Does the Clinical Trials Process Need an Extreme Makeover? - 2 | Transcript | Acute Myeloid Leukemia (AML) | Patient Power


Does the Clinical Trial Process Need an Extreme Makeover?

Please remember the opinions expressed on Patient Power are not necessarily the views of our sponsors, contributors, partners or Patient Power. Our discussions are not a substitute for seeking medical advice or care from your own doctor. That’s how you’ll get care that’s most appropriate for you.

So one is participation, certainly, but can the process be simplified as well, Jim?  What work is going on there, so we can try to get these answers and get to the FDA and present the data quicker, and hopefully there's been lower cost in getting to that point?  

We need to lower costs.  We need to make trials slicker and faster.  Single-arm trials are those in which a patient just get—all the patients get the therapy.  They all get the same treatment.  And FDA has actually approved drugs based on single?arm trials, a much faster and efficient way to get an answer.  

The problem is that the costs are going to be there.  When I think about Mike and all the work that he does in developing his venetoclax (Venclexta) trial that he mentioned, Mike has put in months or years, and it's all above and beyond his normal time.  I mean his day job is to take care of patients, so all of the work that he does to develop a trial is just remarkable in the extra hours it takes and the consistency that Mike gives to doing his work.  We need to make the trials more efficient.  

We need to use biomarkers.  We need to make them shorter.  We need biostatisticians to come up with ways to give us an answer without having to approve so many hundreds or thousands of patients to all these potential new treatments.  

But continuing on that, so this was brought up by Jim, biomarkers, and I know in some of the blood cancers now we're talking about more and more minimal residual disease testing, and we're doing genomic testing to see what genes have gone awry, what's our version of lung cancer or a breast cancer or a myelofibrosis or whatever it is.  

And then do we qualify for a trial?  What's our specific situation?  Do you feel that that sort of precision medicine testing and analysis can help refine this, so we know which trial is right for which person at which time and also some analysis along the way of how is it going? 

So, you know, there are some areas where we don't know enough, and we can't use biomarkers. But there are other areas where we have a biomarker, and there's feasibility, and we can test that quickly. And if we are looking for a large effect size—here I am in jargon mode—but if you're looking for a big, big hit, a home run, is to look for an alteration that is very specific and we think is—a drug can target.  So?called targeted therapy—it's a little bit of a misnomer.  

So—and lung cancer has been one of the hottest places for this.  So there's ALK inhibitors, ROS1 inhibitors, EGFR inhibitors, and now BRAF inhibitors, HER2 targets.  So lung cancer has exploded with precision medicine therapy, and the same with melanoma and BRAF.  So, you know, I think even skeptics will say you don't really need statistics if the prior therapies, nothing worked, and you give something, and 80 percent of people respond.  

There are issues with precision medicines, but the main thing is not response rate but durability.  And I think that's going to be the next iteration of the NCI Match study, which is a large precision medicine study, is stop doing just these small groups of people who are showing activity, but then they relapse quickly. And I think it's going to look at systems analysis, and how do we overcome resistance.  

But one way to get at this and another different take on it is inclusion and exclusion criteria.  So this has to do with access and individualizing and being patient-centric.  Many of the inclusion and exclusion criteria, when somebody says, oh, I have lung cancer, oh, here's a lung cancer trial, and they say, oh, you can't go on the trial. And much of that is because there's language that's been cut and pasted from a previous trial which is not really pertinent.  

So if the new drug is metabolized by the kidney, you don't necessarily need to look at the liver studies.  And we did a small study or I was aware of a small study done by Kaiser where if we improve the inclusion?exclusion criteria, accrual rate can go up 30 percent—so no cost to that.  

So, Jim, inclusion, exclusion, so first of all, we're in this age where electronic medical records, it would seem that at your fingertips there could be some analysis of your record and some matching or offering of trials that could come out of an analysis of your results, genomic results. Do you have ALK or ROS or whatever, if it's lung cancer, whatever it may be maybe JAK2 positive in myelofibrosis, what is various status for us?

And also broader inclusion criteria, and Mike was getting at that, saying some was just—excluding was just cut and pasted. And a lot of us patients would feel, well, that's just unfair.  So what's your comment on all that, about inclusion and exclusion and analysis so we can be matched with trials more easily, can be offered to us?  

And Mike's right.  There's too much cut and paste.  If a trial takes a thousand patients to write a proposal or protocol, too many times researchers will just take the exclusion criteria that might have been from a previous trial and, like Mike said, cut and paste it when perhaps it's not even necessary to have creatinine values or kidney values measured so precisely on this particular drug compared to the other one.  

