Transcript

505:

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Transcript

Originally aired 09.20.2013

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Full audio: http://tal.fm/505

Prologue.

Ira Glass

Sarah Erush was a pharmacist and head of the Drug Information Center at the Hospital at the University of Pennsylvania. And in that job, she had to do one of those tasks that you never heard of, but then when you hear that this job exists, you think, oh right, of course. Somebody's got to do that. Namely, when patients had a bad reaction, a surprising reaction, to the drugs that they were on, Sarah Erush was the person who was supposed to make sure that the Food and Drug Administration was notified about it. The FDA keeps track of these things, drug injuries. It's part of monitoring whether drugs are safe.

And so one day in 2002, she got this unusual call from somebody at the FDA about one of the most popular drugs in the country-- acetaminophen. Acetaminophen is the active ingredient in Tylenol. And every now and then, Erush had sent in a report about some patient reacting to acetaminophen.

Sarah Erush

And they said, we were looking at your reports on acetaminophen, and we were wondering if you had ever really sat and collated this data. And we said, no, not really. We've been reporting it all along, and we look at it when we report it. But we never really looked at it in aggregate.

Ira Glass

"In aggregate"-- they never looked at all the cases together as a group.

Sarah Erush

And they said, well, we have been looking at it in aggregate, and we think it's really interesting. And we think you might want to do that. And we thought that was kind of an odd request.

And so I said, well, why would we do that? What are you seeing? And they said, well, we don't really want to tell you that. We want to see if you think it's compelling as well.

So they sort of opened the door and said, you should go look, but they didn't tell us what to look for. Which was a really good scientific method, because they didn't tell us what we should go find, which would have biased us towards the data. They just said, you should go look. It's interesting.

Ira Glass

Sarah got off the phone and told her office-mate, the FDA wants us to look at our acetaminophen cases. And her co-worker was all, why? They had no idea.

Sarah Erush

Not a clue. We really didn't. Till we started looking at it, and then this little light bulb kind of went on in the back of our heads, where we said, hey, we do remember that one odd case.

Oh, we do remember that other odd case. Oh, we do remember that third odd case. And then it started to occur to us, we have a lot of odd cases.

Ira Glass

Sarah Erush found 23 people in four years at just one hospital who said they took just a little extra, just a few more pills than recommended for a few more days, and severely damaged their livers. Three of them died. Two had transplants.

Now most of these 23 were either chronic heavy drinkers or had a lot of alcohol around the time they were taking the pills, which makes acetaminophen more dangerous. But it wasn't every case. Some didn't report any drinking. And what surprised Sarah Erush most of all was the amounts-- just how easy it was to take too much acetaminophen.

Sarah Erush

It used to be touted as the safest pain reliever you can buy. I mean, that was the big push on selling Tylenol. It's the safest pain reliever you can buy.

And in fact, when we would interview the patients and say, you know, the label says how much to take. Why did you take more than that? And the answers were always, because it always says it's the safest thing you could buy. I figure if two were OK, then I would take three.

When we would say, you know, you realize you're here because here you have a high acetaminophen level and that's affected your liver, And they would be aghast. They would say, from Tylenol? This is from Tylenol? How could it be from Tylenol? I thought that was harmless, or it was so safe, it couldn't possibly happen.

I didn't take that much. That would be the first thing they would all say. I didn't take that much. And when you'd ask how much, it was more than the recommended dose, but they really didn't take that much more.

Ira Glass

Erush says she's also surprised how many doctors she meets who don't know this kind of reaction can happen if a patient takes just a little bit too much acetaminophen.

Sarah Erush

I am stunned and amazed, still, how physicians will almost routinely throw in Tylenol when they're treating pain. Well, here, why don't you take this on top of everything else, because it's only Tylenol. It's fine. It's safe.

My own mother, she had bone pain from cancer, and they had her on lots of big painkillers. And they said, oh, and we're going to give her 4 grams of Tylenol a day, too. And I said, why? And they said, oh, it's good for bone pain.

I said, no, it's not. [LAUGHS] A, it's not, and B, I don't want my mother taking 4 grams of Tylenol a day for no good reason whatsoever. She's also on morphine, and I think that'll probably do it.

Ira Glass

Over the last nine months, our radio show has worked alongside the investigative reporting organization ProPublica-- who's been at this even longer-- looking into acetaminophen and Tylenol, interviewing dozens of doctors and scientists. ProPublica went through hundreds of documents. And what we've concluded is that while Tylenol has built its reputation on the idea that it is safer than other over-the-counter painkillers, it is less safe than many of us believe.

Now I want to be very clear about what I'm saying here. Taken as recommended, Tylenol-- or any drug containing the active ingredient in Tylenol, acetaminophen-- is considered safe by most doctors and experts. The problems that we're talking about with the drug probably affect much less than 1% of all the people taking acetaminophen and Tylenol. After all, one out of six Americans take acetaminophen in any given week-- 50 million people, according to Tylenol's manufacturer.

And as a pharmacist, Sarah Erush says, sure, we should keep it on the market. No question. It's the best medicine out there for lots of situations. Mild chronic pain, like for geriatric patients, two Tylenol a day.

Sarah Erush

They can take that for a lot longer than they might be able to take two Motrin or Advil a day because of the risk of GI ulceration.

Ira Glass

In a pediatric hospital, she says, it's the best thing to give a kid for fever. Won't upset a stomach. It won't interact with other drugs. It doesn't put them at risk for Reye syndrome, the way that aspirin would.

But all that said, it is very easy overdose on acetaminophen. Over 150 people in the United States die on average every year from accidentally taking too much of the drug. 150 people. That data comes from the federal government, from the Centers for Disease Control and Prevention. Federal government data also shows that every year, 78,000 people land in the emergency room and over 33,000 people are hospitalized either from intentional or unintentional overdoses of the drug.

Will Lee is one of the liver specialists and researchers who's been calling attention to the dangers of acetaminophen. He is at the University of Texas Southwestern Medical Center and talked to reporter Sean Cole.

