Dr. Frances Oldham Kelsey: The FDA's Stronghold

Frances refused FDA approval of thalidomide for treating morning sickness until it was deemed safe... which it wasn't. Aarati tells the story of the FDA medical officer who held the line against a shady pharmaceutical company and saved American babies. 

Transcript

Aarati Asundi (00:12)
Hi everyone. And welcome back to the Smart Tea Podcast where we talk about the lives of scientists and innovators who shaped the world. I'm Aarati and today my co-host is my mom. She has graciously agreed to listen to a story. Mom, do you want to introduce yourself?

Jyoti Asundi (00:31)
Hi, I'm Jyoti Asundi and I'm truly privileged and honored to work with my daughter, Aarati. I have great regard for her creative capabilities, her persistence, her absolute dynamism.  I am just so fortunate to have her in my life. And I thank you, Aarti, for ⁓ giving me this chance to come onto your podcast.

Aarati Asundi (00:57)
Aww, you're making me blush.

Jyoti Asundi (01:02)
No, no, no, I'm honored that I have you as my daughter. 

Aarati Asundi (01:06)
Aw well right back at you. I'm honored to have you as my mom.

Jyoti Asundi (01:08)
So thank you. Thank you. I have been a Smart Tea Podcast listener for a very long time...

Aarati Asundi (01:16)
Oh yeah, number one fan. Yeah.

Jyoti Asundi (01:18)
Number one fan. Absolutely. I just wait for your podcast to be out so that I can listen. And it's so wonderful.

Aarati Asundi (01:24)
And I also wait for you to listen so that I can hear your opinion. I'm like, this is a great story, wasn't it? Wasn't it? Did you like it? Did you like it?

Jyoti Asundi (01:34)
Yes, yes, I listen to the story and it's really wonderful because you are with me wherever I go.

Aarati Asundi (01:41)
Yes.

Jyoti Asundi (01:41)
But a little bit more about me is that I am a scientist and I have a Master's in microbiology. And I parlayed that to kind of go through my various work experiences, gathering ⁓ experience in molecular biology, immunology, and all those protein chemistry and all of that. And I'm currently a biotechie in the Bay Area. So yeah, I'm a biotech person.

Aarati Asundi (02:08)
We are a family of scientists, our whole family, yes.

Jyoti Asundi (02:11)
Yes, Your brother, my son, has gone off to the dark side of engineering, but hey. 

Aarati Asundi (02:18)
Yes, chemical engineering. Yes. 

Jyoti Asundi (02:20)
You know, he has his uses. But we are the biology people, the nature.

Aarati Asundi (02:24)
Yeah. He helps me whenever I try to cover anyone related to anything outside of biology. Chemistry, physics, math. He's required for that. Yeah. Yes.

Jyoti Asundi (02:34)
He's our guy. He has his uses. We'll keep him. So tell me, are we in for today?

Aarati Asundi (02:45)
Well today I am very excited for you to listen to this story. I think it's right up your alley. 

Jyoti Asundi (02:50)
Okay.

Aarati Asundi (02:51)
We are going to be talking about a woman scientist named...

Jyoti Asundi (02:54)
Hmm, I love that.

Aarati Asundi (02:55)
Yes, named Frances Kathleen Oldham Kelsey, And she is...

Jyoti Asundi (03:02)
You know how I am with names. You know me and with names. So what I'm going to do is write this down. What did you say? Frances?

Aarati Asundi (03:12)
Yes. Frances. She went by Frankie.

Jyoti Asundi (03:13)
Frankie I like that!

Aarati Asundi (03:16)
Yeah. And she just has an incredible story. So I was writing up this story. It actually turned out to be a little bit longer than my usual stories. And so I was trying to find ways to cut it down, reduce it, but I just couldn't. Every detail was required. 

Jyoti Asundi (03:34)
Nah. Matters. Absolutely.

Aarati Asundi (03:38)
Yeah so she is amazing. She is so strong. She worked for the FDA 

Jyoti Asundi (03:44)
Oh nice.

Aarati Asundi (03:44)
and prevented the thalidomide crisis from coming to the U S. ⁓ yeah. So she is just amazing. 

Jyoti Asundi (03:49)
wow. that's nice. That's a good story. I am excited to hear this one. She worked for the FDA?

Aarati Asundi (03:57)
She did. Yes.

Jyoti Asundi (03:59)
Okay, okay, okay. I'm excited. I'm all geared up. Yes.

Aarati Asundi (04:00)
Okay, okay, yes, all right. So let's jump into our story.

Jyoti Asundi (04:05)
Yes.

Aarati Asundi (04:05)
She was born on July 24th, 1914 in Cobble Hill on Vancouver Island in British Canada, which is a very small kind of rural town. Her father's name was Frank and he was originally from Australia, but was living in England
and was part of the British army and met her mother, Katherine, who was from Scotland there. So they met in the UK and then once Frank retired from the army, they moved to Canada and they had three kids. They had a son named Stuart and then Frances was the middle girl child. And then they had another boy named John after that. 

Jyoti Asundi (04:51)
Okay, nice little sandwich. 

Aarati Asundi (04:52)
Yeah she's sandwiched in there.

Jyoti Asundi (04:54)
That must have been a fun position in the family for her. 

Aarati Asundi (04:57)
I bet it was. 

Jyoti Asundi (04:58)
Either she was the boss of everybody or she got bullied. I have to figure out which one.

Aarati Asundi (05:04)
I'm kind of thinking she was the boss...

Jyoti Asundi (05:08)
Excellent. I love girl bosses. I love girl bosses.

Aarati Asundi (05:08)
...based on what I know about the rest of her story. Yes. Yeah. So she had an interesting education when she was growing up. She learned how to read and write by listening in on her mom teaching her older brother how to read and write. So I don't know, it sounds kind of like the mom didn't actually teach her specifically. It was like, just she was so precocious that she just was like, I'm not going to wait until you deem me to be age appropriate to learn how to read and write. 

Jyoti Asundi (05:39)
This is like those old village schools also where they have only one room and four to five grades are all crammed into the I mean, this is a little bit older. I don't know if it still happens. But in older times, they had those like one room school for the entire village and one teacher and they would kind of divide her time between the 20 students who actually managed to show up that day who were let go from their farming duties. And then...

Aarati Asundi (06:04)
Yes.

Jyoti Asundi (06:05)
...all the different grades were in the same class, the teacher had to manage, and then the four-year-old child knew more than the high schooler because of this kind of situation.

Aarati Asundi (06:14)
Yeah, I think we had another woman scientist who was the same. I think it was Stephanie Kwolek who was the same way, who just learned from the higher grades. So I think that's kind of what's going on here. but she did go to school. Theoretically, it was an all boys school. But Frances, for whatever reason, was allowed to attend. I couldn't figure out why they made an exception, but

Jyoti Asundi (06:37)
Maybe she cut her hair and wore a cap...

Aarati Asundi (06:40)
Yeah, who knows?

Jyoti Asundi (06:40)
...and said, I'm a boy and I'm actually Frankie. What do mean I'm a girl? Who said I'm a girl?

Aarati Asundi (06:43)
Yeah. She was just masquerading. So she said that being in this kind of environment from such a young age is really what set her up to be comfortable in a very male dominated career later. So I can totally tell that.

Jyoti Asundi (06:55)
Yeah, yeah, yeah, I can make out that. So it was good she was sandwiched between two boys.

Aarati Asundi (07:02)
Yeah. Yes, she has two brothers, she's going to an all-boys school... 

Jyoti Asundi (07:08)
She learned how to navigate. She learned how to navigate the, yeah, she learned how to navigate that world. Awesome, awesome

Aarati Asundi (07:11)
Outside of school, she also learned painting, piano, modern dance, and a friend of hers also taught her how to hunt, fish, and drive a car all without her parents knowing about it. I thought that was funny.

Jyoti Asundi (07:24)
I'm impressed. I'm impressed. The fact that she is such an all-rounder. Wow, nice.

Aarati Asundi (07:32)
She did really well in high school and then graduated when she was only 15 years old. At this point, Frances had decided that she definitely wanted to pursue higher education, but she was a bit young to be running after university. She's only 15. And so her high school was talked into offering her a senior matriculation year. So Frances could start doing her first year of college at the local high school.

