What is federal preemption? It’s an easier concept to grasp than you might think.

Think back to when you were a kid, and you asked your mom if you could go to a party. She clearly said, “no.” You then went to ask your dad if you could go to the party, and he clearly said, “yes.” Since you were always taught that both parents ruled your actions, you figured as long as you had one parent’s approval to go the party, that was good enough, and you couldn’t get in trouble for going.

Wrong. That night, as you started to leave the house, your parents stopped you, forbidding you to go to the party after all. Angrily, they explained that since your mom had already determined that you could not go to the party, your dad’s permission was null and void. In other words, your mom’s rule wiped out or “preempted” your dad’s rule. Although you didn’t know it then, that night, you got your first lesson in the basic concept of federal preemption.

Federal preemption is a doctrine based on the Supremacy Clause of the United States Constitution, which states that federal law takes precedence over state law.

When state law and federal law conflict, federal law wipes out or “preempts,” state law, due to the Supremacy Clause of the Constitution. U.S. Const. art. VI., § 2. Specifically, the Supremacy Clause states, “the Laws of the United States …shall be the supreme law of the land …anything in the … laws of any state to the contrary notwithstanding.”

So, if federal law requires you to do something, and state law requires you do the opposite, which one wins? Due to federal preemption, federal law wins. For example, if, hypothetically, federal law requires you to paint your fence blue, and state law forbids you from painting your fence blue, federal law wins due to the Supremacy Clause of the Constitution. The federal law preempts the state law, and you would therefore be required to paint your fence blue.

In many recent cases involving prescription drugs, we have seen tension between federal law and state tort law. See, e.g., PLIVA, Inc. v. Mensing, 131 S.Ct. 2567 (2011). The general pattern among these recent cases is as follows: State law requires all drug manufacturers—whether it be a brand-name manufacturer or a generic drug manufacturer—to design medications safely, and to provide adequate warning labels on all of their medications. In turn, if a drug manufacturer fails to safely design a medication or fails to provide an adequate warning label, and someone in harmed as a result, that person can sue the manufacturer under state tort law.

By direct contrast, federal law only requires brand-name manufacturers to design medications safely, and to provide adequate warning labels on all of their medications. Under federal law, the generic drug’s design and warning label must be identical to that of the brand-name version of the drug, no matter how unsafe or inadequate.

Therefore, if you are harmed by a generic version of a brand-name drug, state law automatically permits you to sue the manufacturer of the generic version, while federal law automatically forbids you from suing the manufacturer. Which one wins? Due to federal preemption, federal law wins.

Most often, manufacturers successfully argue that they cannot be sued because federal law allowed them to sell the unsafe product and that preempts—and immunizes them from—the state laws that would hold them accountable. See http://publicjustice.net/blog/fighting-for-access-tp-justice-part-2#sthash.YBK8uZQ5.dpuf.

However, and fortunately, courts are finding creative ways around federal preemption, which allow plaintiffs to be compensated for their injuries. For examples, see our previous post entitled, Brand-Name Drug Manufacturer can be Liable for Harm Caused by its Generic Version.

Also, please check in soon for more upcoming articles on other specific, recent cases where courts have ruled in favor of plaintiffs despite federal preemption.


Janice L. Weiner
Center for Drug Evaluation and Research
Food and Drug Administration
10903 New Hampshire Ave.
Bldg. 51, Room 6304
Silver Spring, MD 20993-0002


Dear Ms. Weiner,

We are grateful for the opportunity to submit comments in support of the Food and Drug Administration’s (FDA) proposed rule entitled, Supplemental Applications Proposing Labeling Changes for Approved Drugs and Biological Products (78 Fed. Reg. 67985).

Currently, a generic drug’s design and warning label must identically match that of the name-brand version of the drug. In turn, generic manufacturers are prohibited from making any material changes to the drug’s design or warning label. As a result, generic manufacturers cannot be sued for providing consumers with unsafe medications.

It is outrageous that a generic drug manufacturer can know that a warning label is inadequate, sell the drug anyway, and escape all liability. We believe that the proposed rule, which holds both generic and brand-name manufacturers responsible for informing the public about known risks of their medications, will promote health, safety, and equality.

 The Fourteenth Amendment Supports the Proposed Rule

The Equal Protection Clause of the Fourteenth Amendment to the United States Constitution prohibits states from discriminating between the “poor” and the “rich.” A state can no more discriminate on account of financial status than on account of religion, race, or color. See Griffin v. Illinois, 351 U.S. 12, 17, 76 S. Ct. 585, 590, 100 L. Ed. 891 (1956). See also  U.S.C.A.Const. Amend. 14; S.H.A.Ill.Const. art. 2, § 19.

“Courts have confronted, in diverse settings, the ‘age-old problem’ of [p]roviding equal justice for poor and rich, weak and powerful alike.” M.L.B. v. S.L.J., 519 U.S. 102, 110, 117 S. Ct. 555, 560, 136 L. Ed. 2d 473 (1996) quoting Griffin v. Illinois, 351 U.S. 12, 16, 76 S.Ct. 585, 589, 100 L.Ed. 891 (1956). We think the pharmaceutical industry is the newest “diverse setting” where this “age-old problem” must be resolved; and we are grateful that the proposed rule seeks to do just that.

The current law, which holds manufacturers of generic drugs to a lesser legal standard than their brand-name counterparts, essentially discriminates between the poor and the rich. After all, the only difference between brand-name drugs and their generic equivalents is price. Generic brands are often significantly less expensive than their brand-name counterparts.

