A Horse Named Jim: The Biologics Control Act of 1902

In our last episode for season 1, Diane and I dive into the story behind the first US law passed for protecting people from a medical product failure: The Biologics Control Act of 1902. Joining us is René Najera editor of the History of Vaccines (https://www.historyofvaccines.org/). He helps explain the development of diphtheria antitoxin and discusses early product development and public perception.    

Also joining us is Kelly Creighton of Clinipace to discuss how regulations shape product development and help protect patients.

Stay tuned for season 2! 

Transcript

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Aaron Harmon: 0:00

Hi, I'm Aaron Harmon.

Diane Cox: 0:01

And I'm Diane Cox Welcome to Inside Out quality.

Aaron Harmon: 0:04

both Dan and I build and implement quality systems in the biotech and medical device industry. But we often get asked, Is this really necessary? Do we know if we are doing too much too early? Or do we even need a quality system?

Diane Cox: 0:17

Our goal is to explore questions like these through real life events and experiences shared by our guests from various regulated industries. We will show you why quality is not just about compliance and how when it's done right, it can help your product and company improve lives and make a difference.

Aaron Harmon: 0:38

Jim retired from the St. Louis Fire Department in early October 1901 He moved to a country farm adjacent to St. Louis his asylum and poor house with Bill Sam Frank and Aguinaldo in retirement, the forehead new jobs, his producers of anti Sam to treat diptheria and children. Little the gym, no, but he would help create regulations that would begin shaping the FDA that we now have. If you aren't familiar with diphtheria. It's the bacteria caught in childhood years. It grows in the throat and spreads while also producing a toxin that paralyzes the diaphragm muscle, which allows you to breathe. Five to 10% of those infected will die in the US 206,000 Children caught the infection in 1921 alone, over 15,000 of those children died. Right now we have no cases in the US a few cases up here over the last decade, but it's rare. That's because in 1923 the first vaccine for diptheria was developed. So back to Jim, he retired and lived at the St. Louis poor farm where diphtheria toxin was frequently injected into him. When exposed to a pathogen or toxin we start making antibodies to bind and stop it. antibodies can be collected in the patient's serum and used to treat others much like what has happened with COVID-19. Jim was a horse. After injections the toxin his serum was full of antibodies that can be used to treat children struggling with diptheria infections. One day Jim had his own infection to fight tetanus. His serum now had both the antibodies children needed and the bacteria that causes tetanus poisoning is serum was collected and given to doctors to treat patients. But no one knew that a serum was contaminated. The result was loving children died a terrible death while their parents watched helplessly. Sadly, this wasn't the only time this happened. A similar event happened in Milan, Italy, killing eight patients being treated for dip theory as well. There are many more cases of product contamination. So I have a theory. When children are harmed. We are drawn to action because we don't want to repeat that again. When children died in St. Louis from the horse serum treatment, lawmakers took action and the first law regulating therapeutics in the US was launched. Jim's infection got the biologics Control Act in 1802, also called the virus toxin law into place. Several more laws to be passed over time based on tragedies that eventually created the modern Food Drug and Cosmetic Act and FDA. We will dive into these and other episodes. On this episode we'll explore the story of Jim biologics and how this could happen with Dr. Rene Najera, the editor of the history of vaccines at the College of Physicians of Philadelphia. Welcome to the show, Rene.

Rene Najera: 3:12

Hi, thank you for having me.

Aaron Harmon: 3:14

So first of all, if people have not checked it out, I highly recommend they visit the history of vaccines.org. It's a great site full of historical information and infographics and very valuable resource.

Rene Najera: 3:27

Thank you for the plug.

Aaron Harmon: 3:28

So the first question I have is what can you tell us about antisera minutes discovery and how it came to be used for treating diphtheria? Yeah, so

Rene Najera: 3:35

this is this is the late 1800s early 1900s. Microbiology is still in its infancy. What we know now as germ theory, you know that germs cause disease and that they are transmissible from person to person, it's in its infancy. It's been a little over 50 years since that theory was was proven, with diseases like cholera, like rabies, etc. And so a lot of different private laboratories in Europe in the United States are trying to replicate the vaccine successes of the Pasteur Institute, and other places as well. That they they came up with these these novel ideas on how to give people the pathogen that causes a disease without actually making them sick, and that the person would have an immune reaction of some sort that would give them immunity for the long term. They found that that this was hard to do with diphtheria with tetanus with certain bacteria that produce a toxin because it's not the bacterial infection per se that makes you sick. It's the toxin it's what really does you in so in the example of tetanus, you know, you get the bacterial infection, but the toxin paralyzes your muscles to the point that you cannot breathe in the, in the example of diphtheria Yeah, you get that that membrane that covers your your throat might suffocate you. But if you have even a low level of infection, the bacteria makes a toxin and it prevents you from breathing as well. And so they just couldn't figure out a way to make a vaccine against that, that that toxin they could, they could give you some immunity against the bacteria, but not against the toxin because at the time, they didn't know that the two things were separate, they thought that the bacteria itself was the toxin that that the bacteria created toxin. But they did realize that people who had been exposed to the toxin created antibodies created something they didn't, they didn't know that there were exactly antibodies, but they they created something in their serum in the liquid part of the blood that neutralized the toxin, if given to somebody else. And they decided that this was a good way of treating people for many different diseases. The problem was that you needed a lot of that a lot of that anti toxin in the serum of a person who had just recovered from from the infection. And furthermore, you needed somebody to have been sick with that sickness came other risk of other other things. So they decided to give horses and other large mammals, the bacterial infection, in the hopes that they would make antibodies both against the bacteria and against the toxin. And they did, they would lead the horses not to death, but enough lead to to make several leaders of this the serum and then give that to people that in itself carried carried some risks, because as you can imagine, you're given something foreign to a human body. And we kind of react against that as well, people would get what's called serum sickness. But it was also a risk benefit intervention, right where the risk was serum sickness. But the benefit was you don't get to die from diphtheria, tetanus from other toxin like infections. And so that's where the idea came from. And without vaccines, we would have a huge rate of mortality for children, they get diseases because their immune systems are naive, they haven't been exposed to many things. And so in the 1900s, a child would get measles, mumps, rubella, which is German measles, they would get chickenpox, they would get polio, cholera, they would get all these things. And you had, you had a lot of children dying. And so as you said, we come together when when a child is affected in the race was on to find a way to stop diphtheria. And this was this was one way. And so laboratories again, trying to replicate what Pasteur had done in his Institute with other vaccines, starting just getting horses and cows and other large mammals, and experimenting with having them create those of those anti CRF. And diphtheria was one of the most more successful ones than the others, I have to

Aaron Harmon: 7:40

imagine that would have been a huge discovery, going from a state where you'd watch young kids die from this and not being able to do anything as a physician do actually having something you could inject into them that save their lives.

