History of Clinical Trials (Part 3 of Clinical Trials Series):
Podcast Transcript
Original Air Date: May 13, 2022
Introduction
Welcome to the MedEvidence podcast hosted by Dr. Michael Koren and Michelle McCormick. MedEvidence, where we help you navigate the real truth behind medical research with both a clinical and research perspective. In this podcast, we'll have discussions with physicians who have extensive experience in patient care and research. How do you know that something works in medicine, we conduct clinical trials to see if things work. Now let's get to the truth behind the data.
Michelle McCormick
Welcome to MedEvidence! The truth behind the data, MedEvidence is powered by ENCORE Research Group with Dr. Michael Koren he is a practicing Cardiologist and Chief Executive Officer at ENCORE Research Group, which conducts Clinical Trials across Florida he's been the principal investigator for over 2,000 trials and has been published in the most prestigious medical journals. Dr. Koren received his medical degree cum laude at Harvard medical school. For more information on local trials, visit Ecoredocs.com or call 904-730-0166. Well, in this episode MedEvidence! Truth Behind the Data with Dr. Michael Koren, we are talking about the truth behind the data. Dr. Koren, we learned a lot about the beginnings of clinical trials. We are still waiting to see how the Lady with the Tea experiment went, but in the meantime, we have talked about truth, we've talked about the first trials with a vaccine for smallpox with six people, kind of a small trial. But what is next? How have the trials grown since 1721?
D. Koren
Sure, so again looking for truth is what this is all about. The folks that did the experiment in 1721 at the Newgate prison became convinced, based on this relatively small sample size, that they had a solution, and again it was prospective it wasn't just somebody's story; it wasn’t an old wife’s tale; it was an experiment.
Michelle McCormick
It seemed to work
Dr. Koren
There were a couple of interesting things about that I talked to you about deductive reasoning, the key element of deductive reasoning is that all the inputs to the deduction are true, and the question is framed properly. But how do you know that all the inputs into the deduction are true? There is actually an interesting sidebar of the prison story which is one of the prisoners lied about their history. One of the prisoners actually had smallpox before and didn’t disclose that, and they only found out about it when they tried to inoculate that person, the pus would not make a lesion on the leg because that patient immune system was already working and fighting smallpox. That patient had to go back for a second surgery with a bigger cut and more puss before there was any evidence of some problem.
Michelle McCormick
Hmm! okay
Dr. Koren
With any experiment, there are people that will cheat. So, you must be careful if there is a very rigorous design and a lot of caretaking in terms of how you set up all the details, and then you will come up with a deductive reasoning conclusion. The other interesting thing about the Newgate prison story is that they tested the patients after the fact they even had people sleeping in the same room as someone with smallpox to see if they got get sick, and they didn’t.
Michelle McCormick
Yea, that was going to be one of my questions. Even if they were injected or the puss was put in, are they still contagious to the other population?
Dr. Koren
Well, once they get passed the initial response, they are immune they won’t get the virus or spread the virus. Which is true till today. That was our learning from that. That was our early study on that. Anyways, that was a small study, and we needed more evidence, so the next big piece of the puzzle occurred in the same year for the same pandemic. Obviously, when you have a virus, it spreads, and we know that even though travel was not as extensive in 1721 as it is today, people still traveled, so there are ships going back and forth between England and the colonies all the time, and they brought diseases with them. So, in 1721 during this pandemic year in Britain, there was a ship that came over, and all the sailors were healthy when the ship left, but as the ship was crossing the ocean, one of the sailors got sick with smallpox, and people started freaking out of course. They got into Boston, and they know that there is a sailor there that was sick, and the words spread in the community about this person with smallpox. So there is a fellow named Cotton Mather who was a minister at that time, and he owned a slave named Onesimus, and Onesimus was a really smart guy, and they both had a little bit of a friendship going and Onesimus old Cotton Mather that in Africa, where he was born what they do to prevent this was to do inoculations and Cotton matter was open-minded to a degree and said that is interesting maybe we should be doing this to protect the people in Boston. Which is where he lived and where that ship came in. So anyhow, Cotton Mather wasn’t really a “physician”, but he did a little bit of everything and like to think of himself as a man of science he found this guy named Dr. Boylston for those of you that went to Boston, it has a street named Boylston Street. Named after this doctor. I was just there, it’s nice, it’s really nice. And together with his advice and his guidance inoculated 287 people in Boston in 1721 by making cuts in their legs and putting smallpox puss in, and behold, the people that were in that group of 287 had a risk of dying that was less than two percent versus about sixteen percent for the general population. So incredible difference was made even in this very primitive type of inoculation, and so that led to this concept of inoculations and vaccinations ultimately, and the observation was made that not only do previous smallpox victims seem to be protected against smallpox during the pandemic years but also people that get cowpox. So, they found that milkmaids are constantly being infected with cowpox which is a mild infection that seems to be immune from smallpox, and then Dr. Jenner in the UK eventually created a smallpox vaccine based on giving people cowpox. Which is a less serious type of infection than inoculating people with smallpox itself. Resulting in the development of a whole industry based on large-scale clinical trials once we understood statistics better, that's getting back to our R.A Fisher, who created the infrastructure of statistical analysis in the early part of the twentieth century, and then studies like the Framingham study and other studies that became Interventional, were able to show the benefits of cardiovascular risk factor disease prevention and the benefits of inoculation. So, a polio vaccine is a great example of where you literally wiped out a Scourge, the horrible thing was that smallpox has been completely eradicated based on a vaccination strategy. Then most recently, we had this massive effort for covid-19, showing that we can 1. develop the vaccine in an incredibly short time with modern technology, and 2. To inoculate tens of thousands of people, and 3. Does the hypothesis testing require an incredibly vigorous way where we know exactly how effective this thing is and what side effects to worry about. Based on these interventions, we know there will be mortality differences, differences, and hospitalization.