In fact, generic drugs were originally made in an effort to ensure that effective and safe drugs were widely and inexpensively available to citizens who could not otherwise afford medications. Thus, people who are less financially well-off are the ones who were, and are, specifically intended to purchase generic drugs. In other words, poor people buy generic brands.

If someone takes a brand-name medication and develops a disease as a result of taking the brand-name medication, she can sue the company that manufactured the drug. Those who can afford the brand-name drug in the first place are the ones—and only ones—who are allowed to be compensated for injuries sustained from ingesting an unsafe drug.

On the other hand, if a financially less-fortunate individual goes to the pharmacy and inevitably opts for the cheaper generic version of the drug, and develops the same disease or adverse side effect, she cannot sue the generic manufacturer. Instead, she is left to incur medical expenses for the harm she suffers as a result of consuming the unsafe drug, even though she is just as innocent as the financially well-off consumer.

It is heartbreaking that the very people who cannot afford brand-name drugs in the first place are singled out and deprived of the right to be justly compensated. The result is that “rich” people are protected under the current federal law, while “poor” people are not. The proposed rule, by contrast, which protects consumers of brand-name drugs as well as consumers of generic equivalents, works to conform to the Equal Protection Clause of the Fourteenth Amendment.

 The Proposed Rule Will Save Courts Time and Resources

 We had mixed feelings with regard to a recent order issued by a Federal District Judge in Illinois in the case of Dolin v. Smithkline Beecham Corporation d/b/a Glaxosmithkline, which found that, under Illinois law, a brand-name manufacturer owes a duty to consumers of generic versions of its drugs. The ruling was as good as anyone could hope for under the current law.

The plaintiff in the case is a woman whose husband committed suicide after taking a medication called, paroxetine, which is manufactured by Mylan, Inc. Paroxetine is the generic version of the brand-name drug, Paxil, which is owned and manufactured by GlaxoSmithKline (“GSK”). The plaintiff brought a wrongful death action against both GSK and Mylan.

The Judge had no choice but to find that Mylan could not be held liable, because federal law preempts claims against manufacturers of generic versions of brand-name drugs. However, creatively, the Judge found that the brand-name manufacturer could be held liable even though it was not the company that actually manufactured the pill that resulted in the plaintiff’s husband’s fatality.

We are pleased because at least the Judge found that the plaintiff could be compensated by one of the negligent companies. However, we believe that the Judge had to go around his hand just to get to his thumb. The Judge issued an intricate 26 page opinion, exploring vague precedent to “get around” the law that states generic manufacturers cannot be sued. It seems a great deal of the court’s time and resources were wasted as a result.

We believe that the proposed rule, which holds both generic and brand-name manufacturers responsible for informing the public about known risks of their medications, will save the courts time and resources because judges will have a clear, set standard.


Thank you again for the opportunity to submit comments in support of the Food and Drug Administration’s (FDA) proposed rule entitled, Supplemental Applications Proposing Labeling Changes for Approved Drugs and Biological Products (78 Fed. Reg. 67985). As explained above, in addition to saving the courts valuable time and resources, we believe the new rule will promote health, safety, and equality in our society.


We are pleased with a recent order issued by a Federal District Judge in Illinois, which found that, under Illinois law, a brand-name manufacturer owes a duty to consumers of generic versions of its drugs.

The plaintiff in the case is a woman whose husband committed suicide after taking a medication called, paroxetine, which is manufactured by Mylan, Inc. Paroxetine is the generic version of the brand-name drug, Paxil, which is owned and manufactured by GlaxoSmithKline (“GSK”). The plaintiff brought a wrongful death action against both GSK and Mylan. Among other claims, the plaintiff brought negligence claims against both defendants.

The plaintiff’s husband’s doctor wrote him a prescription for Paxil to treat work-related anxiety. However, his prescription was ultimately filled with the generic version, paroxetine. Six days after beginning to take paroxetine, the husband purposefully leaped in front of a train to his death. Blood tests taken with his biopsy were positive for paroxetine.

According to the complaint, the plaintiff and her husband were financially secure, owned their home outright, and had no pressing debts. What caused such a drastic change in the husband’s mind that he would take his own life within six days? He took paroxetine. Besides work-related stress, it seems that, up until the time the husband took paroxetine, he enjoyed tranquility in his life, and never showed any signs of suicide whatsoever.

The paroxetine label in existence at the time of the husband’s death did not warn of the medication’s association with increased risk of suicidal behavior in adults. Instead, the label specifically stated the exact opposite—that no risk of suicide existed beyond the age of 24. However, the plaintiff asserts that the defendant companies had concrete knowledge that paroxetine use carried a substantial risk of suicidal behavior in adults above the age of 24, and yet promoted the medication as safe and effective.

The issue is whether either of the defendant companies can be held liable for damages caused by the medication that resulted in the plaintiff’s husband’s fatality. Here lies the difficult “catch” for the plaintiff in the case at hand, and other similarly situated plaintiffs: GSK argues that because it did not manufacture the actual pill that the husband ingested, it cannot be held responsible, and is entitled to judgment as a matter of law. Mylan, on the other hand, too, argues that it cannot be held liable, because federal law preempts claims against manufacturers of generic versions of brand-name drugs.

