The Future of Clinical Trials

it's not about snack food. No, it is not about putting like sheep organs on French fries and what they would call that in England. Well, I'm a really big fan. Actually if the entire genre of kind of you know, the awful and the chips are delicious. Ye, you're you're talking awful as an o F F a L right, not not a WF you well were We were really really we're really interested in in covering that in the

future of it. But as it turns out, the the what organs on chips actually are is pretty darn fascinating and it's all about transforming how clinical tests would be carried out. But in order for us to talk about transforming, we kind of have to lay some groundwork, right, We need to talk about how clinical trials happen. How, How do how does the medical profession evaluate and regulate things like drugs? For example? Yeah, because you can't just make a drug and put it in a bottle and then

go sell it to anybody. Can Well you can, but legally you'd be culpable for that. Anything that you claim has a pharmacological effect, you would then be probably brought under the uh the attention of the Food and Drug Administration here in the United States or whatever other regulatory body you have, and whatever other countries. What if I call it a natural remedy, So now then you get a little more leeway in some countries. But that's that's

a different conversation. Okay, No, Let's let's look at actual mainstream pharmaceuticals. Let's say that I am a researcher and I've come up with a new compound that I think will help cure some disease. What happens before I can actually give that to people to help them? How? What are all the processes I have to go to find out whether or not it works, whether or not it's safe, to get all the government approvals what happens. Luckily we

have Lauren here, who is our our medical guru. So, Lauren, do you feel comfortable tackling some of this, Yeah, sure, totally. First of all, it's going to depend on what country you're in, because regulations are going to be different under any any different government obviously, but the pre clinical and clinical trial procedures are similar around the world. We're going to talk specifically about the US ones right now, so let us talk about those two phases, the preclinical and

the clinical. During the pre clinical first, Joe, if you have made a compound, that's that's heads above many other people in the research industry right this very moment. It takes a lot of doing to actually create a compound that you think is going to solve a particular problem. You know, you might be trying to inhibit or amplify a particular enzyme that does something or isn't doing something correctly.

And so once once you've got a bunch of computer modeling and in vitro, that's that's lab dish testing done, then you can move forward to the next part. Okay, so I've done initial testing, I've I've got a compound, I've settled on what do I need to do next? Next, you need to test it in living animals. And I know that that this is a very sensitive and squeamish topic for a lot of people. And I absolutely understand that.

I don't think that anyone medical researchers included are twisting their mustaches go and like, yes, we are going to hurt these rats today, at least I hope not that would be I'm very fond of rats personally. But it's incredibly important and we'll get into that a little bit later on. Um, but let us suffice it to say at the current moment that different animals are used for their similarities to two different human systems. For example, pigs

cardiovascular systems are surprisingly similar to humans. Uh though, rats are the go to for lots of drug testing, especially at these early stages that we're talking about, right, So that's probably because lots of mammals are pretty much all mammals share a lot of things in common, even though they don't necessarily share everything. Uh yeah, we also don't share many, many, many things, and that's part of why this whole organ onic chip discussion has been rearing up.

But uh, the things that you're looking for with animal testing include like how much of a compound will be absorbed by the body, or how the body will break it down into into the metabolites, or the toxicity of the compound and its metabolites at levels that are likely to be used for the intended purpose of the drug, or how quickly the compound and its metabolites will be excreted from the body, all of these being of course,

very important to figuring out how a drug works. Right. So, in other words, if I take a drug and it turns out that only a tiny percentage of whatever that substance is actually gets absorbed by my body, then you would you could draw the conclusion that that wasn't a very efficient use of that particular dose of drug. You could say, it's not that the drug is necessarily ineffective. It may be that you need to make up more of that that dose with other inactive elements to make

up whatever that particular delivery system is. Oh sure, maybe you need to tweak the compound itself, or maybe you need to change the delivery method. Maybe we're injecting it but it needs to be taken orally. There's all kinds of I mean numerous multitudes of variables that can go into any stage of this process and it testing and it's safety, uh and and it's so complicated that traditionally computer modeling has never been good enough to substitute for

actual physical animal testing. I mean, just because our bodies are so ridiculously complex and our systems are tied to each other in ways that we really don't understand yet, which sounds ridiculous being that we live in the incredible future. But we've said many times on this show that the human body is kind of one of those science things that we just don't don't have worked out yet. Well, yeah, as it turns out that if you want to learn a lot about the human body, there's some ethical issues

that you have to look into. Like you can't just take a person and then say, all right, we're gonna take this one, one person apart and see what makes a human body tick. That's there are huge ethical problems with that. If you don't recognize that, Uh, why don't you go listen to stuff they don't want you to know? Podcast?

