The Devil in the Details: Chapter One

The Devil in the Details: Chapter One

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Katie Hafner: In 1962, Sherri Chessen’s life was all about kids, round the clock. She was “Miss Sherri” the host of a kids’ TV show in Arizona. It was a local edition of “Romper Room,” a hugely popular show in those years.

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Sherri Chessen: I've always worked with children. I was a camp counselor. I was a swimming counselor. I would, I staged plays with them. I don't know. I just have an affinity for children. Always have, always did.

Katie Hafner: So work for Sherri meant singing songs to kids, reading them stories. At home, Sherri also had four kids of her own, all under the age of 8. And in the summer of 1962, she was two months pregnant with her fifth. And she was excited.

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Sherri Chessen: Yeah, I mean I was excited. I wasn't excited about the morning sickness.

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Katie Hafner: Sherri had dealt with morning sickness with all her pregnancies. But this time it was especially bad. So when she got a rare moment of peace and quiet, she savored it.

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Sherri Chessen: I was sitting on my, my sofa one afternoon, just chugging through the paper, and I saw an article.

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Katie Hafner: It was a front-page story about thousands of babies being born in Germany with missing arms or legs, sometimes with no limbs at all. And it was because of a drug their mothers had taken when they were pregnant. It was called thalidomide. Fortunately, according to the article, the drug was never sold in the US, thanks to an FDA employee who had stalled its approval.

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Still, Sherri started to worry. Months earlier, her husband had brought a drug back from England. It was a sleeping pill, but Sherri thought it might help her with stomach upset too, and started taking it. But what exactly was in it?

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Sherri Chessen: Well, I called my doctor and he says, ah,it's probably not, but bring it in. 

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Katie Hafner: So she did. And a couple of days later, the doctor called back. He said she and her husband had better come in again.

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Katie Hafner: I’m Katie Hafner and this is Lost Women of Science. In the 1950s and 60s, a drug developed in Germany was sold around the world. It was billed as a wonder drug. It was thalidomide. Thalidomide caused thousands of babies to  be born with shortened or missing limbs or no ears, damaged hearts… many died. 

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Katie Hafner: But in the United States, the drug was never approved, thanks to a medical officer working behind the scenes at the Food and Drug Administration. Her name was Frances Oldham Kelsey.

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Today, the first part of our special series, The Devil in the Details: The Doctor Who Said No to Thalidomide.

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Katie Hafner: August 1, 1960 was Frances Kelsey’s first day of work at the Food and Drug Administration. It was typically for Washington D.C. in the summer, hot and humid as she walked into the temporary, prefab building where she’d start her new job.

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It wasn’t glamorous, but it was a new start and a welcome change for Dr. Kelsey. 

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She wasn’t new just to the FDA, she was new to D.C., too. Frances and her family had moved there that summer, after she and her husband both took jobs in DC. And they were relieved to be back in a big city after a few years in Vermillion, South Dakota, where they just did not fit in. Most of the other mothers in their old neighborhood stayed home with their kids. Frances was a professional through and through, totally engrossed by science. Her husband, Ellis, was the same.

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Christine Kelsey: Yeah, she and dad would talk all the time through dinner about their research or about their jobs or whatever.

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Katie Hafner: Their younger daughter, Christine Kelsey, remembers hearing all about her parents’ science when she was a kid. She also remembers how unbelievably boring it was.

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Christine Kelsey: Sue and I would just tune out. Oh, talking about isotopes again, isotopes, always isotopes. Yawn. 

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Katie Hafner: But science had brought their parents together to begin with. Frances and Ellis first met as labmates at the University of Chicago in 1940, where they were both researchers in the pharmacology department. 

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And by 1960, they’d spent two decades supporting each other’s careers, often working and publishing together. They made sure to carve out time wherever possible, so that both of them could work. Christine says her parents never watched TV (except for the news). They hired someone else to do housework. Dinners were planned in advance, and they were very straightforward.

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Christine Kelsey: Every meal was a meat of some sort and a boiled potato and a salad and a vegetable.

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Katie Hafner: After dinner, Frances and Ellis would sit in the living room and read medical magazines together. How romantic.

Christine Kelsey: Which, mm, I suppose technically was working overtime, but that was their interest.