Unknown: 7:53

Yeah, I'm sure you know it. As you said it had a very high mortality rate. And if you were able to get the child to the anti serum, or the anti toxin to the child, then we're more likely to save their life. And so was the case for other diseases as well. By then Pasteur had figured out the rabies vaccination, which was attenuating a virus but here we're talking about a bacteria. Again, this was the the infancy of this whole microbiology movement. And so they didn't quite understand why the rabies vaccine was so effective against rabies. But you couldn't do the same thing with bacteria. It wasn't until later that they kind of started figuring out oh, we're dealing with two different kinds of organisms here. But yeah, it was it was a huge, it was a huge leap. in medicine and in medical technology, giving somebody the antitoxin for the right from the horse's mouth was not a vaccination in itself. It was a treatment, it was a medical treatment. Later on, they learned how to grow the bacteria in cultures. And when that happened, they were able to extract the toxin and neutralize it. And when they neutralize it, they would give that toxoid its toxin, but it's been neutralized, so toxoid to a person and the person would develop antibodies against the toxoid. And so that is what we have still to today we have a toxoid vaccine against tetanus, because we are actually creating immunity against the toxin, not the bacteria itself. So that's the difference between what was being used with the horses. It wasn't a vaccine per se. It was a treatment. Later on, they figure out how to give the toxoid and that provides immunity after being injected. And so you're dealing with a treatment versus prevented. And also there's serum sickness. Yeah, yeah. So the serum sickness happens with the horses and other mammals the with the vaccine, that risk goes away. And so they started figuring out that you could give somebody the toxin, along with an anti toxin, which had a little bit of the antibodies from them from the mammals, but not enough to make you sick, and you would make antibodies against the toxin and would become immune. That was a huge leap right there because that ended the era of diphtheria at least in the United States. Because once that happens, you can prove As a child from a very young age, wherever catching it, and then you just kind of start wiping it out.

Aaron Harmon: 10:04

And just like applying this to our current pandemic, if we had five to 10% of the COVID cases being child mortality in the US, it'd be, it'd be an incredible disaster.

Unknown: 10:15

Oh, for sure, for sure. I think the response would have been much different, right? You see it all the time you see it in social media, you see it in people who are adversarial towards the public health interventions, when they say, Oh, well, it's only a 1% mortality rate, and those who are dying are the sick and the elderly. And from the public health perspective, this is true. But also from the human perspective. If you give COVID to everybody in the United States, you're talking about something like 3.2 million people dead. And if you're not worried it because it's the elderly, then you're losing generations of knowledge, right? They're they're carrying with them a lot of knowledge that they can pass on. And once they're gone, they're gone. Like I said, and like you mentioned, if it weren't children, it would be much different. We all rally around a child being hurt. If you see a child fall into a well, the whole town comes out to try to get them out of that, well, when a child goes missing everybody volunteers to go find the child. It's just one of those, I guess, one of those things that are hardwired into our human existence that we need to protect the younger, younger generations, because they're our future. And so yeah, if it were like that, if COVID-19 had the same death rate as measles, which is one in 1000, for children, the whole thing would have changed dramatically.

Aaron Harmon: 11:28

And something even highlight this is the newspaper from that time. So when this when this happened in St. Louis, the headlines of that paper, talked about these deaths, and then proceeded to list the children's names, the houses they were living in, who's their parent who their parents were so personal. So it was like front page of the St. Louis paper is their address names and their age, and they're currently infected with tetanus or have died. And

Unknown: 11:54

yeah, and up to and up to a certain time, we used to do that in public health, where we actually named the people who were ill because we wanted other people to avoid them. You see this, if you go to the New York Times, the early, very early New York Times in New York City, when they listed the people who have the consumption was it's which is tuberculosis. They list their names and addresses so that everybody will stay away from them. Huge invasion of privacy, right. But at the same time, from the public health perspective, well, we want people to stay away from them. There used to be registries for sexually transmitted infections as well. So it made it very personal because you put a name and an age and maybe even a face to the the burden of the disease, but it was a heck of an invasion of privacy.

Diane Cox: 12:33

So is it surprising that the serum would have been contaminated with tetanus in 1901 and make its way into children at that time?

Unknown: 12:42

No, it's not. The microbiology, it's in its infancy, they didn't really know that. Tetanus, they knew that tetanus happened, right, they knew that there was some sort of an injury like a cut, and something happened, some dirt got in there and would create the tetanus toxin. And that's what made you sick and gave you the paralysis, but they didn't really know how that that whole thing work. They didn't really know that that how the bacteria could do that. And they didn't really know that it happened in animals. And so my theory My personal theory is that the gym probably was not exhibiting the same symptoms exactly the same symptoms as a human would. And so they didn't recognize that the gym had tetanus, and that in extracting the serum, they were not only extracting the the antitoxin against diphtheria. They were extracting the toxin from tetanus. So I don't think the children got the infection. I think they got just the toxin from tetanus. And that's, that's what they determine. And we talk about Botox when you talk about botulinum toxin, that's where we're talking about this is this is that same toxin. And so it's it's very potent, it only takes just a little bit to paralyse a full grown adult. So you can imagine that even if they diluted the the serum to make multiple doses out of it, you're still getting a lot of toxin in there. And that's that's probably enough to kill the children.

Diane Cox: 13:59

So how has vaccine development changed after that discovery of the tetanus infections?

