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Episode #12 - Clinical Trials Part 2

Steve:

Hello everybody, and welcome back to Episode 12 of CCA's Medical Minute Podcast series. I'm here today with Tim Schroeder, Chairman, Founder and CEO of CTI Clinical Trial and Consulting Services, or CTI, as Tim calls it.


Steve:

We're going to talk today about some of the misconceptions that surround clinical trials. I made reference to that before, just some of the negative connotations that have surrounded that over the years, maybe people's misunderstandings of where you're at in your treatment process if someone suggests you go into a clinical trial. So this will be a good opportunity, I think for someone that lives around this each day to really explain that to people, maybe lower some of their concerns or their stress around it, because as you might well imagine, it's something we have conversations with patients about as well because they can be so very beneficial, really.


Steve:

One thing I was hoping maybe you could do, Tim, is to address the concern that people have about being, and I'll put this in quotes, a "Guinea pig." I got these untested drugs; Lord only knows what can happen. There are safeguards built-in along the way, but obviously, it's a little bit riskier on one side of the spectrum than the other. So can you take people through those clinical trial phases and what they mean, starting with the pre-clinical and going all the way through approval?


Tim Schroeder:

Absolutely. First off, Steve, I would say that people's concerns, fears, whatever verb you want to use are well placed. In some ways, in the history of mankind, we only started regulating clinical research in the last 50 years. So when you hear people talk about the Tuskegee experiment, or you hear people talking about a lot of time the Nazi horrors that went on in the name of research, the real safeguards have been put in in the last 50 to 75 years. Here in the US, we have the Food and Drug Administration, the FDA, who oversees all things pharmaceutical-related, as well as other areas. They get involved in device regulation and even nutritional regulation on things.


Tim Schroeder:

But to your point, a typical product starts out many times in an academic research laboratory, sometimes in a for-profit laboratory, but that's usually where the initial properties of a compound are first understood and tested. That is what's considered pre-clinical. Those may involve animal testing, and they may involve more laboratory testing. Anybody who's taking a biology class or a chemistry class may be back in your high school or college days, especially those lab things that didn't work out so well, we're talking about really professional, and in this case, in this day and age, very automated, very computer simulation and model-driven.


Tim Schroeder:

But at some point, we have enough data from the pre-clinical stage that we will go to the FDA or a similar body, in Europe, it's called the EMA, the European Medicine Authority, Canada has a group, it's called Health Canada, so around the world, each country or each region has a group that maybe plays a very similar role as FDA. We'll go to that group with our pre-clinical data. We will also go to them with a protocol that's been designed to move the product from the pre-clinical to clinical stage. We want to do that at the lowest risk to any of the participants in the study, and we also want to do that in a way that gets us the most meaningful data.


Tim Schroeder:

Now, that sometimes is a series of meetings, phone calls, videotaped things of late as opposed to face-to-face meetings, but ultimately we agree on the approach. Once that approach is agreed upon, even the manufacturing of the drug has to be agreed upon, so it can't be something that's made in somebody's garage or something where shortcuts are taken, but once that's all agreed upon, then the next step is another third-party called an Institutional Review Board here in the US, also called an Ethics Committee in Europe or elsewhere, but that's a third-party who then they assess the risk and benefits.


Tim Schroeder:

One of the things they have us do is we put together what's called an Informed Consent Form. In that, it spells out all the risks and potential benefits to anybody who participates in the study. At that point in time, and in the case of CTI, most of our research is what we call cutting-edge, innovative, and first-in-man type studies, so we don't know a lot other than what we know from the laboratory studies and animal studies, and maybe some of the things from sister compounds have been tested, but we're really going at very low doses. Typically, even for a drug that's going to be given every day, say for a year, in our first study, we will give a single dose of that drug. We might give a dose that's one-millionth of the dose that we safely tested in animals. So we start at a very low dose and only a small dose.


Tim Schroeder:

And then we do, what's called a phase one study, keeping in mind, there are four phases. The first three are what get a drug approved. The fourth one is what's done after a post-approval. In that phase one, we do what's called single-dose escalation studies. Let's say that from an animal study, we know one milligram is a safe dose; we'll go to a millionth of a milligram in the first dose. After a series of subjects have no side effects, then we'll go to a hundred-thousandth of the dose. After a series of subjects have no side effects, we'll go from 1000th of dose to 100th of a dose. So we really do these very carefully planned, thoughtful ... and they're always placebo-controlled. When I say that, it is typically for us, these are small, and they've done in healthy volunteers more often than not. Occasionally for certain populations, HIV, transplant, oncology, sometimes we don't do them in healthy volunteers; instead, we do it actually in the patient population. But for most drugs, they're actually tested first in healthy volunteers.