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Katie Hafner: And when Christine thinks back on how she was raised and the values her parents instilled in her, one thing stands out:

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Christine Kelsey: You know, just question everything. That was always a, almost a family motto, you know, don't believe it until you can test it, or until you know it's true.

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Katie Hafner: And that would turn out to be key in Frances Kelsey’s new job at the FDA.

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Katie Hafner: When she joined in August, 1960, Frances was one of about a dozen medical reviewers who assessed the clinical trials submitted with new drug applications. Their job was to make sure there was ample evidence actually showing that these drugs were safe for humans.

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This was not a job a lot of people wanted. I mean little kids didn’t say “Oh I want to be an FDA medical reviewer when I grow up.” The main requirement was a medical degree, but doctors, they weren’t stupid, they knew they could earn a lot more in private practice. So when Frances joined, a lot of the reviewers were fresh out of their residencies, working part time while they set up their own practices.

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Katie Hafner: Frances Kelsey, she was different. She was 46 by then with the experience to match. She had the required medical degree of course, PLUS a PhD in pharmacology... Oh, and she’d had years of experience reviewing papers for JAMA, the Journal of the American Medical Association. Which is all just to say: Frances Kelsey knew good science when she saw it. And bad science? That too.

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So doing her new job at the FDA should have been a cut and dried kinda thing for Frances.

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But there was one little thing that happened just a couple of months before her first day on the job. That summer, Congress held hearings looking into price fixing in the drug industry. And at those hearings, a former medical reviewer at the FDA named Barbara Moulton testified.

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Jennifer Vanderbes: So Barbara Moulton basically has Kelsey's job at the FDA before Frances gets there.

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Katie Hafner: That’s Jennifer Vanderbes, author of the book Wonder Drug about the history   in the U.S.

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Jennifer Vanderbes: She is there as a physician. She's highly educated. She is the first person who starts picking up on this sort of corrupt culture at the FDA where the drug firms are simply too friendly with the medical reviewers. She notices drugs that should not be cleared going onto the market.

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Katie Hafner: Moulton had pushed back against overly cozy relations with the drug industry. Her bosses dismissed her complaints and reprimanded her, and she quit. But not the usual way. She didn’t just tell her boss she’s leaving. That wasn’t Barbara Moulton’s style.

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Nope, instead, she took her story to a Congresswoman named Leonor Sullivan, who’d been advocating for consumer safety. Sullivan sent Moulton over to a senator named Estes Kefauver. He’s the one who’d been leading the congressional charge against pharmaceutical companies, and he invited her to testify in front of the committee. Now, note, at this point, Moulton still hadn’t turned in her official resignation letter. 

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Jennifer Vanderbes: She does not submit to the FDA. She reads this dramatically as her congressional testimony. I mean, she kind of lays out all the problems with the FDA drug approval and big pharma in a way that no one in the country was talking about. She essentially, in, in more sophisticated terms calls, the commissioner of the FDA, a bit of an idiot, effectively that all these guys here are just like buddies with pharma. They don't know what they're doing. Um, dangerous drugs are being put on the market quickly.

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Katie Hafner: But even that didn't seem to make a dent at the FDA.

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Jennifer Vanderbes: She was, I think, to some degree dismissed as a noisy, troublemaking woman in that era. 

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Katie Hafner: Had that whistleblower been a man, the reaction might just have been less dismissive. But I digress.

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In any case, there was at least one person paying close attention: Frances Kelsey. She later wrote that Barbara Moulton’s testimony made her question whether she wanted to join the FDA at all. But whether it felt like it was too late to back out or she saw the FDA as a challenge worth taking on, Frances showed up for work on August 1, 1960. Though she didn’t know it then, the fate of thousands of families depended on that decision.

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Katie Hafner: Frances Kelsey’s first month at the FDA was pretty quiet. Her schedule was full of meetings and orientations that pulled her to different FDA buildings across the city. But after a few weeks, her bosses put two new drug applications on her desk. One was for an enema product—she approved it a few weeks later. The second was for a drug called Kevadon.

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Katie Hafner: Kevadon was the American company’s brand name for a drug that had already been selling like crazy for a few years in Germany, the U.K., and other countries, under other names. In the US, the applicant was an old pharmaceutical firm based in Cincinnati called William S. Merrell. The company was billing Kevadon as an extremely safe sedative. And people needed a safe sedative. For decades, barbiturates had been the sedatives of choice. Drugs like phenobarbital and secobarbital. But barbiturates, as we know, can be addictive. And people can overdose on them. Judy Garland and Marilyn Monroe both famously died of overdoses in the 1960s. 

