Stalling for Survival - A Lonely Fight Against a Deadly Medicine

Pushkin in a neat Washington, DC office with pealing green walls. Time is running out for softly spoken, incredibly thorough doctor Francis Oldham Kelsey. It's November nineteen sixty, two months earlier. A thick bundle of papers several phone books worth arrived on her desk at the Food and Drug Administration. It was an application for a new drug to be approved for the American market. Francis and her small team had been given sixty days to approve or refuse a drug, and this application was expected to sail through. The drug has been given the name Kevedon and reportedly a side effect free sedative that can ease anxiety, insomnia, and morning sickness.

For years, it's been used by millions of people in Europe, Africa and Australia. Manufacturer William S. Merrill is so confident of a swift approval in the States. It's already printed promotional material for the wander drug and gathered the ingredients to make fifteen million pills. But something isn't sitting right with Francis Oldham Kelcey. She would later say.

Here was a drug that it looked like it should be No prodent, but at the same time there was just a feeling that there was something in the data, of the absence of data that was a cause of concern.

The trouble is Francis doesn't have any hard proof that there is a problem with Kevidon, and the end of her sixty day review period is fast approaching. If she doesn't to prove it or reject it by then, the company can sell it regardless. What can she do to buy herself more time to determine the drug's safety. William S.

Merrill is pressing Francis hard. An approval for the mild sedative in time for Christmas would be very lucrative. After all, it's hugely popular in West Germany, where it goes by the name of Contagan, in Britain, New Zealand and Australia or it's called distaval, and in South Africa where people take tero sediv. So many names for the same drug. Forlidamine, I'm Tim Harford and you're listening to cautionary tales. Today, solidamide is synonymous with babies born with terrible injuries suffered during pregnancy. But in the nineteen sixties, no one appreciates the danger. It's a very mild sedative, after all, freely available in forty six countries only. Francis Oldham Kelsey stands in the way of pelidamide entering the American market. Here

to tell us all about this incredible woman is Katie Hafner of the Lost Women of Science podcast. Katie, Welcome to Cautionary Tails.

Tim, Thank you so much for having me. It's a pleasure.

Now. A Lost Women of Science is a remarkable podcast. Just give us the quick explanation of what it is that you do.

Well, armantra Is, We're not mad, We're curious. Okay, we're a little mad. So we started the podcast a few years ago with the idea that for every Marie Currie or Rosalind Franklin out there whose story has been told, there are hundreds, if not thousands, of women whose stories deserve to be told. And we have a growing database of something like three hundred and fifty women, all of whom did remarkable work in science, and we are just chipping away at it and telling their stories.

Well, we're going to tell Francis Oldham Kelsey's story today with your help. So just tell me a little bit more about this woman.

Well, she was, as you say in your introduction, soft spoken, a very serious scientist. She was an MD and a pharmacologist, and she wanted to be a scientist from a very early age, which was at that time fairly on new usual for a woman. And this woman, by the way, was Canadian. She was also a very wonderful mother. We talked to one of her daughters in her spare time, and I just love this. For a good time, she would read medical journals with her husband, who was also a pharmacologist after dinner. The kids remember, oh yeah, mom and dad would do their romantic thing and discuss what they just read in the BMJ.

Or kill upon the sofa and discuss the LA pharmacological trial. I love that Francis had a PhD in pharmacology. I believe she was the first woman in the United States to earn a PhD in pharmacology. And she had early dealings with the FDA because her mentor, EMK Guiling, had been asked by the FDA to look into a medicine called Elixir sulfonilamide, which was this cherry flavored cold medicine that was suspected of having killed over one hundred people many of them children. So in the late nineteen thirties he was asked to look into that. Was Francis Oldham Kelsey involved in that investigation or just here about it?

Second hand?

She was involved, and I think it planted a seed in her head about the need for strict, rigorous requirements for FDA approval for drugs. It was really kind of a free for all, yeah before them, which is how this crazy anti freeze thing happened.

Yeah, so this drug had an anti freeze diathleene glycol, which is potentially deadly to kill people.