Unknown: 14:05

Well, they they started to figure out exactly what you need. So a lot of these previous quote unquote vaccines or treatments were shots, shots in the dark things that worked and, and they worked until we're going to use them, right. And so when you start to understand the mechanism of the disease, and you start to understand exactly what you need to do, and you don't need to do anything further, so instead of getting the serum out of the the horses because they have the antitoxin in it, you learn that you can just give the the toxin in a deactivated way and you'll make antibodies against the toxin. Same thing with the viral vaccines. You didn't need to give somebody the full blown infection, which you did before the days of the smallpox vaccine. When the smallpox vaccine comes around, you just need to give somebody a weakened form of the virus. And so these little leaps in technology and in knowledge helped model the response. Later on, you learn that, for example, the polio virus is actually three viruses, not just one. And you kind of understand why the polio the first polio vaccines did not work it was because there were only against one of the strains. But there's three main polio viruses. And so you were not protecting against the other two, once you learn that, and you're able to see the differences in the in the culture and under the microscope, you can create the polio vaccine that protects it can solve three major polio strains, that kind of thing, you know, it just is progressively gets better, progressively gets cleaner, and that you learn not to give co infections when you're giving vaccines. In the 1970s, you're learned that hepatitis B is infectious by blood. And so you don't long no longer use this gun type of inoculator. You know, where you see it in the movies, or it's like a, it looks like a gun and you inject somebody and then the next person comes on, and then the next person, you're no longer use that use single use syringes, because you want to avoid a blood borne pathogen, and so on and so forth. It's just little, little incremental bits of knowledge like that, that lead us to where we are today. A lot of people now with the mRNA vaccine are saying, Well, how could it be so fast? And I'm like, Look, you didn't have a cell phone at the beginning. At the beginning of the century, you didn't have smartphones. Now you do. Technology moves, moves like that. And it's exponential growth. And so here we are, with vaccines, 220 years of vaccine technology led to this. And so in the 19, early 1900s, we're talking about the middle of that, you know, we're talking about barely a barely 100 years since the smallpox vaccine. And there's still a lot to be learned. But once those those little things are learned how to grow bacteria in the lab, how a toxin is a toxin and not it's not the bacteria, it's actually a chemical that the bacteria is making. Once you start to learn those those things and understand those understand the immune system, the human immune system, then you start to be able to target your intervention better without giving all those side effects.

Aaron Harmon: 16:50

So in speaking about other vaccines, you mentioned to me earlier, the Qatar incident. Yeah, and surprise, I was actually I looked it up. I was surprised. I hadn't heard of it. Because it was pretty, pretty large one, but can you kind of dive into what happened with that story?

Unknown: 17:05

Yeah, so in 1955, the polio vaccine trials, and, and it is very clear that the polio vaccine, the injected polio vaccine, which contains a killed virus is killed with formalin, a form of formaldehyde, it's pretty clear that it works. Children who got it did not get polio and children who didn't get it got polio at a very high rate. And so they decided to just vaccinate all the children in the whole country, and try to do it as soon as possible. So that the next wave of polio which because polio came in, went in waves, usually during the summer could be avoided. And in that rush, they gave the the contract to create the vaccine. And by they, I mean, the federal government gave the contract to five laboratories, independent laboratories, and these laboratories rushed to get the vaccine made and send it out. Now, there is some evidence that it was you want to talk about rush, there is some evidence that it was rushed that it was, you know, in this emergency mode to prevent the next wave of children who are paralyzed and, and or dead from polio, and you want to do things quickly. But there was an oversight by the government, you know, they wanted to make sure that it was safe, because of the things that had happened the 50 years previous. So they wanted to make sure that it didn't have anything that would anything else that would complicate matters. But something happened at Qatar laboratories that in one of the steps to kill the virus, they didn't quite do the job that needs to be done. And they didn't have the technology at the time to put the virus in culture and see if it would grow, thus telling you that didn't kill the virus. And so they just said, Yep, you know, we went through the steps as as we need it, here's the here's the vaccine, and it was distributed, it was 200,000 doses or so. And they started noticing that a lot of the children who received the vaccine a few days after getting the vaccine in the arm, they developed paralysis of that arm. And then others develop full blown polio there were about five deaths that were reported associated with this. And when they went back to check the lots, they realize that they were all from the same lot. And so something must have happened in the in the process of making it and in the process of making sure that it was free of other contaminants that they kind of missed the step of killing the virus completely. And that led to this this incident. It set back the the the polio vaccination campaign a few years because people were scared after that, you know, the the vaccine was such a resounding success and a lot of parents move to get their children vaccinated and then something like this happens. And you see that with other vaccines as well. In 1976, the flu vaccine that was made for a suspected pandemic a new strain of flu that was that had risen, that vaccine increase your your risk of getting a neurological condition called Guillain Barre. A, it was pulled from the market when there was clear evidence that has increased the risk of getting that Guillain Barre Syndrome. You see it in 1998. With the rotavirus vaccine the one of the first rotavirus vaccines increase the risk of children getting what is called into deception. It's an intestinal condition that is life threatening. Getting rotavirus itself leads you to have this disease, but getting the vaccine actually increased the increase the risk of getting of getting that disease without even getting the rotavirus infection. So that that was pulled again it was pulled from the market. There had been some unsubstantiated fears that out of abundance of caution has led to a retraction or the holding from the market of vaccines. So for example, the Lyme disease vaccine was pulled from the market after reports of people who had developed Lyme disease after getting the vaccine studies afterward determined that these folks had already been exposed to Lyme disease. And so they were they were just in the course of getting their natural course of the disease. And it wasn't so much the vaccine, but the vaccine was pulled from the market and never to be seen again anyways. And you see this over and over again in the early 19. And the early 2000s. By Marisol which is a preservative used in some childhood vaccines was blamed for causing autism. There was no evidence for that. It wasn't it was whatever evidence it was it wasn't it wasn't good. But out of an abundance of caution, the procedure was taken away. And so you end up with single dose influenza vaccines for example, for children instead of having the Marisol preservative, you just keep them in the fridge. The only problem with that is that if the vaccine is not refrigerated, well, you run the risk of giving the child a bacterial infection we go back to to step one, right. But it's throughout the history of vaccines that these things happen. There's always been some sort of hiccup in vaccine rollouts and in vaccine development that leads people to be scared of vaccines, and increases a hesitancy and it allows for the anti vaccine groups to to grab a hold of relatively minor incidents. So I don't want to say that the death of five children in the conference and it was minor, it's it's a big deal. But in the bigger scheme of things, it was a low rate right of the vaccine. It these hiccups along the way lead to these kinds of situations that we ended up with now, I don't know if you guys have seen but recently with the COVID vaccine a few weeks ago, Hank Aaron, Baseball Hall of Famer received his vaccine at the beginning of January. And a couple of days ago, three weeks later, after getting the vaccine, he died in his sleep. And by all accounts, he died of natural causes, but that has now led people to be skeptical of the vaccine because he got it and then three weeks later, he died. You see this with the human papilloma virus vaccine, human papilloma causes cervical cancer in women and other cancers in both men and women. And there have been people who have died weeks or even months after getting the vaccine. And for some reason it is associated with the vaccine just because that is the next quote unquote abnormal thing that they suffered, even if they already had risk factors for blood clots or for other conditions. And now they're they're doing this, it just happens over and over again. And that's kind of the fight of public health of biostatisticians epidemiologists like myself is making sure that the observations that we see are not by chance, or if they are by chance to make that clear to the public. So the public can continue to enjoy a successful intervention, like vaccines have been throughout history.