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This new drug, Kevadon, didn’t seem to have either of those problems. You could take as much as you wanted, get a good night’s sleep, and still wake up the next day. The active ingredient was thalidomide.

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Thalidomide had been developed in Germany and it was a BIG moneymaker there. Merrell wanted in. So the company got a license to make and sell it in the US, and on September 8, 1960, Merrell submitted it to the FDA for approval.

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Cheryl Warsh: And they thought because it was so popular in Europe already for a few years, it was a shoe-in and it was a really mild sedative that, you know, just let the new girl rubber stamp it.

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Katie Hafner: Cheryl Warsh is a professor of history at Vancouver Island University in British Columbia and the author of a book about Frances Kelsey that was published earlier this year. And Cheryl says that when Frances joined the FDA, this was a time of great optimism about drugs.

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Cheryl Warsh: After penicillin, there were all kinds of miracle drugs, um, vaccines, and this was the high period of drugs. Drugs were going to save the world. You know, better living through chemistry. 

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Katie Hafner: Still, there’d also been eye-opening screw-ups over the decades. Most famously, a drug called “elixir of sulfanilamide,” sold in 1937 for the treatment of strep infections. The elixir turned out to be a very toxic cocktail of antibiotics, cherry flavor, and diethylene glycol, which is chemically related to antifreeze. It killed more than 100 people, including children. 

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Now, by some cosmic coincidence, Frances Kelsey had had a front row seat to this disaster. She was doing her PhD at the time, and her advisor had been enlisted to help figure out what it was exactly in this Elixir that was killing people. And yes, it was the diethylene glycol. Frances watched lab rats who consumed diethylene glycol get red urine and die. No doubt this whole incident would have left an impression with her about the importance of ensuring drug safety.

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Katie Hafner: Although this is important to note, what happened in 1937 wasn’t actually the FDA’s fault. At the time, the FDA’s job was just to make sure drugs contained the ingredients that the companies selling them claimed they contained. But after the elixir of sulfanilamide disaster, the FDA was required to do something most of us take for granted these days: they had to make sure drugs were safe before they were sold to the public.

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So when Frances Kelsey joined the FDA, here’s how it worked. When a drug company wanted to take its product to market, it would submit what was called a new drug application or NDA to the FDA. 

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Katie Hafner: An application was broken up into three parts. First, a chemistry section, explaining what the drug was made of and how the company ensured the drug would always be produced in the same way each time, free of contaminants. Then, a pharmacology section, with animal studies showing that the drug didn’t have any toxic effects, and that it could safely be taken for a long period of time.

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And finally, the clinical studies. Reports from doctors who had tested the drug on their patients, made careful observations, and reported any adverse reactions to the drug company.

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That last section—the human clinical trials—was the part Frances was in charge of reviewing.

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Cheryl Warsh: The way it would work is that they would take the file and they would divide it up into the three parts, and the three groups would go off to their own offices and their own buildings and look over the report. If one of them who was looking at the medical part found that there was some strange medical reaction that would happen when people took the drug, then the pharmacologist would see if the same reaction was happening or has been shown to happen in the reports with animals.

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Katie Hafner: It was a lot of paperwork, hundreds of pages. Frances later described the Kevadon application as about the size of four phone books bound together.

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She and her colleagues—a pharmacologist and a chemist—set out to review the whole application. If they found anything indicating the drug was unsafe, they could reject it. But here’s the catch: no matter how big the application, even if the application was the size of EIGHT phone books, the FDA team had only 60 days to respond.

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Cheryl Warsh: Otherwise it automatically got put on the market. And you can see the problems with that, right?

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Katie Hafner: Frances’s superiors had good reason to expect this application to be an easy one. William S. Merrell was an old and respected American drug company. Its parent company, then called the Vick Chemical Company, was the maker of familiar brands like Vicks Vaporub. And Kevadon, the drug they were proposing in 1960, had already been on the market for a few years in countries like Germany, England, Spain and Japan.

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But it didn’t take Frances and her colleagues sixty days to realize something was off with this application. Let’s start with the chemistry section. A lot of the paperwork regarding the actual composition of the drug, and manufacturing process… was in German. That’s of course because the drug had been developed in Germany, and marketed there for several years before it was submitted for approval in the U.S. 