I mean, can we just stop for a second and say, how crazy is that?

Okay, yeah it is. I Mean one of the points that last Women of Science mentioned, which I just thought was fascinating and horrifying, is that the FDA wasn't actually in charge of me making sure that that sort of thing was safe. It wasn't the FDA's job to make sure that the cough medicine wouldn't kill you. It was the FDA's job to make sure that the cough medicine had what the manufacturers said it had in it. So they said it had anti freeze in it, and it did have anti freeze in it, so there's no problem.

The law changed after that, understandably.

Right, and we're going to see later on how the law changes even more thanks to her.

And the other thing that she did that I think would later become important as a young scientist was to investigate quinine, which is a drug used for a malaria medication. And one of the things that she and her colleagues discovered was that that drug could pass the placental barrier, so it would get into the fetuses of pregnant animals who were given quinneen.

Yes. In fact, this is how she met her husband. I love it, you say quinn, and we say quinine.

So okay, I'll allow it. So Yes.

This experience she had with the quinine work was really important because again it planted a seed in her head about the placental barrier, which then plays a very important role in her concerns later about the litamibe.

Okay, So she's seen that drugs can pass into a fetus. She's seen that the work of the FDA is incredibly important, and if things go wrong, people die. So these are two parts of her life story, and in nineteen sixty she begins a new job as a medical reviewer at the New Drug Application Division of the FDA, working in Washington, DC, and just a few weeks later, in September nineteen sixty, this application from the drug company william S. Merrill lands on her desk. So just tell me a little bit more about the company and about the drug they we're trying to get approved.

The drug Poaltamide had been developed by the Germans not long after World War Two. This company, Kemi, Grunenthal and Merrill was the American company that was hoping to take this thing to market. It was hugely successful in Europe and elsewhere. Politimide was considered this wonder drug, a sedative substitute for barbituates. In other words, it had none of these hangover qualities. It wasn't addictive, there were no side effects that could be determined, and it was taken for anxiety, for insomnia, and later it was prescribed for morning sickness.

And people were taking this drug just popping them like gum drops. And there was a very cozy relationship between the pharmaceutical industry and the FDA, and a lot of these drugs were just basically rubber stamped. And she was new Francis Kelsey was brand new to the agency, and everyone thought, well, you know, the new girl will just stamp it, and this thing will be on the market by Christmas and we're good to go.

Yeah, the new girl, who's we should say, I think it's in her forties at this point, but yeah, sure, then you go.

Yes, the new girl and her they could I think they actually said the new girl.

Absolutely, I've no doubt that they did. The claim for this drug is that it's completely safe. You literally cannot overdose on it. It's risk free. But Francis Kelsey wasn't so sure. What was it that made her doubt this?

Of course, there was a deluge of paperwork and she was going through all of this. She said, something like several phone books worth of paperwork, and she just didn't see the science. She didn't see the evidence. She didn't see what have come to be known as clinical trials done in any kind of rigor. And she just said, this just isn't working for me, guys, And she did not rubber stamp it. She wanted more evidence that it was safe.

Yeah, And she took her work home with her and she showed it to her husband because he's another pharmacologist. So she's getting a second opinion, and he picked up on this this weird claim that there is no lethal dose. You can overdose on water, but apparently plidamide you cannot overdose on plidamide.

So yeah, so exactly, so that's a red flag. There had been no animal testing, and also others in the office who could read the German because Merril had included all of these so called studies that the Germans had done, and apparently the translations weren't done properly, and you know, there were all kinds of things to him that made her just say, well, wait a minute. I mean, this was a woman who critis and dotted her eyes and it wasn't working for her.

So she looks at this and she goes, well, it seems strange that they haven't done really good studies. It seems strange that they've watched the translation. It seems strange that they've made this extraordinary claim that it's absolutely non toxic. There's no actual evidence that it does any damage. And she's only got sixty days to approve it or reject it, and she can't reject it because there's no evidence that there's a problem. So what does she do.

