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DBL%20Hendrix%20small.png College chemistry, 1983

Derek Lowe The 2002 Model

Dbl%20new%20portrait%20B%26W.png After 10 years of blogging. . .

Derek Lowe, an Arkansan by birth, got his BA from Hendrix College and his PhD in organic chemistry from Duke before spending time in Germany on a Humboldt Fellowship on his post-doc. He's worked for several major pharmaceutical companies since 1989 on drug discovery projects against schizophrenia, Alzheimer's, diabetes, osteoporosis and other diseases. To contact Derek email him directly: derekb.lowe@gmail.com Twitter: Dereklowe

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June 24, 2011

Generic Drug Warning Labels: The Supreme Court Speaks

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Posted by Derek

There are plenty of headlines about the recent Supreme Court decision (PDF) on suing generic drug manufacturers. But this is not so much about generic drugs, or suing people, as it is about the boundaries between state and federal law. That, actually, is why the case made this far - that's just the sort of issue the Supreme Court is supposed to untangle. Readers may decide for themselves whether such distentangling has actually occurred.

Reglan (metoclopramide) is the drug involved here. It's been generic for many years, and for many years it's also been known to be associated with a severe CNS side effect, tardive dyskinesia. This is the same involuntary-movement condition brought on by many earlier antipsychotic medications, and it's bad news indeed. The labeling for the product has been revised several times by the FDA over the years.

In this case, the plaintiffs were prescribed metoclopramide in 2001 and 2002, and their claim was that the generic manufacturers are at fault under state tort law (in these cases, Minnesota and Louisiana). It should be noted at this point that the package insert for the drug warned at the time that tardive dyskinesia could develop, and that treatment for more than 12 weeks had not been evaluated. In 2004 and 2009, the labe was strengthened to warn that treatment beyond twelve weeks should only be undertaken in rare cases. The plaintiffs both took metoclopramide for years, although this was not at issue in this case as it was brought.

What's at issue is the drug label and how it's regulated. The plaintiffs claimed that state law required a stronger safety warning than did federal law at the time, and that they thus have standing to sue. On the other hand, you have the whole process of generic drug approval. A generic company has to show that its product is equivalent to the original drug, and it then uses the exact same label information. Under federal law, the generic companies claim, they have no authority to independently change the labeling of their products.

The plaintiffs (and their lawyers) countered this argument by claiming that there were still mechanisms ( the CBE (changes-being-effected) process and "Dear Doctor" letters) by which the manufacturers could have changed the safety warnings on their own. The FDA, however, disputes that, and the Supreme Court deferred to the agency, saying that this is not an obviously mistaken position and there is no reason to doubt that it represents the FDA's best judgment in the matter.

That disposed of, the question comes back to federal law versus state. And in direct conflicts of that sort, state law has to yield, according to Justice Thomas for the majority:

The Court finds impossibility here. If the Manufacturers had independently changed their labels to satisfy their state-law duty to attach a safer label to their generic metoclopramide, they would have violated the federal requirement that generic drug labels be the same as the corresponding brand-name drug labels. Thus, it was impossible for them to comply with both state and federal law. And even if they had fulfilled their federal duty to ask for FDA help in strengthening the corresponding brand-name label, assuming such a duty exists, they would not have satisfied their state tort-law duty. State law demanded a safer label; it did not require communication with the FDA about the possibility of a safer label.

And that last sentence is where Justice Sotomayor's dissent breaks in. The minority holds that the generic manufacturers only showed that they might have been unable to comply with both federal and state requirements, and that this isn't enough for an impossibility defense. Sotomayor's dissent agrees, though, that the FDA does not allow the generic companies to unilaterally change their labels. But she says that this does not mean that they just have to sit there. Instead of just making sure that their labels match the brand-name labeling, she says, they likely have a responsibility to ask the FDA to consider label changes when necessary, and this wasn't done in this case. And even if you take the position that they don't have to do so, they still can do so, making the impossibility defense invalid.

This is explicitly addressed in the majority opinion - saying, in so many words, that this is a fair argument, but that they reject it. On what grounds? That it would actually

". . .render conflict pre-emption largely meaningless because it would make most conflicts between state and federal law illusory. We can often imagine that a third party or the Federal Government might do something that makes it lawful for a private party to accomplish under federal law what state law requires of it. In these cases, it is certainly possible that, had the Manufacturers asked the FDA for help, they might have eventually been able to strengthen their warn­ing label. Of course, it is also possible that the Manufac­turers could have convinced the FDA to reinterpret its regulations in a manner that would have opened the CBE process to them. Following Mensing and Demahy’s argu­ment to its logical conclusion, it is also possible that, by asking, the Manufacturers could have persuaded the FDA to rewrite its generic drug regulations entirely or talked Congress into amending the Hatch-Waxman Amendments."

