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Dr. Don Benson discusses the benefits of participating in a clinical trial
Dr. Don Benson discusses the benefits of participating in a clinical trial image

Jul 19, 2013 / 11:00AM - 12:00PM MDT
HealthTree Podcast for Multiple Myeloma

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Episode Summary

Dr. Don Benson, MD, PhD, The James Comprehensive Cancer Center, The Ohio State University
Interview Date: July 19, 2013

On this week's show, we learned that less than 5% of myeloma patients participate in clinical trials.  According to the American Cancer Society, if 10% of patients participated in clinical trials, we could reduce trial times from 3-5 years to 1 year, tripling the speed of research. This week's Myeloma Specialist, Dr. Don Benson of The James Cancer Center at The Ohio State University, does a deep dive to help us understand the ins and outs of medical trials. Dr. Benson provides a solid foundation for understanding clinical trials, answers patients' common questions and addresses the unfounded fears of being a "guinea pig" or getting a placebo in a trial.  He discusses how trials are funded, describes who is funding the most out-of-the-box, innovative ideas and explains why you may actually get better, more attentive care being part of a trial.

Full Transcript

Jenny: Thanks for joining us on today’s interview in Innovation in Myeloma. After doing two successful interviews where over 1500 of you have listened in, we are thrilled at the level of interest we are seeing. We hope that we can uncover new ideas together and we welcome your suggestions about additional topics you may want to have covered. You can always email me by going to the mPatient web site and using the contact button or you can email me directly at and make suggestions about future topics.

I thought it would be helpful to give ourselves a foundation for all future discussions. What are clinical trials and beyond the basics and how to enroll, how can we use them to our advantage as patients? I fundamentally believe that patients can add to what is being done by great doctors and researchers. I think we can help drive to a cure faster through knowledge, support and participation – and maybe a little pushing from the patient side. I don’t think we have the luxury of waiting around for a cure to appear, although that would be just terrific, but I don’t think it’s going to happen that way with the current pace and the current process of how that works. We have amazing people in the field that are all pushing towards a cure, including our guest for today, Dr. Don Benson of The James Cancer Center at The Ohio State University. Hi Dr. Benson, thank you so much for joining us.

 Dr. Benson: Hi Jenny, it’s great to be here. Thank you for the opportunity.

Jenny: Dr. Benson is a myeloma specialist at The James Comprehensive Cancer Center at The Ohio State University. His specialties include multiple myeloma, stem cell transplantation with a research emphasis in natural killer (NK) cells and immunotherapy. We are very excited that this will be one of a two-part series. We will interview Dr. Benson again on August 16th to talk about his latest research in immunotherapy. After hearing what he is working on, I will tell you that it is a show you won’t want to miss. I am going to let a patient of his brag about his excellent care on the next interview but for this interview, I can tell you that Dr. Benson has been a principal investigator or co-principal investigator in over 100 trials. He was voted 2012 Professor of the year at The Ohio Sate University College of Medicine and is a world-class researcher, as well as a world-class individual, so he is a perfect choice for today’s topic.

So Dr. Benson, for today’s interview, maybe you want to give us some background on clinical trials, why we have them – the purpose and design.

Dr. Benson: Thanks and thanks for the introduction too, it was very nice of you. I think this is a great topic as a starting point for this series, just to talk a little about what a clinical trial is and how this fits in our quest to cure myeloma. Just to start painting with some broad brushstrokes: A clinical trial is a means by which we evaluate potentially promising new treatments for cancer, for multiple myeloma. I think to understand how this process works, we should first step back a little bit and talk about standard treatments, or standard of care therapies.

Most people with cancer, most people with multiple myeloma receive standard of care treatments. These are treatments in 2013 are the best treatments we have. If you step back and say “Where did these standard treatments come from and how did we get to these treatments?” the answer is through clinical trials. The standards of care we have today, which candidly are better than last year, and better than five years ago and certainly better than 10 years ago, these standards came to be because of clinical trials. When we start to make decisions about standard treatment or standards of care vs. participating in a clinical trial, one thing that we need to remember is that standard treatments of today are clinical trials of yesterday.

A clinical trial is a very comprehensive, very complicated research study to evaluate a new treatment for myeloma. They are very tightly regulated. They are very tightly controlled. They have multiple levels of input. They have ethics boards and regulatory agencies and researchers and scientists – doctors and nurses. Many of these include patients, actually, in their design, in their conception, in their execution. Clinical trials really are the formal way that we answer questions about new treatments, whether these are going to advance our quest; whether they are tolerable, whether they are safe and ultimately whether they will replace our current standards of care.

Jenny: That’s a great overview. I know we talked about this in the last interview, that only 5% and I think I’ve heard your colleague Dr. Craig Hofmeister say that less than 3% of patients with myeloma participate in clinical trials. So do you find this to be the case? And we asked Dr. Orlowski this same question and he said if we were to have larger percentages of participation, then we could have faster outcomes. Do you agree with that?