Jyoti Asundi (08:00)
Okay,

Aarati Asundi (08:00)
So that was nice. So Frances had decided she wanted to major in science, but she had struggled a bit with chemistry. And so she thought, "maybe chemistry is not for me. I want to try biology." But to her disappointment, her high school didn't offer biology, which I thought was so strange. Luckily, though, the summer before she went back to participate in this senior matriculation year. She met a Dr. Anthony Kingscote who was a parasitologist who just happened to be on holiday in her area. And so he heard about her interest in biology. And so he met with her to give her kind of like an overview on the subject and told her that if she wanted to major in anything related to biology, she needed to start now she needed to like do her first her first year of college or her first year of senior matriculation. She had to take a biology course if she wanted to pursue it in college. But again, her high school didn't offer it. So it was arranged that Frances would be able to drop her Latin course and instead travel to Victoria College just to take biology.

Jyoti Asundi (09:17)
Good. That was nicely nice and accommodating. Yeah.

Aarati Asundi (09:20)
Yeah, they figured it out. She kind of stuck out on the college campus because all the other students were really dressed up nicely and she was in her high school uniform. so it was really obvious that she didn't belong, quote unquote. But other than that, totally worth it. She loved it. And so the next year, her following year, she went to Victoria College full time.

And then after that, she transferred to McGill University. And here she was able to take more specialized courses. So on the advice of a friend, she takes her first biochemistry and pharmacology classes and absolutely loves it. 

But when she graduated, it was the middle of the Great Depression. And so although Frances looked around for a research lab job after graduating, it was impossible for her to get one. Any open positions were always given to men.

Jyoti Asundi (10:23)
Of course. Yeah.

Aarati Asundi (10:24)
Of course, but actually, Frances did not see this as sexist. She really kind of understood that this was a time when men were considered the breadwinners of the family, and so it absolutely made sense to her why a position, a paying position should go to a man over a woman so she was like, I get it.

Jyoti Asundi (10:46)
Yeah because she lived in those times. That's how life worked. That was the model by which we lived life in those days.

Aarati Asundi (10:53)
Yeah, and so she didn't get mad about it. She was just like, I totally get it. She said... this is funny. She said, " This situation led me to realize that my choices were either to do graduate studies or to join the bread line. Those were about the only alternatives in those days and I decided graduate work would be more interesting"

Jyoti Asundi (11:14)
Oh my God. When you say join the bread line, you mean like stand in line with your hand out, 

Aarati Asundi (11:18)
Like unemployment, or welfare.

Jyoti Asundi (11:18)
For the handout and unemployment. my God. So she chose grad school because grad school is better than being in the unemployment line. 

Aarati Asundi (11:28)
It's more interesting. Yeah, it's more interesting than, you know, being unemployed.

Jyoti Asundi (11:30)
Okay. Okay. ⁓ yeah. Yeah. I can vouch for the fact that grad school is probably more interesting than the unemployment line. Sure.

Aarati Asundi (11:37)
Probably.

Jyoti Asundi (11:38)
Yeah, probably. There might be something more interesting in grad school.

Aarati Asundi (11:42)
I just loved her attitude.

Jyoti Asundi (11:42)
Oh my goodness. She's just she has. Yeah, she just like, OK, life is giving me lemons. Just make lemonade and take it.

Aarati Asundi (11:52)
Yeah. So she went back to the biochemistry department at McGill and she was looking for graduate student positions. She was particularly interested in studying the endocrine system, which is the study of our hormones. But unfortunately, all the graduate student positions were already filled. But one professor suggested she try the pharmacology department instead because there was a pharmacologist there, Dr. Raymond Stehle, who was working on the pituitary gland, which is a small endocrine gland located at the base of your brain just below the hypothalamus. The only catch was he didn't like taking on graduate students. But Frances was like, you know, I might as well try. 

Jyoti Asundi (12:38)
Yes.

Aarati Asundi (12:40)
So she went up to Dr. Stehle, explained her situation and how fascinated she was by the endocrine system. And to her great surprise, Dr. Stehle agreed to take her on for one year.

Jyoti Asundi (12:50)
She had the power of persuasion. All right. 

Aarati Asundi (12:51)
Yes, she does.

Jyoti Asundi (12:53)
She knows how to get what she wants.

Aarati Asundi (12:55)
Yeah, very persistent, very determined.

Jyoti Asundi (12:58)
Nice, like someone I know.

Aarati Asundi (13:00)
Really? After a year, she got her master's degree, but once again, she still didn't have any job prospects. The year didn't change anything. So Dr. Stehle said he would continue to pay her $50 a month as a research assistant, which back then was enough to live on. 

Jyoti Asundi (13:22)
Good times. $50 a month was enough to live on? Oh, nice.

Aarati Asundi (13:25)
Yes

Jyoti Asundi (13:27)
$50 is pretty good. So he's impressed by her. Obviously, Dr. Steel is impressed by her.

Aarati Asundi (13:32)
The only condition was like she had to actually try to move on and like look for opportunities. So ⁓ he was like, I'll keep funding you, but you need to move on at some point. So work on that.

In 1936, Dr. Stehle heard of a new pharmacology department opening in the University of Chicago. So he told Frances to try her luck there. So she wrote a letter to the chairman, Eugene Geiling, and she was very surprised to receive a letter back saying, "Dear Mr. Oldham, if you can be in Chicago by March 1st, you may have the research assistantship for four months and then a scholarship to see you through your PhD. Please wire immediate decision." So Frances...

Jyoti Asundi (14:22)
Oh wow, what? Ok....

Aarati Asundi (14:24)
So yeah, what are we gonna do? Frances showed the letter to Dr. Stehle and asked whether she should clarify that her name was the feminine Frances with an E and not the masculine Francis with an I, because

Jyoti Asundi (14:39)
Yes.

Aarati Asundi (14:40)
she knew it was very likely that Dr. Geiling didn't realize that she was a woman and that's why he was immediately saying, yes, come, we'll fund your PhD, we'll take you on. So she's like talking to Dr. Stehle, like, what should I... should I clarify this? And Dr. Stehle's like, quote, "Don't be ridiculous, accept the job..." 

Jyoti Asundi (15:01)
oh nice!

Aarati Asundi (15:01)
yeah, "Accept the job, sign your name...

Jyoti Asundi (15:06)
Yes!

Aarati Asundi (15:01)
"...and put Miss in the brackets afterwards and go."

Jyoti Asundi (15:07)
Go! Oh, good guy, good advice! Good advice. The reality is lost in translation. Take advantage of it. Yes, make... if you can't get in through the door, jump in through the window, no problem. 

Aarati Asundi (15:22)
Yeah, you said yes, I'm here. Yeah.

Jyoti Asundi (15:22)
Wow, nice. Yes, you said, yes, I'm here. I took the train and the bus and the boat and everything. And now I'm here and now you can't send me back. Yeah, yeah, and you can't send me back. You can't send me back.

Aarati Asundi (15:28)
Yeah. And now what are you gonna do? I'm on your doorstep. Like you can't send me back now, I'm here.

Jyoti Asundi (15:35)
Fantastic. I love that advice. Just grab the opportunity when it knocks on your door, even if it's little bit of a mask or whatever, no problem. Go for it. 

Aarati Asundi (15:43)
Yep. Don't second-guess it, just take it

Jyoti Asundi (15:45)
Yes, yes. Move it, move it. Yes, yes, yes. Nice.

Aarati Asundi (15:47)
So That's exactly what she did. Frances went to Chicago and she said that Dr. Geiling never owned up to whether he actually made a mistake or not, although she was pretty sure...

Jyoti Asundi (16:00)
I love that. I love that. I love that he kind of went with the flow. He's like, oops, it's a girl. But you know, I knew that all the time. 

Aarati Asundi (16:10)
I meant to do that.

Jyoti Asundi (16:12)
I meant to do that. Nice. I like it. So she got in..

Aarati Asundi (16:16)
yeah, she got in. 

Jyoti Asundi (16:16)
 and she stayed in.

Aarati Asundi (16:19)
Yeah but she was pretty sure that if she had had a name like Elizabeth or Mary or something, she would not have been accepted because Dr. Geiling actually turned out to be a very conservative traditional kind of guy and didn't really approve of women scientists. 

Jyoti Asundi (16:35)
Ha ha ha. 

Aarati Asundi (16:36)
But I also found it pretty ironic that Frances was his first PhD student.