Will Lee

In one of the articles, we actually printed up the little coupon that I got with my Zocor prescription that says, $2 off on your next acetaminophen bottle. And one of the things on the coupon, it says safest. Not safer, or not safe, but safest. Well, this is the number-one drug killing Americans every year.

Sean Cole

Over-the-counter drug killing Americans.

Will Lee

Over-the-counter drug.

Sean Cole

Not the safest.

Will Lee

Not the safest, for sure. So I guess that's-- if you think I have a bee in my bonnet, that's probably where it came from.

Ira Glass

That assessment, that acetaminophen kills more Americans than any other over-the-counter pain reliever, comes from two big databases, the Centers for Disease Control and Prevention-- that's part of the federal government-- and the American Association of Poison Control Centers. The company that makes Tylenol, McNeil Consumer Healthcare, does not agree with that assessment. A spokesperson said in an email that in their view, we here at This American Life cannot responsibly say on the radio that acetaminophen kills more people, because those two databases, quote, "simply do not contain the information needed," end quote.

And in fact, it's true that epidemiologists have pointed out that those databases might not accurately count all of the people who die as a result of taking other over-the-counter pain relievers. But that is a theoretical possibility, that lots of people may be dying from those other over-the-counter painkillers. There aren't studies-- or anyway, we couldn't find any-- which locate real people who died this way and find more of them dying from over-the-counter aspirin or ibuprofen or any of the others than die from acetaminophen. We asked McNeil for studies like that, and they did not send any.

Just last month, McNeil, the maker of Tylenol, and its parent company Johnson & Johnson, announced that they're putting a new warning onto the caps of Extra Strength Tylenol saying, in bright red letters, "Contains acetaminophen," and "Always read the label." The new warning does not go so far as to say that a relatively small overdose can kill you.

Most people already know that acetaminophen can be dangerous. According to a national poll commissioned by ProPublica and our radio program, 86% of Americans know that Tylenol can cause severe liver damage, and 2/3 of the public knows that it can kill you. But I think that many people do not know just how little extra it takes to be dangerous or to kill you. Certainly, I have say none of us who worked on this story, here at our radio show, knew this before.

And why not? Well, today we explain how we got to this point, how one of the most widely-used over-the-counter painkillers in the country, acetaminophen, also kills so many people. And many of us had no idea.

And so even though a lot of you already know that acetaminophen can be dangerous, we're going to spend an hour on this today. Because number one, over 150 people are dying every year. It seems completely unnecessary. And number two, the story of how this drug has been regulated by the Food and Drug Administration-- when we heard it, I have to say we were shocked at the government's behavior, and we think that you will be shocked.

And so from WBEZ Chicago, it's This American Life, distributed by Public Radio International. I'm Ira Glass. Our show today on all of these things. Stay with us. And I turn things over now to the reporter who's been looking into this for our radio show, Sean Cole.

Act One.

Sean Cole

So here's a little drug regulation lingo for you. I know that's why a lot of you tune into this show. That small margin of error between a safe dose and a potentially harmful dose of acetaminophen? That's what the FDA would call a narrow therapeutic index. And the other over-the-counter painkillers don't have it. I'll let T. Miller explain this part. He's one of the ProPublica reporters who spent a long time on this story.

T. Miller

So with a drug like ibuprofen, Advil, it can cause stomach and gastric problems at the recommended dose. Aspirin, same thing. But it takes a lot of ibuprofen to kill yourself. In fact, there's not a lot of cases on record of anybody dying from ibuprofen toxicity.

Sean Cole

In the only case he could find, it took 20 times the recommended dose to kill someone. Same with aspirin. You have to take six or eight times the maximum recommended dose for it to become toxic to your system. With acetaminophen, just twice the maximum safe dose, or even less, taken over several days could possibly get you into serious trouble.

Now I should be clear that there's no hard and fast number for this. Nobody knows for sure. One of the most prominent doctors researching right now is Will Lee, who you heard from earlier. His data shows if you take twice the maximum safe dose-- maximum safe dose printed on the bottle is 4 grams-- if you take twice that amount, you're in the danger zone.

McNeil, who makes Tylenol, said pretty much the same thing in an email, but later changed their estimate to at least 10 grams a day for at least two to three days. 10 grams a day is 2 and 1/2 times the maximum safe dose.

But the danger zone might start at a much smaller dose. The FDA has said that just 5 grams a day could hurt your liver. That's just one gram more than the safety limit listed on the bottle.

A gram. That would mean the difference between a safe dose and a dangerous dose is two Extra Strength Tylenol tablets. Just two tablets.

That number comes from the FDA's national database of adverse drug events. That is, cases of people who were injured by medicinal drugs. The agency cites it in a report prepared in 2008.

But now here's a caveat-- not everyone who takes a little more than they should will get into trouble. It seems that some people are more susceptible to liver damage from acetaminophen than others. Some people can take twice the safe dose, or even more than that amount, and be fine. This is all according to the FDA, and Will Lee and Sarah Erush told us this as well. But the science is still really preliminary.

And truthfully, this wouldn't be as much of a problem if it wasn't for you. And me, before I started working on this story. A lot of us just take too much of this stuff, thinking that if two pills work fine, three must work better.

We found five separate surveys, including one performed by McNeil, that show about a quarter of us take more than the recommended dose of over-the-counter drugs. That would mean because acetaminophen is taken by 50 million people every week, a quarter would be 12 million of us routinely taking more than the recommended dose.

I talked with Dr. Mel Wilcox about these surveys. He's a gastroenterologist and liver doctor at the University of Alabama at Birmingham. He and a couple of other researchers published a paper analyzing two of the surveys, 9,000 patients in all. And he says the numbers confirm what he sees in his practice all the time with over-the-counter painkillers.

Dr. Mel Wilcox

Just in talking to people, oftentimes people would take it two to four times higher dose than on the instructions.

Sean Cole

Two or four times?

Dr. Mel Wilcox

Yeah. Yes. So not insignificant.

Sean Cole

Remember, two to four times, with acetaminophen, could put you in the danger zone.

