Drug Label Failure To Warn

One of the more sobering parts of being a trial lawyer is reviewing intakes of potential cases. We routinely talk with people who have just lost a spouse or child or who have recently suffered an injury that will leave them permanently disabled. Many of these accidents happened in the course of activities we all know to have an element of danger, but many involve doing the same thing a million other people do every day. No one expects that giving their kid Motrin will cause a horrific skin disease or that their tap water might be so polluted that it’s flammable.

Now, a growing body of medical studies shows that acetaminophen (Tylenol in the US, Paracetamol everywhere else) is dangerous at far lower doses than previously believed. It’s been known for decades that acetaminophen overdoses cause liver damage (for example, “acetaminophen hepatotoxicity far exceeds other causes of acute liver failure in the United States,” and some estimates by the American Association of Poison Control Centers suggest more than 50,000 emergency department visits every year related to acetaminophen), particularly when combined with alcohol, but it was generally considered safe if taken at anywhere near the recommended amounts.

Recent studies suggest that’s not the whole story. Just a few weeks ago, a new study in the British Journal of Clinical Pharmacology found that “staggered overdoses,” in which patients repeatedly took amounts slightly higher than the recommended dosage, were the cause of a substantial portion of the hospital admissions for acetaminophen-induced liver damage, and could be more dangerous than individual overdoses, in part because staggered overdoses were harder to diagnose and treat.

In June 2009, the FDA’s Drug Safety and Risk Management Advisory Committee, Nonprescription Drugs Advisory Committee, and the Anesthetic and Life Support Drugs Advisory Committee all voted in favor of:

  • Reducing the current dosage strengths of acetaminophen in nonprescription products to below 4 grams/day
  • Limit formulations of over-the-counter liquid doses of acetaminophen
  • Eliminating prescription acetaminophen combination products (e.g., oxycodone)
  • Requiring a boxed warning for prescription acetaminophen combination product

The FDA disappointingly didn’t act on most of that, and instead took eighteen months to take the weakest action it could:

On January 13, 2011, FDA announced that it is asking manufacturers of prescription acetaminophen combination products to limit the maximum amount of acetaminophen in these products to 325 mg per tablet, capsule, or other dosage unit. FDA believes that limiting the amount of acetaminophen per tablet, capsule, or other dosage unit in prescription products will reduce the risk of severe liver injury from acetaminophen overdosing, an adverse event that can lead to liver failure, liver transplant, and death.

The size of the individual dosage unit was never the problem, though. As the Acetaminophen Hepatotoxicity Working Group for the FDA Advisory Panel found in its report, the problem was far more complicated than the pills being too big:

There is no single factor that leads consumers (also referred to as patients in this report) to develop acetaminophen-related liver injury. The contributing conditions for these cases are multi-factorial and require different interventions that attempt to address each factor. For example, when someone takes an amount greater than labeled, it is unclear whether it is a case of failing to read the directions, failing to understand the directions, failing to understand that severe liver injury can result from not following the directions or failing to realize that more than one of the medications used contained acetaminophen.

The Working Group concluded, “Thus, it is necessary to address all of these causes in attempting to prevent future cases, making clear directions conspicuous and easy to understand and making consequences of overdose unequivocally clear.” (Emphasis added.)

It’s not just the pill size. It’s not just the recommended maximum dosage. The core problem is that consumers and patients have learned, from years of Tylenol advertising and liberal use of acetaminophen by their parents, nurses, and doctors, that it’s a “safe” drug, like caffeine, that can be used every day and without much consequence unless you have a particular susceptibility to it or if you intentionally take way too much. Consumers look at recommended dosages like they do speed limits: you can use that amount without any problems, but try not to go too far above it. Problem is, if you did that with the 4 grams/day of acetaminophen guideline, you had a much higher risk of liver damage, even if you didn’t do it all the time. 
Continue Reading Courts Lag Behind Science In Recognizing How Regular Tylenol Use Causes Liver Damage

The pharmaceutical industry is plagued by the same problem as the entertainment industries: their business models are too reliant on blockbusters.  I’m certainly not the first person to notice that — even drug company CEOs have openly fretted about it — but the problem persists and grows each year. As the pharmaceutical consulting company L.E.K. pointed out a few months ago, “Blockbusters have become the centerpiece of the biopharma industry, growing from 16% of global drug revenue in 1995 to 35% in 2010.”

In the entertainment industry, the consequences of that reliance on blockbusters is merely a string of bad sequels to every hit movie and some unfortunate shark-jumping on television.  In the world of drug sales, though, it usually means a lot of people get hurt when a company fails to take a dangerous blockbuster drug off the market or update it with appropriate warnings.