Although absurd, Mylan is correct. Due to a ruling by the United States Supreme Court, if you are harmed by a generic version of a brand-name drug, you cannot sue the manufacturer of the generic version. This is because, under federal law, the generic drug’s design and warning label must be identical to that of the name-brand version of the drug. As the Supreme Court recently summarized:

“First, the proposed generic drug must be chemically equivalent to the approved brand-name drug: it must have the same “active ingredient” or “active ingredients,” “route of administration,” “dosage form,” and “strength” as its brand-name counterpart.  21 U.S.C. §§ 355(j)(2)(A)(ii) and (iii).  Second, a proposed generic must be “bioequivalent” to an approved brand-name drug.  § 355(j)(2)(A)(iv). That is, it must have the same “rate and extent of absorption” as the brand-name drug. § 355(j)(8)(B).  Third, the generic drug manufacturer must show that “the labeling proposed for the new drug is the same as the labeling approved for the [approved brand-name] drug.” § 355(j)(2)(A)(v). Mutual Pharmaceutical Co., Inc. v. Bartlett, 133 S.Ct. 2466, 2471 (2013).

In accordance with the above ruling, the Illinois Federal Judge in the case at hand had no choice but to grant Mylan’s motion to dismiss, concluding that, “with respect to any alleged defects in connection with a generic drug’s warning label, a generic manufacturer’s hands are simply tied.” With regard to Mylan, the generic manufacturer, federal law simply preempted the plaintiff’s claims. As a result, the plaintiff’s only hope for any sort of compensation hinged on whether the court found that GSK, the brand-name manufacturer, was somehow liable.

Fortunately—and a bit creatively—the court found that, under Illinois law, a brand-name manufacturer owes a duty to consumers of generic versions of its drugs, and thereby denied GSK’s motion for summary judgment with regard to the plaintiff’s negligence claims.

In order to constitute a common law negligence claim, a plaintiff must allege facts establishing (1) a duty of care owed by the defendant to the plaintiff; (2) a breach of that duty; and (3) an  injury (4) proximately caused by the breach. Simpkins v. CSX Transportation, Inc., 965 N.E.2d 1092, 1096 (Ill. 2012). The court found that GSK did indeed owe a duty of care to the plaintiff and her husband, stating:

“[I]t is well understood that any generic manufacturer would be required by law to use GSK’s design and warning label, and that any defects later discovered could only be  cured by GSK.  Under such circumstances, it was entirely foreseeable that negligence on the part of GSK with respect to paroxetine’s design and warning label could result in injury to a consumer ingesting a subsequent generic version of the drug. Continuing with the duty inquiry described above, and again construing all facts and drawing all reasonable inferences in Plaintiff’s favor, GSK has not shown why the likelihood of injury was so remote as to undo GSK’s duty of care.  The principal distinction GSK insists upon – that Mr. Dolin did not ingest a product that GSK manufactured – does not lessen the likelihood that GSK’s allegedly tortious conduct would lead to Plaintiff’s injury. Under the regulatory scheme created by the Hatch-Waxman Act, whether a consumer ingests the name-brand or generic version of a given drug is immaterial as to the likelihood that negligence in the design or warning label of that drug will cause injury.”

As the patent holder, GSK was responsible for paroxetine’s design and warning label. Under the Hatch-Waxman Act, only GSK was legally permitted to cure any warning label defects. We applaud the court for finding that a brand-name manufacturer owes a duty to a patient who fills his or her prescriptions with the generic equivalent of the medication. The plaintiff in this case raised a genuine issue of material fact as to whether GSK, through negligent conduct, breached this duty, proximately causing her injuries.

It is our firm’s stance that a patient should be able to recover for injuries obtained as a result of taking an unsafe medication—whether the medication is the brand-name version or a generic equivalent. We hope that other courts will follow the Illinois Federal court’s example and ensure that plaintiffs harmed by generic versions of medications have an avenue by which to be compensated.

Generic brands. Knock-offs. It’s probably safe to assume that all of us have used one at some point or another. Many of us use them on a regular basis. Why? Because, usually, a generic brand product is pretty much the same thing as its brand-name equivalent. The main (and sometimes, only) difference is price. Generic brands are often significantly less expensive than their brand-name counterparts. This holds true in many aspects of life—clothes, shoes, accessories, groceries, and medications.

But in addition to cost, when it comes to medications specifically, there is one other significant difference between generic brands and brand-name companies: Legally, manufacturers of generic brand drugs are held to a lesser standard.  For example, if you develop a disease as a result of taking a brand-name medication, you can sue the company that manufactured the drug; but on the other hand, if you go to the pharmacy and opt for the cheaper generic version of the drug, and develop the same disease or adverse side effect, you cannot sue the generic manufacturer.

The above logic seems counterintuitive. Yet, in a 5-4 decision last year, the Supreme Court ruled that generic drug companies cannot be held liable for medication design defects. The rationale goes something like this: Federal law requires generic companies to have a warning label that is identical to that of the brand-name drug.  Therefore, if a warning label on a generic drug contains false information, the generic drug company claims it isn’t responsible because it is copying the brand-name label.  The Supreme Court bought that argument, although the dissenting opinion describes the result as “absurd.”  And it is absurd that a generic drug manufacturer can know that the warning label is inadequate, sell the drug, and escape all liability.

Generic versions of drugs are beneficial to society in that they give patients the option to buy medications at a low cost, when they would otherwise simply go without filling their prescriptions at all. However, until manufacturers of generic brand drugs are held to the same legal standard as their brand-name competitors, patients are not truly protected. After all, if one is harmed by a generic drug, the cost savings of a generic drug disappears if consumers or taxpayers have to foot the bill for treatments of undisclosed-but-known side effects.