Aaron Harmon: 23:11

Like one thing that kind of struck me as you're describing that is if you look at automobile deaths, we sit around 10,000 per year in the US, I have not seen the anti vehicle transportation

Unknown: 23:24

method. It's an interesting thing of human human psychology. And it's something that we in public health we fight with all the time. We don't measure risk really well. Humans, we are very bad at measuring risk. We are afraid of flying when flying is statistically the safest way to travel, to quote Superman, but we panic when we get into a plane and there's turbulence right because it's our it's our brain, our brain is playing tricks with us. We see something happen at point A and then something else happened at point B and we associate them just because one thing happened after the other and it's not necessarily they were both related. One of the jokes that I like to make to some of my friends is that we vaccinated my daughter when she was born against hepatitis B. And she was not able to walk for a whole year. You can see there but it's it but it's something that a lot of people do grab onto that because I vaccinated my child against against measles, mumps and rubella at their one year check in like one year and a half they were diagnosed as having autism, when that is the usual age when autism develops or is noticed anyway. And it doesn't mean that the vaccine cost it it just means that that's when that's when it gets picked up because that's when the child is supposed to start speaking as opposed to start hitting some milestones. And with developmental delays like autism, they're not they're not they're not hit and it doesn't have anything to do with the vaccine. The other thing is that we we try to explain to the public that we conduct clinical trials and epidemiological studies all the time, and there's no association but it's very hard to for people to understand what What we mean by that? When I say something like it's a vaccine associated disease versus a vaccine cause disease, they think that the two things are the same. And one of the things that we keep saying is association is not causation. But here we are, you know, that doesn't get through. And it just happens over and over in the in the history of vaccines. I think I think we're getting way off. From what happened back then. But you can see that happening back then, as well, you can see that science is new science is scary is this thing that even even the scientists don't quite grasp? Right. So how can you expect everyday people to understand, it seems miraculous at the time that you can cure the theory, when a lot of people died from it. But then then these things happen, like what happened with the tetanus, and that discourages people from further believing in that, and that causes damage to public health overall. And you can see how that could have influenced some people do not seek treatment, it's left up to history to understand the impact of things like this situation, and others, like the ones that I've mentioned, what the impact they have on overall public health.

Diane Cox: 26:06

So when there is causation between a vaccine and some following disease or death, do you feel that there are sufficient regulations in place when it comes to testing appropriately and doing clinical trials and anything else that might be required when you're going to be marketing a vaccine gives us a little bit of insight in current regulations and their scope as it relates to eliminating or preventing vaccine cause disease? Yeah, absolutely.

Unknown: 26:38

So number one, we need to understand that there's, you know, the protection of human subjects that comes out of World War Two out of the Nazi experiments on prisoners during the Holocaust, that brings brings about a whole set of standards on how to treat people for medical trials, no longer can you just grab anybody and do a medical experiment on them. They have rights, right. And that's kind of interesting that that's so recent in our history. But that's, that's the way it is. And so now, the the people who go into these clinical trials need to be fully informed of what they're getting into, to the best of the knowledge of the researcher. So for, for example, for COVID-19, my wife was in the clinical trial for one of the vaccines. And in the release of information, she was told, Hey, we gave this to about 100 people. And so many of them had an allergic reaction. So many of them reported this and this and that. And this is what you should expect, you can choose to how many have the first dose and not have the second of your experiences bad, all these pages of pages of information, children, that you're going to do a clinical trial on children, the children have to assent it's it's similar to consent, but it's a cent. So you try to explain to the child as best as you can, what they are to expect from from a clinical trial. And if the child is agreeable to it, and then the parent agrees and you move forward. For example, if you tell the child that it's something is going to hurt, and they say, No, I don't want it and they clearly don't want to be involved in something that would hurt. They have not given the giving you their assent, and so they cannot participate in these trials. So human protections is number one. Number two, you have the FDA, you have the NIH, you have the CDC, at the global level, you have the World Health Organization, you have state health department's local health departments, everybody involved in overseeing the regulation of pharmaceutical companies, they're very, very highly regulated. Everything that they do is scrutinized the data that they have, though they may be secretive with it, there's the data still subject for review, I can go and look at the data. I can't publish it, I can't you know if it's if it has trade secrets in it, but I can certainly go and look at it and then give my opinion of saying, Yep, this, this data looks good. And that's what happened. With the FDA review of the two vaccines. If you look at if you are a geek, like I wasn't you sat through the eight hours for each vaccine and listen to the experts as they reviewed the data that was given to them, then you see that you know that there's there's a lot of regulation that goes into what needs to be put into those reports. You know, God help you if you lie, or if you mislead, because it's it's huge penalties, it's huge fines. Usually, that means the end of a corporation, if they ever are caught doing something that is less than that less than honest and informing about the data outcomes. So you have companies being regulated by the government, they're being also regulated by the industry. So you can imagine how competitive a competing company is probably looking at another company and trying to find any fault with their product. And so you have companies regulating each other through analysis of each other's claims. Right. So if, for example, Pfizer says that their vaccine has a 95% effectiveness, I can assure you that a competing vaccine manufacturer has a lot of that vaccine, and they have they're doing their own studies to prove or disprove that that vaccine efficacy, because then they want to say, you know, no, no, it's not that efficacious and my ours is better And then finally, you also have academia, you have academics doing research, or they get grants, not necessarily from pharmaceutical companies. So though sometimes they do partner with pharmaceutical companies, but they can also grants from, from the federal government, the state governments and private institutions to conduct their own trial. So you have a lot of people checking on these things and making sure that they're happening. And you have stiff penalties for anything that is hidden or might not be fully disclosed. And on top of that, in this era of social media, and a lot of public information, if something like that ever gets out, it probably could mean the end of a company. And so you don't want to you don't want to do something like that. You want to be completely transparent. You've probably heard in the last couple of days, Merck said, our vaccine is no good, or COVID-19 vaccine is no good. It's just, it's not gonna, it's not gonna happen. And we're done. We're pulling out of the competition to get yet another COVID-19 vaccine created, if they truly control the world, like a lot of conspiracy theorists would say, Merck would put out a vial of saline and say that it's a vaccine, right? But the deception would be found out, and then that's, that's probably the end of Merck or any other corporation. So yeah, there's a lot of regulation, there's a lot of third parties looking at things, and checking and double checking the claims of each of each of these companies. It didn't used to be like that. And certainly in the early 1900s Those few laboratories who were private without any government regulation, they could just claim whatever they wanted to claim, right and nothing would nothing would come up and if they if they were selling saline instead of the anti Serb all that would happen is that people would say, well, your products not that good. I'm not going to buy it anymore. But but that would be it. Now with with all the the oversight and the regulation, there's there's consequences to things like that.

