Medical Sleuthing Recognized the Risks of Thalidomide

It’s the early Sixties, and Widukind Lenz, a German pediatrician, goes door to door in his efforts to search out out what’s inflicting an epidemic of infants born with shortened limbs and different critical medical circumstances.

Within the U.S. the drug firm Richardson-Merrell is battling with Frances Oldham Kelsey on the Meals and Drug Administration concerning the pending approval of thalidomide. She’s asking for knowledge that present it’s secure to make use of throughout being pregnant (spoiler alert: it’s not).

In the meantime Merrell continues to ship what is going to add as much as tens of millions of thalidomide tablets to docs in so-called medical trials. In November 1961 Lenz goes public with the outcomes of his medical sleuthing and, as host Katie Hafner places it, “the proverbial shit hits the proverbial fan.”

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TRANSCRIPT

Katie Hafner: The autumn of 1961 was a occurring time.

President John F. Kennedy: Time for this nice nation to take a number one function in area achievement…

Katie Hafner: There was a glamorous younger couple within the White Home with a president hell bent on going to the moon. The civil rights motion was gaining momentum.

James Farmer: The experience had change into a logo of the struggle in opposition to segregation not solely in southern bus terminals however all over the place.

Katie Hafner: The swinging sixties have been simply revving up. Bob Dylan gave his first live performance at Carnegie Corridor and Brian Epstein heard the Beatles for the primary time in Liverpool, England.

In Germany and elsewhere world wide , a sedative referred to as thalidomide had been promoting like mad for a number of years. Chemie-Grünenthal, the producer of that sedative, was profiting wildly.

However there was a pocket of individuals in a world of harm.

I’m Katie Hafner, and that is the third chapter of The Satan within the Particulars, a particular sequence from Misplaced Girls of Science. On this episode, we discover the proverbial shit hitting the proverbial fan.

Katie Hafner: Within the fall of 1961 in america, Dr. Frances Kelsey continued to stall the applying for thalidomide, a lot to the frustration of the producer, William S. Merrell.

On the identical time, in Europe, girls by the hundreds had given delivery to youngsters severely injured whereas within the womb.

And several other docs had taken discover.

Most notably, Widukind Lenz, the skeptical pediatrician, had been investigating for a number of months. He and Karl Schulte-Hillen, the daddy of one in every of these infants, have been speaking to as many affected households as they might discover.

However there was no apparent offender.

Then, on November 11, the story started to shift. That day, Widukind had gone to fulfill a household, this time on his personal. They have been the mother and father of a woman born with out arms. The mom talked about she had taken Contergan, Grünenthal’s thalidomide-based sedative.

The next day, Widukind visited one other household. As typical, he launched himself and defined that he was attempting to determine what was making these unusual births. And for the second time in as many days, Contergan got here up. The daddy instructed Widukind plainly he thought Contergan was the trigger.

Okay, Contergan had come up earlier than, but it surely had by no means been on the high of Widukind’s record. Perhaps as a result of lots of the households he’d interviewed did not point out Contergan. Or perhaps he too had been influenced by the corporate’s daring security claims.

However two days in a row? This time, Widukind paid consideration. He requested the daddy, what made him suspect Contergan? The daddy stated he’d learn that these tablets may trigger nerve harm. (bBy then, the information about peripheral neuritis had reached the favored press.)

After the assembly, Widukind referred to as up Karl and he requested him this: Had his spouse, Linde, taken Contergan throughout her being pregnant with Jan? Karl wasn’t certain. He’d have to search out out.

Katie Hafner: Whereas Widukind Lenz was investigating in Germany, over in america, Frances Kelsey was nonetheless jousting with Merrell’s liaison, Joseph Murray.

And if she was feeling the warmth…effectively, Frances, in typical Frances “dare-me-to-raise-my-voice” style, didn’t let on.

Katie Hafner: Sure. That’s all you’re gonna get out of the stoic Frances Kelsey.

So, within the fall of 1961, Frances wasn’t letting Joseph Murray get to her. She wasn’t going to hurry this product via if the applying was incomplete. However Murray was DONE ready.