Longtime readers of this (or any drug-related blog) know that the U.S. Supreme Court ruled that manufacturers of generic drugs cannot be sued for failure-to-warn claims.  The ruling created a legal injustice for those injured by generic drugs.

While every plaintiff’s lawyer has secretly hoped that Congress would fix the law, we’re all savvy enough to know that this polarized and partisan Congress would never do so.  And honestly, I’m not even sure if Obama would sign it – screeds from the right notwithstanding, Obama has not been a friend of lawyers or the injured.

But there is hope!  Pharmalot noted that the U.S. Department of Justice filed a court brief that indicates that the FDA is considering changing the very rule that the Supreme Court based its ruling on.  If the FDA does change the rule, generic drug manufacturers will once again be held accountable for the same conduct brand-name manufacturers are held accountable for:

“This is what the footnotes states: “This office has been informed that FDA is considering a regulatory change that would allow generic manufacturers, like brand-name manufacturers, to change their labeling in appropriate circumstances. If such a regulatory change is adopted, it could eliminate preemption of failure-to-warn claims against generic-drug manufacturers“ (see page 15 of this brief).

To short, if the FDA were to make such a change in regulations, generic drugmakers could be sued in state courts if they become aware of evidence of serious side effects but do not take action to update the product labeling. We were alerted to this by Bob Pollock, a senior advisor at Lachman Consultants, and a former acting deputy director of the FDA Office of Generic Drugs.”

Source: FDA May Change Warning Regs For Generic Labels // Pharmalot

A little late, but better than never.  Especially since the Solicitor General agrees that failure to warn lawsuits against generic manufacturers are not preempted by the FDCA:

The court of appeals correctly rejected petitioners’ contention that respondent’s failure-to-warn claims are categorically preempted by the FDCA, and its decision is consistent with the decision of the only other court of appeals to address the question since Wyeth v. Levine, 129 S. Ct. 1187, 1196 (2009).

This issue will eventually wind its way up to the Supreme Court, but I’m going to guess that it will not be in this case.  (This case was a Reglan lawsuit in which a woman took metoclopramide, which is the generic version of Reglan.)

For your convenience, here is a copy of the Solicitor General’s brief.

Bruesewitz v. Wyeth looks like it will be the Wyeth v. Levine of vaccine lawsuits:

Erwin Chemerinsky, a liberal scholar, and Kenneth Starr, a conservative, may appear to be the Oscar and Felix of constitutional law, but they’re also friends and, perhaps surprisingly, share essentially the same view in one, increasingly hard-fought area of constitutional law. They both believe that federal law should trump state tort actions only when Congress has clearly stated that it must.

* * * *

In their brief in Bruesewitz v. Wyeth, they argue that the parents of a Pennsylvania girl, who was disabled by a vaccine, has the right to sue drug maker Wyeth. That’s despite a decision by the U.S. Court of Appeals for the 3d Circuit that held the claim was barred by federal law.

Source: Big names, high stakes in quartet of pre-emption cases

The fact that Chemerinsky and Starr are both signing onto this brief ought to give Wyeth a little heartburn.  I haven’t yet read their brief, but I’m sure it will be loaded with lots of useful arguments for practitioners who are fighting preemption at all levels.

It came a little late for Diana Levine, but at least it finally came.

TRENTON, N.J. — Makers of injected promethazine, a sedative also used to treat nausea and vomiting, are being required to put the strongest warning possible on the product because it can cause tissue damage leading to amputation, the Food and Drug Administration said Wednesday.

The drug, previously sold by Wyeth Pharmaceuticals Inc. under the brand name Phenergan, was at the heart of a U.S. Supreme Court case this spring that ended in a ruling that consumers harmed by a medication approved by the FDA still have the right to sue the manufacturer.

Wyeth had appealed the case up to the Supreme Court after a Vermont woman named Diana Levine, who once played the guitar and piano professionally, sued because she had to have her right arm amputated after being injected with Phenergan. Levine's lawsuit, which claimed she wasn't sufficiently warned of the risks of using Phenergan, won her a $6.7 million jury award.

Source: The Associated Press: FDA requires strong amputation warning on sedative

A Brief History of Digitek

In 1779, the English doctor William Withering discovered that the Foxglove plant could be used to treat congestive heart failure, and in 1785 he published An Account of the Foxglove and some of its Medical Uses.   Foxglove is the common name for the roughly twenty plants in the Digitalis family.

In 1930, a scientist named Sydney Smith at the Wellcome Chemical Works in Dartford, England was working with the plant Digitalis Lanata and extracted a substance he dubbed Digoxin.  Digoxin is the active ingredient in several heart medications, including Digitek.  Wellcome (now GlaxoSmithKline) brought the first Digoxin product to market in the United States in 1934.

While there was an FDA in 1934, it was nothing like the FDA we have today.  The Federal Food, Drug, and Cosmetic Act that granted the FDA many of its powers wasn’t passed until 1938.  And it wasn’t until 1962 that amendments were passed that allowed the FDA to make pharmaceuticals prove drugs were safe and effective before they could be sold to the general public.

After the 1962 amendments were passed, the FDA began the difficult task of ensuring that existing drugs – many of which had been sold for decades – were also safe and effective.  By the late 1960’s, the FDA was convinced that the drug Digoxin was safe and effective if manufactured properly.  Drug manufacturers in the 1960’s had a very hard time ensuring the Digoxin pills they produced were of appropriate strength.  In April of 1970, the FDA began working with pharmaceuticals to test individual lots of Digoxin tablets.  Between April and November of 1970, there were 79 recalls of Digoxin tablets.  Deja vu, anyone?