Dr. Mel Wilcox

Well, we saw one here probably, I don't know, six months ago or so. I happened to be covering on the weekend, and it was a young woman who came in with liver failure. I can't remember the exact reason for the Tylenol, but it was something related to pain-- back pain, headache, something-- and clearly taking more than the standard dose. And died.

Sean Cole

She died?

Dr. Mel Wilcox

Right.

Sean Cole

Do you know how much more she was taking than the--

Dr. Mel Wilcox

No, the family didn't really know, other than she was taking more. She was comatose, essentially, when I evaluated her.

Sean Cole

And you're sure it wasn't a suicide?

Dr. Mel Wilcox

Generally suicides on the medication is pretty obvious, and the family would tell you. It's the ones like this young lady, that really were taking it more for a pain issue, that are more troublesome.

Sean Cole

The connection between acetaminophen and liver damage-- this is not news. Case reports started showing up more than four decades ago. As long ago as 1975, the British medical publication The Lancet said, quote, "Liver damage has been observed after absorption of as little as 6.2 grams." 6 grams a day would be the equivalent of four extra strength Tylenol beyond the maximum safe dose on the bottle.

Those cases started appearing at the exact same time that acetaminophen was getting more and more popular. Tylenol went on the market in the 1950s, but it really started taking off in the '70s, largely based on the fact that it was better than the alternatives because it didn't upset your stomach or make it bleed, like aspirin can. Acetaminophen really did seem like the safest of all possible painkillers.

And then in the '80s, aspirin was linked to a rare but possibly fatal disease in children called Reye's syndrome, which gave Tylenol even more of a marketing edge. In fact, the fight over our pain medicine dollars got so heated and expensive that it came to be known as the Aspirin Wars.

Pat Malone

This Aspirin Wars thing was something I'd never even heard of, but it turned out that was something that the McNeil Consumer Products Company was obsessed by.

Sean Cole

Pat Malone is a lawyer in DC. He has represented plaintiffs in about a dozen lawsuits against McNeil, so he's had to bone up on a lot of this history.

Pat Malone

And they quickly developed their competitive advantage over aspirin, not based on working better for your headaches and your aches and pains, but just because supposedly, this stuff is safe. Because if you remember, back then, the television was just constantly bombarded with--

[TYLENOL ADVERTISEMENT PLAYS IN BACKGROUND]

Pat Malone

"Recommended the most by doctors," "Used most by hospitals."

Female Spokesperson

Tylenol.

Pat Malone

Tylenol.

Female Spokesperson

Look. Last year, hospitals dispensed 10 times as much Tylenol as the next four brands combined. Hospitals can trust Tylenol to give effective relief without the stomach irritation possible with aspirin or any other type of pain reliever.

Pat Malone

And it worked very well. And any time one of these reports would percolate up in the medical journals about somebody taking Tylenol for therapeutic purposes and winding up with their liver wiped out, that was a threat to McNeil's image.

Sean Cole

McNeil Consumer Healthcare declined, after many requests, to let us interview someone there. And when we emailed them this quote from Malone, the company wrote back and reminded us that Malone has represented people who've sued McNeil, and that he, quote, "Therefore represents a particular point of view." The company goes on. "The fact is that doctors still recommend Tylenol more than any other brand of pain reliever and do so based on their knowledge, training, and experience," end quote.

The federal government got involved with all of this in the 1970s, with the risks of acetaminophen. Back in 1977, a panel of scientists convened by the Food and Drug Administration said the potential harm from an overdose is so severe that it should have a much stronger warning label on the box.

Ninfa Redmond

And the warning should state, quote, "Do not exceed recommended dosage because severe liver damage may occur."

Sean Cole

Ninfa Redmond was one of the people who came up with that wording. She's a toxicologist, one of seven members on the panel. She says her group met every two months for three or four years, poring over reports and studies about 50 different ingredients in over-the-counter painkillers-- acetaminophen, but also aspirin, caffeine, which is in some drugs-- lots of things.

The result was a 1,200-page report with recommendations about each ingredient. But they didn't just recommend this warning label for acetaminophen. They added an extra special emphasis.

Ninfa Redmond

We used the word that it was terribly important, or-- I'm trying to think of the word that we used. Um-- mandatory-- obligatory is the word. And the only time in the whole report that I can remember that we used the word obligatory was in the warnings for acetaminophen. And I remember there was a total unanimity on this opinion.

Sean Cole

The panel was well aware of all the advertising about how safe acetaminophen was. In fact, in their recommendation, they say, quote, "Some advertising for acetaminophen gives the impression that it is much safer than aspirin and implies that the toxic effects of the drug are less than those encountered in aspirin." To be clear, the report said that at recommended doses, acetaminophen was, quote, "Relatively free of adverse effects." But Ninfa Redmond says she was troubled by the reports the panel was reading.

Ninfa Redmond

About suicidal intentions and overdose by accident. And they were just so numerous and so easy to have an overdose, for either one of two reasons. Either because the person has not calculated how many milligrams he should have taken, or takes much more because the headache persists.

Sean Cole

Of course, as we mentioned before, a lot of people disregard over-the-counter drug labels or just don't read them. But a lot of people do read them, and warning labels are still the FDA's main tool to deal with problems like this. But when it came to printing what was supposed to be obligatory language onto an actual box of acetaminophen, the process broke down.

The next action the FDA takes on issuing a warning isn't for 11 years. In 1988, the FDA declares that yes, a warning label is needed for acetaminophen products. And they did put one on acetaminophen products, but they didn't go as far as Ninfa Redmond and the panel said was necessary. Nothing about the liver at all.

And then another 14 years went by. 2002, the FDA convenes another advisory committee-- just for a couple days this time-- and that panel recommended, basically, the original warning again, the same one that Ninfa Redmond's group insisted upon 25 years earlier. And again, no action by the FDA. It took seven years-- so 2009, we're talking now-- for the agency to finally require that liver warning.

We asked Ninfa Redmond what could have taken the FDA 32 years to mandate her warning language. But she said her involvement with the process ended in 1977, when they submitted the report. In fact, Redmond didn't even know it took that long for the FDA to take action. She only found out when she got a call for this story.

