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Clinical Trials Part I: Clinical Trial Basics
Jennifer Litton, M.D.
April 10, 2018

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Dr. Jennifer Litton is a board certified medical oncologist and associate professor of breast medical oncology at the University of Texas MD Anderson Cancer Center in Houston. Her research focuses on the genetics of breast cancer and how the genes of a breast cancer change at the molecular level. She has been principal investigator on a number of research projects and is a member of the Genetic/Familial High Risk Assessment: Breast and Ovarian guideline expert panel for the National Comprehensive Cancer Network.

Listen to the podcast to hear Dr. Litton discuss:

  • the phases of clinical trials and why each is important
  • the benefits and risks of being part of a clinical trial
  • how to withdraw from a clinical trial
  • how care works in a clinical trial
  • how to find clinical trials

Running time: 31:12

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This podcast is made possible by the generous support of MacroGenics.

Jamie DePolo: Hello, everyone. Welcome to this edition of the podcast. I’m Jamie DePolo, the senior editor at Our guest today is Dr. Jennifer Litton, who is a board-certified medical oncologist and associate professor of breast medical oncology at the University of Texas MD Anderson Cancer Center in Houston. Her research focuses on the genetics of breast cancer and how the genes of a breast cancer change at the molecular level. She has been principal investigator on a number of research projects and is a member of the Genetic Familial High-Risk Assessment Breast and Ovarian Guideline Expert Panel for the National Comprehensive Cancer Network. Today, she is going to talk to us about the basics of clinical trials.

Dr. Litton, welcome to the podcast.

Jennifer Litton: Thank you very much for inviting me.

Jamie DePolo: Just in case anyone is not familiar with clinical trials, can you sort of briefly explain to us what exactly a clinical trial is and why clinical trials are important, especially for breast cancer research?

Jennifer Litton: Absolutely. So, a clinical trial is a very structured way of evaluating or testing either a new medicine, a new test like a blood test, or a device with the hopes of improving upon what we’re currently doing. Specifically, for breast cancer, we’ve had many trials that have changed the standard of care that women are receiving today. Years ago we did tests for Taxol and looking at new chemotherapies, and now multiple new trials looking at different ways of treating breast cancer, new targeted therapies, new immunotherapies. So, we may have a trial to look at either a new drug that’s never been tested in people before or a new way of using it for breast cancer, or trying to see if that new drug might be better than what we’re already doing.

So, what happens is a protocol is written -- it is not just an idea and it goes right to patients -- this is a very detailed document, and there’s a detailed background. There has to be a great scientific rationale of why you want to ask this particular question. And this usually details what’s happened in the past, what we know up to now, and what do we know about whatever it is we’re testing. And a lot of times it may be a new drug, and what are the specifics about that drug that is intriguing to look at it for, in our case, breast cancer? So, after the protocol goes through the background about why and what do we know so far, there’s a very detailed study plan: How are we going to ask that question? What is involved for the patient? What is involved for the monitoring? And then we also ask for collaborations with our biostatisticians who will go through and make sure that, if we ask people to participate in this study, are we going to structure it correctly, have the right number of participants to adequately answer that question?

And the plan will then also include eligibilities. So, who are the patients that we are specifically going to ask that question in? And there’s also exclusion criteria. Often these are not meant to limit patients from participating, because we do want to open trials, but these usually are around safety issues. So, for example, in an immunotherapy trial with a brand new immunotherapy agent, patients might be excluded if they have an autoimmune disease that’s active and we think that from what we’ve seen in the toxicity to date, those people might have a higher percentage, or chance, of getting harmed. So, it is a very thoughtful way of trying to minimize risk to the best of our ability. And then, after this huge plan is written -- and these are not small documents -- it then goes through a very rigorous set of regulatory requirements to really make sure that the question is adequate, that it’s appropriate, that it’s scientifically valid and should be asked, and that we’re really trying to monitor and protect the participants and monitoring for safety to the best of our ability.

Jamie DePolo: Just to confirm, it sounds like any of the improvements in standard of care that we’ve seen in breast cancer are all due to clinical trials. So, any new drug that gets approved, anything like that, it’s all because of a clinical trial.