So those are the criteria that let people in or keep people out of trials, and they absolutely need to be widened.  To make a drug more applicable to the general population we need to reflect the general population more in trials.  

So, Mike, here's a question for you, though, and you work with people in the community setting.  So we have patients who have written in and said, you know what, where I go to the cancer clinic they never mentioned trials to me, and Jim alluded to the extra time it may take for physicians and their teams is when there are trials.  You have just treating people with current therapies, and then you've got research layered on top of that.  It's very time consuming.  

But what about just awareness at the community level?  What can we do about that so that wherever I go into a clinic they have a clear picture of what I'm dealing with, and if there is important research going on that relates to me I hear about it?  Now, maybe they say, you've got to go to a university center, you've got to go to Milwaukee, wherever you have to go, but there's that discussion.  

So one of my colleagues, Dr. Verani, told us about—about this, about rural settings how do you get people on trial. So there are different barriers. So one is the trial, and like Jim said, if you can only do some therapy that you have to come in quite a bit for that limits the geographic area you can accrue to for most people.  

There are site issues where if you don't have enough research staff to be there enough the doctor doesn't feel supported to spend time on it.  There are physician issues where they may not care about trials, or they have too much people scheduled in clinic, they're an hour behind, and they can't stop to spend time on it.  

Also in the community setting you may be seeing every type of cancer, and you can't remember everything, versus at many academic settings you may only see one or a cluster of types of cancer.  So if you're seeing lung cancer all day and you have 10 trials open, you probably know those trials very well for lung cancer, because you don't care about the CLL or myeloma trials, you only care about lung. 

And then there are patient factors.  So patients that are in rural Wisconsin may have different characteristics, and the reason they're in rural areas, you know, the motivations is about, you know, going in for things and stuff like that may be different than people who have the capabilities to fly to Boston or Houston or New York, and they can do that.  So all of those areas are important.  

Now, one potential way to help mitigate some of those things is we have got a clinical decisions support tool, which is an IT product, which our physicians have to enter in what they're going to do with the patient.  So it could be observe, no treatment, hospice or various therapies.  And when they put in the cancer and the stage it pops up with the clinical trials, the first thing that pops up.  And so the physician doesn't have to do the trial, but they have to say why they're not doing it.  

And so we can track over time.  It doesn't necessarily help that individual patient, but that doctor has been aware of the trial, and we kind of get an idea of why people are not going on studies, and so that's one way to do it.  

Something we just did the last week is we had a different IT product where the NCI-matched precision study opened up five new arms with different targets for different drugs.  So we looked back at the number of patients that had those targets identified within our entire system, and then we screened those to see how many people were still alive, and were their organ functions still good enough to go on these trials because of the inclusion?exclusion criteria, and we found several.  So we're now able to contact the physicians and the research staff to go back for these patients that had screened for molecular testing and now they have new options.  

So I think there are IT issues that you can do systemically to try to take some of those barriers away, and then each of those points does have barriers which probably have different solutions and different ways of tackling.  But one reason, you know, the accrual rate hasn't gone up a lot is it's not easy. It's a complex problem, so there's not going to be one single thing you do.  There's going to be many different ways to try to improve things, including patient education.  

Patients are very likely to go on the Internet, watching Patient Power.  In my particular cancer, they're going to go to the IMF and MMRF to look at myeloma trials and see what's available.  And they will take that information to their doctors, many times making their doctor aware of trials that perhaps they aren't each advocating or aware of.  

So, Mike's right.  There are many factors that keep patients from trials, but one of the things that patients really do themselves is educate themselves and perhaps even to the extent of bringing or educating their doctor about what can be available for their treatment.  

So people have a concern about cost.  I want to ask you about two aspects of cost related to testing sometimes.  And then also are there programs that can assist with the logistical costs for patients as well?  

So the Affordable Care Act and various other national and state legislative initiatives have tried to make insurance companies pay for the standard costs in clinical trials.  There are some carve?outs for smaller companies and things like that, and so this is, you know, not perfect, but in general insurance companies should pay for the standard cost of clinical trials.  They should pay for standard imaging stuff too, and they try to get out of that.  So it's not a perfect world, but that should be covered.  

And any research?associated costs should be covered by the company.  Even in some NCI trials some people disagree with what should be covered and isn't, and it's complicated.  But in general, a patient, the research cost should be covered.  

Now, that does not include travel, lodging and a lot of incidentals.  So there are a variety of foundations, that could be The Leukemia & Lymphoma Society, that could be other organizations which could help with that.  Individual hospitals or health systems might have ways of approaching that.  And sometimes there are things you can do within the various companies.  