Ninfa Redmond

It's very surprising, and it's sad.

Sean Cole

Sad? Why?

Ninfa Redmond

How many people may have died as a result of that. It's only a hypothetical question. It's a question to myself that has no answer.

Sean Cole

Have you been asking yourself that since finding out that it took that long?

Ninfa Redmond

Yes. Dr. Kennedy, the FDA commissioner at that time, on the 8th of July, said, it will take two years. It's in the press. It's either in The New York Times or The Washington Post, and that he hypothesized it. Let's double, let's triple that-- so six years would have been enough. Nothing that I can hypothesize will explain the 32 years.

Sean Cole

So why did it take that long? This American Life and ProPublica have been asking that question of pretty much everyone we can get our hands on for the last nine months, and no one has a simple explanation. But after all of the reporting that we've done, the main answer that has risen to the top is that acetaminophen was just one little drug ingredient competing for the attention of an enormous, inefficient bureaucracy.

Beginning in 1972, the FDA actually set up 17 panels of experts-- Ninfa Redmond's was just one of them-- to look at all of the over-the-counter drugs that went on the market before drug review laws tightened up. So these were all of the drugs the FDA had never formally approved as both safe and effective. There were two or three hundred thousand of them. But they all boiled down to just 731 ingredients.

Thomas Garvey

They would decide whether the drug was safe and effective and appropriate for over-the-counter use, and in what quantities, and at what frequency, and for what duration.

Sean Cole

This is Thomas Garvey. He's a doctor. These days, he consults with drug companies about their products, and he's testified on the side of people suing McNeil over acetaminophen poisoning.

But in the late '70s and very early '80s, he supervised drug reviewers at the FDA. And he says the process of getting to the final list of rules-- or a monograph, as it's called-- on a given drug at the FDA? He says it's byzantine.

Thomas Garvey

And then there was a tentative final monograph, and where comments were collected, and then a reappraisal, and a rebroadcast of the revised tentative, and on and on and on. And you know, people would send in voluminous responses, which had to be understood and addressed and responded to. And that took a lot of time. That was one reason for the delay.

Sean Cole

All this vetting and opining and drafting up rules and synthesizing comments and everything, that all was supposed to take five years. 10 years in, the job was still only 1/16 of the way done. Things were going so slowly that another government agency, the General Accounting Office, stepped in to do a review of the review to see what was taking such a, quote, "inordinate amount of time." And looking through it, there was a lot of dysfunction at the agency at the time.

"Priorities have little meaning," the review says. "The OTC division is not using its staff efficiently." Stuff like that. But in the end, the review of the review found that the FDA's strategy was reasonable. It was just a crazy huge job. The 2008 FDA report cited, quote, "limited financial resources and large workloads" as obstacles.

The FDA also refused, after multiple requests, to give us a recorded interview for this story. But ProPublica did an off-tape interview with Dr. Sandra Kweder, one of the FDA's experts on acetaminophen. And she acknowledged that the agency moved too slowly getting the final rules written for dosage and labeling and all that. The rules for acetaminophen are still only at the tentative stage.

The drug approval process is usually slow, but not usually this slow. The FDA began with acetaminophen over 40 years ago, in 1972. In that time, science has mapped the human genome, eradicated smallpox. We've cloned a sheep-- and yet we still have not come up with rules for safe usage and labeling of one of the most popular drugs in the country, of which more than 20 billion doses are sold each year. Former FDA official Tom Garvey.

Thomas Garvey

Now I must admit this one is remarkable for its duration of gestation. It's like a vastly overdue child. I mean, this is remarkable and unusual. There's no question about that.

Sean Cole

During the early years of this long process, the maker of Tylenol, McNeil, was understandably not so thrilled with the idea of a liver damage warning label. The brand finally had a significant piece of the painkiller market, and the company did surveys that showed the warning label would scare people away from the drug. Not only that, but when the 1,200-page report from Ninfa Redmond's group came out in 1977, it became a weapon in the Aspirin Wars.

Bayer Aspirin cited the report in a full-page magazine ad. It said, quote, "Leading medical experts have expressed great concern about the occurrence of liver damage with acetaminophen, the chemical name for the ingredient in all Tylenol products." And then it quotes the obligatory severe liver damage language.

And then-- big finish-- "Now, makers of Tylenol," it says, "let's look at your advertising again. Safer than aspirin? Just as effective? Shame on you." Losses, McNeil told the FDA, are already in the millions of dollars.

That was just one point McNeil made in a lengthy response it sent to the FDA about the report from Redmond's panel. Here's another-- McNeil said that the proposed warning label was unfair, that acetaminophen was being singled now, since aspirin can also hurt you. So if that kind of, "If you take too much, then this bad thing might happen" language is appropriate for acetaminophen, the company wrote, then it's appropriate for aspirin, too.

McNeil went as far as to suggest several hypothetical warning labels for its aspirin competitors. One of them read, quote, "Do not exceed recommended dosage because serious potentially life-threatening changes in body chemistry, respiratory failure, coma, convulsions, and cardiovascular collapse may occur," end quote. Again, Tom Garvey, who was at the FDA back then.

Thomas Garvey

It was kind of a, why are you doing this to us when you're not doing it to the others?

Sean Cole

And what did you make of it?

Thomas Garvey

I thought it was nonsense. That's not their job. Their job is not to make sure that the other drugs are labeled correctly. Their job is to make sure their drug is labeled correctly.

Sean Cole

And they weren't doing that. They were instead saying you should label the other guys too.

Thomas Garvey

Well, they were confusing issue.

Sean Cole

Intentionally, do you think? Or was it--

Thomas Garvey

Well, what do you think? Do you think?

Sean Cole

And I guess I keep trying to get at why.

Thomas Garvey

Well, I don't think we need to dig very deep about that, that the most transparent of motives can be adduced.

Sean Cole

And say what that is, if you could.

Thomas Garvey

Well, to do God's work. No, you nitwit! To make money.

Sean Cole

To make money.

