What are Clinical Trials & Why are they Important

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 discuss with physicians with 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! Truth Behind the Data with Dr. Michael Koren. He is a practicing cardiologist and chief executive officer at ENCORE Research Group, which conducts trials across Florida. He has been the principal investigator in over 2000 trials and has been published in the most prestigious medical clinical journals. Dr. Koren received his medical degree cum laude from Harvard medical school. For more information on local trials, visit encoredocs.com or call 904-730-0166. Well, in this episode, MedEvidence! Truth Behind the Data with Dr. Michael  Koren, we are actually going to talk about the truth behind the data. Well, Dr. Koren, in the first segment, we talked about lady-tasting tea, this experiment, and why it's so important to what you're doing now with clinical trials, but you mentioned some statistical concepts let’s dive into those a little bit. 

Dr. Koren

To remind people who missed the first segment, the lady tasting tea experiment was a member of the British royalty who claims that she can tell if milk was placed first or tea was put in first when she had her mid-afternoon tea, the British love their tea and her claim was that she can tell which was put in first whether she saw it or not. A lot of people believed her, and some people were skeptical, and a very famous statistician named R. A. Fisher said I can test this to see if she's telling the truth, and this is the basis of modern clinical trials, believe it or not.

Michelle McCormick

Well, I look forward to finding the response to that. 

Dr. Koren 

There are three important elements of hypothesis testing in modern clinical trials. They have to be prospective, blinded, and randomized. Let’s talk about what each one is. Prospective means you are putting the thing together before you have any information, so prospective means ahead of time. So, for you to do a good research study and run a clinical trial or do a good hypothesis test. You need to set up all the rules for the test beforehand. It will be cheating if you say okay, we will make a bunch of observations, and then we will take a look at it later. And so hard science and a good hypothesis test require that you lay it all out. This is what we are going to do? This is how we are going to do it. And this is the number of observations that will be required to determine whether or not we can establish the truth.

Michelle McCormick 

Yea, it sounds like a very fancy science fair project.

Dr. Koren

Well, remind me to tell you about one of my kids’ science fair projects.

Michelle McCormick

Okay, I will 

Dr. Koren 

So perspective is a very important, planned experiment. We had other sessions where we talked about the very famous smallpox experiment back in 1721 at the Newgate Prison in the UK that was considered the world's first clinical trial because it was a planned experiment of vaccination when the first experimental test showed that vaccination actually works in a clinical trial rather than just based on general observation which is inductive reasoning versus clinical trial which is deductive reasoning. Prospective ahead of time has to be planned. Second, Clinical trials have to be blinded. Why does it have to be blinded? People cheat. 

Michelle McCormick

Well, This reminded me of Pepsi versus Coke back in the day there was the blind tasting either they have blindfolds on, or they have a barrier in front of them.

Dr. Koren

Right, so if you saw it was Pepsi or Coke, which tastes better, it’s whatever you believe, right? If you do not know what it is, it’s more credible that it is blinded. Blinding is very important. We may think we are objective but will have biases, and biases are absolutely impossible to overcome. So, you have to do something very specific to overcome biases. And the most effective way is blinding.  And in science and clinical trials, we call it double blinding. So, in double-blinding, we have a situation where both people who are volunteering for the experiment and the experimenters, both are unaware of which assignment they have. So that there is no bias from either side and there is no bias between interactions. So, for example, if you are tasting Coke or Pepsi and you do not know what it is because you have blindfolds on, but I know what it is, then I could see the bias. 

Michelle McCormick

I was going to say you can direct me, are you sure you don’t like this one better?

Dr. Koren

Right, if you are a Coke salesperson, you can say well, do you like the first one, that incredible fizz one, or do you like the second one? So, if both sides are blinded, there are different ways that you could influence people.

Michelle McCormick

Is that where the placebo comes in place? 

Dr. Koren 

Placebo is one form of control, which is not one of the three things, you are going to the fourth thing. 

Michelle McCormick

I jumped ahead 

Dr. Koren

So, for example, in the lady testing tea, whether the tea was first or milk first, the placebo is that you are just trying to see if someone is telling the truth.  So, you do not need a placebo in the hypothesis testing, but we often have one. And the third thing is randomized. So randomized means that when you are doing your observation when you are going through an experiment. There has to be a random order of things. For example, in the lady tasting tea, if you didn’t randomly mix up the milk first or tea first, you can figure out a pattern, so let’s say that you did five in a row that was all milk first, and then you switched it, and the next five the tea is first. Well, the human brain may be able to perceive a slight difference, the same for a few times, then a different, and so that may actually help the person along the way, so randomization makes it much more difficult for you to find a pattern.  So, for example, let’s say that you are testing a blood pressure drug and you know that the blood pressure drug should work better in people who are overweight if it was a random assignment of patients of all the overweight people in one arm and all the people in the other arm and that may include the results, but if you have a random number generator then you are coming in we don’t know if you are overweight or not. People will be assigned randomly. Any possible differences will sort themselves out by chance, and the number gets big enough that you are almost certain they will sort themselves out by chance. 