Aaron Harmon: 31:46

Going back to like 1901, how much work did it take to bring over that technology into the US of hyper immunizing horses?

Unknown: 31:53

Yeah, you know, I don't have any I don't have any evidence. Since we went since we talked about this before I went looking for some evidence of corporate espionage of somebody actually going to like pester labs in France and hey, you know, tell me all about this, this fancy technology, and then coming over to the US and doing it themselves. I'm sure that there was, um, but you know, if you were wealthy enough, you could start your own lab. You know, you get yourself a few horses and you give them the diphtheria toxin, and hopefully hoping that they make the antitoxin and then hoping that you you get enough serum and purify it in a good enough way to get just the antitoxin out if you could, and then and then selling that not a lot of regulation at all. And you see it you see it another industries right. Upton Sinclair writing about the the meatpacking industry or the meat processing industry, created a whole set of regulations in labor and include the predecessor study FDA, a lot of shenanigans, I like to call it were happening back then, because anybody with enough money could get into the game.

Aaron Harmon: 32:55

So looking at that first law that was passed the biologics Control Act, it was really just off top my head, like three or four paragraphs very short. And essentially outline that you had to have your biologics laboratory had to be registered and needed a microbiologist on staff that was about the extent of that regulation looks a little different

Diane Cox: 33:13

notice.

Unknown: 33:15

No different but I mean, again, this is this is the infancy of the germ theory, you just needed an expert, you can be any any any guy with or gal, I guess, with enough money to start your lab, you actually need an expert, somebody who at least had studied up on this and had the degree to show that they had studied up on this, and that would at least ensure a little bit of quality to your product. And the registration part is also important. Because when you're when you're registered, you can't just kind of open up shop, sell something that hurts people and then and then run, run away with the money. They're gonna find you out. They're gonna know, know who you are and where you live and come after you. So that is another important thing that came out of this as the idea that registers were going to be kept that records were going to be kept that a lot numbers were going to be created and kept. And you saw how easy Well, I say now you know how easy it was to trace back the tenants to Jim, but it would be super easy to it. Now. If you have at least in the United States, when we have a foodborne outbreak. It's only a matter of days before something is traced back to its source of how it happened. A lot of foodborne outbreaks are not, they're not mysteries anymore. It's just a matter of figuring out which food it was and then tracing it back to its source and doing a couple of lab tests. Back then it was probably a little bit a little bit harder to do but with the registration with the these new ways of keeping track of things, and also it also helped

Aaron Harmon: 34:39

without that it would be impossible.

Diane Cox: 34:41

Yeah. Yeah, I'm glad you brought up the traceability because just thinking about the medical device industry. It's either you can figure out and isolate kind of where the problem stemmed from or you end up in situations where there's patient harm has To recall just about everything. And so it really is not only just a good thing for patient care and making sure that nonconforming product is not in the patient's hands, but it also is a good business practice so that you're not having to pull everything off the market now. Yeah, cuz you know exactly what the problem is.

Unknown: 35:21

When we do African investigations, and we go ask people, you know, what did you eat? Or where did you eat it from? We can go to the restaurant, and then they can tell us who, who they bought the produce from. And we go to the produce seller, and they can tell us where they got it. And I mean, it's, it's amazing, we can in a couple of days, we can trace it all the way back to the farm. And a lot of farms now are at the point that they can actually trace, trace it back to this specific area of the farm where they they pick the fruit. And then you just look at the fruit and run it by the lab and see what grows and you can you can identify salmonella, Shigella ecoli, and all those things.

Aaron Harmon: 35:52

The other name for this law that was passed was the virus toxin law. And when we talked on the phone last, Renee, you had brought up the fact that they hadn't been able to even visualize viruses at that time in history yet.

Unknown: 36:04

Yeah. So viruses were not visualized until the 1930s with the electron microscope, before then they kind of went in a hunch that it behaved very much like a bacterial infection. You know, the Cox postulate said that, you know, if you, if you give somebody the disease, and they develop the disease, and whatever you gave them is what caused it and then you can take it from them. And this, and this example was smallpox, you can take it from them and give it to somebody else, and you can cause contagion, but they couldn't see it under the microscope, and they couldn't grow it in any kind of tissue. They only grow it in like live animals, pasture grew rabies in rabbits, and dogs, the smallpox vaccine can only be carried from from one person to another hidden hence the ball Miss expedition to the Spanish overseas territories face like that, because they just couldn't see it. So they call it a virus. It's a it's actually an older word. And it was just something that is infectious. And but you can't see it. And it wasn't until when I think there is they were able to see it. Call in the 19 in the 1850s develop the microscope, and that led to the to the visualization of bacteria. And bacteria were a little bit easier to grow. Not terribly easy, but a little bit easier because you just have to figure out what bacteria like to grow in and then you can just grow that in the lab. But viruses are notoriously difficult even to this day. They're notoriously difficult to grow. When the pandemic started. That was one of my main concerns is it's going to be super hard to get a vaccine against Coronavirus because Coronavirus, just does not like to grow in the lab. But then mRNA vaccines came came along and solve that that problem. But yeah, it wasn't until the 1930s and then you visualize influenza, you realize that it's a viral infection is that the bacterial infection that was causing pneumonia, and you get the influenza vaccine and and during World War Two, and you're off to the races, you get polio, you get measles, you get rubella, you get. Gosh, I'm blanking out now on viral infections. But once you can, once you can see it mumps once you can see it and under microscope, and you can you can grow it in the lab and confirm that it is growing, then you're off to the races on viral viral vaccines. If you want to look into the worker, Dr. Reese Helaman, he developed an awful lot of vaccines on it came with the advent of the electron microscope.