Jyoti Asundi (16:35)
Wow, how life plays games. It's ironic, it's truly ironic fun.

Aarati Asundi (16:48)
Yeah. So for her PhD thesis, Frances worked on the anatomy and pharmacology of the posterior pituitary gland of the nine-banded armadillo. 

Jyoti Asundi (16:59)
No way. Where did she find an armadillo to study?

Aarati Asundi (17:03)
That is a great question. 

Jyoti Asundi (17:05)
Oh my god.

Aarati Asundi (17:06)
So the reason she was studying armadillos is because at the time, endocrinologists were trying to determine where in the pituitary gland certain hormones came from. And in humans, the pituitary gland is kind of separated into the anterior and the posterior lobes, but the two lobes are still connected. So when a hormone is being they don't know if it's being formed in the anterior or posterior because if it's being formed in the posterior, it can kind of travel over to the anterior and vice versa. So they're not sure.

But in some animals like the armadillo, the two lobes of the gland are completely separated, which makes it easier to differentiate where the hormones are created. So it was absolutely a weird model organism, but very useful in this particular instance.

Jyoti Asundi (18:01)
Yeah, I'm just thinking of how the heck did they go study the pituitary gland of every single animal until they found the armadillo? 

Aarati Asundi (18:11)
I feel like somebody else must have been studying armadillo anatomy for some reason,

Jyoti Asundi (18:15)
for some other reason and it was kind of known. Yeah, Yes.

Aarati Asundi (18:15)
...like a zoologist or something. It must have been kind of known that there are just a few animals that have, and I bet it was something like, well, we can either try to study whale sharks or we can try to study armadillos. I guess, yeah.

Jyoti Asundi (18:31)
Yes, and we can travel less to find an armadillo. Yeah, yeah, all right

Aarati Asundi (18:34)
Yes. Yeah. So she finished her PhD in 1938 and then she spent one year as a postdoc studying how the pituitary gland in armadillos developed. And for that, she needed to study armadillo embryos, but you can't breed armadillos in the lab. So she had to fly down to Texas to get them from an armadillo farm. 

Jyoti Asundi (18:57)
Oh my god, okay. Man.

Aarati Asundi (19:00)
So I know she spent a year doing that. 

Jyoti Asundi (19:01)
Man.

Aarati Asundi (19:03)
OK, so now we're getting into the actual meat of things. So while she's working with Dr. Geiling, ⁓ she gets her first exposure to working with the FDA. So at this point, the FDA is only about 30 years old. And if our listeners remember back to episode 22 of the podcast from last year, the founder of the FDA, Harvey

was largely focused on making food safe. So there wasn't really a lot of focus on drugs and certain chemicals. It was more about, let's make sure there's no brick dust in your cinnamon spice and things like that, no chalk in your flour. There was some understanding that there are certain substances like heroin, morphine, cocaine, and alcohol, which were very addictive and those could be dangerous. So those things had to be labeled if they were included in medicines, but that was really about it in terms of regulating these things. So in 1933, so this is jumping back just a couple of years... 

Jyoti Asundi (20:14)
Yeah, got it.

Aarati Asundi (20:14)
...a new drug called sulfanilamide was introduced in Germany. as an antibacterial to fight pneumonia and streptococcus infections. And it was incredibly successful and people started using it all around the world, even though there hadn't been much scientific research on it. The big problem arose when one manufacturer tried to change the formula to market sulfanilamide to kids. So sulfanilamide is not soluble in water or alcohol but apparently it's soluble in diethylene glycol, which naturally has a sweet taste. So he was like, great, we're trying to give this to kids. Diethylene glycol has a sweet taste. Nailed it. 

Jyoti Asundi (21:03)
That's pretty toxic, I think.

Aarati Asundi (20:05)
It is highly toxic. It is the main component of antifreeze. Yes.

Jyoti Asundi (21:10)
Yeah! I was trying to, my brain was not connecting. Oh my God. So you're basically giving kids antifreeze now or even people were... 

Aarati Asundi (21:19)
 Yeah, people, yeah.

Jyoti Asundi (21:19)
Wait a second. So wait a second. So people were taking sulfanilamide dissolved in antifreeze. And then they were like trying to move that over to the kids.

Aarati Asundi (21:32)
No, so they were taking sulfanilamide like as a pill or ⁓ in some other form because like adults can swallow pills. Yeah.

Jyoti Asundi (21:41)
okay. Okay. So adults were not being given sulfanilamide in antifreeze. Okay. Okay. But

Aarati Asundi (21:45)
Originally not.

Jyoti Asundi (21:48)
But the kids cannot swallow pills and so now you're trying to make a syrup out of it

Aarati Asundi (21:53)
Yes, exactly.

Jyoti Asundi (21:53)
...and wow look at this sweet little thing diethylene glycol kids will love that of course ⁓ goodness no way no way no way.

Aarati Asundi (22:02)
Yeah. So he mixes sulfanilamide with diethylene glycol and some strawberry flavor, and all the kids love it.

Jyoti Asundi (22:10)
Of course.

Aarati Asundi (22:11)
And the adults love it too, because why would you want to take a pill when you can have strawberry syrup, right? Like, you know, absolutely. So...

Jyoti Asundi (22:21)
Oh man.

Aarati Asundi (22:23)
So then predictably people start dying.

Jyoti Asundi (22:26)
Yeah.

Aarati Asundi (22:26)
So now the FDA is scrambling because they legitimately don't know what is causing this. They don't know whether it's the sulfanilamide.

Jyoti Asundi (22:35)
because they haven't done any testing.

Aarati Asundi (22:37)
Right.

Jyoti Asundi (22:37)
People are eating and drinking drugs and medicines and they have absolutely no clue what's going in, how toxic it is. ⁓ fun times. Okay.

Aarati Asundi (22:51)
Yeah. So they legitimately don't know whether it's sulfanilamide or diethylene glycol or maybe it's the strawberry mix flavor. Like they have no idea. So they call Dr. Geiling to help and he puts everyone in his lab, including Frances, on various projects around figuring this out. 

Jyoti Asundi (23:13)
Yes.

Aarati Asundi (23:14)
And so Dr. Geiling sets up a number of animal toxicity studies in dogs, rats, and rabbits. And Frances was in charge of watching the rat study. So they set it up so that the animals either got sulfanilamide alone, diethylene glycol alone, the strawberry flavoring alone, or the full mixture that was on the market. And sure enough, the animals that got sulfanilamide or the strawberry flavoring alone were fine.

But it was the animals that got diethylene glycol alone or the mixture that was on the market, their kidneys would rapidly shut down and they would die. 

Jyoti Asundi (23:55)
Yes, good lord.

Aarati Asundi (24:56)
So this work directly led to a new law in 1938 known as the Federal Food Drug and Cosmetic Act or FDCA, which basically empowered the FDA to test, regulate and pre-approved the safety of any new drugs before they could go on the market.

Jyoti Asundi (24:16)
Oh key absolute requirement hello. You need to test it before you let everybody randomly eat it! Oh wow. Hmm those were fun times obviously


Aarati Asundi (24:30)
Yeah, and so Frances contributed to that law happening in a small way. And this really gave her the first clear understanding of why drugs need to be regulated and tested for safety before being sold. 

Jyoti Asundi (24:44)
Yes.

Aarati Asundi (24:45)
So after finishing her postdoc, Frances joined the faculty at the University of Chicago. And at this point, many pharmacologists were looking into cures for malaria, which was widespread during World War II. Japan had invaded and taken over the Dutch East Indies, which was where most of the world's supply of quinine, which is...

Jyoti Asundi (25:07)
Yeah, for anti-malaria. yeah, yeah. Mm-hmm.

Aarati Asundi (25:08)
 Yeah, where that comes from. So since Japan had taken that over for the allies during World War II, they no longer reliable access to quinine. And so pharmacists were looking for a synthetic replacement. And all across the US, pharmacists tested over 14,000 potential drugs over the span of four years from 1941 to 1945.

Jyoti Asundi (25:34)
looking for a quinine equivalent against malaria.

Aarati Asundi (25:38)
Yeah, and they weren't successful, but through studying these drugs, Frances learned more about how certain drugs were metabolized. And one of the most interesting and pertinent to the story things that she observed was when they gave certain drugs like quinine to pregnant animals, sometimes the drug would pass through the placental barrier, but the fetus wouldn't be able to metabolize the drug the same way the mother could because their organs hadn't fully developed yet. 