Francis had a mentor at the FDA named Barbara Malton, who actually left in a very high profile way. And Malton was very outspoken.

Another difficult woman, Yes, another dog.

And Malton said to her, you know, here's what you could do. You could just declare the application, regardless of how many phone books it's taken up, as incomplete. And so that's what she did in order to buy herself time. So this thing came onto her desk in September. In November, she declares it incomplete and infuriates infuriates the people at Meryl.

Yeah, because they want to sell this drug in time for Christmas.

Which is Confuciuscy for Christmas, Like, because everyone needs sedatives at Christmas.

Yeah, yeah, nothing says Christmas like a sleeping pill. Right. Okay, so the clock resets, but it's still ticking. Francis Kelsey's no closer to finding any actual proof that there is a problem. So where should she look for answers? How does the son of a Nazi geneticist come into the picture. We will find out the answers to these questions. After the break, we're back and I am joined by Katie Hafner, the host of Lost Women of Science. So Katie we left Francis Oldham Kelsey having brought herself a little bit more time. But she still doesn't have any proof that this new drug Kevidon aka solidamide is dangerous. She just has this gut instinct that something's not right. So what does she do next?

Well, what she does next thanks to her avid interest in reading medical journals on.

The sofa with hausband yeah on the.

Song with her husband. Is that in late January nineteen sixty one. So now we're several months into this and we have missed the Christmas window. She reads a letter from a Scottish doctor in an old copy of the British Medical Journal BMJ, and the title absolutely gets her attention. It's is solidamide to blame? And what he notes in this letter is that four patients have peripheral neuritis, which is this painful tingling in the arms and feet and loss of sensation. And this happened for all four of these people after taking pholidamide for a year. So he alerts the UK distributor of polidamide, which is called distillers, and they put warnings on their labels in August of nineteen sixty, which is a full month before Meryl even

submitted its application to the FDA.

Did Merrill's application mention no these concerns or the warning nabeles, No, it did not.

The Meryl representative Joseph Murray, the one who's been communicating principally with Francis and has been harassing her to no end. He never even mentions this until he is pressed to do so, and when she brings it up with him, he says, oh, well, no, it's it's all okay.

Right, Well, he says that to her, but then he calls her boss and complains.

Right, And then he calls her boss and complains because this woman is just making his life a misery.

What did her boss do when? Because I understand that he basically accused her of Lionel. He's like, the FDA, your inspector, Francis Oldham Kelsey, she is libeling us, which is a pretty heavy claim.

It is.

But her boss backed her up, which was also infuriating to Merrill. They have so much on the line here and they're getting absolutely nowhere. And in the spring of nineteen sixty one, Francis went so far as to write a letter to Murray and say that the burden of proof that the drug is safe lay with the applicant.

You want me to approve this drug, you prove it safe. Yes, they don't expect me to prove it's dangerous. I want you to prove it safe.

That's correct.

And she was I think possibly influenced by her work on quinine. Yes, she was particularly concerned to prove it safe for use during pregnancy.

That's absolutely right, because of this whole idea of crossing the placental barrier. And that was something that she asked about time and again. And also what's very important is that Meryll had only looked at late pregnancy and what about the entire term? And Francis wanted to know about that as well.

So this dance goes back and forth between the FDA and Meryl. Francis Oldham Kelsey keeps storing the process. This takes eighteen months. Merrill keep coming to the FDA office. I think they come about fifty times. But over in West Germany there are miscarriages and children being born dead, but those who were born alive are born with these really serious.

Injuries, including at Grunental itself, Gruntel that the company that makes the drug.

So in fact, this is where some of the earliest injuries.

Yes could Yes, employees were taking this home to their pregnant wives. The very first case was a baby born with no ears in the late nineteen.

Fifties, which is several years before Franst starts stalling the process. In America, there's a.

Lot of suppression of information. There's just a lot of information that isn't getting out. And let's not forget tim as this is happening, babies are being born on many different continents, born with this severe, severe set of injuries, the most harrowing of which is folk which literally means sort of seal limbs, and babies born with very, very truncated arms and legs. And this was actually happening while this whole thrash between Meryl and the FDA was going on.