Aaron Harmon: 38:19

Did you imagine doing vaccine research on the virus without PCR cell culture for a seamless process? Or sequencing? Yeah,

Unknown: 38:26

that would be And again, that's that's what gives me hope for the for the pandemic we're that we're going to get through it and survive as a species. Unfortunately, we're losing a lot of people, but that's a whole other discussion. But you know, Snow did it without knowing what a virus was. So that pasture, you know, they develop vaccines against some very deadly things without having much knowledge. I mean, at the in the era of Pasteur or germ theory was just starting, they didn't, he kind of proved that bacterial and viral diseases didn't come out of nowhere, in germ theory began there. They had limited knowledge and they were able to do great things. And so now we have all these things that you mentioned. And so that that gives me hope for what we can we can do. And technology advances by leaps and bounds. And so I'm hopeful that in the next pandemic, because we are going to have another pandemic, soon enough, we'll be able to have the vaccines even even faster, because we've learned from the experiences of this one,

Diane Cox: 39:18

given what we know now about vaccine development and the experiences with the vaccines that we talked about today. Is there anything different or more that could be done to ensure the safety of the COVID-19 vaccine? In your opinion?

Unknown: 39:31

Yeah, that is that is that is hard to answer, right? Because we're at the cutting edge of time, like we're living in the future. And so it's difficult to say it's much better than it used to be obviously, it's as good as it's going to be at this point in time, but not in the future might get better. I think that we do have maybe a little bit more to do with open data, with clinical trial data being open and available to citizen scientists to to others. Other researchers to just share the data a little bit better. You don't have to share trade secrets, but you can share data on outcomes instead of summaries instead of getting non disclosure agreements to people who are going to review it. That might be the next the next step is freeing up the data a little bit better. Instead of journal articles that you you have to pay a lot of money for or be associated with a an academic institution to be able to read, you would just get the journal article on some open source online. And with that, the responsibility of teaching the public how to read those things critically, and how to understand the science better. But yeah, I think that's that's probably going to be the next step in all this is going to be open data, and being able to to go into any any vaccine manufacturer, website and downloading the data. As they're collecting it from their their test subjects. There's a lot of work to be done towards that there's a lot of resistance for you know, trade secrets, or they don't want to reveal that their product is bad because they have investors that they're responsible to. But I think that's that's probably where we're we're heading because you see that that push towards that you see a lot of people asking for that. And you have more and more of an opinion, including mine, that that would not be a bad thing. So we'll see. We'll see if that's, that's where we go.

Aaron Harmon: 41:16

I do have one counter to that idea. Yeah. Which is the news and the news, getting a hold of trial data and trying to make their interpretations and then present that back to the public.

Unknown: 41:27

Yeah, yeah. Yeah. And that's, that's why I said the caveat comes with the responsibility of teaching people how to how to how to read it, you know, it already happens. You know, you have a lot of, especially with coronaviruses, every single day, I was surprised by you know, new research out of so and so shows that Coronavirus, you know, does this or does that or that this medication or that medication, we have a little bit of maturity to do that as a species yet with social media and mass mass communications. I'm hopeful that we'll get there. We've done that with other technologies. You know, it used to be when I was a child, that TV was going to be the end of me, and it was going to lead me to do something bad if I watch too much television and here I am a Doctor of Public Health, working for universities like Hopkins for the College of Physicians, etc. We mature with technology. And hopefully we'll do that with social media. And with the era of mass mass news and mass misinformation we'll learn how to discern between good information and bad. I'm hopeful in that in that regard. But yes, you're correct. That is that is one of the dangers that you're into that it will be it will be misleading. And it will be used for nefarious purposes.

Aaron Harmon: 42:37

Maybe that's a good way to put this the way our maturity of it. Our product development is mature, docile. So we went from being whoever wanted to set up a shop and make a product to what we have now. Well, thanks for being on the show today.

Diane Cox: 42:52

Yeah, thank you so much. I learned a ton today.

Unknown: 42:54

Yeah, thank you. Thank you for having me. And I look forward to next time.

Aaron Harmon: 42:59

Now we'll take a quick break to hear from one of our sponsors.

Unknown: 43:02

Today's startups become tomorrow's growth engines. In South Dakota, we're entering a new stage of expansion for a biotech industry, and you'll want to be part of it. Hi, I'm Tony Johnson, Executive Director of South Dakota biotech, where the state affiliate of the International bio organization and we're proud to be leading a state that's driving innovation to feed, fuel and heal the world. South Dakota biotech is here to inform, to connect and to advocate for our critical industry. Whether you're directly involved in biotechnology, or looking to learn more about it, we want to hear from you. Find us at www that SD bio.org. Now back to the show.

Aaron Harmon: 43:42

To continue discussing Jim, and the biologics Control Act. We have Kelly Creighton with us again, welcome to the show again, Kelly,

Kelly Creighton: 43:48

fine, great to be here, again,

Aaron Harmon: 43:50

my theory on regulations is that when something goes wrong, and that's something tugs that are hard enough, it causes people to have an action and that action, in this case being political. And that political action leads to laws, laws read lead to regulations. And that's how we get the regulations that we have. The biologics Control Act was one of the very first laws put in place. And before then, manufacturing drugs, devices, biologics was a free for all, we could do all of it, it was leave well enough alone, there is no reason they're regulated until something went bad. And since then, every time something has gone significantly bad, bad enough to get at us. We ended up creating laws and more regulations to prevent it from happening again. And in this case, it was children that were impacted. People watch their kids die, washed it through the front page of the St. Louis times. They can see the kids names and that child is dying because of the drug they got. So trying to like myself imagine back, what would it be like Kelly in a world where there's no regulations, and you could just make anything you want and market it? Right?