In 1974, the FDA enacted a series of regulations designed to ensure the safety of Digoxin tablets.  Even with those regulations in place, there were still safety problems with Digoxin; the problems continued into the 1990’s.  By that time, the FDA believed the only solution to the Digoxin safety problem was to treat Digoxin as a new drug, and require pharmaceuticals to submit new applications to the FDA.  Treating Digoxin tablets as a new drug would force pharmaceuticals to run tests and studies that didn’t even exist when Digoxin first came to market in 1934.

The FDA went to GSK (who merged with Wellcome, the original inventor of Digoxin) and asked them to submit a New Drug Application for a Digoxin product.  in 1993, GSK submitted an application for a Digoxin drug it called Lanoxin.  The drug was approved in 1997.  Lanoxin was approved as a new, brand-name drug, which means that other pharmaceuticals could choose to make a generic form of Lanoxin.

One such manufacturer was Amide Pharmaceuticals, who asked the FDA to approve a generic drug it called Digitek.  (Actavis bought Amide Pharmaceuticals in May of 2005.)  The FDA approved Digitek on December 23rd of 1999 and Amide began manufacturing Digitek in Little Falls, New Jersey.  Here’s an overhead shot of the factory, courtesy of Google Maps:


In February of 2001, Amide and Bertek (a distributor of Digitek and the source of the “B” stamped on Digitek tablets) wrote to the FDA urging it to eliminate the 1974 Digitek regulations.  Amide wanted the FDA to require all Digoxin manufacturers to submit the same applications to the FDA that it did to bring Digitek on the market.  In this excerpt of the letter, Amide specifically acknowledges the difficulty in manufacturing Digoxin tablets:


Just seven years later, Actavis would recall every drug made in the Little Falls plant  – including Digitek – because  it couldn’t maintain consistency between product batches.

The FDA finds Serious Problems at the Little Falls Plant in 2006

The FDA inspected the Little Falls plant in January & February of 2006 and issued a warning letter to Actavis on August 15th of 2006.  (Yes, the warning letter was issued six months after the inspection.)  The FDA found several problems which they determined were “serious:”

  • Pharmaceuticals must tell the FDA about any patients who experience an adverse event while taking any drugs the pharmaceutical manufactures.  Actavis (and Amide before it) failed to report at least six  adverse events related to several drugs, including Digitek.
  • Actavis didn’t have a proper system to monitor adverse events, and it wasn’t properly following up on the adverse events it learned about.
  • Actavis never filed the “periodic safety report” it was legally obligated to file with the FDA
  • Actavis was also manufacturing drugs that had not been approved by the FDA.  Amide had a similar violation some years earlier.

The FDA warned Actavis that, “The specific violations noted in this letter are serious and may be symptomatic of underlying problems.”  (Emphasis added.)

The online archive of FDA warning letters only goes back to 11/1996, so a search for Amide leaves out the 13 years it operated prior to 1996.  That said, a search of the archive only turns up one warning letter for Amide: In 2002, they were manufacturing an unapproved extended-release version of an expectorant.  In other words, the Little Falls plant hadn’t failed any inspections since at least 1996.  So what happened between May of 2005 when Actavis bought the plant and the January 2006 inspection?  Did too many people quit or get fired for Actavis to run the plant safely?

Considering the first failed inspection took place just months after Actavis bought Amide, it’s possible that the FDA missed problems in prior inspections and that Actavis merely inherited existing problems.  But even if that’s the case, Actavis knew that there were serious problems at the Little Falls plant but didn’t correct them.

The Problems Had Worsened By July of 2006

The FDA inspected the Little Falls plant again in July and August of 2006, and things had gotten decidedly worse.  Now, Actavis wasn’t just failing to report adverse events, it was failing to follow “Good Manufacturing Practice” regulations.   Here’s what Actavis has to say about Good Manufacturing Practices:  “Good Manufacturing Practice (GMP) is a regulatory gui
deline imposed on all manufa
cturers of pharmaceuticals to ensure that finished products have the identity, strength, quality and purity they are required to have.”

Here are some of the most disturbing parts of the warning letter the FDA sent Actavis in February of 2007:

  • “Significant deficiencies were found in the operations of your firm’s quality control unit, and as a result there is no assurance that many drug products manufactured and released into interstate commerce by your firm have the identity, strength, quality and purity that they purport to possess.”
  • “Our investigators observed numerous instances where your firm’s quality control unit either ignored or failed to recognize that some tablets that did not meet in-process specifications.”
  • “[W]e are concerned about the quality of drug products that have been released from your facility under the serious lack of cGMP controls found during the inspection. Your  response provides no assurance that the records and conditions of manufacture and testing of each such lot of drug products released and marketed by your firm will be evaluated to assure that the released drug products have their appropriate identity, strength, quality, and purity. “

Remember, Amide had previously told the FDA that it’s very difficult to maintain consistency in the manufacture of Digoxin tablets.  Yet the FDA found “significant deficiencies” in the quality control unit and the manufacturing unit.  These violations are never excusable at any facility, but they’re even worse when the facility makes a highly toxic drug like Digitek that is so easy to manufacture incorrectly.

Why Did It Take So Long To Recall Digitek?

On April 25th of 2008, over a year after receiving the February letter, Actavis issued a recall notice for all of its Digitek tablets.  A remarkably tight-lipped recall notice; the notice doesn’t indicate how many tablets are being recalled or a time range for the recalled tablets.  You can read the actual recall notice here.