Jennifer Litton: Everything that we do now in practice with new drugs is because a clinical trial happened before. And we’re always trying to improve on what we know, who we can help, to improve survival rate. I mean, that’s the end goal, to improve survival and decrease toxicity from what we’re doing. And so every incremental step has happened because people participated on the clinical trial and we were able to understand how to do things better.

Jamie DePolo: I know clinical trials have different phases, usually talked about as phase I, II, and III, sometimes those are combined and sometimes there are letters after the phases. But could you sort of briefly tell us, just as far as phase I, phase II, phase III, just briefly what each one does. Why are they separated out that way? Why is it important to have each one of those phases?

Jennifer Litton: Absolutely. So, in somewhat more of a general term, the phase I studies, these are usually the very first time we’re using this drug in humans, and we’re trying to understand the toxicity of the drugs. Now, it might be also that we’ve used these drugs a lot of different times, but maybe we’re combining them differently than we’ve done before or we’re using them in a new way or a new dosage than we’ve done before. Those will require phase I, and usually we start at lower doses and slowly increase to understand how we should dose the drug and make sure that we don’t get to a point where we’re causing too many side effects or toxicity for our patients. And that really informs not only the tolerability of the drug, the toxicities, but what’s the dose that we need to move forward, if this drug looks really promising, to the next phase?

And the next phase that we look at are phase II trials. Now, these can be single arm, they can be randomized, but their biggest question is overall efficacy. How well does this drug work? Does it look like it has enough of a signal that we really should continue to investigate this drug? And we usually continue to get more information about the side effects and side effect management. If the drug still looks very promising in a phase II trial, it can move on to the phase III. And these are usually randomized trials that compare the new drug, in this case for breast cancer, versus standard therapy that’s currently in the guidelines. And so patients will get randomized to the standard of care, which is what they would get off of a clinical trial, or participate in the clinical trial and be randomized to get either the investigational agent or the standard of care. And that is really the gold standard of understanding if the new therapy is better than what we’re currently doing.

Jamie DePolo: If a new drug -- say it’s in a phase III trial, and it works well, but it’s just about as well as the standard of care -- who makes the decision then whether it should go forward and be an option, or somebody says, “Oh, it’s really not any better, so why should we move forward?” Is that the manufacturer of the drug?

Jennifer Litton: Well, I think a lot of things come into play for that. So, maybe even if something is just as good as the standard, what if it’s easier for the patient to take? Or what if it’s so much less toxic than what the standard is? So, even if it’s just as good but for some reason it’s benefiting the patient, I think that’s really important as well. I also think it’s important that every advance that we make doesn’t mean to add. Sometimes some of our advances is to see where we can actually de-escalate and make things easier on our patients if we can get the same outcome for them. Now, I think a classic example of that has been in patients with HER2-positive breast cancer, where we’ve actually been able to take away some of the toxicities with some drugs in patients with smaller tumors and really concentrate on the targeted therapy as well.

So I think there’s a lot of ways that we need to look at what are we testing, why are we testing, and, at the end of the day, the question is, "Does it benefit a patient?" There are certainly trials that are "positive," where a statistically significant number pops up and says, "Yes, this is better," and yet you do have to put in the rule of common sense where, is that change in survival of a difference of one week worth the toxicities that that agent adds? Or not just the toxicities, but also potentially if it doesn’t make them feel better, but is so expensive, you will see physicians choose not to use those drugs. So, it’s a very complex question.

At that end of the day, I think that caregivers, patients, and, a lot of times, drug companies, can be aligned -- it has to provide some benefit, even if the outcome’s the same. If the outcome’s better, but it’s so toxic that it’s hard to take, that might be a challenge to make that drug be one of the ones we tend to use. And so looking at the totality of the data by the medical community, the patients, patient advocates, I think are really important here. Eventually, obviously, going to the FDA, who will make that final decision whether or not it has an indication, will play a huge role.

Jamie DePolo: How do you as a researcher receive approval to do a clinical trial? I know there are institutional review boards at clinics and then there are also national review boards. I know it’s very complicated, but if you could sort of give us a hint as to how that might work?

Jennifer Litton: I think that’s a great question because I assume, not only for me as a researcher but as a patient waiting for a trial, it can be very frustrating at how long... from the idea to the first time a patient can go on the trial actually takes awhile. But if you think about how important getting the trial right and making sure all the safety assessments are in place, it is important not to just rush right in.