Jyoti Asundi (26:12)
Yes, yes. 

Aarati Asundi (26:13)
And so Frances, in fact, ended up co-authoring a paper about how quinine was metabolized in embryonic rabbits with another faculty member, Fremont Ellis Kelsey. And Fremont Ellis Kelsey ended up marrying her in 1943. 

Jyoti Asundi (26:32)
Oh! Nice. Ok. Like minds....

Aarati Asundi (26:34)
Yeah. But this actually posed a bit of a problem because at the time it wasn't allowed that two family members were employed by the same department at the University of Chicago. So what would you do?

Jyoti Asundi (26:49)
Go to the FDA and ask them, "Hello I'm Francis with an I. Can you take me? Can you take me in?" And in the bracket I'll write Mrs. now. 

Aarati Asundi (27:08)
Apply for a job. Yes.

Jyoti Asundi (27:09)
I'll apply for a job at the FDA.

Aarati Asundi (27:11)
Which would maybe be logical, but Frances decided to take another route. She decided that the most logical way out of this was for her to go to medical school.

Jyoti Asundi (27:22)
OH she's very ambitious, fantastic. Good for her. Yes. 

Aarati Asundi (27:27)
Yes. She's already got her PhD, she's done her postdoc, she's been co-authoring these papers and

Jyoti Asundi (27:31)
And she says, I need to learn more. This is just not enough what I have done so far.

Aarati Asundi (27:38)
And she thought it made sense because she was like, you know, I've been studying so much about biochemistry and, you know, anatomy and things like that, even just in general to figure out how certain hormones move around your body and how certain drugs are metabolized. So she kind of felt like she probably would already know what was taught in the first one or two years of medical school. And so that would give her a leg up over the other mostly male students. 

Jyoti Asundi (28:05)
Yes.

Aarati Asundi (28:07)
And even though she didn't actually plan on practicing medicine, if she joined the University of Chicago Medical School, her husband could continue working as a faculty member and then they could stay together. 

Jyoti Asundi (28:17)
Yes.

Aarati Asundi (28:19)
And plus she figured if she had an MD and a PhD, people might take her more seriously as a woman in the field. 

Jyoti Asundi (28:26)
What hoops you have to jump through...

Aarati Asundi (28:29)
I know.

Jyoti Asundi (28:29)
to be taken seriously as a woman. A ⁓ PhD, a postdoc, papers. No, I need a medical degree to be taken... All right.

Aarati Asundi (28:41)
Yes. So while she's in medical school, she has two daughters, Susan and Christine. And based on what she knew about from her work, she was very, very careful about what she consumed during her pregnancies, which included no smoking and no drinking. And this was 20 years before people knew about fetal alcohol syndrome. So she's way ahead of her time here.

Jyoti Asundi (29:07)
Good for her.

Aarati Asundi (29:09)
She graduated in 1950, and because of the connections she had made in Dr. Geiling's lab, she had a job lined up for her as an editorial associate the Journal of the American Medical Association, or under Dr. Austin Smith. Smith was

Jyoti Asundi (29:26)
Now she's a doctor and she's being on the editorial board of things.

Aarati Asundi (29:32)
Yes, so she's working like as an editor at a scientific journal. Yeah. So Dr. Smith was particularly interested in publishing articles about new drugs that were coming onto the market. And so Frances was tasked with reading through these manuscripts and evaluating how thorough the science was.

About two years husband got an offer to head the pharmacology department at the University of South Dakota Medical School in Vermillion after the previous head passed away. So the family decided to move to South Dakota. But Frances then had to figure out what to do about her job. Because again, women were, you know, not really given positions very easily. and so Frances was like, well, I can either go to law school or I could do a medical internship. 

Jyoti Asundi (30:30)
⁓ Wow.

Aarati Asundi (30:31)
Thankfully, thankfully she chose the internship. 

Jyoti Asundi (30:36)
Okay. ⁓ gosh. 

Aarati Asundi (30:42)
The fact that she even considered law school was like, yes. ⁓

Jyoti Asundi (30:44)
Yeah, after all this, she's like, I can do law. Wow. My God.

Aarati Asundi (30:50)
Yeah, so thankfully she chose the internship at the Sacred Heart Hospital in Yankton. And then afterwards she was awarded the Lederle Teaching Fellowship, which supported faculty members to pursue any kind of research they wanted. So at the time radioisotopic drugs were becoming very popular. So she started learning about that. So every so often she would commute overnight to the University of Chicago to get training on radioisotopic drugs. She would stay there for two to three days and then she would head back to Vermillion, South Dakota. 

Jyoti Asundi (31:27)
How far is that? 

Aarati Asundi (31:28)
That is a good question. I don't know. Let's see. 

Jyoti Asundi (31:23)
Because these are days where you don't have airplanes to just whizz back and forth.

Aarati Asundi (31:37)
Yeah, she's going by train.

Jyoti Asundi (31:39) 
Train is it? Oh at least trains were there.

Aarati Asundi (31:42)
Yeah so it's like an 8 hour car ride. 

Jyoti Asundi (31:46)
Today.

Aarati Asundi (31:47)
Yeah today, it would be an eight-hour...yeah, I would say at least probably 12 hours by train. And so that's why she would probably stay there for two or three days. 

Jyoti Asundi (31:57)
Make sense.

Aarati Asundi (31:58)
It said she would commute overnight to the university. So I guess they, yeah, at least 10, 12 hours probably. Yeah.

Jyoti Asundi (32:00)
Okay. All right. Yeah. It's like taking the red eye. It's like taking today you take the red eye like

Aarati Asundi (32:10)
Yes. But because she did this, she became the first person, not the first woman, but the first person to get licensed to use radioisotopes in medicine in South Dakota. 

Jyoti Asundi (32:24)
Wow. Nice.

Aarati Asundi (32:27)
Yeah. So she's just nailing it. After her fellowship, Frances spent a few years practice sitting, which basically meant that when some physician in South Dakota needed to leave their clinic to go to a meeting or take a vacation, she would fill in. This worked out really well for her because she was able to stay home most days with her two young daughters. It also gave her a lot of variety in the types of medicine she was able to do. So it kind of rounded her out as a physician because until now she's been like doing a lot of drug and medication type of things into these like diseases like malaria and things like that and now it's like this little boy came in with a broken bone you know or like someone has a case of the measles.

Jyoti Asundi (33:13)
Yeah, like giving her a broad perspective on what medicine is all about. Yeah, got it.

Aarati Asundi (33:24)
Hi everyone, Aarati here. I hope you're enjoying the podcast. If so, and you wish someone would tell your science story, I founded a science communications company called Sykom, that's S-Y-K-O-M, that can help. Sykom blends creativity with scientific accuracy to create all types of science, communications, content, including explainer videos, slide presentations, science, writing, and more. We work with academic researchers, tech companies, nonprofits, or really any scientists. To help simplify your science, check us out at sykommer.com. That's S-Y-K-O-M-M-E r.com. Back to the story. 

Aarati Asundi (34:06)
So then in 1960, nearly simultaneously, both Frances and her husband got job offers in Washington, DC. Frances's offer was from Dr. Ralph Smith, who offered her a position as a medical officer at the FDA to review new drug applications. 

So at this time, the way it worked was when a company had a new drug that they wanted to sell, they would submit a new drug application or NDA. Each NDA was reviewed by a team of three people. There was a chemist who looked at what the drug was made of and all the ingredients and their properties, a pharmacologist who reviewed the animal studies and toxicity, and then a medical officer who reviewed the human clinical trials to determine safety and efficacy in people. 

Jyoti Asundi (34:57)
Ok.

Aarati Asundi (34:58)
The team had 60 days to review a new NDA and at the end of 60 days they had to either reject it or approve it. And if they didn't reject it... 

Jyoti Asundi (35:10)
It was considered approved?!

Aarati Asundi (35:12)
Yeah automatically approved.

Jyoti Asundi (35:13)
Hey! Wow! Things were different. Things are not done like that today. I mean, ⁓ the important pieces are there. I'm glad they had the animal testing and the human testing, but the FDA can take as much time as it wants. This is not right. Yeah, okay. Wow. There's lack of stringency there. So it's basically favoring the drug makers actually, then that law.