Thomas Garvey

Well, I mean, isn't it the job of these firms to make money and to maximize profits for the shareholders? Isn't that what they're supposed to do?

Sean Cole

Here's McNeil's version of all of this. First, to Garvey's point, the company writes, quote, "Thomas Garvey has been a paid witness for individuals who have filed lawsuits against McNeil, and his statements do not accurately reflect our conversations with the regulatory agency regarding label changes. We are a company of caring people who believe deeply that our first responsibility is to the families and health care professionals who rely on our products. We stand behind the safety profile of acetaminophen when taken as directed, and over the years we have led the efforts to educate and warn consumers of the dangers of acetaminophen overdose," end quote.

But the way McNeil would tell the story of the last four decades of regulation is that the scientific research wasn't always so clear-cut. For instance, all of the studies that measure how many pills lead to liver failure-- well, when people overdose, they sometimes misremember how many pills they took. Or they lie. And for years, McNeil officials, and the scientists and doctors who testified on the company's behalf, argued that most if not all cases of acetaminophen overdose were suicides, people intentionally swallowing lots more of the drug than anybody would take for pain relief.

McNeil itself has funded studies of acetaminophen that back up its point of view. Again, McNeil declined to give us an interview on tape, and it objected to the tone of the written questions that ProPublica and the show submitted to them. In a letter back to us, it said our questions were, quote, "inflammatory, misleading, and unwarranted."

And along with the written responses to our questions, we received an eight-minute recording of a statement read by Ed Kuffner, the vice president of Over-the-Counter Medical Affairs and Clinical Research. He says as more data piled up, the company's position evolved in the way it should, according to the science.

Dr. Ed Kuffner

Opinions about medicine labels, they've changed over time, as have the labels. We believe that any label change should be medically accurate, and it should be based on research.

Sean Cole

And this is from slightly later in the tape.

Dr. Ed Kuffner

After careful consultation with the FDA, over the years, we've made changes to the labels of Tylenol in an effort to help consumers understand how to use the medicine safely. The FDA recognizes that labels will change over time and that a label change does not mean that a prior label was inadequate. In fact, label changes are an indication that our medical understanding is evolving and that the public health system really is working.

Sean Cole

But while McNeil says it always took new data into account as it emerged, here's how that looked in practice.

Male Speaker

OK, please take your seats. Please take your seats.

Sean Cole

This is the 2002 FDA advisory meeting where McNeil, to its credit, got in front of the warning label issue, after many years, and called on the FDA to mandate a specific liver damage warning for acetaminophen.

Dr. Debra Bowen

Today we are recommending an organ-specific overdose warning. These labeling and education--

Sean Cole

This was the company's VP of Research and Development at the time, Debra Bowen. This meeting was convened after more evidence started showing up of people accidentally overdosing on acetaminophen. There was a big 1997 paper by researcher Will Lee and the numbers from Sarah Erush, who you heard from earlier. In fact, this whole day was devoted to the problem of accidental overdoses. And even at this meeting, McNeil still held that most acetaminophen overdoses in adults were not accidental, but suicides.

Dr. Debra Bowen

Harm is rare and is caused by overdose. Serious harm caused by inadvertent misuse is very rare.

Sean Cole

Sarah Erush, the University of Pennsylvania pharmacist who got the call from the FDA, she was at this meeting presenting her findings, that half of the overdose cases she saw were accidental. And she says, yes, it's a drug company's job to defend its product, but she wishes McNeil had shown more interest in the data that she and some of the other scientists and doctors were there presenting.

Sarah Erush

So they really seemed to me to try to be bulldozing over what we were just-- we had a crack in the door open, and saying, hey, there's something over there. You should take a look at it. And they were just trying to keep that door shut as tight as they could. So I think that's all I got out of that meeting, was I thought, you're not even listening. You need to listen. There's some interesting stuff here.

I think that was the thing that bothered me the most, is it was still-- you must have it wrong, was their attitude, as opposed to, wow, this is really interesting. Can we take a closer look and see if we can figure this out together? I have partnered with the pharmaceutical industry in my past life to do research and things, and have encountered companies, or facets of companies, that are very much like that. So it was very offensive to me that they didn't want to take that tact.

Sean Cole

I ran this quote by McNeil officials. They pointed out that they did in fact reach out to Erush for more information when they learned of her findings, and she didn't give it to them. She told me she wanted to protect the patient's identities and didn't feel like the company needed to root around in their case files.

McNeil also said, quote, "We are constantly assessing information on overdoses and today use databases and web searches to seek out information and further improve our reporting systems." In other words, they say they're on top of this. They look for any problems related to their drug and actively try to reduce the number of overdoses.

Ira Glass

Sean Cole. Coming up, kids and babies and problems in acetaminophen labeling-- for me, I have to say the most disturbing part of this story, we haven't even gotten to yet. That's in a minute, from Chicago Public Radio and Public Radio International, when our program continues.

Act Two.

Ira Glass

It's This American Life. I'm Ira Glass. Today's program, "Use Only As Directed." Today's show reported alongside the investigative reporting team at ProPublica. And we're bringing you the story of one of the most popular drugs in the country, acetaminophen, the active ingredient in Tylenol. It also, according to federal data, causes more deaths than any other over-the-counter pain medication.

Each year, on average, over 150 people died of accidental overdose, 78,000 people land in the emergency room, 33,000 people are hospitalized-- again, this is all based on data from the federal government. McNeil Consumer Healthcare, the maker of Tylenol, as I said earlier in the show, disputes that its product is the deadliest over-the-counter pain medication.

And in the first half of the show, you heard about the FDA delaying action on labelling acetaminophen to a degree that was unusual, even for the FDA-- and, in fact, kind of mind-boggling. A panel recommended a warning about liver damage in 1977. It took 32 years for the agency to rule on that.

But you know, in a certain way, that pales compared to the confusion and delay surrounding infants' and children's acetaminophen. What's interesting about these products and this situation is that this is a situation where the maker of Tylenol, McNeil, did not oppose a new label on the packages. In fact, it was the opposite.