Consider Propecia. Propecia is a 1 mg dose of finasteride, a drug originally used for the treatment of symptomatic benign prostate enlargement in 5 mg doses and marketed by Merck as Proscar. Finasteride, in turn, is a type II 5-Alpha reductase inhibitor that prevents the conversion of androgen testosterone to dihydrotestosterone (DHT).

In many ways, the mechanism of finasteride is quite simple: it inhibits the production of testosterone, a male sex hormone, and so it decreases the problems of high testosterone or testosterone sensitivity (male pattern baldness, prostate enlargement) while creating the same problems as if a man had low testosterone (decreased muscle mass and sexual function, impotence). The FDA-approved label for Propecia warns:

What are the possible side effects of PROPECIA?

Like all prescription products, PROPECIA may cause side effects. In clinical studies, side effects from PROPECIA were uncommon and did not affect most men. A small number of men experienced certain sexual side effects. These men reported one or more of the following: less desire for sex; difficulty in achieving an erection; and, a decrease in the amount of semen. Each of these side effects occurred in less than 2% of men. These side effects went away in men who stopped taking PROPECIA. They also disappeared in most men who continued taking PROPECIA.

Most of that is known and to some extent foreseeable by Propecia users.  It’s similar to the symptoms of low testosterone because that’s pretty much what Propecia does: inhibit androgen conversion to testosterone.

But hormones are funny things.  The endocrine system is as complicated as the immune system, with the added complication of all the hormones working together in concert, and many of the glands responding to any changes in the system.  Tampering with the system often results in mild improvement in symptoms and then some drastic side effect. We saw that with estrogen plus progestin hormone replacement therapy: HRT was conventional wisdom in the medical industry throughout the late 1990s — due in no small part to Wyeth and Pfizer marketed the heck out of Prempro — until the Women’s Health Initiative trials in 2002 revealed a substantial increase in breast cancer, prompting a complete about-face in treatment for post-menopausal women.

Coming back to Propecia, the warning label in the United States didn’t mention until June of this year, but the warning labels in the United Kingdom have said for some time:

In addition, the following have been reported in postmarketing use: persistence of erectile dysfunction after discontinuation of treatment with PROPECIA; male breast cancer (see 4.4 Special warnings and precautions for use)

Propecia in Sweden and Italy has similar warnings. The big problem there — the persistence of sexual problems, even after stopping the medicine — has been known for years. The Wessells et al. study (“Incidence and severity of sexual adverse experiences in finasteride and placebo-treated men with benign prostatic hyperplasia“) found that 15% of finasteride-treated patients (more than double the placebo patients) had sexual adverse experiences arising from Proscar use, and that half of those had problems continuing even after they stopped taking Proscar.

Over time, others have followed up. Earlier this year, the Irwig et al. study confirmed (“Persistent Sexual Side Effects of Finasteride for Male Pattern Hair Loss“) what the Traish et al. study (“Adverse side effects of 5α-reductase inhibitors therapy: persistent diminished libido and erectile dysfunction and depression in a subset of patients“) had suggested: use of finasteride at their the Propecia or Proscar doses results in persistent sexual problems for a number of patients.

Merck responded in June of this year, by adding a new warning, the type of language by-of-and-for the drug manufacturer’s lawyers that I like to refer to as a “wink, nudge” warning:

In general use, the following have been reported: breast tenderness and enlargement; depression; allergic reactions including rash, itching, hives and swelling of the lips and face; problems with ejaculation; testicular pain; difficulty in achieving an erection that continued after stopping the medication; and, in rare cases, male breast cancer. You should promptly report to your doctor any changes in your breasts such as lumps, pain or nipple discharge. Tell your doctor promptly about these or any other unusual side effects.

The language used is, of course, designed to make doctors and consumers ignore the warning. “The following have been reported” indicates Merck doesn’t really believe Propecia causes any of them. Just in case consumers didn’t get that wink, nudge message, it’s emphasized again that these are all “unusual” side effects, not the side effects attributed to the drugs.

So, what gives? Why didn’t Merck update its U.S. labels back in, say, 2008, when it updated the Swedish warning? Why does the Propecia label still claim all instances of erectile dysfunction and decreased libido “went away in men who stopped taking PROPECIA?” Nobody these days thinks drug companies exist for the benefit of mankind — they’re all just profit-seeking enterprises that spend more on advertising than research — but many assume the companies at least worry about getting sued. 
Continue Reading Why Merck Still Doesn’t Warn About Propecia Causing Impotence

[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).
Continue Reading Off Label Drug Use Should Be Regulated For Patient Safety

It’s no secret that pharmaceutical companies are among the more litigious businesses in America. Up until 2003, when Congress stepped in, the big drug makers had a good thing going: whenever the patent was about to expire on one of their blockbuster drugs, they would file a new patent for trivial modifications to the medicine, and thereafter would sue generic drug manufacturers claiming that the generic version of the old drug somehow infringed on the new patent.