Michelle McCormick
Do you think that with the covid-19 vaccine, the trials are still ongoing?
Dr. Koren
Sure, yes obviously, the wonderful people who volunteer for the trails in the first place are still being followed. So, we appreciate them obviously, in the beginning, they were involved in a prospective blinded randomized trial with a placebo arm, so the early people that participated didn't know for sure if they would get a real vaccine or a placebo. Eventually, everyone crossed over, so again they stayed blinded, but the people who didn’t get the vaccine initially got it a few months after. This is called crossover design, the concept of fairness everyone eventually gets it, but there is a time lag. So, you can see if the people who got it earlier do better than people who got it later.
Michelle McCormick
Do the boosters piggyback on the initial trial?
Dr. Koren
There were the booster trials, we participated in the booster trials here in Northeast Florida, and other places, and that showed that the third dose was also effective. People who got their initial vaccination, the other two-part series, either Moderna, Pfizer, or Novavax, were protected, but after a period of time, the protection wanes. So, they are more likely to get infected with covid again after six months. It is a much less severe illness, but they still have some vulnerability. So, giving the booster reduces the vulnerability after a 6-month time lag. What was very interesting is that this gets into the concept of faith and truth. That we were proving that the third dose worked, and then the FDA approved 4th dose based on faith. we know vaccines are safe and effective in the beginning. We know that the booster works and seems to kick in and can become necessary for high-risk people after 6 months. So, the 4th dose should also be beneficial, but the crazy part about this is that the FDA approved the “fourth dose” as the data were coming out for the 3rd dose, so even though it was known that the 3rd dose worked, the formal presentation which was the data that I was part of didn’t even come out until the FDA was having to discuss the 4th dose and some people in the scientific community was actually upset with the FDA by jumping the gun. They were saying were all about deductive reasoning, we are all about clinical trials, and you're making an assumption rather than looking at things from the standpoint of certainty.
Michelle McCormick
How interesting! Do you think this will come like a yearly flu shot, a situation for folks to continue?
Dr. Koren
I think so. We know that viruses mutate, we know that certainly coronavirus mutates rapidly, and covid-19 has mutated. It seems that it's, fortunately, mutated to a more benign form, thank God for that, but who knows it can mutate to something else that may not be quite as benign, so we must be on the lookout for it. And we know that our immune systems are is incredibly capable of fighting the virus 6 months after your exposure to the vaccine. It only makes sense to use a strategy as we do for the flu and other things where we can hopefully give the vaccine regularly to the people at high risk and prevent them from having severe complications. Now there will be some discussions about who is a high risk, there will probably be a high-risk definition based on your exposure risk, people in the healthcare, people who are first responders, etcetera. People who are very vulnerable if they get infected, like cancer patients, people with diabetes, etcetera, so we'll look at that over time, but that's also true for other viruses, so covid-19 was the talk of the last few years, but we have some other nasty viruses out there, Chikungunya, we are doing studies on that. It’s a problem in the tropical area now coming to Florida, and we are working on that. RSV is a virus that can be as nasty or worse than covid for some people, and it will kill vulnerable people. Flu, of course, some years of the flu seems to be more pathogenic than other for a reason that is not always completely understood, but the flu is a virus that mutates, it's a virus that, if you're vulnerable, can put you in a really bad spot and so as we speak, we're doing studies about all these things. We know vaccinations work we're trying to get to some of the nuances of the strategy, so once you know that the vaccines work, then the question is, okay, do you change the vaccine each year, was a basic vaccine important, should it be every six months of every year or every two years. Certain vaccines we give less frequently, and some we give more frequently. So, a vaccine against pneumococcal pneumonia must be every five years which seems to be enough time to keep the immune system on guard. Shingles vaccines are another example. Shingle vaccines are based on the virus that we typically get as children.
Michelle McCormick
Chickenpox, now there is a chickenpox vaccine too. Could we stop there quickly with the chickenpox? My kids got the chickenpox vaccine I never had it, I never had the shingles vaccine, but I had the chickenpox. So, I am probably vulnerable to shingles vs. my children, who have had the vaccine as they age.
Dr. Koren
Right, that would be expected. Actually, one of the rationales for giving the chicken pox vaccine rather than getting infected is that the virus can live in the dormant stage in your nerves if you have actually been infected, it's placed on your body, whereas your kids who are vaccinated probably won't actually have that in their nerves so that hopefully that'll prevent them from getting shingles down the road.
Michelle McCormick
So, is your singles vaccine, is that ongoing
Dr. Koren
This is the learning of clinical trials.
Michelle McCormick
Yes, it’s fascinating.
Dr. Koren
It is fascinating. This is how we establish the truth. And again, through the process of deductive reasoning using deterministic statistics and prospective, blinded, and randomized studies were able to figure out really what was going on in the world.
Michelle McCormick
I am your host Michelle McCormick, and we want to thank Dr. Michael Koren for his clinical and research perspective behind the science in this episode of MedEvidence the truth behind the data.