The show for sociopath Love should buy oh snap, if Josh and Chuck ever listened to our show that you oh no, they're totally scy and they love us so at any rate at this stage, UM that the compound can go through a lot of these little tweaks that we were just talking about. UM, And if all goes well, the company developing the drug would submit a Investigational New Drug Application or i n D to the f d A, which is of course the Food and Drug Administration UM.

The application will include the chemical and manufacturing data, the animal test results featuring a whole bunch of different safety margins and whole body effects of the compound UM, and then the reasons for proceeding to a human trial, the plans for protecting the human volunteers, and the overall testing strategy.

It's going to be laid out. It's it's not it's longer than a book report, y'all right, Because I mean again, this is why animals are so important in this phase, right, Because, like you were saying, the human body being so complex. If you're taking a treatment that's targeting a specific part, like let's say it's for a disease that's found in the liver, Uh, that does not necessarily mean it won't

affect other systems in the body. Yeah, the drug is not going to magnetically go to the liver and just hang out there. It's gonna get into other systems and might have unannounced side effects and announced unpredictable side effects. And and that's true in animal bodies at least as much as it is in humans. And so all of this is very sticky. But once once they've been approved on their I n D, they can move on to clinical trials, which is the official human element in all

of this. So this occurs in three different phases, phases one, two, and three, which take approximately one, two, and three years to complete, respectively, although they can take very much longer than that depending During Phase one, volunteers are given very low doses of the compound, the volunteers might be healthy or, in the case of very severe diseases, actual patients, and the doses are then gradually increased to test the effects and the safety of the drug. About phase two UM.

About two thirds of drugs tested will proceed onto Phase two UM, during which one hundred to three hundred patients are given the compound to help determine the most effective dose and delivery method and to continue assessing the compounds, effects and safety at at these street levels all right, um and I don't have an exact number on this one, but a lot of drugs drop out of the trial phase right here and have to kind of go back to the drawing board to be retested and reevaluated, um now.

To mitigate potential harm, these first two phases are conducted with the smallest number of volunteers possible in order to gain statistically significant results. But during phase three, the testing has opened up to thousands of patients across many different populations, which um uh, population is medical jargon for a group of people with vaguely common denominators in terms of health

or age or anything like that. And this is where final dosage and safety data are are sessed out, and some ten percent of drugs that have made it this far will fail to be deemed safe, all right. But for the drugs that actually make it through those three phases, they just go out into store shells, right PLoP right there. Not at all. Now now we are we are we

are certainly not done yet. All of this pre clinical and clinical data is wrapped up into a new drug application or n d A in the industry and submitted back to the FDA for independent review, which can take up to an entire additional year UM during which they might ask for more data or corrections, or even stipulate

a Phase four of testing. And in the end of this entire process, only one out of every five thousand to ten thousand compounds that entered pre clinical testing to begin with will ever be approved by the FDA to be marketed to the public um And even after that approval, the manufacturer has to check in quarterly with the FDA for the next three years, and prescribing physicians have the responsibility of reporting adverse reactions and and the company itself

might choose to continue clinical trials to assess like long term effects and continue tweaking dosage recommendations and safety and stuff like that. Or might have side effects that just happened to be really useful for curing other problems. Ah, Yes, like a like a medicine that might be used for cardiovascular purposes that perhaps addresses a completely different issue for people who are looking for a particular solution to a

particular problem. I think I know what you're talking about, But biagraa I believe is that would be the one I was specifically dancing around. So now that we've covered what about some of the issues that we've got this this incredibly large, encompassing process that is meant to make sure that whatever comes out at the end of it is the most beneficial right, that that is going to not cause harm ideally and will actually be efficacious for what it's intended to do, or the at least the