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But the FDA chemist reviewing that paperwork happened to be fluent in German. And she noticed that the original German reports didn’t perfectly match the English translations Merrell had provided to the FDA team. The errors weren’t necessarily huge ones, but it was enough to kinda make Frances and her colleagues cock their heads a little bit.

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Katie Hafner: So that was the chemistry section. Next, pharmacology. Now, the pharmacologist actually thought the animal studies looked pretty good on the whole, but there was something curious. The drug was supposed to be non-toxic, but… this drug was almost too non-toxic. Usually a drug that has some useful effect also has side effects, and at a high enough dose, it kills test animals.

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But in its application to the FDA, Merrell reported that no lethal dose could be found in animal tests. Even at very high doses, the animals always survived. And counterintuitive though it sounds, Frances was bothered by that. This drug was a sedative, and a very effective one in humans, but it didn’t seem to knock out animals. So what was happening here? Were test animals even absorbing this drug? And if they weren’t, well, then of course it wasn’t toxic to them! But it might still be to humans.  

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And that’s why testing drugs in animals alone isn’t enough. Here’s the hero of our season, Frances Kelsey herself, a couple of years later, in an interview with NBC’s Today Show:

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Interviewer: In testing any new drug, drug, don't we eventually get to the point where we have to try it out in human beings?  

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Frances Kelsey: Uh, certainly that is the only way in which you can, uh, find out their, uh, limitations, uh, and their good effects, too, in humans. Because, uh, although animals will give you a tremendous amount of information, the last analysis, the human is the person that we're concerned with, and sometimes the human may handle a drug differently from the usual laboratory animals.

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Katie Hafner: The voice you just heard is classic Frances Kelsey. Matter-of-fact. Monotonic. Just this side of bland. She could be remarking on a shift in the weather or she could be in a heated debate, and she would sound the same. Cool and professional. You probably have people like this in your life. Even when you’re getting all worked up, they remain infuriatingly unflappable. And here’s what’s even more annoying: they’re right. At least a lot of the time. 

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And in the fall of 1960, Frances Kelsey was right when she flagged the strange non-reaction animals seemed to have to Kevadon. But her job was to find out how humans reacted to it, based on the evidence that Merrell had submitted to the FDA. Because as she pointed out, in her affect-free Frances way, humans don't always handle a drug in the same way that animals do.

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So Frances’s job was to carefully look at the evidence Merrell had submitted about Kevadon’s effects in humans. According to Merrell, a few dozen doctors helped run the company’s clinical trials, and 1,589 patients participated. And about the same number participated in studies in other countries. But as Frances leafed through hundreds of pages of the company’s so-called evidence, she grew frustrated. 

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Katie Hafner: To a less experienced, less skeptical reviewer, maybe this would have looked like a good application. 

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There were doctors who’d submitted forms or letters indicating they were trying out the drug and the results so far looked “highly encouraging.” There were summaries of studies. But where were the detailed reports? Merrell should have submitted information about every patient who received the drug: their age, their sex, what they were being treated for, the dosages they were given, how long they got the drug, a description of any adverse effects…. You know, what you would need to know in order to determine whether the drug was safe! The data wasn’t there.

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Like, one doctor wrote up a summary of his tests with 30 patients who were suffering from insomnia and 15 more hospitalized for psychiatric conditions. And he mentions rashes, vomiting, convulsions in a few patients. But what doses were these patients given? And for how long? There was no placebo control in the study, so it’s hard to say whether it was the drug or maybe existing conditions. It’s just hard to draw any conclusions from this kind of data. 

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Here’s Frances herself in an interview many years later.

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Frances Kelsey: “Here was a drug that looked like it should be no problem, but at the same time there was just a feeling that there was something in the data or the absence of data that was a cause of concern.”

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Katie Hafner: Cause of concern. You can say that again. In other words, Frances was underwhelmed.

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Jennifer Vanderbes: She was the worst person as far as Merrell could imagine to have all this paperwork land because she could understand all of it.

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Katie Hafner: That’s Jennifer Vanderbes again.

Jennifer Vanderbes: Frances was extraordinarily overqualified for this particular job that she had. She had a very global overview of the mess that they had submitted to her and was very confident in the fact that what she'd been handed was really dodgy.

