The Devil in the Details: Chapter Two

The Devil in the Details: Chapter Two

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Katie Hafner: It was the 1950s, and Germany had climbed its way out of the rubble of World War II—out of famine and chaos and national shame—and its economy was roaring back to life.

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Toine Pieters: We know it as the Wirtschaftswunder, the miracle of the Germans. 

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Katie Hafner: Toine Pieters is a historian of pharmacology at Utrecht University in the Netherlands. And he says pharmaceuticals were a big part of this German Wirtschaftswunder, or economic miracle.

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Toine Pieters: There was a strong belief in miracle drugs. Very much so. In magic bullets. And we had really brilliant inventions in the era of pharmaceuticals with the new antibiotics, new antipsychotics, et cetera, et cetera., life saving drugs that came on the markets.

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Katie Hafner: Pharmaceutical companies were raking in the cash. And the second-biggest seller, right behind Aspirin, was a sedative called Contergan. Active ingredient: thalidomide.

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Contergan was made by a small but aggressively ambitious company called Chemie Grünenthal. And it was thanks to the wild growth of Contergan sales that the company’s revenues soared.

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And if you believed the hype from Grünenthal’s marketing men, Contergan was a wonder drug, a sedative that was non-toxic, meaning no side effects.

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Toine Pieters: It's fascinating just that you claim to have a sedative that's non toxic. I mean, there is nothing non-toxic in the pharmacy. Every medicine we know about has side effects. I'm always amazed how can people so stupid?

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Katie Hafner: But let’s step back for just a moment. In 1956, the year before the company’s official launch of this miracle pill, something curious happened.

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A Grünenthal employee took some thalidomide samples home and gave them to his pregnant wife. When the couple’s daughter was born on Christmas Day, 1956, she didn’t have ears.

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I’m Katie Hafner, and this is Lost Women of Science.

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Today, in the second episode of our special series, Devil in the Details, how the dangers of thalidomide managed to fly under the radar for FOUR years, and how Frances Kelsey at the FDA finally got the evidence she needed that this drug was not as safe as its U.S. manufacturer was claiming.

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Katie Hafner: In the fall of 1960, Frances Kelsey was sitting at the long metal table in her office that served as her desk, working her way through William S. Merrell’s voluminous application to sell thalidomide in the U.S.. Frances had no idea what was happening in Europe, where more and more babies were being born with serious, sometimes fatal, injuries. In fact, neither did Merrell.

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From what she’d seen of Merrell’s application so far, Frances was not impressed. She had sixty days from the date of submission to respond to the application. In order to deny it, she had to be able to prove it was unsafe. But here’s one problem: She didn’t have any data to prove the drug was dangerous. But Merrell just hadn’t given her any convincing data showing it was safe either. And the clock was ticking. 

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Which brings us to another problem: If the FDA didn’t respond by the 60-day deadline, the drug would go to market automatically. That’s how the agency worked back then. 

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But Frances had a secret weapon. Someone with insider knowledge of the FDA’s drug approvals process. Someone who was principled…

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Trent Stephens: Cantankerous.

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Christine Kelsey: Very strong. Very opinionated.

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Jennifer Vanderbes: She was a dynamo.

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Katie Hafner: She was Barbara Moulton, the FDA whistleblower who testified before the Senate just before Frances Kelsey joined the agency. Everyone we talked to made it clear that Barbara left an impression. She was a chain-smoking, straight-shooter, just not hung up on social conventions. When she got married, it was on her big old family farm in rural West Virginia, and the story goes that she interrupted her own wedding to help birth a cow.

In DC, Barbara rubbed a lot of people the wrong way. But even though she wasn’t everyone’s cup of tea, Frances took a shine to her. 

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By all accounts, these two women couldn’t be more different. We don’t know what it was about Barbara that Frances was drawn to. Maybe she admired Barbara’s courage, her moxy… In any case, The two became fast friends. 

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Christine Kelsey: Dr. Barbara, we always called her. 

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Katie Hafner: Christine Kelsey, again, Frances’s younger daughter. 

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Christine Kelsey: She was just very, in our minds, almost coarse because she really told it like it is. And mum being Canadian and being reserved, would not be so direct and forthright in her speech, although they very much agreed with each other on pretty well everything.

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Katie Hafner: So as the sixty-day window drew closer to a close, Frances asked Barbara for advice. Here’s Jennifer Vanderbes, author of the book Wonder Drug, again.

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Jennifer Vanderbes: So Barbara Moulton says, well there's, you know, there's option three that no one tells you about. You don't necessarily approve or reject a drug application. There's this loophole where you can essentially just delay- you can call the application incomplete, right. You can just ask for more information and stall.