Unknown: 44:55

I mean, yeah, it's a great question because in an ideal A world, everybody would do the right thing. And we wouldn't require regulations, and everyone that was involved and the drug or the biologic, or the device arena, was doing it purely out of altruism, right out for the betterment of man and mankind. But the reality is, is that money and economics creep in into the industry, right? People do it because of economic incentives. Because of that, you will always have people who will try to take advantage of an industry if it is not regulated. So in this in this case, right, you look back to the biologics act, you'd look back at what the the Selenium IDE with the dye ethylene glycol, that caused the FD and C act to be to be implemented. Right. There's always something that triggers that. And it's typically, because you had one bad actor or a couple of bad actors out there, that were willing to do whatever, to be able to make a buck. I would like to say that, in reality, do we really need government regulations, because the industry does a pretty good job regulating itself, the marketplace does a pretty good job regulating products that that aren't safe or efficacious. But the reality is, is that you need these early checkpoints in the system. Prior to most products getting to the market, you need somebody there pumping the brakes to make sure that before anything goes into a human, that it is safe. And that's why these regulations really have have come into play. I do think it is, you know, a requirement for our industry, because FDA, the government check is the first check in the system. Great. And without that, if you relied solely on industry, or the commercial place to basically regulate itself, you're you'd have a lot of products going into folks, that would likely cause a lot of adverse events, likely a lot of deaths, you know, because you did not have these early checks. So these regulations really help the industry prevent things that these really tragic cases that we saw back with a Tyrian toxins and contamination to know so yeah, it's an it's a necessary evil, that is there to protect the subjects to protect the industry itself, right. Because if the industry did not have a well regulated environment, the general public would lose faith in it anyway. Right. And they would get to the point to where they wouldn't trust products coming out, they wouldn't trust innovation, they would not allow for testing of these products that ultimately get to the market and help save lives. So So yeah, it would be a, it'd be an interesting time if we lived in the air without those types of regulations. And as you see, right, as technologies emerge, the regulations continually have to kind of shift and change to account for these new emerging technologies. Because products, the way they're manufacture drugs and biologics, the way they're manufactured back in the 70s, and 80s. And 90s, is totally different from a way that a lot of products are manufactured today. And so those regulations have to continually be changing, and FDA is pushing on the forefront of that, to ensure that, again, the industry is meeting a certain level, a certain standard, to allow those products that go into clinical development, and ultimately to the marketplace.

Aaron Harmon: 48:39

I hadn't thought of the financial thing until you mentioned it. But one thing that I I'm drawn to is this concept of the triangle of quality, where if you take quality, you take speed, you take cost, you always have attention when bring a product to market between those three, yes. And there's, there's always a desire to get things to market quick. And that could be something as simplistic as there are people that are dying because of a pandemic, there are people that are dying from cancer or other diseases, and we want to get to them quickly. And that come from a very good place. And we want there to be the safety aspects of it. We want to make sure that all the things are there, the dosing and all that. But there's always a financial constraints. Yes. And what these regulations these laws do is they essentially draw a line and say, the quality can't dip below this line, you're always going to be constrained to here, and then the tension becomes cost versus speed to market. And I think that's what really helps provide protection.

Unknown: 49:32

Exactly. Now it is it's right because we have those standards. Now. FDA applies those standards across the board across all companies, right? The big pharmaceutical companies don't get a pass on quality versus the small guys or vice versa, right? Just because just because you're a smaller company and you may not be able to afford to easily apply those quality standards to a product. FDA is not going to give you a pass and unfortunately that slowed development for that program because it takes them a while longer to ensure the safety and quality of their products before they get in the clinic. But it does level that playing field because everybody has to comply with those standards. And it is it's, it's good in a way because it hopefully de risk programs going into, you know, into clinical development and ensures that we we try to avoid, like I said, these these tragedies of the past that were in place before the regulations. Were there.

Diane Cox: 50:36

Like you said necessary evil. Evil. Right, according to US quality people. Beneficial, right, yeah. Alright, so 120 years later, approximately, of course, we are still producing antibodies in animals for human use. So what is different now versus then the level

Unknown: 51:00

of scrutiny, that I would say that not only of the product itself, but of the source materials. And so of course, for a lot of these biologic products, a lot of times they are still made in a biological system, either in vitro through cell culture process that may use you know, human embryonic kidney cells or Chinese hamster ovary cells, or directly in in vivo as well right to where you're generating monoclonal antibodies against certain toxins, like, like Jim, the horse, and so in horses or cattle. So a lot of these biologics still are manufactured in a biological system. And the regulations and requirements to qualify those source materials of sources of those biological products be at the the cell cultures, or the animals have is a much higher bar. Now, there's extreme testing and characterization to demonstrate the safety of the either the cell culture or the animals being used to generate those products. So FDA has extensive guidelines now, where you have to look extensively at adventitious agents that may be presence, those include viral or microbial contaminants. And you have to go through a huge screening process to qualify your cell banks or your donor animals in order to generate biologic products out of those now. And that's all spun out of, you know, out of the biologic Control Act, and has developed as the industry has developed. And so yes, there is there are much more rigorous standards that we have to do, and that's part of the CMC side is, before you can ever manufacture those products to allow them to go into to humans, you have to do all this qualification testing. So this is a part of the the stuff that's done as clinical development continues. These are all requirements that are in place prior to that product ever seeing the first human. So there is this huge qualification exercise that has to be done. And it's always evolving, right? With this whole SARS cov COVID. Two aspects, FDA had to determine whether or not a testing for SARS cov. Two was required for cell banks or I work a lot with with human cell therapy products and whether or not donors had to be screened for COVID to and so there's always right, it's always moving back in the 90s. It was the bovine spongiform encephalopathy. And now all of that testing has been incorporated. So it's always evolving depending on outbreaks and pandemics that occur. So those those requirements are always changing. But today, right, you can rest assured that any product that comes out of a biological system like that has been appropriately vetted to ensure that we don't have these issues like from Jim the horse in today's biologic products.

Aaron Harmon: 54:08

Have you ever heard of a recent case of somebody getting like tetanus products?

Diane Cox: 54:14

Just gonna ask my question. You had the words perfect.