Okay, so babies are being born with these injuries, but what's the connection to fldamite. How is the connection to this drug first suspected?

So in West Germany, in Hamburg, in April of nineteen sixty one, a couple, Carl and Linda Schultehillen, had a son born with shortened arms and three fingers on each hand. And obviously it was tragic and it was shocking, but Carl's sister had recently given birth to a baby with similar problems, and Carl decides that he needs to find out what's really happening. And Carl went to talk to a pediatrician and the pediatrician was named Viticant Lens and he is, I must say, very much one of the main heroes of our story. But what's very ironic is that he was the son of a Nazi geneticist, a very very high level, really heinous human being named Fritz Lens, and the son Viticant recognized this folkomelia seal limbs in

the baby. What's very important to remember is that focomeilia is extremely rare. I think it's one in one hundred thousand births or something like that. He and the father, Carl Schultz Hillen, go off in this VW beetle across Germany and they basically they do this road trip looking for more babies who had been born with these injuries.

And in November, Vita Kent met parents who blamed contragan aka thlenamide for their child's injuries. The father says it was this pill, contragan. He's sure of it. He points the finger directly at the pill, after which Linda Schulta Hillen remembers that she has taken one and I repeat one pill that was given to her, which was Contragan aka thlenamide one, and it caused all this injury to their baby. And Viticant lends then at a pediatric's conference very boldly names Grunental, names the drug as the culprit for the epidemic, and that then gets into the papers.

I mean they push back. He's quite robust about this because there are various potential legal threats, but he's very brave. He stands his ground. And at the same time, in Australia, a pediatrician is spotting the same thing that babies seem to be suffering these injuries in the womb when their mothers are taking the lidamite. How are the drug companies responding as these patterns are starting to be observed and the concerns are being raised.

How did they respond? They did nothing. So distillers in the UK, which also had the license in Australia, did nothing. And then in Germany in West Germany. Grunenthal was extremely hostile to viticant lens and threatened legal action, but did agree to a warning label advising against the use of the drug during pregni and see, so it's all beginning to unravel for them, Grunental and so then and this is when things get truly dramatic. A story leaked to the press in late November, around Thanksgiving of nineteen sixty one, and the headline of this story was birth defects due to pills question Mark. And so that's when the company finally, finally, after years of tragedy, removed it from the market. And

then the Ministry of Health in West Germany put out an urgent warning.

Yeah, so years of tragedy in West Germany. The drug has only been on Francis Kelsey's desk for fourteen months, correct, I mean, I say only fourteen months. That seems like a very long time to Merril. So Merril are told what's happening in Germany? What do they do?

They do not believe it or not withdraw their application? Can you believe that?

I mean just right?

It's a bold move. Yes, What do they tell Francis Kelsey? What is Joseph Murray, this man who who has been complaining about Francis Kelsey to Francis Kelsey's boss, what does he say?

He calls her and he says that they're not withdrawing their application for licensing this drug, and.

Does he have any explanation as to what's going on in Germany? Does he think the Germans have just made a mistake, They're making a fuss about nothing.

Joseph Murray, the Meryl rep, calls Francis and he says, oh, yeah, not to worry. This is probably just an unfortunate coincidence, and we're going to send a rep to Germany to sort this all out. But they do not, I repeat, they do not withdraw their application.

Incredible. It seems that Francis Olden Kelsey is is vindicated. At this point. The evidence is starting to grow that this is a very dangerous drug for pregnant women. Her rather bold move of saying I want to see more information, I want to see more evidence that it's safe. I want to see more evidence that it's safe during pregnancy has been I think, utterly vindicated by events in Germany.

Right, And what's interesting is that she didn't know specifically what was happening and how what the actual mechanism of the drug was to injure the fetus. But she just knew it didn't sit right with her. So there's a lot to be said for going with one's gut right in.

This case, for sure, Francis Oldham Kelsey clearly had a very well developed gut based on all of her training, all of her reading, and all of her experience.