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Katie Hafner: So on November 10, 1960, just as her time ran out, Frances Kelsey sent Merrell an official letter. The gist was this: the application needed work. The animal studies were incomplete. The clinical human studies were incomplete. They hadn’t looked at long-term safety. There were inconsistencies. There were confusing parts. Frances’s list went on and on. In conclusion, the  whole application was incomplete. Not rejected. Not approved. But incomplete. The clock reset to 60 more days.   

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The company was not happy, in particular, one of its employees, Joseph Murray.

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Cheryl Warsh: Dr. Murray was the doctor for the most part that would run back and forth to the FDA. And he had a very nice relationship with the other FDA people before that.

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Katie Hafner: Cheryl Warsh again, a history professor at Vancouver Island University.

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Cheryl Warsh: They go for, like, long lunches and they would meet each other to have martinis. And it was all pretty old boy kind of thing because everything just kind of got passed. So it didn't really matter.

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Katie Hafner: Well, it mattered now. Merrell had a lot riding on this new drug, and Joseph Murray was growing impatient. A few days after Frances sent out her letter, he called her to ask what was going on with the Kevadon application. The FDA’s letter still hadn’t arrived. Frances assured him it was on its way. He asked if it were okay, and she told him that there were some areas that were incomplete, but she didn’t have a copy of the letter on her. 

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Okay, the guy was a pest, but he was under pressure. His higher ups were still waiting on FDA approval. They had lined up dozens of sales representatives to start hawking the drug in hospitals. The sales machine was raring to go. 

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The next day, a very unhappy Joseph Murray called Frances again. He’d gotten the official letter declaring the application incomplete. And he wanted her to know he was distressed by the contents.

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Katie Hafner: We don’t know exactly what happened in that phone call, but we do know Frances wasn’t budging. 

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And Joseph Murray grudgingly, no doubt, kept trying to win her over. A month passed, and finally, in mid-December, Joseph Murray and a colleague arrived in DC in person to present their case. Frances, along with several others from the FDA were in attendance. 

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At the meeting, the Merrell crew trotted out all kinds of new data, but Frances found none of it convincing.

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This meeting wasn’t going to clinch the deal for Merrell. On and on it went. The FDA had questions. Merrell tried to supply answers. The FDA asked yet more questions. Joseph Murray grew more frustrated. In January of the new year, Murray even called Frances’s bosses to complain.

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Cheryl Warsh: He started talking to her superiors and say, why don't you get a different reviewer and the rest of it?

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Katie Hafner: But Frances was kept on the case. 

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Weeks passed. It seemed like they might be stuck in this dance for a long while. And how long could Frances really keep this up? Sure, their application was inadequate, but she still didn’t have any evidence the drug was actually harmful. 

But in the middle of this tussle with Murray, Frances came across a disturbing bit of information. It was a letter to the editor in the British Medical Journal about thalidomide. A doctor in Scotland had found a side effect.

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Katie Hafner: When Frances Kelsey’s daughter Christine thinks back on what was going on in the Kelsey household in early 1961, she just remembers it as being a pretty normal time. Christine says her parents didn’t work overtime. The family ate dinner together. Whatever pressures her mother might have been experiencing at the FDA, she didn’t bring them home. Still, science and pharmacology pervaded everything. 

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Christine Kelsey: In the 50s and 60s, doctors would get samples through the mail. So, like, every day, we'd get one or two pill bottles of whatever from the pharmaceutical companies, and she always kept her medical license so that she could get those samples, so that she could see what are they were sending. We would always open the bottles and put them in a big jar. So we had a big jar of multicolored pills that we finally threw out in 2014 or 15.

Katie Hafner: There were pamphlets for new drugs too, testimonials, thinly-veiled ads basically.

Christine Kelsey: And she would read the flyers every night. That would be her after-work relaxation would be reading the medical flyers to make sure that false advertisement wasn't happening.

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Katie Hafner: And then there were the medical journals that Frances and her husband, Ellis, used to read in the evenings. 

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It was on one of those evenings that Frances read something that alarmed her. It was a letter to the British Medical Journal with some news about thalidomide. 

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It was in an issue of the journal published in December of 1960. But because of a postal strike, it would take several more weeks until Frances’s copy arrived, sometime in late January or early February of 1961.

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The letter was written by a Scottish doctor named Leslie Florence. The title: “Is Thalidomide to Blame?”