A full yr had handed for the reason that firm had first submitted its utility for Kevadon, Merrell’s thalidomide drug. And with one other vacation season looming and visions of capsule bottles dancing within the heads of Merrell’s executives— Murray determined to name within the large weapons.

He introduced a bunch of medical investigators to the FDA to speak about their experiences with Kevadon. They have been physicians and a few professors who have been consulting for the corporate or working in some capability below contract.

The concept was to indicate Frances that credentialed docs and researchers backed Merrell’s claims about Kevadon, and put extra strain on the FDA to carry the drug to market rapidly.

However as pro-Kevadon as these hand-picked attendees have been, a few of them requested questions on Kevadon.

Questions Frances had been asking for months.

And one in every of her questions was concerning the security of this drug in being pregnant.

Katie Hafner: Frances occurred to know fairly a bit about how medicine may have an effect on embryos… As a result of throughout World Warfare II, Frances and her future husband, Ellis, labored in Eugene Geiling’s lab investigating new antimalarial therapies. It was a part of a nationwide effort to deal with troopers preventing in malaria zones.

Trent Stephens: It put her in a novel, a fully distinctive place for my part.

Katie Hafner: Trent Stephens is the co-author of “Darkish Treatment,” a guide concerning the historical past of thalidomide. He’s additionally a developmental biologist, who’s studied thalidomide’s results on embryos. And he says that in her time in Geiling’s lab, Frances started working with quinine—a well known antimalarial treatment. She and Ellis Kelsey have been testing how rabbits broke it down of their livers. And that included pregnant rabbits.

Trent Stephens: One of many issues they discovered throughout their analysis on quinine is that it passes the so-called placental barrier.

Katie Hafner: In quinine’s case, Frances was fascinated to find that rabbits in utero processed quinine very in a different way than grownup rabbits did.

Grownup rabbit livers are superb at breaking down quinine. Which is necessary as a result of in case your physique doesn’t break down a drug, it may possibly accumulate in your system past what’s secure.

And it turned out that fetal rabbits can’t break down quinine in any respect.

Katie Hafner: So Frances Kelsey knew that simply because a drug didn’t appear to harm an grownup, that didn’t imply it wouldn’t harm a growing embryo. In actual fact, throughout her personal pregnancies, she was very cautious about taking ANY medicine.

And truly, across the time Frances joined the FDA, there was a rising understanding of this: youngsters, infants, and fetuses aren’t simply adults in miniature. Their our bodies work in a different way. So you may’t assume that as a result of a drug is secure for an grownup, will probably be secure at different phases of improvement. So regardless that within the fall of 1961, Frances knew nothing about what was occurring in Europe, she requested Merrell about security throughout being pregnant. And it wasn’t the primary time. She’d requested about it just a few months earlier too, and he or she didn’t get a passable reply.

Now, Merrell did have some proof about the usage of thalidomide in being pregnant. The corporate instructed Frances they weren’t conscious of any issues—however the firm solely tried it out in late being pregnant.

Frances didn’t suppose that was adequate. The FDA wanted to know what occurred if thalidomide was taken all through being pregnant. And she or he was proper to insist on that. As we all know now, thalidomide is most damaging when taken within the first few weeks. However Merrell refused to conduct such a examine, in fact, conducting one other examine would imply one more delay in getting this drug to market. However Merrell did agree so as to add a warning to its labels indicating that thalidomide’s results on being pregnant weren’t recognized.

Nonetheless, Frances Kelsey was not able to approve the drug. And that ought to have been sufficient to maintain People secure, proper? The drug wasn’t on the market within the US.

However right here’s the issue: whereas Merrell and the FDA went forwards and backwards about labeling and research and paperwork, a whole lot of pregnant girls have been already taking thalidomide in america. Some had introduced it again from abroad. However lots of them obtained thalidomide from their docs. As a result of Merrell had distributed Kevadon, its thalidomide capsule, throughout america, with none FDA approval or oversight… And again then, that was fully authorized.

Gwen Riechmann: The canine are going to, that is going to take a second. Sorry.

Elah Feder: It’s okay. I believe- I believe it’s inevitable the pets are going to characteristic on this.

Katie Hafner: Gwen Riechmann lives in Cincinnati with a menagerie of pets.

