Clinical research has been around for over 300 years. Todd Nicklas explains why it still isn’t perfect but still offers benefits for patients and healthcare providers to Jim Cagliostro. 

 

Episode Introduction 

Todd explains the history of clinical research through Paul Offit’s You Bet Your Life, asks the big question of ‘’replacement or supplement’’, and explains why patients are always their own biggest advocates. He also explains the need for monitoring the ‘’gray line’’, and why the key focus in all clinical trials is failing early.

 

Show Topics

 

• Clinical research isn’t always the answer for patients 
• Supplement or replace? The big question for balance
• Handling complexities in replacing medication 
• The high cost of getting drugs to market 
• Focus on failing early 
• Patient benefits: a case study with Camzyos
• Teamwork helps the growth process

 

03:35 Clinical research isn’t always the answer for patients 

Todd highlighted the importance of a balanced view in clinical research, highlighting ‘’You Bet Your Life’’ by Paul Offit. 

‘’So I kind of wanted to start out with that sometimes it is the answer, clinical research for a patient, or sometimes it's not the answer.. I appreciate reading a book by Paul Offit called You Bet Your Life. And ..he went through the past few hundred years in some of the early medical interventions in development and when they were very early starting off, the first blood transfusions that were tried or first types of anesthesia. And when he would dive into those stories, I mean, Jim, there were dangerous approaches. We look back today, really wild, crazy ideas or people died or people had maimed arms and legs from radiology exposure and such, but it leads us to where we are today with radiology procedures and blood donation and transfusions and anesthesia. Just a few examples. He did a few others…So his approach was, there's a point, and maybe we'll get to this later, where you can kind of know where the risks are worked out, but you can't just write it off and throw the baby out with the bath water. There might be something still good here that we need to learn. And so sometimes it could be the answer like, look where anesthesia and blood donation is today. But sometimes it's not the answer. You can look back for the past few hundred years and health authority figures or people at various companies thought that lobotomies were a good idea or sterilizing the mentally ill or bloodletting. You can look at some of these things that today we'd say, yeah, they were dangerous or inappropriate or not what they were intending to. So people can be wrong and people can be right. And so you have to understand that balance first and foremost. I kind of wanted to stress that upfront.’’

 

06:01 Supplement or replace? The big question for balance

Todd explained why this question is essential to balance in patient trials. 

‘’But I think the two questions you have to ask when you're trying to balance it is first, does the present, shall I say medication or intervention, does it supplement what is presently trying to treat or help my disease or does it replace the present? And the reason I wanted to lead with that or categorize that is because when I was a research nurse for many years in the hospital, you're working with sometimes doctors that really love the research that you're doing and are an investigator with that research. Some doctors could care less and tell you to go away and say, "Don't bother me. Really, you're going to bother me with this research?" Some doctors might have no clue because they're not even connected with your hospital system. And so how do you interact with doctors A, B, and C that I just gave as examples because you're going to have to approach them differently? I think that's probably self-evident. So you have to say, "Well, listen, it's meant to supplement and here's how it could work already with the present medical regimen that these patients are getting or it's meant to replace the treatment and this is why and this is how you should manage them." So I guess first, does it supplement the present treatment? This is I guess a question that research has to answer: how does the present treatment alone that they're already on affect a certain lab level or a MRI scan or a vital sign that might be concerned about your blood pressure or what have you, versus how much does it affect that measurable point with the two together or the research medication or intervention? We get a lot of time to dive into that, but I just want to leave that hanging out there to think about that.’’

 

10:08 Handling complexities in replacing medication 

Todd emphasized the need for clarity with patients, hospitals and in documentation in ‘’replacement’’ trials. 

‘’When you're intending to replace the present treatment, well, then the doctors will say, "Well, wait a minute. When does that happen? Is there a washout period? What's the half-life of the drug that they're presently taking and the one that you want them to take in the research study? How quickly can it come on board and give a therapeutic benefit?" These questions, like I said before with the previous point, you need to be very careful in how you convey that to the patient, to the doctors, to the nurse practitioners, how it's in the documentation. Things can get forgotten, as you know. So it has to be clear in the documentation as well. You and I worked with LVADs, which are the heart pump devices. Could it replace their heart failure meds across the board? Maybe. If they have a really great response, maybe you can get rid of a good bit of them. And then the doctor would say, "Well, when would that occur? And how do we do that in the hospital?" So there are tough questions to ask and you might say... Oh, sorry, I forgot to mention this to you with the supplement. These studies are often with supplements, placebo controlled. Well, how do I handle... If I'm not supposed to know if they're on placebo or not, but it could supplement and have some impact, what do I watch for? What blood levels do I keep an eye on? But with replacement, that doesn't typically happen because they need a therapy, they need to be treated for something. So you have to either be getting the old medication or the research medication. It's not as much. So I wanted to mention that real briefly too, but that is another point I wanted to get across.’’

 

15:10 The high cost of getting drugs to market 

‘’Jim, let's say you have a compound, an asset, a drug for your company, and it looks like it could affect a therapeutic area or a disease process that could pull in two million in sales and another avenue that might pull in two billion in sales. Some people might be more led to the two billion regardless of everything else. So I respect that. However, you have to keep in mind, so I've acknowledged that there is some negative approaches to things that are not good and can be shady, but at the same time, research, if you're not in the space, it takes so much money to get a drug approved in the United States with the FDA because the FDA is very careful with understanding all the components that need to be in place and the data that needs to be understood to say this medication should be on the market….. the typical cost to develop a drug is $2 billion on average. And the average time it takes from saying, "Here's our asset in preclinical," which is kind of working with animals and such, to the time it gets approved is about 13 and a half or 14 years.’’