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He’d noticed a strange constellation of symptoms in four of his patients. To start, paresthesia – a sensation of prickling or burning or numbness. It would start in their feet and then move to their hands. Also their extremities would get cold. And they had leg cramps and poor muscle control. 

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And there was something else. Each of the four patients had been taking a nightly dose of thalidomide for more than a year.

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The doctor noted how everyone said thalidomide was remarkably non-toxic. And yet, when he took patients off thalidomide, there was “marked improvement.” So maybe, he wondered, thalidomide was toxic after all? Was anyone else noticing this kind of thing?

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It was a disturbing revelation. Thalidomide was supposed to be this miraculously non-toxic drug. But these symptoms sounded like peripheral neuritis, also known as peripheral neuropathy, basically, damage to the nerves that send signals from the brain and spinal cord to the rest of your body.

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This article had been published weeks before, and yet Frances had heard nothing about it from Merrell. Did the company not know about it?

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Murray had been calling repeatedly in February to check in on the Kevadon application, but hadn’t mentioned anything about this. So when he called again, on February 23, Kelsey waited to see if he’d say anything. He didn’t. When she asked him directly, he admitted he’d seen it. But only recently, and he made it sound like he wasn’t too worried about it.

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Except that just a week before his phone conversation with Frances, Joseph Murray had sent an urgent letter about this very issue to Distillers, the British distributor of thalidomide. Murray wanted to know if they knew anything about this peripheral neuritis report. Oh yes they did. Distillers, it turned out, had known about the peripheral neuritis even longer. The same author of the BMJ letter had contacted them about his peripheral neuritis concerns almost two years earlier, in February 1959, and by August 1960, Distillers put warnings on the labels. So before Merrell had submitted its application to the FDA, there was Distillers putting warnings on its label.

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And Distillers weren’t the only ones that knew it. It turns out back in Germany, the men at Chemie Grünenthal were already aware of the possible neurological side effects of thalidomide. Historian Toine Pieters again:

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Toine Pieters: We know about the neurological side effects because they were reported. It's not that the doctors testing the drug were blind. They weren't. 

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Katie Hafner: Grünenthal had its first reports of adverse side effects even before the drug went on sale. And the first report of possible nerve damage came at least as early as 1959. And despite these reports, the company promoted the drug as non-toxic.

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Now, we could give them the benefit of the doubt on this point. Whenever you give a drug to lots and lots of patients over a long period of time, some of them are going to get sick, just randomly. Some of them will have heart attacks, some of them will get cancer. And that might have absolutely nothing to do with the drug. The best way to find out a drug’s specific effects is to conduct randomized, placebo-controlled studies over a sufficient period of time on a big group of patients. But it appears that in Germany in those years, a drug could be approved without that kind of rigorous study. 

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Toine Pieters: We didn't have compulsory clinical trials at that time. Primary evidence was the evidence of individual doctors on the basis of observations of their patients taking a new drug. It’s anecdotal evidence, literally.

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Katie Hafner: What he’s saying is that doctors would be given new experimental drugs, and in a totally non-rigorous way, they would sort of let the companies, you know, know how it’s going. 

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Grünenthal is still around today. We contacted them as we were reporting this story, and a company representative told us that in response to these reports of nerve damage, the company did take action. They eventually applied for prescription-only status instead of over the counter. That didn’t happen until May 1961. But they also did something in 1960. It added a warning label.

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The label said that after more or less prolonged use of thalidomide, symptoms could occur in patients predisposed to them. Such side effects, said the label, “may include sudden skin rashes or constant restlessness, trembling, tingling or numbness in the hands or feet. These allergic reactions subside after immediate discontinuation.” That was the label.

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Now note, that the label calls these “allergic reactions” - more importantly, it says these reactions will go away after you stop taking the drug. We now know that’s not always true. For some patients, nerve damage from thalidomide is irreversible.

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In any case, if it was shown that Grünenthal was deliberately discounting these nerve damage reports, that might have turned into a scandal for the company. But as it happens, Grünenthal was about to have a MUCH bigger scandal on its hands that would turn that side effect of thalidomide into a footnote.

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On April 24, 1961, in a hospital in Hamburg, Germany, Karl and Linde Schulte-Hillen were about to become parents.

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Jennifer Vanderbes again:

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Jennifer Vanderbes: So Karl and Linde are this, you know, gorgeous young student couple living in Germany they're wildly in love, they're newly wed, they're having a baby, over the moon. 

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Katie Hafner: Karl was in his last year of law school, and was in a meeting on campus when Linde delivered their baby boy. He rushed back to the hospital as quickly as he could.