Gwen Riechmann: I’ve two Shelties. and two cats.

Katie Hafner: Elah, our senior producer, referred to as Gwen up on Zoom just a few months in the past. Gwen closed the door to maintain the pets out, however some have been insisting on becoming a member of anyway.

Gwen Riechmann: Um, that seems like Arwen. The small feminine who’s making all of the noise for the time being. She has to say one thing about the whole lot.

Katie Hafner: Gwen is in her early 60s now, and he or she’s a thalidomide survivor. She was born in Cincinnati in Could 1962. And take note of that date. Could 1962, no less than a yr after Frances Kelsey first requested Merrell for proof that thalidomide was secure to take throughout being pregnant.

Gwen Riechmann: I used to be born with phocomelia of each arms, which implies my arms are quick and misshapen. One arm is eight inches. The opposite arm is 12 inches in size. And each ft are clubbed, which means they actually seem like golf golf equipment.

Katie Hafner: Till she was about 5, Gwen may stroll and play tee ball along with her brothers within the yard by transferring round on her knees. However later, surgical procedure that was meant to assist her really made it tougher for her to stroll, and he or she began utilizing a wheelchair. Gwen says that when she was rising up, her mother and father inspired her to be as impartial as potential, and basically, took a “robust love” method to elevating a baby with a incapacity.

Gwen Riechmann: For example, if I attempted to get them to do one thing like go get one thing for me that my mother and father knew I may do, my mother and father would say, are you handicapped or one thing? Go do it your self.

Katie Hafner: Gwen says she didn’t ask her mother and father a variety of questions on her incapacity as a result of it was clear they didn’t need to discuss it. So, for years, she assumed her phocomelia was genetic. There are, actually, very uncommon genetic circumstances that trigger phocomelia—the shortening of the limbs. However Gwen’s situation wasn’t genetic.

Gwen Riechmann: I did not really hear the phrase thalidomide till I used to be like seventh, eighth grade.

Katie Hafner: Gwen went to a public faculty for youths with bodily disabilities. And, like at most faculties, round center faculty, the lecturers break up up the boys and the ladies to speak about intercourse schooling.

Gwen Riechmann: And so they stated if anyone desires to, discover out in case you may move your incapacity on to a child we’ll be blissful to speak to you. And so once I got here residence that evening, mother stated, “So how did it go?”

Katie Hafner: So Gwen instructed her mother concerning the child dialog, and he or she stated she didn’t have a variety of questions for the nurse as a result of she already knew her situation was genetic.

Gwen Riechmann: And my mother stated, effectively, that is not really the case. And I stated, effectively, what’s it then? And that is when she stated, it is from a drug referred to as thalidomide that I used to be given once I was pregnant with you. And that was it. Dialog over.

Katie Hafner: Gwen finally discovered that her mother had been given thalidomide someday round October, 1961, throughout her first weeks of being pregnant.

In October, 1961, Kevadon was, in fact, not on the market in america. Frances Kelsey hadn’t authorized the drug. However simply because the drug wasn’t authorized, didn’t imply the corporate could not distribute it in “medical trials.”

Now, once I use the phrase “medical trials,” you may be imagining a rigorous, placebo-controlled examine, with sufferers systematically recruited, and signs fastidiously tracked on clipboards.

Effectively, that’s not how issues labored again then.

Drug firms didn’t really need approval from the FDA to conduct a medical trial. All they needed to do was flip in no matter outcomes that they had provide you with once they submitted the drug to the FDA for approval. Okay, we do not know for certain, however theoretically, for example, they might ask, , 100, a thousand, ten folks. Gee, how do you’re feeling on this drug? And someone may say, Oh, yeah, fairly darn good. …

However what Merrell had carried out to provide you with its outcomes…. Effectively…it virtually defies perception.

Katie Hafner: In 1958, after Merrell first obtained the license from Grünenthal to promote thalidomide, the corporate obtained busy recruiting docs to check the drug. Merrrell was primarily based out of Cincinnati, and a type of docs was a Cincinnati obstetrician named Ray Nulsen. He simply occurred to be a good friend of Merrell’s director of medical analysis, Raymond Pogge. And I believe the Nulsen/Pogge story tells you the whole lot it’s worthwhile to find out about these so-called medical trials.