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Katie Hafner: Frances knew there was no way she could approve this drug, not without more information. But she also didn’t have what she needed to reject it outright: a smoking gun in the application, data proving that the drug wasn’t safe. And in the fall of 1960, while she pored over the application, reading and re-reading the studies and the doctors’ testimonials… Merrell turned up the heat.

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Jennifer Vanderbes: Merrell's FDA liaison says, you know, we really want to get this on the market for Christmas. They're- they're convinced this drug is going to be a blockbuster for the holidays. And I think this, as a pharmacologist and physician, I think this probably just, made her head explode [laughs] with outrage.

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Katie Hafner: Merrell already had brochures printed, and enough raw material to make 15 million pills. That’s a lot of pills.

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And they had every reason to be confident. Their application to Canadian authorities was chugging along nicely and would in fact be approved in late November, less than three months after they’d submitted it.

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But this FDA newcomer, Frances Kelsey, was proving to be a real pain in the butt, asking questions, dragging her feet. And really, there was nothing she could point to that was wrong with thalidomide exactly. She just couldn’t say for sure it was safe. She wanted more data, more evidence.

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If Merrell had been right, if thalidomide was as safe as the company promised, this whole incident might have gone down in history or just been forgotten as one very nitpicky bureaucrat tying up a fantastic new drug in red tape. As it turned out, Merrell was dangerously wrong. And boy, did we get lucky that Frances Kelsey was in that job at that precise moment in time.

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Katie Hafner: Because in the fall of 1960, as Frances and Merrell jostled back and forth about data and documentation, what neither of them knew was that across the Atlantic, doctors were just starting to take notice of a mysterious epidemic in babies. Usually affecting their arms or legs, sometimes their intestines or their hearts. The list of injuries went on. It was just a few babies at first, not enough to raise an alarm. Then more, and more, until it couldn’t be denied. Something strange was happening in Europe. Something was hurting these babies. But no one had any idea what it was.

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Over the next four episodes of this series, you’ll hear about arrogance and greed, about months and months of unconscionable inaction as tragedy was unfolding. And you’ll hear about women: women’s healthcare, and the women who took action to safeguard it.

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In fact, women are involved in every aspect of this story–Barbara Moulton, whom you’ve already met who blew the whistle on the FDA, Helen Taussig, another scientist, who went overseas to investigate an alarming epidemic before almost anyone in the US caught wind of it. And of course, Frances Kelsey, who took a stand in an era when we seldom if ever questioned our doctors or the medicine they gave us or the companies that made and sold that medicine.

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Katie Hafner: The story is complicated. It played out around the world over the course of years.

Many bad things happened during those years to many good people. What makes the story even more complicated is that different things were happening in different places at the same time—ultimately, everywhere, to tragic effect.

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Time plays a central role in the story because of the maddeningly slow trickle of information. And it wasn’t just because the world didn’t have the Internet back then; it was because information that could have prevented disaster was withheld intentionally.

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So in the fall of 1960, here’s where things stood: In the United States, a questionable drug had been submitted for approval. And although the drug  had been on the market for three years elsewhere in the world, a keen-eyed doctor at the FDA had spotted problems in the application. And in theory, this could have been the end of our story. But it wasn’t because each day—despite the warning signs in the application, despite a string of strange births in Europe—people around the world kept taking this drug. And they would do so for years to come.

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The drug had many names. Contergan in Germany, Insonid in Spain, Talidomida in Brazil, and sometimes it was called Distaval, like the pill that a man brought back from England, a supply of which sat in a bathroom cabinet for months and months until his pregnant wife, the beloved children’s TV host, Miss Sherri, started taking it in 1962. 

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Katie Hafner: Next week on the Devil in the Details, a father in Germany decides to investigate what caused the injuries to his baby.

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Jennifer Vanderbes: So they set out on like a road trip in an old VW Beetle, and they go sort of house to house. And they decide that what they need to do is some kind of survey. They suspect that some kind of toxin has entered the system of these pregnant women.

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Credits

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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. Hansdale Hsu mastered this episode. 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, and to 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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If you’d like to read a transcript of this episode or to learn more about Frances Kelsey, please go to our website, lostwomenofscience.org

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See you next week!

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*We’d also like to thank Lily Whear for art design.

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