The "supremacy clause" in the Constitution, the majority says, clearly treats pre-emption conflicts as real problems, and therefore any line of argument that just makes them go away is therefore invalid. At about this point in the majority opinion, Justice Kennedy bails out, though. Thomas and the remaining three justices have a point to make about non obstante provisions that he does not join in - and since this is not exactly a legal blog, nor am I a lawyer (although that's easier for me to forget on morning like this one), I'm going to bypass this part of the dispute).

For those of you who are still with me, there's one more feature of interest in this case. Metoclopramide has already been the subject of an important lawsuit - in this case, going back to Wyeth, the original brand manufacturer. That's Conte v. Wyeth, which I wrote about here. The dispute in that case was not about labeling, it was over who was liable for the tardive dyskinesia in the first place. A court in California held that the originator of the drug was on the hook for that, no matter how long the compound had been generic, and the California Supreme Court refused to hear an appeal. That issue is not yet laid to rest, though, and we'll be hearing about it again.

Given these cases, though, let's say that someone takes metoclopramide and is affected by tardive dyskinesia. Who can they sue? Well, the way the labeling is now, if you take it for more than a few weeks, you're doing so at your own risk, and in the face of explicit warnings not to do so. If your physician told you to do so, you could presumably sue for malpractice.

And what about the whole labeling dispute? Well, the language of the majority decision, it seems to me, is basically a message to the FDA and the legislative branch. If you don't like this decision, it says, if it doesn't seem to make any sense, well, you have the power to do something about it. We've shown you what the law says now, and you know where to start working on it if you want it to say something else.

One more point: on the train in to work this morning, I heard the argument advanced that because of these cases, once a drug goes generic, that brand-name manufacturers will probably want to consider just exiting the market in the case of drugs that have significant warnings in their labels. That will put the whole pharmacovigilence burden on the generic companies - which they won't like, but someone's going to have to soak it up. We'll see if that happens. . .

Comments (14) + TrackBacks (0) | Category: Regulatory Affairs | Toxicology


COMMENTS

1. Lacerta Bio on June 24, 2011 8:47 AM writes...

"I heard the argument advanced that because of these cases, once a drug goes generic, that brand-name manufacturers will probably want to consider just exiting the market in the case of drugs that have significant warnings in their labels."

That's an interesting hypothesis, given that there are a lot of companies (existing and in-formation) that are looking to acquire branded products that pharma is not promoting. The idea here is that some marketing muscle will revitalize these dormant brands and increase sales for a few years. Some of these companies are also taking the extra step of creating generic subsidiaries to simultaneously sell the authorized generic. Will this "warnings" issue kill some of these opportunities? We'll see...

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2. emjeff on June 24, 2011 9:28 AM writes...

"One more point: on the train in to work this morning, I heard the argument advanced that because of these cases, once a drug goes generic, that brand-name manufacturers will probably want to consider just exiting the market in the case of drugs that have significant warnings in their labels. That will put the whole pharmacovigilence burden on the generic companies - which they won't like, but someone's going to have to soak it up. We'll see if that happens. . ."

Derek, it is already happening. Many companies are stopping the manufacture of their products once generic competition is a reality.

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3. CMCguy on June 24, 2011 10:39 AM writes...

This does appear to make situation more convoluted and to grant Generic firms Preemption that SCOTUS denied to Pharma regarding Drug Labeling requirements vs. rights to sue in States (by a flawed case/reasoning IMO). You may be correct that this is a challenge to FDA/Congress that says that according to what's in place now that the conclusion so if wish to fix then do so (my guess is Generic Lobby currently has power to thwart efforts and/or Congress/FDA won't make a priority).

I doubt this decision has any impact on brand name manufacturers dropping drugs because it's about money and image for most companies. Most brand-names can't compete with Generics because Pharma's are too stubborn to reduce their Patented product prices (often exorbitant) even when they could to match generic competition.

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4. luysii on June 24, 2011 10:58 AM writes...

Certainly CNS drug side effects aren't widely known. Even in retirement I've been a hero more than once just by stopping drugs. Two examples.