A golden gut exactly.

You would think that the story ends there, job done. Validamide not approved in the United States. However, Francis Kelsey is about to learn that actually pregnant women have been taking this dangerous drug all across the United States. Caution retales will be back after the break. We're back. I am with Katie Hafner, the host of the Lost Women of Science podcast, and she is telling the story of Francis Oldham Kelsey. So, Katie, by now it's December nineteen sixty one. Terrible things have emerged in Germany, but in America, the merial application for kevdon akahldamide is still active. Francis Olden Kelcey, the dogged data detective, has been vindicated in repeatedly deferring the approval of this drug, and as a

result that she saved thousands of Americans from being born with severe injuries caused by thlidamide. So a happy story at least the United States. No.

Merrill was getting this drug to doctors all over the United States who were then giving it to patients in little envelopes and patting pregnant women on the head and saying, here, this will easier morning sickness. Take this. This is a new drug that's just coming down the pike. And aren't we lucky that we happen to have samples? And these samples were given by the thousands to American women.

And I mean, the extraordinary thing about this is this wasn't for profit, at least not directly. They weren't selling these drugs. They were distributing them because it was part of what I think we might very loosely call a clinical trial. But there's no clinical trial I've ever heard of.

I think they were priming the market for this drug, and by the time it was approved, people would already be taking it. It's an anchoring bias. Oh, I'm anchored in this particular drug. And what happens with doctors is that they get anchored in prescribing a particular drug, and that kind of seeding is very very common to this day.

We know that Francis has been suspicious about some of these sloppy doctor's reports that she read as part of the Meryal application. They hadn't recorded doses or length of time on the drug, or the reason for prescribing anything like that, But was there anything more untoward?

This is just horrible even just telling you this, Tim, just I'm so ashamed of my fellow humans. There is this one doctor who was a golfing buddy of one of the guys from Merrill, and on the golf course, you know, while they're you know, teeing off, they're kind of talking about the drug. And then this doctor allegedly writes this paper in a journal declaring the drug very safe and it was actually written by the Meryl people.

Hello, yeah, all basically he signed his name to it, but Merril wrote it.

Right I.

Meanwhile, he's giving these pills to his patients who are pregnant women whose babies may well be being harmed by it.

Who are being harmed by it, Yes, yes, that's all happening.

Please tell me that Merril at some stage with through the application.

Merril at some stage withdrew the application, thank you. How long did it take Meryl withdrew the application? Not days after it was taken off the market in Germany, not weeks months. In March nineteen sixty two, Barrel finally with Drewett's application.

Yes, not before time, at least at least it was never approved, even if it was widely distributed, and it was never approved thanks to Francis Oldham Kelsey. Was she recognized for this work at the time.

Yes, she became a total national hero. In July of nineteen sixty two, word of her work made its way to the Washington Post and there was a front page story with the headline heroine of FDA keeps bad drug off market, with a wonderful photograph of her above the fold. Just great. Even though many, many, many babies were born with focomelia in the United States, she prevented thousands more.

In nineteen sixty three, she was given the highest possible award by the President for civilian service. And there's a lovely photograph of her clearly beaming as JFK. John F. Kennedy is presenting this to her. It was a shining moment, not just for her individually, but for the United States. And this woman, by the way, was Canadian. Let's not forget that. So what was more important was that this led to really the modern FDA as we know it, which is very very rigorous trials and studies done before.

Now it's become what some people do think is a very cumbersome process. But to get a drug approved in the United States, many people trace it back to the whole polidomide tragedy.

I mean, as a professional statistics nerd, I think it's probably worth distinguishing the insistence on caution and with the insistence on rigor.

Yes, it's a balance.

Yes, there definitely is a risk of having bureaucrats who say, oh, I'm not sure, I'm not going to approve this. I want to see more, I want to wait and see, I'll see it. Because some drugs save lives, and if you make it incredibly expensive to get approval and you delay approval, then that can cost lives just as much as approving the wrong drug can. But I think it's absolutely essential to demand rigor and to say, you know, you need to do the proper clinical trials, you need to disclose the appropriate information. It's not okay just to include some letters from some doctors, which by the way, the doctors didn't even write.