 

19:34 Focus on failing early

Todd said that failing early would save costs further down the line. 

‘’Because the big focus today, and I think I might've mentioned the last podcast, is to fail early. So what a lot of companies like to do is to do a lot of high throughput, testing thousands of different compounds and various disease processes and targets in the body to understand where they might fail down the road, and there's amazing technology to figure that out, so they can hopefully pick the right one to go down that rabbit hole, shall we say, and hopefully get an approval because we know-it's such a big investment. And, oh, I didn't say this, but I think a compound, once it first gets found to get FDA approved through all the phase ones, twos and threes, it's like 5% or 10%, something really low. Even if things sound really appealing, the amount of drugs that actually get approved after all these things, we talked $2 billion, 13 and a half years, is still pretty small. Because the FDA is trying to be careful, they want to make sure something's safe and effective, that's the big thing. And it is great that we have both of those things that are important. You don't want something that's just one of those things, I mean safe but not effective, or effective but not safe. I mean both of those don't sound appealing to the modern consumer.’’

 

31:35 Patient benefits: a case study with Camzyos

Todd provided an example of how individuals can benefit from research. 

‘’This is probably six, seven years ago now. I did a study with what's now Camzyos, or mavacamten, a BMS drug, and it helps patients that have hypertrophic cardiomyopathy, apologies if I used this last time, but I don't think I did, where it is an overdevelopment of the muscles of the heart to the point that it's typically pushing into the left ventricular outflow tract, which is the exiting tunnel, shall we say, out to the aorta, which goes to the rest of your body and provides blood to the rest of your body. So the muscle as it pushes into that area, it makes the opening smaller and smaller so less blood can go out to the rest of your body to provide blood to your tissues and organs. And at the point that we were doing the study, the only fixes or treatment were either surgery to cut down that muscle or beta blockers and things to reduce the blood pressure that maybe reduces pressure in that area, but those are difficult to really target long-term or even midterm. It does affect the small muscle fibers and you actually see a reduction in that muscle area. So the reason I say this is because I had a patient that did this and it was a very involved, I think it was early Phase 1b or 2a, pretty early on study where he had to come in weekly for 12 weeks and do echoes and MRIs and a lot of blood work. And some of the visits I remember with him, he was in his 20s, were maybe three, four or five hours long, very busy visits for sure. So the question is, I mean, he's a young kid, does he want to have this burden on his life to do all this? He had a good relationship with the physicians there that saw him, and I think that he really thought this could help him prevent downstream problems or give him a few years before that muscle was impacting enough that he might need surgery or what have you. So it was certainly his decision and it was inconvenient, like I said, those visits and such. But he had good results and I was able to, I believe it was actually open label, so I kind of got to see how things were going from his echoes and data and such. But even within the first week or two, we saw really impressive results from him.’’

 

36:41 Teamwork helps the growth process

Todd said delegation prevents people from working in silos. 

‘’And I think that what I'm getting at is good delegation is not a negative thing and it doesn't reflect like you don't know what you're doing. I think we as human beings feel like, "Oh, I'm delegating so I clearly don't want to learn that, or I'm not good enough versus someone else." But no, what I found is, and especially now in larger pharmaceutical companies where there's a lot of team members, it's really beneficial to say, "Hey, you're really good at X, you're really good at Y. I should know them a little bit, and I do, and I oversee that, whatever, but I'm not going to jump in. I'm going to let you do it. Can you get back to me in a certain timeframe? Can you help me with this? Can you help me with that?"’ It's very beneficial because not only do you kind of know the lines in the sand where people are working and not working, you're respecting your skillset and theirs, and you're working together as a team rather than like, I'm in my own silo. I'm not going to look both ways. I am my own person. I found that to be really, really helpful, and you can learn a lot at the same time. It really helps you learn a lot more than just saying, "I'll do my own thing." I mean, yeah, you might be baptized by fire and learn it kind of, but you might learn it a wrong way, actually. So I think that's probably what I would say and what I've really appreciated in my growth process.’’

 

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You’ll also hear: 

 

The longevity of clinical research, starting with James Lind in 1747. ‘’We can't avoid research. We've been using the clinical research approach for the past 300 or so years….and then there were some studies that you can go back to even in the 1500s, that people would try various things to see what worked better than others.’’

 

Patients don’t live in a health vacuum: ‘’…..every patient you have is not going to be in a vacuum and have one disease and have nothing else. They're going to be 80 years old, they're going to have 10 other medications they're taking or four other disease processes that are going on. You need to know what's on board, what's working, what's not working.’’

 

Why the patient is the biggest advocate: ‘’..the thing I really appreciated most was telling the patients the nitty-gritty and really driving home the educational points because then they are there with doctors B and C that might not know or want to be involved in the study and they can say, "Wait, wait, hold up. Don't do this. Or maybe talk to Todd first because this might affect that." 

 

Monitoring the ‘’gray line’’ in patient trials: ‘’Because some cancer patients do very early phase one and twos because they have to because of the development process or because of their cancer diagnosis or what have you, you might have to do early on. But are we past that line? Are we not? And what might that line look like? And that's why consent forms nowadays are extremely long because patients have to read all the safety data.’’

 

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