horror outweighs or the benefits outweigh the horror exactly. So So what what are some of the problems with this process? I mean, clearly, we want something that's very uh you know, meticulous, so that we don't cause large amount of harm, But what are some of the drawbacks here? Well, for one, thing, sounds like it takes a really long time. Yeah, I think eight to twelve years is the average. So meanwhile, you have people suffering from whatever the drug was intended

to address. I mean, assuming that it's a good drug that does work right, yeah, yeah, and it can be sped up in certain circumstances like for example, during the the the aid's outbreak in the nineteen eighties. Uh, some some drugs were pushed through very very quickly, and and that is a thing that can happen in that kind of case an extreme circumstances. But it also sounds to me like this process might might have a bit of

a price tag to it. Yep. According to the Pharmaceutical Research and Manufacturers of America, as of the year two thousand, it costs more than five hundred million dollars to bring the average drug to market. And that was fourteen years ago,

so as of today, it's probably a low ball. Um. Of course, not all of that is um specifically wrapped up in clinical trial, which is kind of the part that we're dancing around with the entire topic of this episode, and wherein organs on chips are going to come back to us that that might take umasily um two million dollars at the kind of low end of estimate. Now, keep that you might wonder about, you know, the pharmaceutical industry.

Everyone talks about being a multibillion dollar industry, but as we've set up this this process, it requires you to have a huge amount of of cash. Just yeah, you can't you can't just jump into the market willy nilly, simply because you do have to meet these very strict standards in order to move forward. Another problem I would see with this whole process is the concept of animal testing, which can be a problem for multiple reasons. I mean, number one, there is just the the ethical concern. I

mean that it's a hard question to way that. Like, you know, obviously we want to be able to create drugs that can save human lives, but you know, how many animals do you have to kill to do that, and what's what's the scale there? But beyond that, there is the question of how much can we necessarily learn

from animal testing. Obviously we can learn something, so it's not saying that that's worthless course, but you know, at a certain point when you're when you move from animal testing into human testing and you realize that that things that you had previously assumed based on your animal tests are completely incorrect in a human it's it's heartbreaking for everyone involved. Yeah, there's it's a waste of time and

money in life, and it's also an increase in risk. Yeah, there's there's a chance that something that had no toxicity in your animal models may be toxic in humans. Um, it's or vice versa. I mean, there are things that we humans can consume that are fine, and if an animal consumed it, it might not be able to survive or it could end up suffering at least some form of poisoning. So it's uh, the animal models are not always predictive for what will happen when you transfer that

same sort of treatment over to a human. Also, keep in mind we're talking specifically about testing drugs, but other types of chemicals are also tested on animals because of similar reasons, things like cosmetics or just chemicals that humans would come into contact with than it. And so anyone who's making said chemical for some product has to be able to demonstrate what are the parameter for safety, parameters

for its use. So all of that requires animal testing, and obviously, uh, you know, depending upon your personal feelings towards animal testing, this may be very disturbing to you. Oh sure, sure, I mean, you know, I think that we can all agree that. Um, if you're testing cancer treatments, then you know, I'm really sorry, Fluffy, but it's for the best. It's for the best for all of us. But if you're testing mascara, then I get that upsets

people a little bit more. Yes, clearly, So one of the potential solutions for this this ethical issue is this concept of an organ on a chip, and really this would mostly concern those pre clinical phases. Lauren talked about the ones that are animal testing in particular. Potentially this particular type of technolo oology could help reduce or even eliminate the need for animal testing if it proves to be an effective enough platform. Okay, so what is an

organ on a chip? All right? So it looks kind of like a little plastic chip about the size of a USB flash drive, little thumb drive. Um, not a not a full drive, but you know, just one of those little things you up on your key chain. It's about that same size. So it's a it's got these hollow micro fluidic channels that are lined with actual human cells, like living human tissue exactly. I mean, it's obviously not connected to a human but yeah, the actual the actual

cells are viable cells. They aren't just you know, just just desiccated cells that actually do live. And the chip replicates the functions of a particular organ, and the organ is all dependent upon what you've lined the these micro