I dug a little deeper, and found a copy of the recall notice  that was sent to pharmacies at the North Carolina Board of Pharmacy.  According to that notice, the recall applies to Digitek that was distributed between March of 2006 and April of 2008.  Even still, that notice doesn’t give us any idea of how many tablets were distributed.  Normally, a pharmaceutical company tells the FDA the quantity being recalled.  But in the latest Enforcement Report, the FDA only states that there are 166 Lots being recalled.

An even more important question than how many tablets are being recalled is why did Actavis wait so long to recall them?  In August of 2006, the FDA told Actavis that it had serious problems at the plant.  Just six months later, the FDA told Actavis what it likely already knew: Serious deficiencies in its manufacturing and quality control process were putting lives at risk.  Actavis should have been recalling drugs by April of 2007, not April of 2008.

What’s even worse is that despite being thoroughly warned by the FDA in February of 2007, Actavis continued manufacturing defective drugs for another year before initiating the recall.  After receiving that letter, shouldn’t Actavis have stopped manufacturing potentially deadly drugs and fixed the problems?

One has to wonder just how bad the “significant deficiencies” that the FDA found in Actavis’ quality control unit when one considers what the defect was: Some Digitek tablets were twice as thick as they should be.  What kind of quality control program can’t spot pills coming out twice as thick as they should?  The FDA found that the quality control department was ignoring some defects.  Surely they couldn’t have been so incompetent as to ignore a double-thick tablet, could they?

Actavis Recalls “All” Drugs Made at Little Falls

On August 2nd of 2008, Actavis issued a recall of “all drug products manufactured at its Little Falls, New Jersey facility.”  There are two interesting facts about this recall.  First, it was triggered after an FDA inspection that presumably didn’t go well.  Second, the recall notice states that it applies to “all” drugs made at the Little Falls factory, and enumerates them.  One drug is missing from that list: Digitek.  Did Actavis cease manufacturing Digitek?  Did it move production to a safer factory?  Or is Digitek still being produced and distributed at Little Falls?

Four days after the recall, Actavis’ CEO stepped down for purportedly unrelated reasons.

How Could This Have Been Prevented?

It’s too early to put attribute a death toll to the defective Digitek, but I’m aware of several individuals who were taking Digitek pills subject to the recall and died from Digitalis Toxicity.   Countless others have likely been hospitalized and suffered other injuries because of Actavis’ incompetence and a weak FDA.

The warning letters the FDA sounded harsh but amounted to not much more than a dog with a big bark and a little bite.  Where are the multimillion dollar fines?  Where are the criminal prosecutions?  How many strikes does a pharmaceutical get before they’re out?

Thankfully, preemption won’t prevent injured individuals from suing Actavis because their injuries were caused by manufacturing defects, and not design defects.  But the Digitek recall shows us that the FDA either cannot or will not keep us safe from pharmaceuticals who place profits above all else.

The crux of the argument that FDA approval of a drug should preempt state lawsuits over that drug is that it should be experts at the FDA who decide whether a drug is safe and what warnings that drug’s label should carry.  Implicit in this argument are the assumptions that the FDA has access to the information it needs to make expert decisions and that it will make its decisions quickly when lives are at risk.  The Trasylol story proves these assumptions to be false.

Aprotinin is a naturally-occurring enzyme produced by cows.  It was first discovered in the 1930’s, and brought to market under the name Trasylol by Bayer in 1959.  Trasylol increases the rate at which blood clots, and Bayer sought FDA approval to use the drug during Coronary Artery Bypass Graft (CABG, pronounced cabbage) surgery to reduce blood loss and minimize the need for blood transfusion.

The FDA mistakenly approved the usage of Trasylol in 1993, and it rescinded that approval in 2007 after mounting evidence showed the drug was causing patients to suffer from renal failure, have strokes and heart attacks, and even die within thirty days of using the drug.  The total number of lives lost to Trasylol will never be known, but at least one researcher has pegged the death toll at 1,000 lives per month during 2006/2007.

Bayer Ignored Evidence That Trasylol Caused Renal Failure

Trasylol had been available in Germany (Bayer is a German company) since 1959, and a number of prominent German researchers began to suspect that Trasylol caused kidney problems as early as the 1970’s.  One such researcher was Dr. Juergen Fischer, the Director of the Institute for Experimental Medicine at the University of Cologne.  In the early 1980’s, he went to Bayer with evidence of Trasylol’s kidney toxicity.  60 Minutes interviewed him about his experience with Bayer and he stated that “I felt that Bayer wasn’t interested to examine these side effects” of Trasylol.  This is actually an understatement.

It appears that Bayer actually tried to hide information about those side effects.  In 1984, Bayer held a symposium in Luxembourg entitled “New aspects of the TRASYLOL therapy.”  Dr. Fischer attended and presented his findings.  Here’s what Dr. Fischer had to say about the symposium:

What were the reactions to your talk?

[Dr. Fischer] It turned out that this would remain the only critical contribution. Within the session attended by all participants great interest was shown in my presentation, so I believed to have given good reasons for clinical studies to be initiated. Later I spoke on different occasions to colleagues working at clinics, but the further development is well known: German clinics predominantly issued publications in favour of TRASYLOL, sometimes with a small remark that nothing significant was found concerning the kidneys. And in the publication of all the lectures of the symposium almost every evaluation and warning of my lecture had been deleted. (Emphasis added.)

In spite of this, the publication includes your conclusion “when using high dosages of Aprotinin with already damaged kidneys and particularly when reducing the temperature, the renal function should be closely supervised”. Hence the dangers of TRASYLOL (active substance: Aprotinin) for the renal function was already known and published for a long time?