Unknown: 54:20

So no, not not in recent memory have I? Do I recall hearing anything that have a gross contamination like that, where you know, in a biologic product, now, they're always are

Aaron Harmon: 54:33

you supposed to stop and say thanks to biologics

Unknown: 54:35

control? Why? Yeah, well,

Aaron Harmon: 54:40

if things still go wrong,

Kelly Creighton: 54:42

yeah, right. But the reality is, is is there are still, you know, breakdowns in the system some time where contaminated products can get introduced into clinical trials or, unfortunately into the market space, but those Enough checks and controls that are those very rare. And when it happens, right, typically, those products can be recalled very quickly, those mechanisms are now in place to support where your calls are, or to pull those products out of the clinic quickly. If that. And again, it is very rare that that you would have a contaminated product out in the market. And I truly I can't remember the last time I remember hearing about something like that. So the proper controls are in place, again, because of the development of the regulations that have now been implemented across the industry,

Aaron Harmon: 55:41

in the newspaper in 1901, where they're describing this tetanus contamination, there is kind of a little bit of a dialogue that's mentioned where the manufacturer was accusing the physicians of improperly treating the patients and that's what they got to contamination wasn't actually their product. And when I saw that, it immediately reminded me of so many investigations that I've done, where the very first thing you do is you blame the user, it must about that data. It wasn't Yes, actually. Yeah.

Unknown: 56:10

Yes. And I still see that every now and then, right. Anytime you have a contamination issue like this pop up, right. And as as the should be through any proper investigation, right, you should look at look under every rock. And again, right, it's always somebody wanting to point the finger somewhere else, that it wasn't us, we delivered a great product that had to be somewhere downstream from us. And so I agree, right? You do need to look at that. But the reality is, is that most of the time, it does come back to the manufacturer, and at least in my experience, is where something happened. So but again, like luckily, we have enough checks and balances in the system anymore, that it is rare for, for bad product to get out into the market.

Diane Cox: 56:55

people's reputations at stake here. Point the fingers. So

Aaron Harmon: 56:59

the biologics Control Act was very small. I think there is a few basic requirements. One was that biologics manufacturers had to register with the state, and then they had to have microbiologist on staff. Now, when these laws get passed, they're much more elaborate, lengthy, and significantly more other any future ones you see coming up, I know there's things in the news, we see future laws coming up that you hear about or

Unknown: 57:24

right, and there's there's always new issues popping up, right? Once a lot of these products get out there. And people start doing massive reviews on the history and use of these products that you know, you start doing a lot of a guest post hoc analyses on things and people finding signals, things you think about, like the dino toxin purities, that the last year, and like the valsartan, and a lot of those products, right? The MDMA in MA D and impurity that people knew about, but then it got linked to be a Geno toxic impurity. And so then that created this whole issue within the industry to kind of go back and start looking at all these products that may have this these very specific impurities. And a lot of them started getting recalled and then retested. So right, so there's ever evolving issues that that come up, that the industry has to be prepared to address and that create new requirements. If I had my crystal ball I wish I did, I could tell you exactly right, what might be on the horizon, because then I could be out in front of it and selling it to people and saying this is coming, you know, be prepared. But in reality, FDA, in general is typically slow to move with regards to getting new regulations in place. And so a lot of times right they issue may be known for several years before we actually get legislation or any type of guidance from the FDA around no specific industry. And that's just because right government is typically slow. So what is great though, is that you see industry implementing those controls, a lot of times when they start seeing those signals, there, they are now proactive, more proactive, because they want to be ahead of the issue as well. And they don't want to then get to a certain point in their development and FDA come back and be like well, you need to address XY and Z now because we you know, we now think that these are these issues are particular to this type of products. So the industry is trying to be a lot more proactive in addressing them. And again, it's just because they a want to ensure that they have a safe and quality ish product out there development and trying to get to the market, but be right they also don't want any hindrance. Once they try to get to that marketing application phase and FBA create new requirements for him. So I can't say that there's anything off the top of my mind that says you're going out that these regulations are coming. But as the industry evolves, as technologies evolve, right, the industry is the industry and FDA are constantly trying to stay ahead of the technology, and develop guidelines for the industry to comply with, for, you know, for new product types that are coming to the market. So it's an ever evolving type of system.

Aaron Harmon: 1:00:28

I genuinely believe that people get into this industry, because they want to do good. They want to create products that help people and make a difference in the world. And so, having tragedies happen and things go wrong is very against that very nature. And I feel like these stories should help give us cues and kind of guide us and saying, hey, you know, we want to get get our market there, and we want to help people. But oftentimes, it was this unawareness of those risks and what could go wrong, and in the race to get it to market, some of those things get overlooked. And then you end up having these kind of tragedies. And in the case of this horse, getting tetanus, I'm highly confident that the people making that product, we're making a difference in the community. They were saving children's lives from diphtheria, and then along comes this contamination, and they just didn't have the practices in place, because they partially weren't aware. And so hearing you say that industries embracing it earlier, to me kind of lines up with how have you this? Yeah,

Unknown: 1:01:25

and it is right. I mean, I think all of us that are involved in an industry, right, we all always have that, that mine that that thought in the back of our mind that we are in this for the betterment of public health for for patients, right there, there is that level of altruism that I think drives everybody in history. And we want to make sure, right, I know for any my clients, any of the sponsor companies that I work with, that the last thing we want to do is put anybody at risk. And so that is, you know, at if we see these issues emerging, people are being very proactive. And that is refreshing, right that you do not have to wait necessarily for the FDA, or the the regulatory agencies to implement the controls for products, right, that people are trying to be out in front of it. Now, some companies may take that and try to leverage it as a competitive advantage right over other products. But at the end of the day, right, as long as somebody is leading that charge to ensure that that safety that we are keeping up the standards of safety of products. I think we all win.

Diane Cox: 1:02:45

Couldn't agree more.

Aaron Harmon: 1:02:46

Well, this concludes Season One of Inside Out quality. So thank you, Kelly, and thank you, Diane for being part of this laughs a whole season moved on. Stay tuned for season two.

Unknown: 1:02:59

Thanks for listening to my dad's podcast. But I want you to know today people use horses for riding, driving pets and showing and more and don't use them for blood.

Diane Cox: 1:03:11

We hope you enjoyed this episode. This was brought to you thanks to South Dakota biotech Association. If you have a story you'd like us to explore and share, let us know by visiting www.sd bio.org.

Aaron Harmon: 1:03:23

Other resources for quality include the University of South Dakota's biomedical engineering department where you can find courses on quality systems, regulatory affairs, and medical product development. Also, if you live in the Sioux Falls area, check out quinnbet A local Quality Assurance Professionals Network. You can find out more about wibit by clicking on the link on our website to the end and I would like to thank several people, but a few who stand out or Nate peple for his support with audio mixing Barbara Durrell, Christian or support with graphics design and web. And lastly, the support from South Dakota bio