fluidic channels with. So, for example, a lung on a chip would include a membrane that on one side is lined with lung cells, and on the other side of the membrane, the flip side, you would have human blood cells lining it, and you could have air essentially circulating across the lung cells and blood or some sort of blood simulated fluid moving across the other cells on the other side of the membrane, and the membrane itself can

actually expand and contract, thus mimicking the physiological function of a lung. Okay, but we already test drugs, I believe in the pre clinical phase on like cultures like lab dishes full of cells, don't we yes, So what kind of difference would the organ on a chip make? Well a culture of living cells. Obviously it's really important to

use that and to see what the effects are. But the culture of cells doesn't have the physiological function of the organ it comes from, right, It's just a collection of living cells that represent that tissue, but it's not performing functions of an organ. Okay, so we don't get to see them in action. Yeah. Yeah. It's kind of like if you were to take a gear out of a clock and just look at the gear. It's not

doing anything. Uh yeah, And that the metabolic processes that any of our organs go through are going to change physically change the way that the cells are functioning. So this is a very important piece of the puzzle. So depending upon what organ you're talking about, the chip is going to perform in a specific way. Right. It's not like a lung on a chip is going to behave the same way as a bone marrow on a chip. But not unless you've got something very strange going on

with your bone marrow. Yeah, that then you have some other issues. So if we go to that lung on a chip example, the chip has this air flow across the lung cells and the blood like fluid across the other cells on the other side, and this is what allows it to simulate the performance of a lung. UH. These particular types of chips are being developed by a couple of different groups. The one that I specifically was really interested in was the VS Institute, which is a

biological research institute that's part of Harvard University. UH. They've created ten different organs on a chip models, including liver, gut, kidney, and bone marrow UH and UH they're looking to partner with pharmaceutical companies. UH with biologists with chemists to test these out to make sure that they are in fact

good analogs for actual human organs. Um And in late July of two thousand fourteen, the department that was specifically working on organs on a chip within the VS Institute has spun off a new private company in partnership with a startup called Emulate Incorporated, which has a worldwide license to commercialize this technology platform and try and move it forward to the next phase, which would involve using these

and very very uh controlled tests too. You know, you probably start actually with stuff that's already been thoroughly tested to make sure that the organ on a chip behaves in the way you would in a predictable manner exactly, so that you can prove that the technology works. Um. There's another company called Nordis in O R T I S that's also working on organ on a chip platforms. They have a goal of launching a product in two thousand and fifteen. They the company itself launched back in

two thousand and twelve. They spun off from a research group at the University of Washington UH. They developed a chip that actually mimics the blood brain barrier, which is pretty awesome. That's one of those things in medicine that fascinates and confuses me every time I hear about it. It's one of those, uh difficult issues, is how do you get things that either do not breach the blood

brain barrier or do breach the blood brain barrier. So with the startup, I think we're gonna see some partnerships between Emulat Incorporated and other companies to really test these out and check to make sure that these actually do work as an analog um and it's interesting. They've even come up with a a version where they can hook up the different organs on a chip together in a

system to simulate an entire human body. So essentially you have all these different chips operating as the different organs, uh, And that way you can check whole body effects. Yeah. So if you again, if you have that drug to treat the liver and you want to make sure it's not going to put too much stress on some other organ, you could introduce it and this will behave as if it were a human in miniature in a way. I mean, we're talking about teeny tiny elements that are replicating the

basic functions of the organs that they represent. Yeah, it's it's really really mind blowing to think that such a tiny sample of cells could be representative of an entire organ and its functions. But it is. That's that's at least the pitch will find out. Yeah, and you know what, while we're we mentioned cost earlier, and right now, this

sounds like it would not be cheaper. Probably then the goal is that by using just very tiny amounts of cells and having a streamlined production method, you could actually produce a whole bunch of these with just a tiny amount of actual cultured material. Right, So you wouldn't have to have a whole lot of of of raw material to start with. We're talking about just tiny amounts of cells.