McNeil wanted the change. It actively urged the FDA to get clearer, better labeling on those products for years, saying that would make the product safer. And for years, the FDA did not fix the problem.

And McNeil didn't step in and fix the problem-- which, as you'll hear, it could have taken steps to do. And the problem lingered in a way that's kind of stunning. Again, here's reporter Sean Cole.

Sean Cole

Again, this all has to do with the nature of acetaminophen and how relatively easy it is to overdose. In this case, there's the added complicating factor of parents giving the drug to their kids. And these two formulas, Infants' Tylenol and Children's Tylenol, they're different. Infants' is actually for kids up to three years of age, and Children's is for kids up to 11 years of age. And this next part is going to sound really counter-intuitive, so I'll say it slowly.

For the longest time, Infants' Tylenol was three times stronger, three times more concentrated, than Children's Tylenol, the rationale being that it's harder to make a very young child, and especially a baby, swallow medicine. So if you make the medicine stronger, the parents will have an easier time of it. Makes sense on one level.

But if you ask toxicologist Barry Rumack, who's done research funded by McNeil and has testified as an expert witness on the company's behalf, there's a big problem, again with the labeling. Confusingly, he says, there aren't any dosing instructions for children under two on either product. All it says on the box is, "Ask a doctor." And for years, McNeil has been urging the FDA to change that. Here's Rumack.

Dr. Barry Rumack

I've been trying, and Tony Temple's been trying--

Sean Cole

Tony Temple is a former McNeil executive.

Dr. Barry Rumack

And everybody else has been trying since at least 1983 to get a dose on these labels that goes down preferably to two months of age.

Sean Cole

Because for one thing, if a baby's feverish and irritable at 3:00 in the morning, and there's no doctor around--

Dr. Barry Rumack

The mother or father want to give the Tylenol, and it says, under two years, ask a doctor. What are they going to do? They're going to guess at a dose. And they're going to say, you know, he's a little big for his age. You know, maybe I'll give him half of this.

Sean Cole

Half a dropperful.

Dr. Barry Rumack

Maybe I'll give him the whole thing.

Sean Cole

That's one scenario. Another is that parents might get the two different formulas mixed up, give their child the stronger medicine based on the instructions for the weaker medicine. It can happen.

Christina Hoyt

This is her when she was coming home.

Sean Cole

And it has.

Christina Hoyt

She's about three, four months there. She was a very, very big baby. Very big.

Sean Cole

Christina Hoyt had her first baby, Brianna, when she was 17 years old. Her then-husband Eric Hutto was 18. This was about 10 years ago, back in Louisiana, where they're from.

Christina lives near Denver now. Eric flew into town so we could talk to them both together. Both of them kept mentioning how big Brianna was when she was born.

Christina Hoyt

And it wasn't just that she was fat, but she was long, too. She would hang outside of her infant seat. It was just awkward.

Eric Hutto

Yes, if you walked behind, you could see her feet sticking up.

Christina Hoyt

[LAUGHS] Yeah.

Sean Cole

And she was pretty healthy.

Christina Hoyt

Yes.

Sean Cole

But then when she was about five months old--

Christina Hoyt

She got a cold. Chest congestion. She wasn't eating. She was extremely fussy.

Eric Hutto

High fever.

Christina Hoyt

Yeah, 102.

Sean Cole

Fever?

Christina Hoyt

Mm-hm. So they gave her Tylenol at the triage.

Sean Cole

The emergency room. Christina's mother came along, too. Now Christina had already started Brianna on Infants' Tylenol, and she says she showed the folks at the hospital the type she was using.

Christina Hoyt

And it came in a little bitty bottle, and the purple kind is what we gave her. I even pulled out the dropper, showed them how much I was giving her, and it was the first line on the dropper. Because we didn't know how much to give her. It says to consult a physician. So without knowing how much to give her, we just gave her the lesser of the doses of the Infants' Tylenol.

So they wrapped her in warm towels, broke her fever. The doctor came back in, said she just had a virus and that it would pass. So he gave us a script, wrote on a piece of paper, "3/4 teaspoon of Tylenol every four to six hours for pain, as needed."

So my mom questioned it and said, don't you think that's a little much for a baby of her size? And so the doctor gave it back to the nurse, the nurse went away, came back, scratched it out, and says 1 teaspoon of Tylenol. Nowhere does it say--

Sean Cole

Wait, she said, don't you think that's a little much? And he scratches it out and writes more?

Christina Hoyt

Yes. And he says because of her weight, that's how much she needs to be given.

Sean Cole

The hospital was going off a dosing chart it got from McNeil. McNeil had sent the chart around to doctors and hospitals as a kind of stop-gap until it was able to convince the FDA to put more specific dosing instructions on the boxes of Infants' and Children's Tylenol.

Now the FDA held its first public meetings about all this label confusion eight years earlier, in 1995. Christina and Eric were still in middle school when that happened. When Brianna arrived at the ER, it was 2003, and the problem still wasn't fixed. In fact, 2003 was the year that the FDA finally said, OK, now we're going to address this issue. And said the same thing in 2004, in 2005, 2006, 2007, and 2008.

T. Miller

And each year, the FDA doesn't act.

Sean Cole

Again, T. Miller with ProPublica.

T. Miller

And they actually put on their calendar for the year that we're going to address this this year, and then they just don't. And it just goes by and by and by, year after year after year.

Dr. Barry Rumack

The FDA's response was, it's a public health issue.

Sean Cole

Again, Barry Rumack, the toxicologist who argued for the dosing label. If this says, call a doctor under age two, then the parents are going to be required to call a physician, and they will get into the health care system. And that would be safer and better than trying to treat them by themselves.

That's the FDA's rationale for this?

Dr. Barry Rumack

Yes.

Sean Cole

The thing is, the Huttos did see a doctor. They had instructions from a doctor in their hands.

Christina Hoyt

So we gave her Infants' Tylenol, what we had given her before, a teaspoonful every six hours. And it was too much.

Sean Cole

As it turned out, the 1-teaspoon dose the doctor recommended was for the less-concentrated Children's formula. The hospital didn't normally use Infants' Tylenol.