Okay. So, after you write that entire protocol that we just talked about earlier, and this is a very detailed document -- it’s usually in the hundreds of pages for a lot of these drugs -- you then, well I can tell you at my institution, MD Anderson, before it even goes to the regulatory, our group will discuss it first -- the concept -- before we even start writing, because we all have to be in agreement that this is an important and worthy question that we want to get behind. I think at the end of the day, you have to ask a question that you could see, is it going to move forward and help someone and is it a worthy question? Because there are a lot of trials out there that might get stopped in that process, and we have to always come back to that basic question. Is it a worthy question?

Once we get there, we go to, in our case, the Clinical Research Committee. They will look at the protocol and say, "Is this a worthy scientific question? Is this scientifically sound?" If it goes through that, then it goes to the Internal Review Board. Now, the Internal Review Board will then review everything -- the informed consent, the safety, the language, the inclusion, the exclusion -- and decide whether it’s safe to proceed. Now, I will say that at each of these steps, the investigator is getting feedback and having to respond to each of these steps, and they’re being reviewed by different investigators who are not involved with the study.

Once the IRB approves, it can be something that moves forward and then go ahead and activate with a very large research team -- usually a data coordinator, a research nurse or a research coordinator, the regulatory, who is putting all of the required paperwork into the required FDA reporting, and, in some cases, if it’s a brand new drug, it might have to go to the FDA first and make sure that the FDA feels that it’s safe to proceed. And then they can come back again with more review and more questions, and once they say, "safe to proceed," you can go ahead.

Or it might go to a big cooperative group -- and these tend to be these big phase III trials we just talked about, because it’s really hard for any one group to do the studies we need to do to push this research forward for patients. So, large groups such as The Alliance, and SWOG, and ECOG that the NIH helps to run and fund really helps bring investigators together across the U.S. And then we have many collaborators in other parts of the world that come together in bigger research collaborations, so we can ask questions that can be done in a timely manner, but also ask across different groups, not just in the U.S. but in other countries and making sure that we’re seeing similar outcomes. So it can often be over a year from the time of the first idea to the time you get approval.

Now, remember also with these new drugs, we have to really partner with drug companies who are developing these drugs and spend a lot of time thinking how is the best way to use this drug, get their approval, get their support... because, as you can tell from how long it gets there and how many people you need to now run the trial, there are funding issues. So, funding can come from national grants, from local grants, from the NIH, from the National Cancer Institute. They can also come from the drug companies. I know it looks like these drug companies might be sending a lot of money to specific people at an institution, but they send it to that person to go to actually run the trial -- so, it goes towards all the patient care and the running of the trial. Or, there’s so many different ways -- sometimes you have to piece together the funding from philanthropy and from grants and some from the company to get the trial done.

These trials, unfortunately, are very expensive to run just for the personnel and really all of the regulatory and paperwork that happens with each and every patient that goes on the trial. I know that was a really long-winded... but these are very complicated procedures, but they need to be to be as safe as possible for our patients. And I think going on a trial can certainly be very scary for some patients -- and then I have them go on the trial and they realize they have an extra set of eyes looking through every lab. They’re seeing more people in my clinic than just the physician. Things that are being done are being done for their safety, and I have a lot of patients who say they were scared to be on their first trial but, once they were on one and saw how regulated it was, they wanted to be on future trials, and that seems to be a trend I definitely see in our patients.

Jamie DePolo: Is it possible -- and it may not, but I’ll just ask -- to offer, say, an average cost of a trial? I realize it depends on how many locations and how many people are in it.

Jennifer Litton: It really does. So, the other thing is that the days of “we’re just going to put patients on and see how they do” are gone because these drugs now are so targeted that I feel really strongly that we need to learn as much as possible outside of just the survival. We need to understand: Are we hitting the target we’re trying to do? Are we affecting the pathways in the cancer cells we’re trying to do? And so a lot of the trials will have a lot of very complicated what we call 'correlative studies,' so, multiple blood draws, maybe there’s different times where I’ll take tissue, because I’ve seen a lot of times where very promising drugs get thrown away, likely because we weren’t using them in the right people. And so trying to understand that up front and really targeting the right patient population that could benefit from that is important. Those are very expensive. What I’m talking about is taking the tumor and looking at the DNA, the RNA, looking at things like that. So, depending on how the trial is written, it can be from $3,000 per patient that goes on the study to, you know, $30-40,000 per patient that goes on the study, depending on what is the question being asked and what’s the technology being used in the background as well. That was a very vague way of… these are usually hundreds of thousands, if not millions of dollars, depending on the phase of the study and what the objective is.