I'm in drug development. So I would like that, but no, the stringency is required. You have to make the drug... you have to put the drug through its spaces and figure out its full toxicity and all mechanism of side effects and everything. Can't just be like, yeah, let's go with this.

Aarati Asundi (36:02)
Yeah. This process is a lot more intense today, has a lot more oversight and requirements. So Frances started at the FDA in August 1960 and she was looking over the clinical trials portions of the NDA. She was a medical officer 

Jyoti Asundi (36:19)
Okay.

Aarati Asundi (36:20)
And a month later, one month later in September 1960, she was handed an NDA from the William S. Merrell Company in Cincinnati for a drug called thalidomide. So the thalidomide was already being sold in Germany and was marketed as a sedative and was also being used to alleviate morning sickness in pregnant women. And it had originally been sold over the counter, but later had become available by prescription only. That'll become important. Yeah.

Jyoti Asundi (36:54)
Over the counter. How did thalidomide get over the counter status? 

Aarati Asundi (37:02)
Yes.

Jyoti Asundi (37:03)
Good Lord. And for it to go absolutely backwards, that's absolutely backwards where you're first over the counter and then, ⁓ wait a second, we'll add some regulation to it. Let it be by prescription only. And a drug like thalidomide that I think many people might have heard of because has a horrible, horrible history. 

Aarati Asundi (37:26)
Yes.

Jyoti Asundi (37:27)
So women in Germany are being able to either go to the doctor and get it as a prescription or maybe even, hey, over the counter, I'm pregnant. I need something for my morning sickness and I want a sedative. Let me go get thalidomide. Wow. Okay. Nice.

Aarati Asundi (37:43)
Yeah, yeah. And so that's exactly how it was being treated. So Frances' bosses figure "Oh! Thalidomide is being sold in Germany, this is gonna be a really easy case for her to handle. She's only one month in, she's still getting her feet wet. Let's give her like a really easy NDA that she can just like look through and you know, like this is gonna be super easy." 

Jyoti Asundi (37:47)
Easy. Wow.

Aarati Asundi (38:06)
Yeah, so they're still trying to ease her in. They think they're being nice. Yeah. right off the bat, all three people on the team, the chemist, Lee Geismar, the pharmacologist, Jiro Oyama, and Frances all had problems with the NDA. 

Jyoti Asundi (38:23)
Thank goodness.

Aarati Asundi (38:24)
Yes. Interestingly, Frances' biggest problem was that the clinical trials just looked too good. A lot of the so-called data were more testimonials from doctors rather than actual scientific or clinical lab data.

Jyoti Asundi (38:39)
What? Wait, what? Hang on. You know, I was actually just going back in the story just slightly. You said the FDA had three people looking at the animal testing and then the clinical data. And I thought, okay, that's very comparable to what we have today. No way, no way is clinical data comprised of testimonials from doctors today. No way does that happen. 

You have very regimented what studies are called dose escalation studies today. And what that is, is you start off with what is called a SAD. It's called a single ascending dose. So you start with the smallest possible and then you watch and give only one dose and you're done. One and done. That's it. And if the person is okay and you have a certain set amount of time that you wait for them to not keel over, not show side effects, then after all the data has come in on patient number one, then you go to patient number two, somebody completely different person. And they are given slightly more. 

So if you started to say, for example, at 5 milligrams per kilogram or 5 mg/kg, then you go to the next level, 10 mg/kg. And you do the same process again and go on and on and then you go through the whole thing until you reach where you know you need to be to actually get to the point where you have efficacy. There is a point, you know fully well when you start at your single ascending dose, the whole thing.

Aarati Asundi (40:22)
Yeah, you know you need to get to 100. Yeah, but you're starting at five.

Jyoti Asundi (40:22)
You know you need to reach 100. You know five is not going to do anything, but you start at five. And then you slowly go up step by step by step until you reach 100. And you give this last person the 100 and you watch them and you get all the things in. And then you say, okay, now let's do the second phase of it, which is multi-ascending dose. Then they are, again, you start back at five because this time you're given five multiple times over a certain amount of time. And then if that is OK, then you kind of say, OK, this person can now go to 10 and then you can go to 20 like that. There's such a regimented way of doing this.

Aarati Asundi (41:01)
Yeah, and this is all after animal studies too. Like animal has to be okay first. Yeah, yeah, yeah.

Jyoti Asundi (41:05)
Yeah, after all the animals, Yeah, the animals. And it's not one animal, because there are so many cases where everything looks good in one species, actually. Like humans versus rodents, like that. The rodents may be fine, but then you kind of have to go to some other, like say, for example, dog or something. 

Aarati Asundi (41:29)
Mm-hmm. Yeah. Something with a different system, yeah, because...

Jyoti Asundi (41:31)
Something with a different system here to try different systems because the metabolism the way the drug passes through our systems is very different in different species. So you can't just be like, I'll give it in some ants and over the ants did not die and everything is fine. Oh the fish were okay afterwards. No, that's not how it works. You have to give it properly. Oh my goodness, testimonials? So you were saying to me that they were going off based on text testimonials from doctors. ⁓ Good Lord

Aarati Asundi (41:57)
Basically, the clinical lab data was some doctors saying, we gave it to a patient, the patient responded favorably, worked great. Yes.

Jyoti Asundi (42:04)
The patient didn't die and they, wow, wow, no way, no way,

Aarati Asundi (42:09)
Yeah, so three people on the team reported that the NDA was deficient and needed to be resubmitted with more information. So Merrell, the company who's submitting the NDA resubmitted again, but all three still found it deficient and sent it back again.

Then in February of 1961, Frances was shown a letter by Dr. Leslie Florence in the British Medical Journal that had been published a couple of months prior in which he wrote that when he treated patients with thalidomide, they developed negative side effects like peripheral neuritis, which is a painful tingling in the arms and legs. 

Jyoti Asundi (42:53)
Yes, yes.

Aarati Asundi (42:54)
It was pretty severe and often irreversible especially if the patient had been taking thalidomide for a long time. So Frances and her team wrote a letter to Merrell citing this letter that Dr. Leslie had given them. And they asked for more proof that this drug is actually safe. 

Jyoti Asundi (43:16)
Yes.

Aarati Asundi (43:17)
But it turned out that Dr. Leslie Florence was not the first one to report peripheral neuritis as a side effect of the thalidomide. And it turned out that Merrell, the company, actually knew about this. 

Jyoti Asundi (43:29)
Yeah. Ah! They had suppressed it! Oh my goodness.

Aarati Asundi (43:32)
Yeah. Yeah. They rather, so this is where rather than pulling the drug from the market, they had just decided to make it available by prescription only. And that's where, that's why it got pulled back from being, yeah, over the counter to prescription only.

Jyoti Asundi (43:43)
⁓ my God! No way! my God! They knew of the problems and yet allowed so many women in Europe to continue to take it.

Aarati Asundi (43:56)
And while this is happening, they're actively trying to push thalidomide the US markets. Yeah. 

Jyoti Asundi (44:00)
Into the USA. Wow. Oh, I'm so glad we had such strong gatekeepers so early on.

Aarati Asundi (44:07)
Yes. So Frances', like to that point, Frances' contact at Merrell was a Dr. Joseph Murray. And he was getting more and more annoyed that Frances was not just approving the drug. Yeah. 

Jyoti Asundi (44:21)
Of course. Why don't you, why don't you just roll over and say yes? Why? 

Aarati Asundi (44:28)
Yeah. Yeah. Come on. Irritating woman. Yeah. Why are you using your brain? 

Jyoti Asundi (44:30)
Yeah, you irritating woman. Why are you using your brain? Nag, nag, nag. my God. Why do you have so many questions?

Aarati Asundi (44:38)
Yeah he had thought getting approval in the US was going to be really easy since it was already being marketed in Europe. But Frances just kept on delaying it, kept on asking for more clinical studies and more scientific data. 

Jyoti Asundi (44:52)
Good for her.

Aarati Asundi (44:53)
He tried to reassure her that the side effects were not common and probably due to extenuating circumstances, like pre-existing conditions that the patients had. But Frances was not buying it because from her perspective, it was really obvious that he knew about these side effects and deliberately had left them out of the NDA application.

Jyoti Asundi (45:11)
Yes. Yes. And the fact that you lied once casts a major pallor on everything else you're telling me. You are trickle-truthing! He's basically trickle-truthing her. 