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Jennifer Vanderbes: He's met on his way in, something's wrong. 

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Katie Hafner: His son was born with shortened arms, and three fingers on each hand. 

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Jennifer Vanderbes: And his wife has been there alone in the hospital with these nurses acting very strange. She's confused and devastated. They're both fraught. But the really stunning moment for this is that his sister several weeks earlier had given birth to a baby with similar malformations.

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Katie Hafner: Six weeks earlier, Karl’s sister had had a baby with shortened arms. But Karl hadn’t told Linde. He didn’t want to worry her. But now that his own son, a smiley baby named Jan, had the same condition Karl was desperate to know why.

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Jennifer Vanderbes: He starts kind of asking around, he finds out, he hears a rumor that there are more babies born like this at other hospitals in the area. So he starts trying to find someone with medical expertise who's willing to engage in a conversation and not just a kind of cover up. And he finally gets connected with this pediatrician and geneticist, Widukind Lenz.

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Katie Hafner: Widukind Lenz was the son of Fritz Lenz, a notorious Nazi geneticist who was a staunch advocate of racial cleansing and the sterilization of disabled people in Germany. In fact, Fritz Lenz thought something like a third of Germans shouldn’t be allowed to reproduce. His son, Widukind himself was part of the Hitler Youth. Now, we don’t know if that was something his father pushed him into or if he was a true believer as a teenager. But we do know his legacy would end up being very different from his father’s. Widukind Lenz’s first meeting with Karl Schulte-Hillen would set him on a course to become one of the most prominent advocates for disabled people in 20th century Germany.

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Jennifer Vanderbes: So he took the meeting. and he listens to Karl's story. And, the first thing he says is, Oh, this is probably genetic.

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Katie Hafner: But Widukind agreed to examine Karl’s son, Jan. And when Karl brought Jan into Widukind’s office a week later, Widukind immediately recognized Jan’s condition as something called phocomelia.

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Jennifer Vanderbes: Which roughly translates to seal limbs, where you've got kind of hands and feet almost sprouting directly from the shoulders or hips.

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Katie Hafner: Phocomelia is incredibly rare. Less than one out of every 100,000 babies is born with it. Almost all obstetricians will go their entire careers without ever seeing a single case. And here, Karl was telling Widukind all about two cases, born within weeks of each other.

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Widukind and Karl started compiling a list of other babies born with phocomelia. In Munster, which is about six hours southwest of Hamburg, twenty babies had been born without arms at one hospital. And thirteen more in two neighboring towns. In the summer of 1961, when the two men put ads in newspapers, more reports flooded in. So they went to see what they could find. Here’s Jennifer Vanderbes again.

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Jennifer Vanderbes: They set out on like a road trip in an old VW Beetle, and they go sort of house to house. 

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Katie Hafner: They also go to restaurants and bars and they ask if anyone knows of babies with short legs or short arms. Karl shows people a picture of Jan. And the answer is yes. 

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Jennifer Vanderbes: And they very quickly realize that there is actually what could probably be called an epidemic of this very specific birth malformation. There are hundreds of these babies all over Germany all of a sudden.

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Katie Hafner: They interview one family, then two, then more. They ask them as many questions as they can, trying to figure out what’s causing this.

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Jennifer Vanderbes: They suspect that something has somehow–some kind of toxin has entered the system of these pregnant women.

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Katie Hafner: But what kind of toxin was it? There was no obvious link between the foods these mothers had eaten, the cosmetics they used, the places they’d been.

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And I want to pause here for a second. This is the summer of 1961. Thalidomide has been on the market for almost four years at this point. Thousands of babies have been affected. So you might be thinking, how was this missed? How is it that it took this long for people to even notice there’s an epidemic happening? How was it no one made the connection to thalidomide? 

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Well, part of the problem is that phocomelia does occur naturally too. If one baby is born with shortened arms, well, that happens. But several babies in one hospital in a short span of time? That’s strange, but maybe there’s something happening locally. Could it even be something in the local gene pool? Or a coincidence?

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To uncover the cause of an epidemic, what you really need is good record keeping over a long period of time across a large area and someone to look over all that data. Pair that with reliable case histories for all the patients, and you might even identify the cause with some measure of efficiency. Apparently, none of that happened.

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But despite all those obstacles, it’s not like Widukind Lenz was the only one that noticed. In September 1961 a doctor from Krefeld not too far from Dusseldorf, published a paper describing a surge in strange births. He’d found 27 cases of babies born with severe malformations, and often blocked intestines, heart defects, and missing ears. 