Here’s the kicker: the big drug makers knew these patent infringement claims were frivolous, so they would enter into a “settlement” in which the big drug company — which nominally brought the case to recover monetary damages — would pay the generic company not to manufacture the generic drug anymore. Crazy, huh?

So crazy and so hopelessly anticompetitive that in 2003 Congress amended the Hatch-Waxman Act to force the major drug companies to report all of these “exclusive-payment” patent settlements to the Federal Trade Commission. The FTC still keeps an eye on them and keeps filing amicus briefs to make sure courts realize how damaging that practice is. As I’ve discussed before, some unions and health plans, stymied by the Illinois Brick decision precluding antitrust claims by indirect purchasers, have tried recovering the inflated health care expenses by filing unfair trade practices lawsuits.

The pharmaceutical companies are also not strangers to deceiving the federal government; over the past decade they’ve paid several billion dollars in qui tam cases, the result of brave whistleblowers exposing the fraud at great personal cost.

So pardon me if I don’t think that pharmaceutical companies deserve a special exception from the basic legal responsibilities we all have to one another just because they claim litigation is expensive or because they claim that always tell the FDA the truth. That sort of special treatment is what they’re trying to get with “tort reform” in the Pennsylvania legislature, and what they’re claiming they’re owed in the courts:

In questioning during oral argument Tuesday in Philadelphia, a state Supreme Court justice characterized the drugmaker Wyeth as asserting that there is enough protection for persons harmed by prescription drugs in federal regulation of the release of drugs onto the market, and limiting plaintiffs to lawsuits for drugmakers’ alleged failures to adequately warn of risks.

Plaintiffs are arguing in a case that could change the landscape of pharmaceutical products liability law in Pennsylvania that drugmakers can be sued for the negligent design defect of their drugs.

Questioning the plaintiffs’ lawyer, Justice Max Baer also said that Wyeth asserts that Pennsylvania would chill the manufacturing of prescription drugs if pharmaceutical companies can be sued for the negligent design defect of their drugs. He asked the lawyer to address why that may not be so.

The case, Lance v. Wyeth, arises from a primary pulmonary hypertension death allegedly caused by Redux, a hopelessly dangerous diet drug that causes a host of medical conditions which was yanked from the market for causing valvular heart disease. No one credibly disputes that the drug should never have been marketed or sold in the first place: it combined two drugs known to cause cardiovascular problems. Had Wyeth (now owned by Pfizer) properly tested it, they probably would never have sold it. Had they properly warned doctors and patients of the real risks, no doctor would have prescribed it and no patient would have taken it.

If dangerous drugs were automobiles with defective air bags (like Gaudio v. Ford Motor Co.), or rollover-prone all-terrain vehicles (like Smith v. Yamaha Motor Corp.) there wouldn’t be a question of the applicable law. Everybody — you, me, lemonade stands, multinational corporations, and everyone in between — has the same general legal duty to exercise reasonable care not to cause injuries to others. If we don’t exercise that reasonable care, we’re negligent, and we’re responsible to pay for the damage we cause.

That’s how the tort of negligence works. It’s quite simple.

In addition to their responsibility to pay for all negligently caused damages, everyone who sells products — again, from the lemonade stand to the multinational corporation — has “strict liability” for all damages caused by defective products. Consider that defective air bags case above:

[W]e will briefly review the history of products liability law and the crashworthiness doctrine in this Commonwealth. Our Supreme Court first adopted section 402A of the Restatement (Second) of Torts in Webb v. Zern, 422 Pa. 424, 220 A.2d 853 (1966). To state a section 402A products liability claim in Pennsylvania, the plaintiff must prove that the defendant sold a product “in a defective condition,” that the defect existed when the product left the defendant’s hands, and that the defect caused the plaintiff’s injuries. See, e.g., Hadar v. AVCO Corp., 886 A.2d 225, 228 (Pa.Super.2005). A product is “in a defective condition” when it lacks “any element necessary to make it safe for its intended use or possessing any element that renders it unsafe for the intended use.” Azzarello v. Black Bros. Co., Inc., 480 Pa. 547, 559, 391 A.2d 1020, 1027 (1978). Because the key inquiry in all products liability cases is whether or not there is a defect, it is the product, and not the defendant’s conduct, that is on trial. See, e.g., Hutchinson v. Penske Truck Leasing Co., 876 A.2d 978, 983 (Pa.Super.2005), affirmed, 592 Pa. 38, 922 A.2d 890 (2007).