Aarati Asundi (45:26)
Yes. And so then they tried another tactic of comparing thalidomide to the harmful effects and sometimes lethality of barbiturates, which was also being marketed as a sedative.

Jyoti Asundi (45:39)
Hmm.

Aarati Asundi (45:39)
So unlike barbiturates, didn't seem like people could overdose and die from taking thalidomide. But Frances was like "Saying, 'at least it won't kill you like barbiturates will' is a pretty terrible argument for, yeah, letting it go through".

Jyoti Asundi (45:56)
Absolutely. Yeah. Yeah.

Aarati Asundi (45:58)
So because of these reports of peripheral neuritis, Frances and others at the FDA became curious about the effect of the thalidomide that it might have on fetuses because so many pregnant women are taking this and it is being marketed towards pregnant women.

Jyoti Asundi (46:12)
And she has this previous history where she has actually studied that when something is ingested by the mother, the baby armadillos are not doing the same thing as the mother.

Aarati Asundi (46:25)
Rabbits. Quinine and rabbits.

Jyoti Asundi (46:26)
Rabbits, yeah, quinine, sorry, thank you. But she has done this before where the... what's ingested does go through the placental barrier and is not treated the same way by the fetus as the mother metabolizes it differently than the fetus.

Aarati Asundi (46:42)
Exactly. 

Jyoti Asundi (46:43)
Good for her. Wow. She's putting all, she's piecing it all together.

Aarati Asundi (46:48)
Piecing all of her knowledge together. Yeah, and this is being marketed towards pregnant women. So she's like, what is it doing to the fetus? ⁓ And that hasn't been properly studied. So the FDA asked Merrell, the company, to conduct this type of study, but they were not willing to.

Jyoti Asundi (47:10)
Ha! They probably already knew something.

Aarati Asundi (47:11)
Yup, they probably did. They agreed to putting a warning label on the drug saying pregnant women shouldn't take this because the side effects on babies was unknown. That was the only- 

Jyoti Asundi (47:22)
Smoking is injurious to health. Oh how interesting. I'll smoke anyway. 

Aarati Asundi (47:26)
Just so you know, but if you want to do it anyway, we can't stop you. 

Jyoti Asundi (47:28)
Yeah. Take it. You'll feel so much better. You won't have the morning sickness.

Aarati Asundi (47:32)
Yes. 

Jyoti Asundi (47:33)
And I'll tell you, as a mother, I would endure any problem as a... I would endure any difficulty. Morning sickness is nothing compared to the health of my child. If somebody said to me, take this drug and you'll feel better today. But your child may or may not be okay. As a mother, no way. It's like a no brainer. It's like, no, I am the mother. I will sacrifice anything to make my child healthy, happy, vigorous.

Aarati Asundi (48:07)
Yes. And that just makes it more insidious, I feel like, because if they knew something was up with this drug and doctors are saying, no, it's totally fine, you can take this drug, you'll be fine, your baby will be fine. And unsuspecting mother is like trusting the system and is trusting their doctor and being like, okay, well, yeah, I'm having really, really bad morning sickness or whatever. And my doctor says it's safe, so I guess I'll take it.

Jyoti Asundi (48:33)
Yeah, I'll take it. And there are so many women who are, who really were in positions who could not afford to be down with morning sickness because this is their third pregnancy or fourth pregnancy. So she's already dealing with a house full of children. The husband is off to work and earning, you know, keeping a roof over their head and all that. She's dealing with so many children. She's like, I can't afford, I can't afford to be sick and down. So if this pill is going to make me get through my day and be good to my kids for now, I'll take it. I'll take it. It'll help the whole family. And she has no clue that the much-awaited to the family is going to have such an issue. Oh my God.

Aarati Asundi (49:14)
Yes. Very...

Jyoti Asundi (49:18)
very deceptive.

Aarati Asundi (49:21)
Yes. So in the meantime, Dr. Murray, who is Frances' contact at the Merrell Company, is just getting more and more frustrated because Frances is continuously on this case. She is consistently filing the paperwork every 60 days to make sure the NDA does not lapse and get automatically approved. 

Jyoti Asundi (49:44)
Good on her, good on her.

Aarati Asundi (49:50)
⁓ Yeah, and she's been doing this for about a year now, even though the drug had been at this time approved in 46 other countries around the world. she is not letting it through.

Jyoti Asundi (49:55)
Wow. Wow. Wow. Wow. What a lioness. I love her. I love her spirit. She stood up. I mean, this is a true warrior. She went out to battle. She went out to battle. She is nothing less than a soldier who goes out and defends the borders with a gun. She is with her paper and her NDA and her making sure it doesn't She is a true soldier American and American women. Awesome. Good on her.

Aarati Asundi (50:33)
And Dr. Murray kept on trying to go over her head too and kept trying to go to her superiors and say she's being nitpicky, she's being unreasonable. But her superiors at the FDA supported her all the way. They were like, 

Jyoti Asundi (50:45)
Good for good. Excellent.

Aarati Asundi (50:46)
Nope, yeah, we're standing by her. By her delaying it and delaying it by now, reports had started to come in of an apparent worldwide epidemic of babies being born with defects to their heart, urinary tract, eyes...

Jyoti Asundi (51:05)
Limbs!

Aarati Asundi (51:07)
Yeah, a condition called phocomelia, which affected the limbs.

Jyoti Asundi (51:11)
I didn't know about all the others. I knew about the limbs, that something was wrong with the limbs. What was it that was wrong with the limbs?

Aarati Asundi (51:18)
So, phocomelia is when the limbs grow abnormally short flipper-like appendages. So, the limbs are not like the hand, the arms and the feet are not fully formed properly.

Jyoti Asundi (51:32)
And then in addition to all that, they had others like heart defects and blindness or vision impairment and everything. Oh my God.

Aarati Asundi (51:36)
Yes. Yes. In the early 1960s, it's estimated that over 10,000 and potentially up to 20,000 babies born worldwide had physical defects, and about 40% of them died as infants.

Jyoti Asundi (51:54)
Oh heartbreaking! 

Aarati Asundi (51:56)
I know.

Jyoti Asundi (51:58)
I mean, all you do and it's not like... it's a high punishment for doing something that seems highly innocuous when you do it. Like, hey, morning sickness, I need to get through it because I have X, Y, Z and my life is full of things. So I can't deal, I don't have the bandwidth to deal with morning sickness. And you take it and the consequence is way disproportionately high.

Aarati Asundi (52:28)
Yeah. And I think the thing that was even kind of worse was that the link between the thalidomide and the birth defects wasn't immediately clear because the mother that takes the thalidomide is perfectly fine. Like they get over their morning sickness, they're fine, they don't report any negative side effects. And then months later, the baby is born with these defects. And so linking it back to the thalidomide that you took months ago for your morning sickness was...

Jyoti Asundi (52:59)
is hard to yes yes there is a gap. Yes and the primary the primary ingester did not have any effects it's the subsidiary secondary well hidden. Hidden cost. Oh my goodness.

Aarati Asundi (53:12)
But after a while, it did became kind of clear that this is what was happening. And so on November 30th, 1961, Dr. Murray called the FDA and said that Merrell would be pulling the thalidomide from the German markets and would no longer be pursuing the drug's approval in the US. And by March 1962, they had submitted a formal withdrawal of the NDA.

Jyoti Asundi (53:37)
Wow, wow.

Aarati Asundi (53:39)
So eventually doctors and scientists were able to link thalidomide to the birth defects. And this is interesting. So the first time I heard about the thalidomide crisis was when I was taking a biochemistry class and the professor was introducing the concept of chirality, which is basically when a molecule can exist in two different forms that are mirror images of each other. Yes. So.

Jyoti Asundi (53:56)
Oh yes, yes.

Aarati Asundi (54:06)
These are called the left and the right enantiomers, or R for right and S for left, because I guess for whatever reason they decided to go with the Latin sinister word for left chirality. ⁓ But the point is that although the atoms that make up the molecules are exactly the same, the two enantiomers can have different properties. 

And that is what the was happening in the case of thalidomide. So the R enantiomer, the right ⁓ mirror image of the version of the molecule is perfectly safe, but the S enantiomer is teratogenic, meaning it causes abnormalities during pregnancy. 

And so Merrell, the company, was selling a 50-50 mix of the S and R enantiomers, but actually, even if they sold it, as just the safe R enantiomer, it's been shown that the R enantiomer can convert randomly, I guess, to the S version. Yeah.