Nulsen handled just a few hundred pregnant girls every year, and Pogge requested Nulsen to check out thalidomide with these sufferers to assist calm their nerves at evening. In June 1961, Nulsen printed a paper within the American Journal of Obstetrics and Gynecology titled

“Trial of thalidomide in insomnia related to the third trimester”. The paper had a really upbeat conclusion: thalidomide was a secure and efficient sleeping agent to be used in late being pregnant.

However right here’s what would finally come out: Ray Nulsen didn’t really write that paper. Afterward, in a authorized deposition he admitted that Raymond Pogge, his buddy at Merrell, had written the entire thing. The lawyer doing the deposition requested him, how about all of the papers cited in that article? Did you learn these? Nope. Okay, so what about all the info—do you’ve copies of the studies you despatched to Merrell?

Nulsen stated, no, it was all verbal and he defined it was quote “by phone, or it might have been that we had lunch collectively, or it might have been after we performed golf.”

Dr. Ray Nulsen… was the physician who handled Gwen Riechmann’s mother.

Gwen Riechmann: she did say that she had solely taken one dose of the thalidomide that she was given.

Katie Hafner: However that one capsule was sufficient.

Neil Vargesson: There are research going again to1990s, early Nineties that counsel only one pill is sufficient to trigger harm to the embryo.

Katie Hafner: Neil Vargesson is a professor of developmental biology on the College of Aberdeen in Scotland. He’s carried out in depth analysis on thalidomide’s results. We now know that one of many most important ways in which thalidomide harms embryos is by blocking angiogenesis, the event of blood vessels.

Neil Vargesson: It is the motion of the drug on the blood vessels that is inflicting the harm. And as you destroy the blood vessels, you then get cells dying off. And it does it in a time dependent manner.

Katie Hafner: So if an embryo is uncovered to thalidomide when the arms are forming, the blood vessels feeding these tissues will die and the arms gained’t develop. Similar with the ears, the guts, the mind…

Neil Vargesson: It is so simple as that. You have to keep in mind that, oads of issues are forming at that time. It is not just like the limbs kind, after which the ears kind after which the nostril types.Now, they’re all forming on the identical time. In order that’s why many survivors have gotten a number of damages and no two survivors look the identical. All of them look distinctive as a result of it was relying on when their mum took the drugs.

Katie Hafner: There’s a important two-week window for the sort of hurt usually related to thalidomide, and that window begins roughly three weeks after fertilization. When thalidomide is taken in that window, you will discover results on arms, legs, hearts… all of the signs we’ve talked about earlier than. However hurt isn’t restricted to that two-week window.

Neil Vargesson: in case you took the drug earlier than the so-called time delicate window, you’d find yourself in a miscarriage as a result of you may think about all of the blood vessels can be destroyed.

There can be no blood vessels, so there is no embryo. And in case you took it after the so-called time delicate window, you may not see harm to limbs. However you’d see inner organ harm and probably mind harm as effectively.

Katie Hafner: In October 1961, when Gwen Riechmann’s mom took that capsule early in her being pregnant, she wouldn’t have recognized any of this. Her physician wouldn’t have recognized both. On the time there have been, at most, suspicions about thalidomide. But it surely was only some weeks later, throughout the Atlantic, that Widukind Lenz had two fateful interviews with two households in Germany, each naming the identical suspect: Contergan. So after years of ladies taking this rattling drug, Lastly Widukind Lenz was about to set issues in movement

And right here’s the way it all unfolded. In November of 1961, after months of investigating these mysterious births, aggrieved father, Karl Schulte-Hillen, and dogged pediatrician, Widukind Lenz, had gumshoed their technique to a main suspect: Contergan.

Right here’s creator Jennifer Vanderbes once more:

Jennifer Vanderbes: The robust a part of this story is that after Karl realizes it is this drug, he has to return and ask his spouse if she took it.