So there's a new target called Entrek, and the company Loxo, I've heard will fly people who wherever there's a site and pay for them to go on the study, which I think is amazing.  That's not true for every company and every drug being developed. But that's one way to do it.  

One of the issues that comes up with IRBs if you're giving people money, are you coercing them?  And, you know, if you're just recovering the cost to travel, I don't think you are, right?  But those are one of the things that come up.  But certainly there are lots of disparities.  And just like in different countries, they don't have access to the drugs we have as standard drugs here, and not all of these disparities are going to be fixed because we have—outside of cancer we have lots of disparities in the United States, but cost is a big issue.  

And then value, which we've been increasingly talking about in the oncology community, which is utility over cost. And that's more for once we've done the trial figuring out even if shows like it works, how do we figure out how to use it based on those characteristics?  

We have—you know, some people wrote in as we were preparing for this program and they were bitter because they thought they had a spouse, let's say, that had died in a clinical trial.  And that relates to a couple of things.  One is transparency.  Is the data from a trial and any dangers that show up, is that reported and analyzed in public, Jim?  And also what are the risks being in a trial, and what is the monitoring to try to have trials be at safe as possible.  So, Jim, maybe you could talk about that from a patient perspective.  

I want to make sure I know what I'm getting, I know what the risks are, and if any have come up along the way I want it to be reported, and I want to know that there's a team looking out for me.  

The presence of institutional review boards review whether trials should go forward or not.  Patients who are in trials actually get very, very good medical care and medical coverage.  In fact, I would maintain, Andrew, that they get better care than just standard care. They have experts that are watching them even more carefully than would be in a general routine care setting because they're looking for these concerns and problems.  

The person who mentioned the bad outcome, we can't ever say that every trial is going to be perfect.  There are going to be concerns.  That's why trials are done.  But they're relatively rare, and we do have boards and review organizations during the trial, not afterwards, but during the trial to be looking out for your benefit, Andrew, so that you're not hurt by the trial.  

Or in one case, there was a drug, venetoclax we know about, there were some deaths early on when the drug was far more powerful than was originally understood.  So what do we do?  I mean that's the real world I guess of scientific study, but that's a concern, you know, Mike, of people saying, oh, my God, I'm worried about being a guinea pig the unknowns on the subject of dangers. 

And a couple years ago, there was a presentation from the group at Dana?Farber on the precision medicine program, and the issue was they were taking so long to get people evaluated that their performance status or how well they felt was good, and by the time they got through the evaluation many of them had died.  Because the disease, you know, when you get to fifth, sixth, seventh?line therapy it can often progress very rapidly.  

And so I think that's one of the issues, that people can feel the drug did it, and it's hard to know.  And we get these—doctors get these things called adverse events reporting forms, and we have to try to come up with is this probably related, possibly related, and we also get these forms that say you have a patient on the study. The study is open in three countries, thousands of people on it.  One person died of a heart attack, and you have no idea as the physician, well, is that the same rate as—you know they're 70 years old.  Is that the same rate as this other 70-year-old.   

So you need the enumerator and the denominator, and that's what the DSMB or the Data Safety Monitoring Board is supposed to do, which is look at the data and say, is this beyond what we would expect? And they can stop the trial.  They can do expanded cohorts.  They can do things to try and figure that out.  

Now, we know from like even car companies lying about their exhaust systems that if the Data Safety Monitoring Board gets false data, well, you can't fix that.  But that's pretty nefarious.  Like that I think is not something that's commonly happening and would be a very serious thing to happen.  

Now, one thing for transparency is that almost all studies I'm aware of get registered on clinicaltrials.gov or maybe some other sites but usually that site, and they're supposed to report out the outcomes.  It's not also a perfect process, but you should be able to see how long the study has been open, are there any complications related to it and those types of things.  

So this whole process is not perfect, but I would say in general the people at the companies are trying to develop something they think is going to work.  They're trying to do it safely, both to help develop their drug well as well as to avoid a bunch of regulatory issues, and the people on the Data Safety Monitoring Board are trying to do their best to answer these questions.  But the smaller the number of patients which increasingly will take the trials we are doing and almost are aiming for, it's harder to be definitive about when these things happen and what caused it.  

Please remember the opinions expressed on Patient Power are not necessarily the views of our sponsors, contributors, partners or Patient Power. Our discussions are not a substitute for seeking medical advice or care from your own doctor. That’s how you’ll get care that’s most appropriate for you.

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Page last updated on July 2, 2019