Gaudio v. Ford Motor Co., 976 A. 2d 524 (Pa. Super. Ct. 2009)(remanding for trial a crashworthiness claim).

But Section 402A of the Second Restatement of Torts has a pesky “comment k” for defective drug cases which says:

There are some products which, in the present state of human knowledge, are quite incapable of being made safe for their intended and ordinary use. These are especially common in the field of drugs. . . .  Such a product, properly prepared, and accompanied by proper directions and warning, is not defective, nor is it unreasonably dangerous.  The same is true of many other drugs, vaccines, and the like, many of which for this very reason cannot legally be sold except to physicians, or under the prescription of a physician. . . .  The seller of such products, again with the qualification that they are properly prepared and marketed, and proper warning is given, where the situation calls for it, is not to be held to strict liability for unfortunate consequences attending their use, merely because he has undertaken to supply the public with an apparently useful and desirable product, attended with a known but apparently reasonable risk.

Defense lawyers contend that comment k promises pharmaceutical companies total and complete immunity from all potential theories of liability except for a narrow class of “failure to warn” claims. Wyeth argued that the sole question is “whether the risk information conveyed to prescribing physicians was sufficient to permit them to conduct an individualized risk-benefit analysis.”

Nonsense.

The plaintiffs in Lance were smart to hire Howard Bashman, friend of the blog, for their appeal, and his excellent opening brief and reply are both online. So, too, is the joint American Association for Justice and Pennsylvania Association for Justice amicus brief.

The briefs quite adequately cover Pennsylvania law on the subject, all the Incollingo v. Ewing, 444 Pa. 263, 282 A.2d 206 (1971)(a Jim Beasley case), Baldino v. Castagna, 505 Pa. 239, 478 A.2d 807 (1984), and Hahn v. Richter, 543 Pa. 558, 673 A.2d 888 (1996) a drug liability law nerd could ask for.

Personally, I think two arguments should decide Lance v. Wyeth.
Continue Reading Pennsylvania’s Defective Drug Design Laws Hang In The Balance

They say you learn something new every day. Here’s what you’re going to learn today:

Over-the-counter Motrin can burn the skin off your face.

Commonly prescribed drugs like the yeast-infection treatment Nystatin and the antibiotic Azithromycin can do the same. All of them, and over a dozen other drugs, can also cause ulcers and lesions to develop on the membranes in your mouth and on your lips, making it impossible to eat.

Take a step back and think of how many of those you took in the last year. Who didn’t take Motrin or some other ibuprofen in the past year?

Who didn’t give it to their kid?

Janet Leland gave Children’s Motrin to her nine year old daughter, Kiley Wolfe, just like her pediatrician told her to, to relieve headache, stomach pains, and a fever. As the District Court for the Eastern District of Pennsylvania described last week:

Despite taking Children’s Motrin, plaintiff’s symptoms did not improve. Instead, she developed a rash on her cheeks. Nonetheless, nurses at plaintiff’s pediatrician’s office advised Leland to continue administering the drug to plaintiff. Leland proceeded to give plaintiff doses of Children’s Motrin until Saturday, June 1, when she noticed blisters on plaintiff’s ears while the family was staying in Boston.

Later that day, Leland took her daughter to Boston Children’s Hospital. Doctors there diagnosed her with Stevens-Johnson Syndrome (‘SJS’) [2] While hospitalized, plaintiff exhibited symptoms of acute Vanishing Bile Duct Syndrome (‘VBDS’). [3] Because of damage to her liver, plaintiff eventually required a liver transplant.

FOOTNOTES

2 SJS is ‘a rare, serious disorder in which your skin and mucous membranes react severely to a medication or infection.’ Mayo Clinic, Stevens-Johnson Syndrome, http://www.mayoclinic.com/health/stevens-johnson-syndrome/DS00940 The disease is ‘sometimes fatal.’ Dorland’s Illustrated Medical Dictionary 1833 (30th ed. 2003).

3 VBDS is a condition where the bile ducts in the liver are destroyed.

Wolfe v. McNeil-PPC, Inc., 2011 U.S. Dist. LEXIS 34714, at *4–5 (E.D. Pa. Mar. 30, 2011).

Continue Reading Failure To Warn Quiz: Do You Know Children’s Motrin Side Effects?

As you’ve probably heard at sites like Overlawyered and Drug & Device Law, the sky is falling upon us because the Supreme Court didn’t override Congress and the FDA and decide to pre-empt state failure-to-warn tort suits against prescription drug manufacturers.

If you don’t know the basic facts, see SCOTUSBlog. Some initial commentary