m not sure why he bothered with that long and winding factual argument, leaping from assumption to assumption and begging his own questions; he could have just said, “I’d prefer they lose” and be done with it.

In short: under a variety of names (“implied preemption,” “learned intermediary,” “unavoidably unsafe product,” etc) the drug manufacturers routinely claim that FDA approval is the be-all, end-all of drug safety, and so no injured patient should ever be allowed to sue the manufacturer of an FDA-approved drug. It’s thus more than a little hypocritical for them or their lawyers to now claim that FDA approval is irrelevant to patients. It’s the sole reason they believe they’re entitled to special legal immunities not granted to other manufacturers.

Although every defective drug lawsuit these days alleges a variety of claims like strict liability, negligence, breach of warranty, and violations of consumer protection laws, in the end most of the prescription drug lawsuits tend to boil down to one type of claim: the “failure to warn” of a certain side-effect or problem with the drug. The Supreme Court held in Wyeth v. Levine that failure to warn cases could go forward, so patients’ lawyers have held on to that will all their might. All the big prescription drug cases these days — Accutane, Actos, Chantix, Darvon-Darvocet, Depakote, Fosamax, Plavix, Topamax, Yaz — are primarily failure to warn cases. The Accutane plaintiffs allege that Roche failed to warn about side effects like inflammatory bowel disease and birth defects. The Actos plaintiffs allege that Takeda failed to warn about an increased risk of bladder cancer. The Chantix plaintiffs allege that Pfizer failed to warn about the risk of depression and suicidal thoughts. Et cetera.

Lurking under the surface of many of these cases is the scourge of off-label marketing. You wouldn’t know it from Beck’s critique, but doctors and medical researchers have long fretted about off-label prescription. One study in 2006 found over 150 million off-label mentions by physicians each year — totalling over one-fifth of overall prescriptions — and found that three-quarters of those off label prescriptions had “little or no scientific support.”

Worse, many patients don’t know that doctors are allowed to prescribe drugs for unapproved and unsupported uses: “A 2006 poll suggests that much of the U.S. public is confused and ambivalent about off-label prescribing, with about half the respondents believing that physicians are permitted to prescribe drugs only for on-label indications and about half believing that physicians should be prohibited from prescribing drugs for off-label indications.” (Source).
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