My aunt had dyskinesia on reglan which was getting progressively worse. She'd been on it a few months, and the dyskinesia left when the metoclopramide was stopped.

A friend's 84 year old mother had been semicomatose for months in a nursing home. She did have a chronic neurodegenerative disease (frontotemporal dementia), but she was on Seroquel, an extremely strong drug for someone that age. The dose was tapered slowly (it had to be as she'd been on the damn so long) and the patient woke up and was able to talk to her daughter in her remaining time. I basically gave my friend her mother back.

I never got satisfaction like that from chemistry, even though it so much cleaner intellectually than medicine.

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5. stevedoc22 on June 24, 2011 11:10 AM writes...

I have a question. Where is the PHYSICIAN in all this? As a physician, you must know about this side effect. Who was renewing these Rxs week after week? Besidies being in the label, this side effect of metaclopramide is taught in every medical school.

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6. luysii on June 24, 2011 1:01 PM writes...

#7: Good question. You get what you pay for, and society isn't paying physicians much to think, paying much more to do procedures. I don't think Medicare pays very much for nursing home visits, and here the emphasis is on throughput. It's only going to get worse.

It's already bad. I had to use pull to get my wife and into the practice of an excellent internist (we're both on Medicare -- there is essentially no alternative medical insurance for someone over 65), despite being a retired MD. I can only imagine what's going to happen to the average patient.

Google the 'doc fix' which supposedly will balance the budget.

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7. Dylan on June 24, 2011 1:15 PM writes...

"on the train in to work this morning, I heard the argument advanced..."

Different worlds I guess...on my morning train ride people tend to discuss whatever was up with the Situation last night...

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8. SteveSC on June 24, 2011 1:15 PM writes...

There is no alternative medical insurance for someone over 65 because the government essentially prohibits it. If you want to bail on Medicare you have to give up your Social Security at the same time.

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9. DCRogers on June 24, 2011 1:28 PM writes...

#10: "There is no alternative medical insurance for someone over 65 because the government essentially prohibits it."

Perhaps, but I can't imagine it any better than trying to get health insurance under 65. I'm 53 and without work-sponsored health care, and because of minor "pre-existing conditions" [glaucoma, well-managed by drugs] found all insurance companies unwilling to offer insurance -- any insurance, at any price.

I can't imagine this market failure being anything but worse for seniors if they were forced to fend in the private market.

On-topic: several readers hit the key issue -- how long will Generic companies keep their free ride on pharmacovigilence?

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10. Anonymous on June 24, 2011 1:50 PM writes...

"Where is the physician in all of this?" On the golf course?

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11. Fred on June 24, 2011 10:34 PM writes...

@9: Before ObamaCare, U.S. federal law required that every state offer medical insurance to people who were denied private insurance as a result of a pre-existing condition. Most states had subsidized high risk pools, the others had an insurer of last resort.

So, people under 65 were guaranteed the ability to purchase a health insurance policy. Though the supposed lack of insurance for people with pre-existing conditions was a major talking point prior to the passage of ObamaCare, it simply was not true.

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12. John Thacker on June 25, 2011 8:16 AM writes...

"Google the 'doc fix' which supposedly will balance the budget."

Actually, the "doc fix" is generally used to refer to something that makes the budget much worse, the suspension of the "Sustainable Growth Rate" that was supposed to limit Medicare spending. Supposedly letting the "doc fix" go away would help balance the budget, by slashing Medicare spending.

"You get what you pay for, and society isn't paying physicians much to think, paying much more to do procedures"

Well, society pays physicians to write the prescriptions. The problem is that since physicians are required to write the prescriptions, people will shop around in order to find someone to write the prescription. Oftentimes it's the same sort of people who buy dubious supplements on their own, but at least that kind of self-medication doesn't waste the doctor's time, the insurance company's money, and the government's money. (And the last two eventually means my money.)

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13. cliffintokyo on June 28, 2011 5:00 AM writes...

Regulatory people don't have time to chew the fat with FDA about what we MIGHT do to tweak the labeling of a product for which we should be able to assume the originators are the experts.
We are too busy with what we MUST do to keep the Reg Agencies happy. FDA is correct to protect the generic ind in this instance.

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14. Dan Spinato on July 1, 2011 1:10 AM writes...

I honestly think generic drugs are just as good as the expensive ones. Since it is made for those who aren't as well off and couldn't afford the meds they originally need, cheap doesn't necessarily mean it doesn't work just as well. But I have to admit we have to be aware of some generic drugs that might be bad for your health.

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