Tim Schroeder:

Once we have that information from a single dose, we're able then to do a lot of computer modeling. We look at the safety of the drug. In fact, from your studio here, our Phase One Research Center is literally about a 20-minute walk from here or about a three-minute ride, right down Montgomery Road. We're at the corner of Montgomery and Dana. Every day we're doing these types of studies there. You have physicians, nurses, pharmacists, everyone watching these subjects.


Tim Schroeder:

Sometimes the subjects are kept for weeks at a time so that we can make sure their diet is controlled. We can make sure that there's no intake of alcohol or tobacco or things like that. We can also make sure that if it's a drug, for instance, to study sleep, we're able to follow them in 24-hour sleep patterns to see what impact it has. If it's a drug to test for high blood pressure, we're going to have them on a cardiac monitor the whole time. They're really, really closely monitored. All of that research can take anywhere from, say, as short as six months to as long as a couple of years. That's the phase one portion of the research.


Tim Schroeder:

As we are doing those studies, we constantly go back to the Institution Review Board. Every time we complete a dose, we send them a set of data, so there's a third-party looking at it. They have the ability to tell us no more, stop, modify things, slow down, whatever. At the end of each study, though, we go back to the FDA or if it's done outside the US to the local authority, like the FDA, and they get to review all the data again. So before we ever move into phase two, which is the setting where we're actually looking for it in the population at risk, so for instance, let's say it's a breast cancer therapy, or let's say it's an anti-hypertensive drug for somebody with high blood, or a cholesterol-lowering drug, before we ever go into that population, we already have the phase one data completely analyzed.


Tim Schroeder:

The phase two data is usually to confirm, for instance, we typically start out in phase one with healthy individuals. By the time we get to phase two, we now have not-so-healthy individuals. We want to see how does a drug behaves in older patients, how does it behave in younger patients, how does it behave in patients with diabetes, how does it behave in patients with asthma, things like that. Those are typical; while the first studies are small, 50 or fewer subjects, by the time you get into the phase two sets, a lot of times in a non-rare disease, those study populations can be anywhere from say 100 to 500 patients that are part of it.


Tim Schroeder:

Those are then followed for much longer periods of time, and they receive the dose more frequently. So if it's a daily administered medication, we're going to administer it to them, for instance, every day for a month and follow them. Once we have safety there, we'll do it every day for two months, then three months. That's how you build up your safety profile. Ultimately the same thing, once again, the phase two situation might take two to three years for us to complete.


Tim Schroeder:

We get finished, go back to the FDA, and then we negotiate, what is the final, what we call pivotal phase three approval study looks like. These studies always are compared against either a placebo or the best standard of care. So if we have a drug or a combination of a drug that's working really well, for instance, to treat breast cancer, and we're looking at new breast cancer, we have to be better than that. So typically, we'll either add that drug on top of the other two or three drugs, and now we've got quadruple therapy instead of triple, or we might take one of the drugs out because it has a lot of side effects and sees if can we get just as good results but with better safety profile.


Tim Schroeder:

Once again, phase three could be as long as two, three, four years. So when you add the pre-clinical and the three phases of clinical together, you can be eight or ten years. We can sometimes speed that up. There are ways to accelerate things. I think that COVID research has shown us some particularly novel ways to do things. Try and take all the dead periods out where we had lapsed before; we now compress those together.


Tim Schroeder:

But anyway, once you finish phase one, phase two, and phase three, that entire dossier of results is then sent to the FDA for them to review. They have about one year actually to review it. They get back to you. They ask for additional data. They can ask for you to analyze it differently. They can ask for additional patients. But ultimately, that's what they make the basis for approval on.


Tim Schroeder:

And then finally, very briefly, phase four or post-approval is maybe we did a study, and we were looking specifically at women with a certain type of breast cancer between the ages of 18 and 50, now the FDA might say to us, we want you to study this in older patients. We want you to study this in patients who are on a different type of treatment who have failed other treatments. So phase four is the post-approval setting to expand our knowledge about what we know about a drug.