Eric Hutto

They didn't tell us to give Children's or Infants' Tylenol, either of them.

Sean Cole

They just said Tylenol?

Eric Hutto

Right. So being that she was an infant child, you know, it was Infants' Tylenol. Because you wouldn't think to give a child Children's Tylenol at an infant's age, because you can't give a child adult Tylenol, you know?

Sean Cole

Eric and Christina said they followed the directions to the letter. Soon, Brianna Hutto wasn't fussy anymore. She was listless. Eric said it was like she was there, but not there, and her stomach felt hard. Eric and his father took Brianna back to the hospital.

Eric Hutto

Then they said, well, is she on any kind of medication? And I actually said, yeah, the Tylenol y'all prescribed her.

Sean Cole

When the doctors figured out she'd overdosed on Tylenol, Brianna was airlifted to New Orleans Children's Hospital, and then to a transplant center in Omaha a day and a half later. She just kept getting worse-- went into a coma, had tubes and wires all over her. The plan was to give her part of her mother Christina's liver, but first, Brianna would have to start breathing on her own again. The Omaha hospital put up Eric and Christine in a room down the hall from their daughter's.

Eric Hutto

I walked down there to go see here. And when I was walking down to go see here, they had a bunch of doctors running to her room, and they turned me around. And not long after that, they had a priest come walk in, and-- there was a couple people.

Christina Hoyt

Priest and a preacher.

Eric Hutto

Priest and a preacher. And they had a doctor or someone. They had a couple people came in, started talking to us, telling us what was going on, that her kidneys had shut down, her heart failed and everything, and that she had passed away.

Sean Cole

That's so awful.

Christina Hoyt

I don't really remember much after that.

Sean Cole

The Huttos ultimately filed suit against the doctor and the hospital, but also against McNeil. Their lawyer made the case that there should have been better dosing on the box, plus a severe liver damage warning. All of this happened about two years before McNeil put the liver warning on the Tylenol label.

The hospital admitted fault almost immediately, but McNeil fought. In the end-- this is just how the court system works in Louisiana-- the jury divvied up the blame, saying the hospital was 70% at fault, McNeil was 23% at fault, and Christina and her mother together were 7% at fault. McNeil was ordered to pay $1.1 million, but the company appealed. And appealed, all the way up to the Supreme Court. Just last October, the Supreme Court refused to hear McNeil's case.

Christina and Eric broke up after that. Both got remarried. Christina went on to have three more kids with her new husband. She says living with Eric would have been a constant reminder of what happened. And given the three-year appeals process, she already had to think about it too much.

From the reporting we've done, it seems clear that McNeil genuinely tried to make dosing infants and children less confusing for families like the Huttos. It argued for better instructions. It gave caregivers the dosing chart. Here's former McNeil executive Tony Temple at an FDA hearing in 2009.

Dr. Tony Temple

I believe the most important labeling improvement that could be made now would be to add dosing instructions for children less than two years of age to the label. If that had already been done, the other pediatric issues would be of much less concern. This is at the heart of the product confusion and misdosing issue we've heard so much about.

Sean Cole

When we asked the FDA about this, it said in a written statement basically that dosing instructions for babies, quote, "pose a number of challenges." They said parents might not know the weight of a child unless they've been to their pediatrician recently, so they should just go to the pediatrician. We asked, if weight- and age-based dosing present such a problem, why infants' and children's ibuprofen has it. The agency said, because it's a newer drug and went through a different drug approval process.

But where McNeil was arguing for clearer instructions, there's another strategy they could have taken, one that would have ended the confusion between the two products, and it wouldn't have had to have asked the FDA. The company could have just yanked the stronger-concentration product off the market. That's what PeterMax Miller says he would have done. He used to be involved in decisions like this-- whether to pull products from the market-- when he worked in the industry years ago, when he was at Bristol-Myers Squibb and at GD Searle. Now he teaches marketing ethics at the University of Colorado.

Petermax Miller

So I would not have had any hesitation at all about yanking it off the shelf overnight everywhere. And Johnson & Johnson knows how to do that.

Sean Cole

Johnson & Johnson, again, is McNeil's parent company. You might remember it pulled a ton of Tylenol off the market in the '80s due to a tampering scare in which some capsules were laced with cyanide.

Petermax Miller

And having said that, overnight is not fast enough either. But that's as fast as we can get.

Sean Cole

What would the trigger be?

Petermax Miller

If there was an infant death due to confusion, that's the time to pull it.

Sean Cole

One infant death?

Petermax Miller

Just one infant death. That is-- I want to say more than a trigger. That is a huge cannon.

Sean Cole

And ultimately, McNeil did pull the stronger concentration off the market, in 2011. Now when you go into a drugstore, you'll see both Infants' and Children's Tylenol, but it's the same stuff in two different packages.

Of course, more than one child died in the 18 years McNeil was asking the FDA to let it include better dosing instructions on the box. Tony Temple was asked about this on the witness stand during the Huttos' lawsuit. Again, he's the former McNeil exec who'd been vying for weight-based dosing.

Temple testified that you might go two, three, or four years without any death reports, and then there might be one in a given year. The attorney questioning him said, "And rather than pull the products off the shelf, that's sort of the cost of doing business?" Tony Temple-- "McNeil felt that the benefit as-- really, it's the FDA, because it hasn't pulled it off either. But the benefit to children having the product available was appropriate to keep it in the marketplace, yes."

I read that excerpt to PeterMax Miller. He said Temple's argument doesn't really make sense to him, because McNeil didn't need to wait for the FDA to take action with Infant Tylenol.

Petermax Miller

You know, from an industry standpoint, we know it's going to be slow at the FDA. So I cannot-- if I have a drug that's causing problems, or labeling that's causing problems with confusion, I cannot blame the FDA for being slow. The FDA does not care if you take something off the market, that I know of. You can do it overnight.