Once we can mass manufacture livers on a chip, then just livers for days, right, and then you just think, you know, you don't have to worry about procuring animals. You don't have to worry about all the other issues that would come along with that. So this would at least, in theory, like I said, reduce or perhaps even eliminate

animal testing. If in fact they worked as perfect analogs for humans, then you could say, well, let's test it on this and if it works here, then we can start looking at this replacing the animal testing portion of pre clinical trial. Yeah, you know, even hopefully. We've talked a lot about the dangers to animals in these trials, but the dangers to the human volunteers, especially at the very start, short of the clinical phase of trials, is

also huge. Uh So absolutely, Yeah, you might be able to find out that something that you thought was going to be perfectly acceptable might be toxic, and in which case you would know immediately like, well, this is a this is a failure. We're going to have to completely rethink this. Uh and then not put any actual person in danger. You've just all you've done is destroyed some

chips that can easily be replaced, whereas people irreplaceable. Okay, so this sounds like crazy science fiction, but it is happening right now in various places around the world. What is the crazier science fiction version of this? Let's let's blow this out into the future. My favorite version of this. I mean, it's beyond the whole idea of of using

this for drugs or or cosmetics or chemicals. I would love a world where we can test chemicals and cosmetics on this kind of platform and never have to worry about subjecting animal as to that. That would be fantastic. But beyond that, imagine a world where you go in to let's say that you you have a serious disease and you need to have it have treatment for that disease.

Let's say you go in and you have you get some the doctors get some samples of your various the cells and your various organs and create a specific body on a chip analog to you, specific to you, like your body chemistry, and then test out the various potential treatments on that analog before giving it to you, and then they know which ones are potentially the most efficacious, the ones that are most guaranteed to get you better.

We're talking about customized healthcare to the patients exactly the same same sort of level that we talk about when we talk about nanotechnology being used to diagnose and treat patients, so that the care is so specifically applied that uh, it reduces side effects as much as is possible. Yeah, that would be It would be amazing. Like I have so many friends who have had various incredibly difficult treatments

for various ailments. Throughout their lives, and to think of something like this potentially being able to reduce that level of stress and anxiety of patient feels, as well as just that the hardship of going through treatment, it would

be amazing. And even on even on really basic medication levels, you know, people are all so different, and even with all of those hundreds or or thousands of volunteers that they get to test out any given drug, you have no idea how it's going to interact with your specific physiology. That's true, and so that's that that really is a beautiful that's the worldless statistics. Right, statistics tells you what the likelihood is that you will have any given reaction

to any given treatment. But statistics, that's just that's a percentage. When you get down to an individual basis, things can go sometimes outside those parameters. It can happen if there's a if there's a statistical percentage that it's possible it will happen at least with some people. So this is a way of being able to spot those outliers early.

Or maybe you notice that perhaps because of your body chemistry, you might have an allergic reaction to something that for most people in your condition would be a completely valid treatment that would be good to know before getting it done. So uh so really promising work, fascinating stuff, and uh

there are a lot of different articles about it. Most of them are just kind of relate back to the individual websites of the companies that are are doing this or the division of of Vise institute that's doing this. But it's I'm really curious to see how this goes along. I'm hopeful that it will pan out and be a viable testing procedure for for pharmaceutical chemicals, cosmetics, that kind of thing down the line, because if it is, then

that's gonna be good news for everyone involved. And uh, maybe it will mean that we'll be able to have more effective drugs on the market, maybe a little faster, not necessary. It won't necessarily speed up everything because clearly there will still be the need for full clinical trials. It's not like this is going to replace the entire process, but it might be able to fix part of it, or at least streamline part of it. So, uh, anything else you guys want to say about organs on a

chip besides the fact that, uh, we're still disappointed. It's not snack food. I'm not disappointed anymore. Now you're not, no, because now now you've got this hopeful view of the future. Right, yeah, I'm not disappointed by I'm still a little bit hungry. Okay, Well that's probably a good queue for us to wrap things up then, so we're going to end up concluding.

But you guys, if you have any suggestions for future topics of forward thinking, maybe there's some specific element of science or technology, or you're just wondering, like what's it gonna be like, Like what's my commute going to be like in twenty years? Is it going to be easier or will there be way too many people everywhere and I'll never get to where I need to go? If you live in Atlanta, it's going to be the second one. Let us know what you want us to talk about.

Drop us a line on Facebook, Twitter, or Google Plus. Our handle at all three is f W Thinking and we will talk to you again really soon. For more on this topic in the future of technology, I visit forward thinking dot Com, brought to you by Toyota. Let's go places