Jyoti Asundi (55:10)
In the body to the S. Okay, okay all right.

Aarati Asundi (55:13)
and Frances actually caught that. She had noticed that this property of chirality, that thalidomide could exist in these two different forms, was not mentioned at all in the NDA filing. So it's missing from all of the reports that there's two different versions of this drug. Yeah.

Jyoti Asundi (55:34)
Yes, so they are missing the fact that the nerves are affected. They are missing the fact that there's chirality to the molecule. A lot of key pieces about the molecule were missing in that NDA.

Aarati Asundi (55:46)
Yes. In July of that year, a senator from Tennessee, Estes Kefauver, been holding a hearing on drug prices and safety. And he and his aides leaked the thalidomide story to a reporter for The Washington Post named Morton Mintz. Mintz published an article about Frances titled "Heroine of the FDA keeps bad drug off market". And this story basically went viral for the times. Frances was hailed as a savior with the article saying, quote, Kelsey prevented the birth of hundreds or indeed thousands of armless and legless children, end quote.

Although Frances insisted that the credit should be shared with her team members, Lee Geismar and Jiro Oyama and her superiors at the FDA who had defended her, she still received most of the credit because of her consistent documentation, both in requests for more data and for submitting the rejection papers every 60 days without fail. Yes. Yes.

Jyoti Asundi (56:54)
In time, yes, awesome, awesome, wow, wow, that is really good. Sometimes good things do happen to good people.

Aarati Asundi (57:06)
Yes. Yeah. And I think what made it even more inspiring to the American public was that she wasn't the stereotypical, like, unsociable, tragic, spinster woman scientist. 

Jyoti Asundi (57:19)
Yes,

Aarati Asundi (57:20)
She was happily married, she had two teenage daughters, she did normal things, she had friends over, she played golf and tennis, and she liked to spend time in her garden. She's just a normal woman who happens to be a scientist, and this was mind-blowing. Yes.

Jyoti Asundi (57:34)
Extraordinary. Yes. Yes. And she saved so many American families from having to have the heartbreak. My God.

Aarati Asundi (57:45)
Yes.

Jyoti Asundi (57:46)
I almost want to call her an unsung hero, but in this case, luckily, she did get the credit that was due to her. That is very wonderful.

Aarati Asundi (57:53)
And by the way, leaking that the thalidomide story also turned out to be a very smart political move by Senator Kefauver because the public interest and pressure on the government to make sure a drug like the thalidomide never came close to getting on the market again, led to the Kefauver Harris Amendment or the Drug Efficacy Act of 1962 which required drug manufacturers to prove their drug was safe and effective before it could be approved. So not only does the FDA have to approve the drug, manufacturers have to prove that their drug is safe and effective. Yeah.

Jyoti Asundi (58:30)
Yes, yes. Increase the, increase the onus on the manufacturers to show that you're not just, you know, packaging something and calling it, calling it effective. Excellent. Much needed, much needed.

Aarati Asundi (58:47)
And patients who were being given experimental drugs, like for clinical trials and such, now had to be informed of the fact that they were being given drugs that were not yet being approved by the FDA. So that's also a little piece that's very important. 

Jyoti Asundi (59:02)
Yes, not eyes wide shut.

Aarati Asundi (59:05)
Yes, exactly. Senator Kefauver also nominated Frances to receive the President's Award for Distinguished Federal Civilian Service, making her the second woman to win that award. 

Jyoti Asundi (59:18)
Nice.

Aarati Asundi (59:19)
President Kennedy said, quote, "Her exceptional judgment in evaluating a new drug for safety for human use has prevented a major tragedy of birth deformities in United States. Through high ability and steadfast confidence in her professional decision, she has made an outstanding contribution to the protection of the health of the American people." ⁓

Jyoti Asundi (59:42)
Nice. wonderful.

Aarati Asundi (59:43)
Later that same year, the FDA underwent some major reorganization to make two separate divisions, one that handled INDs or investigational new drug applications, which a company has to submit before starting clinical trials in humans, and then a separate NDA branch, which handled approvals before going to market.

In 1963, Frances was named director of the new investigational drug branch. The group was small. Frances oversaw 12 to 13 physicians that were all going through 200 to 300 IND applications a year. A few years later, Dr. James Goddard was appointed as the new FDA commissioner, and he really cracked down on drug industry regulations.

Jyoti Asundi (1:00:33)
Yes. 

Aarati Asundi (1:00:34)
He restructured the FDA again and instead of having an IND branch and an NDA branch reviewing all the different types of drugs, they decided to have separate branches reviewing different types of drugs instead. So Frances was made chief of the division of oncology and radiopharmaceutical drug products. So her work in radioisotopes came back around in handy.

Jyoti Asundi (1:01:01)
Yeah, every piece is being beautifully stitched together so that her expertise in all these different areas are coming together to protect the American public. 

Aarati Asundi (1:01:13)
Yes.

Jyoti Asundi (1:01:13)
That is amazing. It's wonderful to see how slowly but surely these huge foundational pieces were put together to make the FDA so very strong and having the FDA with teeth basically so that it could protect the American public. And it is somewhat sad to see that the importance of that has been forgotten now in the current climate many times for political clout, people blithely talk about dismantling the FDA, rid of all the people who do all the stuff in the FDA. are talking about things like that today. And it's, if you just can go back and tell people, hey, look at this, look at what the FDA did. They prevented thousands and thousands of deformed babies from being born because they knew what they were doing. And they... not only were the scientists knowing what they were doing, but they had politicians helping them to spread the word to the public and that way giving them teeth and saying, look, you can't just willy nilly throw drugs at people and say, take it, it's safe. You can't do that. 

And that key message has been lost today. And that's really sad to see, actually. I'm very sad to see that ⁓ somehow due to the various reasons, I don't know, is it...Maybe we have been safe too long and people have forgotten how it was to live in those days. ⁓ Everything has been running so smoothly and the FDA kind of greases the wheels and makes life smooth for all Americans very nicely, but quietly without much fanfare, doing its work diligently.

Aarati Asundi (1:03:28)
Yes, I think that's the thing. Quietly without fanfare, it's like we need to be- we need to do-

Jyoti Asundi (1:03:08)
Yeah, we need to toot our own horn and say, Yeah, we need to say, look what we did, but nobody does that. Scientists don't do that. are like, no, no, we rejected that bad drug. Yes, we approved that good drug, but within these parameters, within these constraints, and they do it so quietly and efficiently. And the American public has been so well protected that it has forgotten that the whole system is operating because of this wonderful safety net, which has been given good teeth. And now slowly we are trying to declaw and de-teeth the FDA. So that is very sad.

Aarati Asundi (1:03:43)
Yeah and that's why think stories like this are so important to show this is how it was. This is what they could get away with at the time. This is why it doesn't happen anymore.

Jyoti Asundi (1:03:56)
Yeah if the FDA, like the onus used to be on the FDA to file papers in time. God forbid somebody fell down with something like COVID and the key piece of paper did not get filed. Boom, the drug got approved. You know, no, you that's not how things work today.

Aarati Asundi (1:04:12)
Yeah. The whole system was hinging on one person to keep filing that paperwork if she had... if anything had happened to her...

Jyoti Asundi (1:04:21)
Then that's it. She's out of commission and The drug company was then able to take it forward. That's how it would have gone. The American public has been very fortunate that she was right on the ball with that one.

Aarati Asundi (1:04:35)
Yes, And we're very fortunate that the system is no longer like that, that if one person fails, the entire system fails. 

Jyoti Asundi (1:04:40)
Yes. Absolutely. No, no.

Aarati Asundi (1:04:43)
Okay, so Frances was made head of the Division of Oncology and Radiopharmaceutical Drug Products. And according to Frances, because the group is now handling both INDs and NDAs, This is really the first time when the chemists, the pharmacologists and the medical officers all started working together in the same office. So this is something that I hadn't realized before is that those three people who were in charge of the NDA, they all worked in different offices. So there was no like, hey, really quick, can you look at this graph or really quick, can you do this? She would have to actually like.

Jyoti Asundi (1:05:19)
Yeah, so a lot of things can fall through the cracks when that happens. Mm-hmm.

Aarati Asundi (1:05:23)
Yeah, she would actually have to make an effort to go to another building or go to another part of, you know, the city. Yeah.