Katie Hafner: At first Linde Schulte-Hillen couldn’t bear in mind even taking Contergan—the German model of thalidomide. However then a reminiscence surfaced. A yr earlier, when Linde was just one month pregnant, her father had died. The household had traveled to attend his funeral. It was a anxious time, nerves have been frayed, and on the finish of the day, the entire household took a sedative, together with Linde who was pregnant.

Jennifer Vanderbes: She took one or two and that, within the first trimester of being pregnant early on, instantly affected Jan in his improvement.

Katie Hafner: On November 15, 1961 Widukind referred to as Grünenthal. He reached a person named Heinrich Mückter. We may dedicate a whole episode to only this man. However the necessary factor to know proper now could be that he wasn’t simply any Grünenthal worker. He was the corporate’s chief science officer, and he had performed a key early function in thalidomide, and he obtained a lower of each package deal of thalidomide bought.

Widukind instructed Muckter that Grünenthal wanted to take the drug off the market instantly, and the subsequent day, he put that request in writing. And he didn’t mince phrases. He wrote in his letter that merely ready for proof that the drug was innocent was indefensible. This drug shouldn’t be bought till it was conclusively proven to be SAFE.

After which, that weekend, Widukind attended a pediatricians’ convention. And through a session concerning the uptick in phocomelia circumstances being seen across the nation, he stood up. Widukind stated that he had recognized a substance that may be accountable. He couldn’t but show that it was the reason for these accidents, but it surely was conceivable, and in order a citizen he may now not stay silent.

Jennifer Vanderbes: He did not need to identify the drug, however he says there’s a drug. We’re fairly certain it is inflicting this epidemic of phocomelia.

Katie Hafner: And he made an pressing plea–proper there in public–that the unnamed “substance” be withdrawn from the market instantly. He warned that every month’s delay meant dozens extra infants could be harmed.

Early the next week, Grünenthal despatched three representatives to fulfill with Widukind Lenz in individual. He was able to current his case, however he needed witnesses current for this dialog, and so within the afternoon of November twentieth, they met together with three representatives from the Hamburg College clinics and 4 from the Hamburg well being authorities.

It was, by all accounts, a tense assembly. Grünenthal needed Widukind at hand over all of his supplies. However a few of that was confidential affected person info, and a few was property of the Hamburg clinic, and it wasn’t his at hand over. The Grünenthal facet stated if he didn’t flip the fabric over to them, then any delay in motion could be his fault. He stated he’d seek the advice of with a lawyer and the group would reconvene the subsequent morning.

The next morning, he gave them copies of his redacted notes. Now Grünenthal tightened the screws. The representatives stated there could be authorized ramifications if Widukind made false accusations in opposition to the corporate. And Widukind requested them flat out— would they assure they’d not use the fabric he introduced in lawsuit in opposition to him? No, they stated, they couldn’t assure it.

So They scheduled one other assembly for later within the week Friday, November twenty fourth, this time in Dusseldorf with representatives of the regional well being ministry. Widukind later described being repeatedly interrupted by the Grünenthal’s representatives as he tried to current his proof, however this time, he took an excellent firmer stand. No, he stated, he couldn’t say the case was definitively confirmed, however the proof was overwhelming and there may very well be no affordable doubt.

Katie Hafner: I need to take a minute – or perhaps a minute and half – to speak about this man, Widukind Lenz. Right here you’ve the son of a Nazi, and never just a few run-of-the-mill Nazi… Fritz Lenz, let me remind you, was a outstanding eugenics specialist who endorsed racial cleaning even earlier than Hitler. And he believed that disabled folks needs to be sterilized – i.e. forcibly prevented from reproducing. Fritz Lenz was nonetheless very a lot alive and espousing his eugenic theories when his son took on Chemie Grünenthal, within the identify of each single toddler severely disabled by the hands of dangerous medication.

Like his father, Widukind later grew to become a geneticist. However not solely did this apple fall removed from the tree, it rolled as distant as potential. I can solely think about the braveness it will need to have taken for the youthful Dr. Lenz to do what he did in 1961, nonetheless not even a era faraway from the Third Reich.

Like Frances Kelsey, Widukind Lenz was no grandstander. The 2 folks hadn’t met one another, in fact. From what we are able to inform from the scant little bit of audio we’ve heard, Widukind was soft-spoken however confident. And like Frances, he got here throughout as …. perhaps slightly dry… a radical dot-all-your-i’s-and-cross-all-your-t’s individual.