So those are the three key elements of good hypothesis testing, and that was what R. A. Fisher was able to teach us and to use this incredible and powerful concept to establish the truth. Now you have the fourth one, which is placebo control. When you say placebo, it means the control is inactive, when we do medical drug testing or a medical product evaluation, we often use a placebo. For example, a new drug is coming on the market and we want to see whether or not it is effective the best way to do that is to put it in a form where you can’t really tell what it is and compare it with something that is inactive and give it one or the other in a prospective or randomized fashion to a group of patients and see what the outcome measurement is to see if it is different. For example, if you are testing a blood pressure drug against a placebo, you will have a pill or an injection that looks identical whether it is active or not then you would give it to a bunch of people, and then you measure the blood pressure and if its an effective treatment the people who have the active product will have lower blood pressures after some time after the intervention than the people that were on the placebo but there are other forms of control. So controlled experiment doesn’t necessarily mean a placebo so for example, if you want to show that drug A  is better than drug B,  but you really are testing drug A,  that is your permanent hypothesis, then drug B is called a controlled substance, and that is comparative. Now we often do that when there is extensive care when for example, in a lot of blood pressure studies, you wouldn’t want not to treat patients for an extended amount of time because it will be unethical because we know blood pressure lowering saves lives, prevent stroke and does other things that are positive for the human body. you may get away with a short-term drug versus a placebo. So, in that case, you need to use some controlled agent, so that way everybody is getting something so you can see the new agent is an incremental improvement compared to the controlled agent. That is a key part that we do in development. That is a key point that we make every day.

Michelle McCormick

What is the history of clinical trials? When did they first begin? 

Dr. Koren

So, there is a lot of debate on that, getting in the faith thing, in the bible, there were choices people had to make, and there is a passage about Daniel in the bible and the Babylonians. So we sometimes talk about that for the first experiment it is really not a clinical trial because they didn’t have all those elements such as prospective, blinded, or randomized. 

Michelle McCormick

Right, which grew over time, I am guessing?

Dr. Koren

But basically, Daniel said that if the Babylonians eat rich food and I eat basic bread and water and healthy foods, then I will be stronger than you, and in 10 days, that was true. His hypothesis was that he chose one diet, and there was a control; basically, the outcome he picked he did better. So that is an example, but we don’t consider that modern-day clinical trial.

Michelle McCormick

You mentioned smallpox was that the first modern clinical trial?

Dr. Koren

Right, and even that is not perfect by any means, but back in 1721, there was this theory based on observations from Africa that if you had smallpox, you could protect yourself from severe complications of smallpox by purposely infecting yourself in the leg or other parts of the body with small amounts of the smallpox virus in your body. Smallpox was very devastating for hundreds and hundreds of years, and the mortality rates during the smallpox pandemic were 33 % about a third of people in the community would die of this infection. So obviously, people were scared to death when they learned that a smallpox pandemic was coming their way. And what people observed is that the smallpox pandemic survivors are much less likely to get sick during the next round of the pandemic. And so, they said, why is this? Ultimately, they figured out that if you expose yourself to this virus in a certain way, you can protect yourself. if you get smallpox in the respiratory means and you are not protected, you can get really sick and die, but if you got injected with smallpox, they found that you had a small local infection that seems you can protect yourself. This was an observation in the middle east in Africa, and during the pandemic of 1721, the British royalty was so worried about this that they took these crazy ideas from the middle east and said let’s, try it. So the researchers went to prison because, at that point, it is considered ethical that if you want to get out of jail, then you would be part of the study, and we will set it up and give consent, that we actually practice every day, but in that case, it was not the consent of the patient but the consent of the king, but it was prospective, and it was consent-based, and it was an organized trial where they took six people and gave them these surgeries cut their leg and put smallpox in those wounds made sure they had an infection and saw how these people compared to the prison population in terms of whether they contracted smallpox or died from it. And all six people in the experiment seem to be immune to the effects of smallpox. It was considered the first clinical trial because they looked at a group, and they had a control group and a comparative group. 

To continue listening to the MedEvidence Clinical Trial series, listen to June 22, 2022 episode on the History of Clinical Trials.

Michelle McCormack 

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. 

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.