Jyoti Asundi (1:05:28)
Mm-hmm. Yeah, yeah. Yeah, I'll get to him. I have to talk to him kind of thing, and then it never happens. Yeah, yeah.

Aarati Asundi (1:05:33)
So she did this only for a short time before it came to their attention that amidst all of this restructuring, no one was really responsible for double checking that the data being submitted in the INDs or the NDA reports were accurate. 

Jyoti Asundi (1:05:48)
Oh no.

Aarati Asundi (1:05:48)
So if the data was falsified or if people were not carrying out their studies according to standard protocols and then lying about it, people would end up back in that problem of the data looking really good and the drug getting approved. And only after it hit the market, people would start to see negative health effects. So a new department called the Office of Scientific Evaluation was formed to keep track of things like investigator trainings, patient consent, animal study ethics, and adverse drug reaction reports. 

And this was interesting because they helped form regulations and oversight committees around drug trials being done on prisoners and in nursing homes where drug investigators were almost definitely taking advantage of people in kind of vulnerable situations. So Frances was in charge of that now that, yeah.

Jyoti Asundi (1:06:45)
Doing, bringing in, bringing patient protection basically. Yeah. Yeah.

Aarati Asundi (1:06:48)
Yes, and making sure that these studies were done ethically and that data was not being falsified.

Jyoti Asundi (1:06:54)
And yet ⁓ a big piece that has come now more recently, the patient privacy part, that came much later.

Aarati Asundi (1:07:03)
Yes, so this is still like the 70s or 80s, think, like how far we've come even since then. It's just mind blowing to me that some of these things even had to be like,

Jyoti Asundi (1:07:18)
talked about or said, yeah, yeah, yeah.


Aarati Asundi (1:07:18)
 ⁓ we need to do that. Yes, we need to make sure companies aren't falsifying their data. We should have a committee that oversees that. Yes, yes, you should.

Jyoti Asundi (1:07:26)
Yes, yes, that's right. That's right. It's likea duh obvious. Yeah.

Aarati Asundi (1:07:30)
Yeah, to us it's so obvious now, but back then they were like, wait, people might not be ethical.

Jyoti Asundi (1:07:34)
Yeah. No, and it's funny because, you know, this is one of the reasons why the at the end of the whole process, I am grateful actually, in spite of being on the drug manufacturer side, I am grateful that these stringent regulations are in place so that everybody is protected. 

⁓ The flip side of that is definitely the fact that there is a cost associated with it. By the time you have all these boxes checked and got everything lined up exactly the way it should be done and do the testing correctly in animals and in humans and making sure that the data didn't get falsified, the cost of making that drug and getting it to market does increase. And that is definitely one of the reasons why drugs are more expensive. So, I often hear people say something like "Making that aspirin didn't cost that much?" Why are they charging me so much? Well, it's because of this kind of things. The effort to make sure that the little pill that you pop is actually safe for you.

Aarati Asundi (1:08:41)
Yeah like one pill can take more than 20 years to get on the market. 

Jyoti Asundi (1:08:45)
to actually get on the market. But it's absolutely crucial. It has to be done. Yes.

Aarati Asundi (1:08:51)
Yes, it has to be. And in the process, thousands of similar drugs fail. Thousands of drugs fail this process. Yeah.

Jyoti Asundi (1:08:58)
Yeah, it's a huge funnel. It's a huge funnel where so many molecules are tried and then one trickles through. It's not like you making, it's not like software where you make an app or something and if it fails, it crashed and it killed my computer. No, if this crashes and burns, it's going to kill you. So sorry, we can't just let it go and you pop a pill because somebody says it's good for you. All right.

Aarati Asundi (1:09:21)
Yeah. So Frances stayed at the FDA for the rest of her career. In 1994, when Frances was 79, a secondary school in Mill Bay, British Columbia was named after her. Frances was scheduled to go to the groundbreaking ceremony and give a speech, but the day before the ceremony, she was in a bit of a boating accident. She was with family on a fishing trip when a large wave from a powerboat hit her fishing boat, causing it to rock violently. Frances was tossed up in the air and landed hard, fracturing her spine.

Jyoti Asundi (1:10:02)
Oh that's painful. Oh goodness.

Aarati Asundi (1:10:04)
Yeah, she stayed overnight in the ER, but the next day she took some aspirin we were just talking about and some bourbon and she went to the groundbreaking ceremony and gave her speech. 

Jyoti Asundi (1:10:15)
No, no way.

Aarati Asundi (1:10:17)
Yeah. 

Jyoti Asundi (1:10:18)
What is she? Iron woman or something? ⁓ my God, I would up in a ball somewhere crying and feeling sorry for myself. Wow.

Aarati Asundi (1:10:25)
I know. Yeah. She's just like, nope, I'm going to just take a little bit of painkillers, take a stiff hard drink and go to that ceremony.

Jyoti Asundi (1:10:35)
A true warrior. Man, she's so inspirational. I really should learn to live life like that. Wow, I'm so impressed.

Aarati Asundi (1:10:44)
In 2000, Frances was inducted into the National Women's Hall of Fame. Although she suffered with back pain as a result of that accident, Frances stayed at the FDA until 2005 when she retired at the age of 90. That gives you something to aim for, huh?

Jyoti Asundi (1:11:04)
Yeah, man!

Aarati Asundi (1:11:06)
Yeah. I know you never want to retire, so yeah. 

Jyoti Asundi (1:11:07)
I don't want to retire. I like what I do. I truly believe it's a passion. I truly believe that making sure that the right drug is generated and given to the right people, it is important. You know, we as human beings find
so many ways to fight and mostly people fight with each other finding various ways to find divisions between ourselves but you should these are the things to fight against cancer and fight against these horrible diseases that are ravaging us like Alzheimer's and things like that. Fight those things.

Aarati Asundi (1:11:51)
Yeah, why fight with each other when we're already like....

Jyoti Asundi (1:11:53)
Why fight with each other? Let's all get on one side and fight these diseases and make the drug safe. That's the fight we should all be engaged in.

Aarati Asundi (1:12:04)
I totally agree.

Jyoti Asundi (1:12:06)
I'm a warrior also. 

Aarati Asundi (1:12:07)
Yes, you are. You are.

Jyoti Asundi (1:12:08)
Sometimes I'm a worrier too. I'm a worrier and a warrior. But ⁓ yeah, I am a warrior against diseases. So yeah, I'd like to fight against these diseases like Frances did all the way till I'm 90, if I get there. Yeah, or even more and beyond. 

Aarati Asundi (1:12:20)
All the way till you're 90 years old. I can picture it. I can totally picture it. You in a lab being like, yeah, I'm so fighting. Yeah.

Jyoti Asundi (1:12:27)
Yeah, I'm fighting it. I'll figure this out. I'll figure this out. Yeah.

Aarati Asundi (1:12:32)
in 2010, the FDA created an award named the Dr. Frances O. Kelsey Drug Safety Excellence Award, which was established to "recognize recipients for their outstanding accomplishments in this important aspect of drug regulation". 

In 2014, Frances moved back to Canada to live with her daughter in London, Ontario. And in August 2015, Ontario's Lieutenant Governor Elizabeth Dowdeswell named her to the Order of Canada, which recognizes outstanding merit or lifelong to a field. Less than 24 hours later, after this award, on August 7th, 2015, Frances passed away at the age of 101.

Jyoti Asundi (1:13:23)
Yes, yes, yes, she did.... 

Aarati Asundi (1:13:24)
Yes, long, long, amazing life.

Jyoti Asundi (1:13:27)
She lived well and she did good by everybody.

Aarati Asundi (1:13:31)
Yes, and that is the story of Frances Oldham Kelsey, woman a major health crisis in the US. Really an amazing story, right?

Jyoti Asundi (1:13:40)
Wow, That was simply amazing, simply an amazing story. A true inspirational woman and everything she is, you know, and she's a warrior in the same, mean, I'm nowhere in that class


Aarati Asundi (1:13:55)
I see a lot of similarities between you and her. And so I was like, this is gonna be a good one for my mom to listen to. She's gonna, she's really gonna like this. Yes. Yeah. Yes.

Jyoti Asundi (1:14:01)
Thank you. This was a good one for me. I liked it a lot. Thank you. Thank you for sharing this one with me.

Aarati Asundi (1:14:07)
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