Jamie DePolo: That’s what I was going to say. It sounds like millions of dollars for a large phase III study is...

Jennifer Litton: Absolutely.

Jamie DePolo: For a patient looking at a trial, overall are there risks and benefits that are part of any clinical trial?

Jennifer Litton: Absolutely. I would first say there’s risks and benefits from everything we do right now that’s standard of care. That’s why when patients are deciding if going on a standard of care chemo, their oncologist will go through, “Well, here are the side effects. Here’s why we think it might benefit you.” The same thing is going on with the clinical trial. And it’s very clear to say, “Well here’s what we know about the side effects, but we’re going to be monitoring it.” The benefit is that we’re hoping to do something better than what we’re currently doing and that they might have access to this drug years before it would be ready outside of a clinical trial. The risk is that the drug might not do what we hope it does, and the only way we’ll know is if we put it into a clinical trial.

That being said, any person that’s in a clinical trial... if they’re having too much toxicity or it’s just too difficult for them in whatever way, they should talk with the investigator. But they’re not obliged that they have to stay on if they’re having problems with the drug, and I think that’s one thing that people say that they’re worried about is, “If I sign up and it’s horrible, I’m stuck and I can’t get out.” Absolutely not. Any participant has the right to withdraw their consent for continuing on the study, and I think that’s really important for people to know. The risks, obviously, can be side effects, or unexpected side effects, or the drug not working, and that’s why usually patients on clinical trials are watched at frequent intervals with safety being evaluated at very frequent intervals.

Jamie DePolo: Is there a rule of thumb or a checklist that would help somebody decide if she is a good fit for a clinical trial? Do most doctors or oncologists, are they available to counsel their patients on that? Do they suggest that a patient might go on a clinical trial?

Jennifer Litton: I certainly hope that people are understanding the importance of encouraging patients on clinical trials, and one of the things I will tell you is that even though I’m at this academic institution, I have a very busy clinical practice as well. And, this is totally aside from this question that you put to me, but I do want people to understand with the advent of the electronic medical record, with the number of patients we’re seeing, with the decrease in medical oncologists, with the needs that we’re trying to meet, it is very challenging now to fit in extended times for counseling for clinical trials. We have to just acknowledge that as a situation across our country right now.

I can tell you as a physician clinician, I have significantly less time with my patients than I did when I started my career to meet the needs of the patients I’m trying to see and also all the regulatory now on the back end with the paperwork that needs to be done. That’s not my institution. I’m talking about medicine as a whole in the U.S. now. When we first started with coding, there was a certain number of different codes. In breast cancer, now there’s over a million and you have to spend time looking for “Was the cancer in the upper or the outer quadrant.” It is an extensive difference.

That being said, I think that and organizations like you are going to be invaluable to our patients to have a place to go to to look for “Why should I be in a clinical trial,” and may be helpful guidance to supplement what we can do in the clinic. What we do at my institution is that we will look at patients before they come into clinic. If there’s a potential clinical trial, we’ll ask the research coordinator to be ready to speak to that patient if the patient’s interested, as well, in addition to what the physician will talk about. I think that talking to their doctor or nurse practitioner that’s caring for them would be their absolute first step. I think and I think sites like yours are going to be very helpful in trying to find potential trials.

Jamie DePolo: Now, one of the questions we do see quite a bit on our Discussion Boards is questions about care in a clinical trial and how that works. And I’ll sort of throw in the added question, too, that’s also there as far as insurance coverage -- people wonder, “Do I still see my regular doctor? Do I have to only see the doctors that are doing the study? What if I have an emergency? And how do I talk to my insurance company about it?”

Jennifer Litton: I can’t speak for every practice since every practice will probably do this differently. I will say that for every clinical trial there is a very important piece of paper called the 1572, and what that is is a list of the people that can care for the patients while they’re on the study. So, for example, at my institution my entire breast cancer group is on that for every studyso that we can all care for the patients on each study. It does require training to each of us for each of the studies, especially for updates. It is very time intensive. In other practices, they might have a limited number of people on that piece of paper who are specifically trained to care for the patients on that study, and so they might need to see a different doctor during the time that they’re on that trial, but that would be very site-specific and very protocol-specific, so that’s a great question for them to ask.