Contrary to the allegations of the BAYER company, at least since 1984 many German heart surgeons as well as those responsible for this drug were aware that studies on animals published by various authors from 1970 to 1984 had shown massive side effects of TRASYLOL upon kidneys. What could be a better proof than a conference book published by BAYER itself?

Source: Massive side effects of TRASYLOL known for a long time

To be fair, just because a drug causes kidney problems in lab rats doesn’t necessarily mean it will do so in humans.  But Bayer had every incentive not to study the problem further.  Evidence produced during a lawsuit against Bayer over the drug Baycol illustrates Bayer’s apparently longstanding philosophy regarding drug side effects: A note written by a Bayer official read, ”If the F.D.A. asks for bad news, we have to give, but if we don’t have it, then we can’t give it to them.”  Remember that it is the pharmaceuticals, and not the FDA that conducts studies to determine whether a drug is safe and effective.  How can we count on the FDA to make the right choice if pharmaceuticals can simply bury their heads in the sand to avoid learning about drug side effects?

The FDA Mistakenly Approves Trasylol

In 1993, the FDA clearly made the wrong decision when it approved Trasylol for use on patients undergoing CABG surgeries at “high risk” of blood loss.  To their credit, the FDA noted the drug carried a risk of kidney toxicity, but their decision that the benefits of Trasylol outweighed those risks was incorrect because there were already two other drugs on the market that were just as effective as Trasylol and that carried none of the side effects.  Perhaps even more importantly, those other drugs cost about 1/10th of what Trasylol cost.

Unfortunately for patients everywhere, Bayer hoped to turn their bovine drug into a cash cow, and pressured the FDA into approving the usage of Trasylol for all patients undergoing CABG surgery.  In 1998, the FDA did and Bayer began heavily marketing the expensive drug.  By 2005, the drug was used in 1/3rd of all CABG surgeries, and Bayer estimated the drug’s sales would hit $600 million by 2006.  2006 didn’t turn out quite as Bayer planned.

More Evidence of Renal Failure

In January of 2006, the highly-respected Dr. Dennis Mangano (M.D. and Ph.D. in Math/Physics) published the results of a 10-year, $45-million dollar study in the New England Journal of Medicine.  Dr. Mangano, like Dr. Fischer, found that Trasylol increased the risk of renal failure:

Given our findings, especially with regard to serious renalevents among patients undergoing either primary or complex surgery,and given the cost of aprotinin therapy, which is at least 10times that of aminocaproic or tranexamic acid, we estimate thatconsiderable global health care savings would accrue if aprotininwere replaced by either aminocaproic acid or tranexamic acid.Specifically, extrapolating international-use patterns, we estimatethat for renal complications alone, the replacement of aprotininwith aminocaproic acid would prevent renal failure requiringdialysis in 11,050 patients per year, yielding an indirect savings(from the saved cost of dialysis) of more than $1 billion peryear, in addition to direct savings (from reduced drug costs)of nearly $250 million per year. Replacement of aprotinin withtranexamic acid would prevent 9790 complications necessitatingdialysis each year, yielding similar direct and indirect savings. [Considering that the majority of patients who undergo CABG surgery are eligible for Medicare or Medicaid, that means the taxpayers paid the majority of this $1.25 billion dollar expense. – JCL] 


In conclusion, the observed association between aprotinin andserious end-organ damage indicates that continued use is notprudent, whereas the less expensive generic medications aminocaproicacid and tranexamic acid are safe alternatives.

Source: NEJM — The Risk Associated with Aprotinin in Cardiac Surgery

What did the FDA do when confronted with this data?  It moved at its typical glacial pace.  Eight months after receiving it, the FDA convened a meeting to discuss Dr. Mangano’s study and to allow Bayer to respond.  Here’s what Dr. Mangano had to say about the meeting:

“The whole thing was a set-up,” he said. “We did not have anything to gain financially by this. We were making an observation about safety.”

Mangano noted that the chairman of the panel, Dr. William R. Hiatt, has written papers underwritten by Bayer, and that three committee members received waivers to vote because of financial interests in drug companies.

“The system is ridiculous,” he said. “It’s all pro-industry. Who’s protecting the patient?” [The court system… until preemption eliminates an injured patient’s right to sue. – JCL]

Source:  Worldandnation: Drug warnings fall flat

Predictably, the FDA caved into Bayer once again, and the committee voted 18-0 to approve the continued use of Trasylol, but only for “high risk” patients.  In other words, the FDA admitted its 1998 decision to approve the drug Trasylol for all patients was a mistake.  And who paid for that mistake?  The thousands of people who died or suffered health problems because of Trasylol, and the taxpayers whose tax dollars paid for Trasylol and Trasylol-related medical expenses.

While the FDA panel voted to restrict the usage of Trasylol to “high risk” patients, it might have voted to withdraw the drug entirely if Bayer hadn’t suppressed important information from the panel.  Bayer had commissioned its own study of the effects of Trasylol, and the results of the study it paid for were the same as Dr. Mangano’s: The study found that Trasylol was causing renal failure and killing patients.  But rather than disclose the existence of the study to the FDA, all of the Bayer representatives kept quiet.  Unfortunately for Bayer, the FDA learned about the study:

Days after the advisory meeting, the FDA was contacted by a researcher who said Bayer had hidden important evidence from regulators.


When contacted by the FDA, Bayer said it had “mistakenly” neglected to mention the giant study. The company said the data was “preliminary in nature and raised significant questions on the study population, outcomes and methodology.”