Sean Cole

We asked McNeil why it didn't move to a single concentration sooner, among other questions about this part of the story. The response said the company has a long history of being a responsible health care partner with regard to pediatrics. Then McNeil laid out a brief history of Infants' and Children's Tylenol, including the 2011 decision to take the stronger concentration off the market, which it said was not just something McNeil did, but all acetaminophen manufacturers. The company also said it made the dosing devices themselves safer for kids.

The company didn't send us any comments specifically about the Hutto case or any of the specific lawsuits we asked about. But it did address those cases more generally in that recorded statement from Medical Affairs VP Ed Kuffner.

Dr. Ed Kuffner

We're committed to preventing acetaminophen overdose. Even one patient who takes a significant overdose is one too many. Our hearts go out to those who've overdosed and gotten sick, and to the families and loved ones of those who've died.

Sean Cole

So let's run down what McNeil has done to try to prevent acetaminophen overdose. Again, there are now both alcohol and severe liver warnings on Tylenol, and the company has taken the stronger Infants' concentration off the market. The company put the alcohol and liver warnings on its products before it was required to by the FDA-- though after FDA advisory panels recommended them.

Also, as we mentioned at the beginning, the words, "contains acetaminophen-- always read the label," are going onto the cap of every Extra Strength Tylenol bottle. In addition, McNeil has done a bunch of its own public outreach on the issue, especially in the last few years, including a public service campaign called "Get Relief Responsibly." Plus McNeil was the one who funded the development of an antidote for acetaminophen poisoning, which surely has saved thousands of lives.

But despite its efforts, right now McNeil faces more than 85 lawsuits related to acetaminophen, many of them saying the company failed to warn the public about the true risks of the drug, and particularly the narrow margin between a safe dose and a toxic dose. At least 10 other countries have taken steps the US hasn't to try to prevent acetaminophen overdose. According to a 2008 FDA report, Australia, France, the UK, New Zealand, Germany, Finland, Denmark, Sweden, and Switzerland have limited how much of the drug you can buy at one time. Or they say you can only buy it from a pharmacy.

In the UK, for instance, they simply limited the package sizes. A lot of times it comes in those little blister packs, those little plastic-and-foil chewing-gum-looking packages, so you have to pop them out one at a time. Those rules went into place in 1998.

Since then, deaths from acetaminophen poisoning have dropped by more than 40%. That's all deaths, including suicides, and it's only for England and Wales. Scotland didn't see a decrease in deaths, for some reason.

In Canada, the package warnings say an overdose can be fatal. That word is not on over-the-counter acetaminophen products here. I also noticed, last time I was in Canada, that the stronger Infants' formula of liquid Tylenol is still on the shelf, but weight- and age-based dosing is on both Infants' and Children's Tylenol packages.

Here in the States, you could argue acetaminophen labeling has gotten a little more confusing lately. In 2009, an FDA advisory panel suggested that the recommended daily dose drop from 4 grams a day to 3 grams a day, hoping fewer people would end up overdosing. The FDA still hasn't taken action on that recommendation. But in 2011, McNeil did. It lowered the recommended dose on the label to 3 grams a day.

But the company still says 4 grams a day is a safe dose, so now this is what the label says. "The maximum daily dose of this product is 3,000 milligrams in 24 hours. Severe liver damage may occur if you take more than 4,000 milligrams of acetaminophen in 24 hours."

With so many people already buying acetaminophen, one of the ways companies can still boost sales is to put it in more and more products. More than 600 products contain acetaminophen now, including Excedrin, Theraflu Dristan Tablets, Sudafed Cold and Cough, Robitussin Cold and Flu, Alka Seltzer Plus Cold and Sinus, several types of Mucinex and Midol, most kinds of NyQuil, and stronger prescription painkillers like Percocet and Vicodin. The problem is, having it in so many products means that it's that much easier to accidentally take two drugs with acetaminophen in them at the same time-- say, Tylenol and NyQuil-- and inadvertently overdose yourself. McNeil, responsibly, makes a big point of this in its outreach these days.

Nonetheless, an independent national poll commissioned by ProPublica and This American Life shows a third of the public thinks it's safe to take the maximum recommended dose of Extra Strength Tylenol together with NyQuil. It's not. And a third say it's OK to give your kid the maximum recommended dose of Children's Tylenol along with Children's Tylenol Plus Multi-Symptom Cold Medicine. That's not OK either.

The proliferation of products, just how easy it is to double up, might be one reason why deaths from acetaminophen toxicity are much higher now than they were 20 years ago. An FDA report in 2008 noted that acetaminophen poisoning quadrupled and deaths went up seven-fold between 1995 and 2005. They're even higher today.

Ira Glass

Sean Cole. ProPublica has its own version of today's story, with all kinds of videos and graphs and charts and pictures and interactive stuff. You can find that at propublica.org. Special thanks today to the two ProPublica reporters who did the heavy lifting in researching acetaminophen, finding documents and scientific studies and sources-- Jeff Gerth and T. Christian Miller. Also, editors Mark Schoofs, Robin Fields, and Stephen Engelberg.

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Credits.

Ira Glass

Well, our program was produced today by Ben Calhoun and myself, with Alex Blumberg, Sarah Koenig, Miki Meek, Jonathan Menjivar, Lisa Pollak, Brian Reed, Robyn Semien, Alissa Shipp, and Nancy Updike. Our senior producer is Julie Snyder. Production help from Dana Chivvis.

Elliot Stapleton is filling in as our operations director. Emily Condon is our production manager. Elise Bergerson's our administrative assistant. Adrienne Mathiowetz runs our website.

Research help today from Julie Beer. Music help from Damien Graef and Rob Geddes. Special thanks today to Antonio Benedi, Kate Trunk, Willis Maddrey, Raymond Woosley, Sameer Thapar, Sidney Wolfe, Lisa [? Swersky ?], Lisa Gill, and Missy Adams.

Our website-- thisamericanlife.org. This American Life is distributed by Public Radio International. Thanks as always to our program's co-founder, Torey Malatia, who does not always make the choices that others would. For example, the reason that he got into public broadcasting?

Thomas Garvey

Well, to do God's work. No, you nitwit. To make money.

Ira Glass

I'm Ira Glass. Back next week with more stories of This American Life.

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