As far as the funding, now usually for these trials, anything investigational, are not charged to your insurance. But the standard of care, the patient visits, the standard of care that we would be doing whether or not you’re on the trial, usually is. You can understand where it has to be that way or else, for the expense, we wouldn’t ever be able to do a trial. But anything investigational, anything outside of the standard of care, should be charged to the study and not to the patient.

Now, many states have great regulations saying that people who are on clinical trials should be supported by their insurance companies. Unfortunately, there are several states where there isn’t a law protecting that, so what we will do at my institution is we will call and get clearance from that particular person’s insurance company to make sure that they can participate. But I certainly wish for a day that all patients can participate, regardless of their insurance. But we’re not there in 2018, unfortunately.

Jamie DePolo: Just to clarify, I know you talked about standard of care being covered by insurance. If a person is part of a study, and, say, this study is looking at standard of care -- say, a chemotherapy combination versus one of the chemotherapy drugs given along with a new, experimental chemotherapy -- so the people who would be getting the chemotherapy arm in the trial, so would that be billed to the insurance company? But the people who were getting the tested...?

Jennifer Litton: It might be a little more complicated than that. If the drug is FDA-approved and it’s a standard, that’s probably... unless the protocol specifies that one way, it could be, if standard, it would be charged the way it normally would. Now, there might be extra blood draws that we wouldn’t normally do if the person wasn’t on the study. Or there might be an extra imaging test that isn’t on the national guidelines of how we would normally treat. Those should be then charged not to the insurance but to the trial. So the question is, for the patient they’re going to see what they normally would be seeing had they been continuing on their treatment. On the back end of that, the investigational side would be billed -- or any other testing that is not part of our routine care -- would be billed on the back end to the trial.

Jamie DePolo: I see. Okay. Thank you.

Jennifer Litton: Does that make sense?

Jamie DePolo: Yes. Yes, it does. I was just wondering if the study were blinded, and so the person didn’t know which arm they were in per se, how did that work for the insurance company? But it sounds like that’s not...

Jennifer Litton: That’s not an issue, yeah, because if it was blinded there’d be a placebo, right? And so, they’d be getting an infusion or pill either way, but neither of those would be billed to insurance.

Jamie DePolo: Thank you for helping me understand. And I think you talked about this briefly before, but, if somebody is very interested in being part of a clinical trial, I know we have many people who have been diagnosed with metastatic disease and perhaps the standard of care isn’t working for them anymore or the side effects are a problem, and they’re very interested in looking for a clinical trial -- you mentioned I know we have a list on our site. Are there any other sites or places to go?

Jennifer Litton: You know, I think those are really good places to start because remember these trials, they can open and close in the phase Is and the phase IIs can be very quick, so I think that those can be some of the best places to start. I can certainly imagine, and have seen, that it can be frustrating for some patients where they think, “This trial will fit me,” but, when they actually talk to the caregiver they understand, “Well, with the inclusion, this might not fit you exactly.” Sometimes that takes a visit to that area to find out if they’re actually eligible or not. So, it might not... I think that is a great place to start. Your website is a great place to start. A conversation with their physician and then if there’s something really interesting, to reach out to see, or have their physician or nurse practitioner that’s helping to care for them reach out to see, is this a possibility for this patient?

One other thing we certainly, here at my institution, we might say, “Okay, we’ll take care of you while you’re on this trial and then you’ll go back to your local oncologist and do your standard of care there.” Sometimes I have patients that do standard of care and then when it’s time to change therapy for their metastatic breast cancer, come and check and say, “Oh, you do have a trial? I’m going to stay with you, do a trial,” and I keep their local doctor apprised, and then they might go back between sites. That’s understandable, too, for trials, especially if they’re in an area where trials aren’t immediately available where they’re getting their treatment. It doesn’t mean that they have to get rid of their local oncologist if they’re seeking a trial at a bigger center.

Jamie DePolo: Thank you so much. This has been extremely helpful, and I think this is going to answer a lot of the questions that come in on our Discussion Boards.

Jennifer Litton: Oh, great, well, thank you for the invitation.

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