That response sounds hollow to several advisory committee members still stung by Bayer’s behavior. Dr. Michael Lincoff, vice chairman of cardiovascular research at Cleveland Clinic in Ohio, said that several panelists had commented during the meeting on the need for more data.

“At no point did the Bayer folks say, ‘It’s on its way,'” he said.

Steve Findlay, a panel member and health care analyst with Consumers Union, said Bayer’s actions were “intentional and very disingenuous.”

Source: Worldandnation: Drug warnings fall flat

Committee members were understandably upset at Bayer’s deception, but corporate apologist and preemption-promoter Ted Frank downplayed Bayer’s failure to disclose the existence of the study:

But 60 Minutes reports that Dr. Alexander Walker “bl[e]w the whistle,” when in fact, Bayer self-reported the existence of the i3 study on September 27—only six days late.

Source: PointofLaw.com | PointOfLaw Forum: Trasylol: what 60 Minutes didn’t tell you

Alanis Morissette might compare Bayer’s “six-day-late” disclosure to a “death row pardon, two minutes too late.”

Bayer’s late disclosure was not ironic.  It was another instance of a pharmaceutical company withholding data from the FDA in order to keep a profitable drug on the market.  If the FDA had the same subpoena power that trial lawyers have (and that preemption will take away from them) the FDA would likely have known about this study in time for the September 2006 meeting.  Instead, it would be an entire year before the FDA would meet again to discuss Bayer’s study.

Trasylol is Killing Patients

Just four months after the September 2006 meeting, the Journal of the American Medical Association (JAMA) published another study by Dr. Mangano, this time about the long-term risks of using Trasylol.  Analyzing his previous data again, Dr. Mangano now found that Trasylol was literally killing patients:

We estimate that over the past year, aprotinin was prescribedworldwide to at least 200 000 cardiac surgery patientshaving a profile similar to patients in our study. For suchpatients, our study found a 5% absolute increase in 5-year mortality(1% per year for 5 years) associated with aprotinin use, comparedwith either aminocaproic or tranexamic acid use. Thus, in 2006alone, had aprotinin been replaced with either of these genericagents, we estimate that approximately 2000 deaths per yearfor the next 5 years (or 10 000 total deaths) might havebeen avoided.


The association between aprotinin and long-term mortality indicatesthat serious safety concerns extend beyond the perioperativeperiod. Therefore, continued use of aprotinin in this populationdoes not appear prudent, given that safer alternatives—aminocaproicacid and tranexamic acid—are available.

Source: JAMA — Mortality Associated With Aprotinin During 5 Years Following Coronary Artery Bypass Graft Surgery, February 7, 2007, Mangano et al. 297 (5): 471

The two alternative drugs mentioned cost about ten times less than Trasylol, by the way; about $150 dollars vs. about $1,500 dollars.

The FDA: Hurry Up and Wait

Let’s put this in perspective.  The FDA is tasked with protecting the public from dangerous drugs.  A week after reviewing a study from a highly respected researcher that showed Trasylol was causing renal failure, the FDA learned that the drug’s own manufacturer had concealed a study with similar results.  Four months later another prestigious medical journal concludes Trasylol is killing patients.  Instead of immediately convening an emergency meeting to determine once and for all whether Trasylol should stay on the market, it waited another eight months to meet.  When thousands of lives are at stake, it’s simply unacceptable for the FDA to wait eight months before acting.  Dr. Mangano would later state that the FDA’s delay in acting was responsible for the deaths of 1,000 patients per month.

By the time the FDA met in September of 2007, there was a mountain of evidence that the risks of Trasylol outweighed the benefits of the drug.  There were Dr. Fischer’s studies from the 1980’s, there were of course Dr. Mangano’s two studies, and Bayer’s own study – all of which showed drastic increases in mortality and renal failure associated with the use of Trasylol.  Faced with all of this evidence, the FDA nevertheless voted 16-1 to ke
ep Trasylol on the market.  How did it justify that decision?  By criticizing the methodology of the various studies.

The studies were what is known as observational studies in which researchers examine medical records of thousands of patients and draw conclusions.  For example, if one conducted an observational study of victims of people who ingested cyanide, one would likely conclude cyanide to be dangerous.  The FDA prefers to make decisions based on clinical studies.  To continue the analogy, a similar clinical study would give some patients cyanide and others a placebo.  There is no question that clinical studies are less subject to bias, but shouldn’t the FDA err on the side of caution when faced with this type of evidence?

Americans Are Safe Because of Canada

The very next month after the FDA’s decision that Trasylol was safe, a clinical study of Trasylol was halted in Canada because of patient safety.  The study was conducted in order to compare the effectiveness of drugs in the same class as Trasylol.  The researchers conducting the study were ethically obligated to end the study when they discovered that patients using Trasylol died 50% more often than those on competing drugs.  As a result of the Canadian study, the FDA finally – finally – corrected its 1993 error and revoked its approval of Trasylol.  Put another way, if it weren’t for the Canadian study, thousands more patients might have died because of an FDA error.

Even when it has all of the necessary information, the FDA may still make an error that results in the loss of lives and taxpayer dollars.  When that happens – especially if a pharmaceutical hid or misrepresented data – it’s important for injured patients to be able to seek appropriate compensation from the pharmaceutical that made the drug.  Preemption will force innocent patients to bear all the costs – human and financial – of FDA mistakes and pharmaceutical deceit.   Unless and until the entire FDA pre and post drug approval process is reformed to put patients first, preemption is bad public policy.