Who were on the golf course when they thought about it.

Yeah, yeah, and bury the information from the British Medical Journal kind of cough and divert attention from what's going on in Germany and basically say, well, look, we really want the drug available by Christmas. Why do you hate capitalism? Rigor is important, even if we don't just want to turn down every drug on principle exactly.

Well, let's talk about this for a second. There are two things that come to mind for me. One is that there's a very interesting coda to the whole story, which is polidomide actually has proven to be quite efficacious, quite effective for treating leprosy and multiple myeloma. Isn't that interesting?

Which is a cancer, isn't it?

Yes, So it's having kind of a you know, a renaissance, and so that's interesting. But the other thing, on a kind of darker note, is ugh, so our new Secretary of Health and Human Services.

The nephew of President Kendy.

Yes, yes, the nephew of the very man who bestowed this honor upon Francis Kelcey our FK. Junior. During his confirmation hearings, he invoked Francis Kelcey to the horror of us that lost women of science, and he said, my uncle gave this medal to this woman, Francis Oldham Kelsey in nineteen sixty three, which is when the medal was given.

So he was right about that, but he was wrong about a few other things. He said she worked at the NIH. He said she was young.

She was not.

She was in her forties. And he said that there was like a panel of people who had approved the drug. And then he said, and she was screaming. She never screamed, and she prevented all of this horror and tragedy from coming into the United States. But then he said something very interesting. He said, she stood up to science.

And yes, stood up two, stood up four two.

Two those were his words. It's funny you say that, because I went back and listened to it three times. And he said she stood up to science, and in others words, she took a stand against science. You know, this is the whole anti vaccine movement is. You know, we don't believe these scientists. But she was just she was reacting to bad science or nonexistent science.

No science at all in many cases.

Yes, exactly, And so he has twisted this this history really to align with with his agenda, which was really unfortunate.

Yeah, if the lesson is you need to stand up to science, I think that's well, that's certainly not what Francis Kelsey would have said or indeed what she did.

Oh, she would be horrified to see her name used that way.

Well, let's let's end on a slightly cheerier note. What did she? What did she? What did she do? The rest of her career, she.

Stayed at the FDA, and you know, she maintained a surprisingly low profile, and later she helped spearhead this new division at the FDA called the Division of Scientific Investigations. They were known informally as Kelsey's cops, and they were tasked with inspecting clinical sites to test the integrity of data.

And she never wavered, and she lived well into her nineties. But you know, her name eventually sort of disappeared to the point where very few people recognize it.

Yeah. Was she retired at the age of ninety in two thousand and five. She lived at the age of one hundred and one, which is quite quite incredible.

And she was in Canada in her final years and she received the Order of Canada medallion and she was too sick to leave her house, so the medal came to her. I love that.

Yeah, thank you so much, Katie. I've been talking to Katie Haffner, who was the host of Lost Women of Science. Wonderful podcast. You can get it in all the usual pod places. This has been fascinating, Katie. Thank you so much. Thank you Tim, thank you for everyone else. I will be back next week with another cautionary tale. Cautionary Tales is written by me Tim Harford with Andrew Wright, Alice Fines, and Ryan Dilly. It's produced by Georgia Mills and Marilyn Rust.

The sound design and original music are the work of Pascal Wise. Additional sound design is by Carlos San Juan at Brain Audio. Bend Daf Haffrey edited the scripts. The show also wouldn't have been possible without the work of Jacob Weisberg, Greta Cohne, Sarah Nix, Eric Sandler, Christina Sullivan, Kira Posey, and Owen Miller. Cautionary Tales is a production of Pushkin Industries. If you like the show, please remember to share, rate, and review. It really makes a difference to us. And if you want to hear the show ad free, sign up to Pushkin Plus on the show page on Apple Podcasts or at pushkin dot fm, slash plus

Stalling for Survival - A Lonely Fight Against a Deadly Medicine

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