Steve:

Awesome. Great. Just a great explanation. I think it's really important too. If I ever volunteer for a clinical trial at CTI, make sure I don't end up in one of the no-alcohol ones. I at least want two glasses of red wine a night if I'm going to do that.


Tim Schroeder:

We do have some studies that sometimes involve alcohol.


Steve:

Well, there you go. I'll sign up for those.


Steve:

We'll have fewer questions on this episode because that was really important. I wanted you to explain that, but you led perfectly right into the next thing that I was going to ask. Even though we're not scripted, literally you didn't know until you sat down what we were going to talk about, but I certainly am no apologist for the drug companies and their pricing. Personally, I'm on a drug that costs about $11,000 a month, so I don't make apologies for the drug company. I think most people don't appreciate this process, and you just kind of hit on it, maybe eight to 10 years. Can you just give a very brief explanation of the number of investments some of these drug companies can have by the time they get a drug to market? Oftentimes these drugs can fail, and then whatever you've spent is lost, I would assume. If you can, just kind of touch on that aspect because it does all feed into the pricing.


Tim Schroeder:

Yeah. I think one of the things that's interesting, Steve, just like yourself, you've had a career that's touched multiple industries is when you're in a leadership role, you get to know other leaders of companies in other industries. I think one of the things where the proverbial light bulb went off for me probably 20 years ago was conversations with people in leadership roles, for instance, in consumer goods. You take an executive of Proctor and Gamble. What they'll tell you is we test lots of products, and ultimately if they don't meet our needs, we kill them quickly. And basically, by the time we move things along into our research pipeline, we're pretty confident they're going to be successful, whatever our definition of success is. I think where we're different in the pharmaceutical or healthcare area is the pipeline is very long very expensive, but many of our failures occur at the end.


Tim Schroeder:

So what ends up happening is right now, just to give you a sense is there are more than a hundred thousand different drugs being tested across the world, and the FDA will likely approve three to four dozen new drugs a year. So when you think of the failure to success ratio, so when somebody says a drug cost X, to your point, it's not only recouping the research dollar spent on that product, but it's also recouping the research dollars spent on all of the other ones that have failed. That's the main driver of cost.


Tim Schroeder:

Now the other driver, I would say, and this is something you probably may want to have multiple podcasts around this whole topic, but in general, the vast majority of healthcare advances have come out the United States of America. We can get into all the reasons behind that and the positives and the detriments, but at the end of the day, we fund healthcare research for the rest of the world. One of the things is most of those companies that fund that healthcare research is either based here in the US or their biggest commercial base is here in the US.


Tim Schroeder:

They also look at it and say this is where the biggest opportunity to get some of our investment back is. You could say the model's flawed, and those certainly have been beaten up by economists who are much smarter than I am, but it is a unique model. I think the one thing, and you point this out from personal experience, what we've seen change over the last 15 years, and I don't want to say it was no rationale behind it, but the rationale behind pricing today is extremely sophisticated. Within CTI, within companies like us, some of our fastest-growing groups is a group called real-world evidence. That's basically the group that dealt with all the pricing and reimbursement studies. So at the same time, we are doing the research for therapy on the side effects, the efficacy, the kinetics, how does it behaves; we're also looking at the economics.


Tim Schroeder:

Today when you go to the FDA, the FDA does not ask for pricing information, and they do not approve or disapprove based on it, but that information is gathered over that same eight or ten-year period. In a lot of cases, you get to an argument where you say, look, here is a treatment. And if you're developing the 10th drug in a class that has a marginal benefit over the other nine, I would argue your ability to price that higher is not there at all. But if you're the first one in, and you've got a life-saving therapy or a therapy that transforms the quality of life, the issue is, what is that worth? Well, the reality is we actually can now do studies that say, what's it worth. What is it worth to the payer, what's it worth to the patient, what's it worth to the employer, all those different groups. Those all come into the discussion, the negotiation, and the pricing model today.


Steve:

Interesting. All right. Well, it sounds good. We had some weighty topics this time around, but we'll go ahead and wrap up Episode 12 here, and we'll be back here just shortly with Tim, and we'll do our third episode on clinical trials.


Steve:

Thanks, Tim. I really appreciate it.


Tim Schroeder:

You're very welcome.

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