Katie Hafner: So you may think about the extent tones he will need to have used when assembly with Grünenthal’s representatives. In the long run, the Grünenthal folks did agree so as to add a label warning to not use Contergan throughout being pregnant.

However then they left, and Widukind stored speaking to the federal government folks. This time, with out the Grünenthal crew within the room, Widukind introduced his supplies extra totally. And it was determined – a warning label was not sufficient. Quietly withdrawing the drug from the market wouldn’t be sufficient. No, as one physician on the assembly put it, “It should disappear out of the final drawer in each home,” The phrase needed to get out. The state Ministry of the Inside would instantly ship cables to native well being departments telling them to cease the sale of thalidomide and make contact with different state governments to warn them as effectively.

Then issues actually exploded. Somebody who’d heard Widukind’s speech at that pediatrician’s convention had gone to the press and on Sunday, November 26, the newspaper, Welt am Sonntag printed a narrative that shocked the general public. The headline: “Delivery defects resulting from tablets?”

Jennifer Vanderbes: Grünenthal fully loses its thoughts in panic the second they notice that the sport is up.

Katie Hafner: Inside just a few hours of the publication of that story, Grünenthal introduced that it was eradicating Contergan from circulation till questions on phocomelia have been resolved.

And the subsequent day, Grünenthal despatched out warnings to docs and pharmacies however they didn’t say this was a doubtlessly harmful drug that they have been withdrawing to maintain the general public secure. Take heed to this wording from a message they despatched to the West German Federal Medical Affiliation. As Grünenthal defined it, the choice got here quote “as a result of press studies have undermined the premise of scientific dialogue.”

However the strain continued to mount. The West German Ministry of Well being put out an pressing warning to girls, telling them the capsule suspected in these births was thalidomide. And urging them: DO NOT TAKE THIS DRUG.

One different factor that occurred—Grünenthal needed to alert all the businesses it had licensed this drug to. And so, on November twenty ninth, William S. Merrell obtained a cable from Grünenthal letting the American firm know that there may be a difficulty with thalidomide–a potential affiliation with injured infants—they have been withdrawing it from the German market. The following day, Joseph Murray referred to as the FDA. He had some disquieting information.

Katie Hafner: Subsequent time on The Satan within the Particulars…

Sherri Chessen: “My physician stated, the abortion has been canceled. They do not know who it’s, however the county legal professional is aware of that somebody right here in Arizona goes to have an abortion and they’re going to do a citizen’s arrest.”

Katie Hafner: Elah Feder was senior producer for this episode, and Deborah Unger was senior managing producer. Sarah Wyman was producer. Our affiliate producer is Mila Rahim. Sophia Levin and Eva McCullough supplied analysis help.

Our music was composed by Lizzy Younan – apart from the very first piece of music you heard on this episode, which is named “Brit Pop,” by Scott Holmes Music.

We had truth checking assist from Lexi Atiya. Alexa Lim edited the audio. Morgane Fouse mastered this episode. Lisk Feng created the artwork for the season and Lily Whear did the artwork design.

Thanks, as all the time, to my co-executive producer, Amy Scharf, and to Eowyn Burtner, our program supervisor. Thanks additionally to Jeff DelViscio at our publishing companion, Scientific American. We’re distributed by PRX.

Funding for Misplaced Girls of Science is available in half by the Alfred P. Sloan Basis and the Anne Wojcicki Basis.

For a transcript of this episode or to be taught extra about Frances Kelsey, please go to our web site, lostwomenofscience.org and don’t forget to hit that all-important omnipresent donate button.

See you subsequent week!

HOST: Katie Hafner

SENIOR PRODUCER: Elah Feder

SENIOR MANAGING PRODUCER: Deborah Unger

GUESTS:

Trent Stephens, developmental biologist and author

Jennifer Vanderbes, novelist, journalist, and screenwriter

Gwen Riechmann, thalidomide survivor and vp of the USA Thalidomide Survivors

Neil Vargesson, chair of developmental biology, College of Aberdeen