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It was an odd assortment of symptoms, with no obvious connection between them. Dr. Wiedemmann ruled out infections, endocrine disorders, and a variety of other possible culprits, and just like Widukind Lenz and Karl Schulte-Hillen, up north in Hamburg, this physician concluded it had to be some kind of toxic substance. And, just as the traveling duo from Hamburg, Dr. Wiedemann was stumped. What could that toxic substance be? 

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It’s not as though there were no clues pointing to thalidomide. The timing seemed roughly right. Wiedemann traced the earliest cases in the samples he’d received back to 1959. Grunenthal had introduced its hit drug two years earlier. And another interesting thing was that the epidemic didn’t seem to be affecting East Germany, which was then a separate country. Contergan wasn’t sold there.

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But there were also other things that threw these sleuths off the trail. And get this one: Dr. Wiedemann in Krefeld was under the impression that thalidomide was being taken widely in the United States. We don’t know where he got that impression, but that’s what he thought. 

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And so this is just so ironic. In the United States, Merrell thought thalidomide must be safe because as far as Merrell knew, it had been in Europe for a few years without incident. Well, apparently, some Germans thought the same thing about the United States. Wouldn’t they have heard if there was a problem over in the US? Totally wrong on both sides. And as my husband, the medical mistakes expert, would say: This was to become one gigantic patient safety problem.

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But we digress. 

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So over in Germany, doctors were puzzling over these births, not quite connecting the dots. But as we know, thalidomide was used all over the world, so why weren’t others noticing the problem? Well, actually, someone did. Over in Australia, an obstetrician named William McBride began to suspect thalidomide right around the time Widukind and Karl started their investigations. McBride had delivered three babies with serious malformations within just a few weeks of each other, and realized the mothers had taken thalidomide in every case. He even called the British company, Distillers, to warn them, but nothing came of it at the time.

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And so for months, doctors were circling around thalidomide, getting closer, then thrown off the trail. And that was the state of affairs in Germany in September of 1961, four years after Contergan first went on sale, and five years after a baby without ears had been born to a Grünenthal employee.

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Back at the FDA, that same month, late September 1961, Frances Kelsey got yet another call from the very persistent Joseph Murray at Merrell. Another holiday season was just around the corner, so he really wanted to get those drug brochures printed in October. They needed to get a move on if they were going to meet their Christmas deadline, right? The season for sedatives was upon us!

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For her part, Frances still found things of concern. First, there was the unresolved issue of peripheral neuritis. But Frances also mentioned another, more urgent concern. What about the use of the drug during pregnancy? It was a question she had asked before but had never received an adequate response.

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It wasn’t that Frances Kelsey had any special knowledge of thalidomide’s effects at this point, or that she’d heard anything about the rise in these unusual births over in Europe. That news hadn’t reached the US.. And even in Germany, Widukind Lenz only had his suspicions, no firm conclusions at this point. But Frances Kelsey just knew that the company hadn’t shown thalidomide was safe in pregnancy. So no, there weren’t going to be shortcuts, or fast tracking or a guarantee of a Christmas launch. No FDA approval for now. 

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But here’s the thing. FDA approval or not,  Merrell was already distributing the drug. It had already been given to thousands of patients across the US–And the first American thalidomide babies had already been born.

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Next time, on The Devil in the Details:

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Gwen Riechmann: I said, I know this is genetic and I'm going to pass it on. And my mom said, well, that's not actually the case. And I said, well, what is it then? And that's when she said, it's from a drug called thalidomide that I was given when I was pregnant with you. And that was it. Conversation over. 

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Katie Hafner: This episode was produced by Sarah Wyman with our senior producer Elah Feder and me, Katie Hafner. Our associate producer is Mila Rahim. Sophia Levin and Eva McCullough provided research support.

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Our music was composed by Lizzy Younan. We had fact checking help from Lexi Atiya. Sophie McNulty and Alexa Lim did audio editing and sound design. And Lisk Feng created the art for this series.

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Thank you, as always, to my co-executive producer, Amy Scharf, and to Eowyn Burtner our program manager, Deborah Unger, our senior managing producer, as well as to Jeff DelViscio at our publishing partner, Scientific American.

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We’re funded in part by the Alfred P. Sloan Foundation and the Anne Wojcicki Foundation. We're distributed by PRX.

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For a transcript of this episode or to learn more about Frances Kelsey, please go to our website, lostwomenofscience.org, and don’t forget to click on that all-important, omnipresent, donate button!

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See you next week!

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*Morgane Fouse mastered this episode. Art design by Lily Whear. [not in audio]