Dr. Benson: That’s absolutely true. Nationally it’s estimated that only 5 or 6 percent of adults who have cancer in the United States participate in a clinical trial of a new therapy at some point in their care. That number is probably a little bit lower in multiple myeloma and we know there are other demographic issues than other patient populations where the numbers are even lower than that. One of the best analogies I’ve ever heard about clinical trial participation is to compare how many adults with cancer participate in clinical trials vs. how many children with cancer participate in clinical trials. The reason that I think it’s interesting is that if you look at the differences in outcomes between pediatric cancers and adult cancers and all cancer. With children, if a child gets cancer, they will have like a 75-80% chance of being treated in a clinical trial compared to adults where is it certainly much less than that - probably around 5%.

The interesting point comes where you compare the incredible progress that’s been made in curing pediatric cancers to all the work we have left to do in finding cures for many adult cancers. This isn’t solely responsible, but it gets honed that point that the more people who join clinical trials, the faster that clinical trials can be done, the quicker we get to the answers we all want.

Jenny: I would think as a parent, I would pick my child up and take them to a research facility that was doing the most innovative thing that I could find. I think as adults I think we may have a tendency to say, “Well, I have job, my kids are here, my family is here, so maybe I won’t travel if I don’t need to.“ Do you think that is part of the participation issue?  Are there other participation issues that account for the big difference?

Dr. Benson: That’s a great question. I think we could spend an hour talking just about that. I think there are a lot of reasons why that is the case. From a patient’s perspective, or from a parent’s perspective, I think that part of what drives this is just like you said, the altruistic motivation you have for your child to get the best care possible. In pediatrics, there are very good, dedicated pediatric centers that all work together that are all doing similar clinical trials. Our motivation as a mom or a dad is to get that kid to the best place and the best care. Ultimately for most kids, that is a trial. I think that same altruism we have as adults gets translated differently exactly as you said when one of us gets cancer. Our thoughts go to how is this going to affect my family, how is this going to affect my job, and how is this going to affect my ability to make ends meet? So the same intentions may lead to a different conclusion when it’s us as opposed to our children. I think that’s a big part of it. I don’t think it explains the whole story, but I think the reaction and feelings that drive those decisions ultimately end up in a different place when it’s us compared to our children.

Jenny: I agree. I would feel that as a parent also. Can we step back a little bit and maybe you can give us some background on the different types of trials because I’ve heard of R01 trials or SPORE trials and I don’t necessarily understand the difference between the different types of trials there are.

Dr. Benson: Sure. Let’s talk about how a drug gets developed and that will make sense with what kinds of trials there are. So typically the process of developing a treatment for cancer could be 15 years long or more. When you say, o.k. “How long does this take from an idea in somebody’s mind in a laboratory to a commercial treatment that becomes a standard of care?” I would say that’s roughly 15 years. So before a drug ever gets tested in a clinical trial, there could be 5 or 10 or more years of the drug being tested in a laboratory. Some of this is in vitro work in a petri dish, cell culture work, some of this is done in animal models, some of the pre-clinical testing is with healthy human volunteers too sometimes. But at any rate most treatments will have up to a decade of research before the drug ever gets into a human being. When a researcher gets to a point where they are ready to test a drug in a patient, they go to the FDA and file some paperwork summarizing their background, summarizing their ideas, summarizing the data that they have where they propose what is called a Phase I trial. This is the first time that the drug is ever going to be given to patients. Generally speaking we talk about three phases of clinical trials. A Phase I trial is that first step: it’s the first group of people who are going to get that medicine. Then a Phase II trial follows that then a Phase III trial comes next and if everything works our right then the drug goes up to the FDA to determine whether it can be approved for commercial use as a standard of care type of treatment. Even after that decision is made, there is something called a Phase IV trial, which is a longer study to collect more data to verify what’s been found in the earlier work. Let’s go through each one, does that sound good?

Jenny: Sure.

Dr. Benson: A Phase I trial: So at this point, a group of researchers and scientists and doctors have all gotten together and they’ve done all of their basic science and all of their translational science and they really think they’ve got something really promising, something that’s going to advance the cure for patients with myeloma. They get approval from the FDA and they start their Phase I trial. The important thing to know is that a Phase I trial, the first time you are giving it to a patient, for me it’s helpful to go back to the Hippocratic oath. The oath we take as physicians the first thing is to “Do no harm.” You can think about a Phase I trial as a way to ask that question: Is this drug going to do more harm than good? What happens in a Phase I trial is the researchers are trying to figure out is this drug safe - is it tolerable, does it have side effects that we weren’t predicting, is it too toxic? The fundamental question in a Phase I trial is, is this drug safe?

Jenny: Does that include dosage too like at what dose is this toxic or not?

Dr. Benson: Absolutely. That’s really the key question in a Phase I trial is can we give this drug safely? Typically what they do is start with, not an infinitesimally low dose, but they start with a very, very low dose of the medicine and they have statistical methods of very rigorous ways to figure out a good starting dose and then they will typically give that dose of the medicine to three people and if they do o.k. with it in terms of side effects and safety, then they will use a larger dose and then they will give that to three people and if everybody does o.k. with that dose, they will use an even larger dose on the next three people and so this process will proceed until they give a dose where someone has a side effect or someone has a significant toxicity. At that point, they will go back down to the next lower dose and give the drug to several more people to verify that that’s a safe dose and that’s the end of that trial. The Phase I trial really is just to determine is this drug safe or not.

Jenny: And how long does that trial last typically?

Dr. Benson: Phase I trials generally, are relatively small. They may have at most 20 or 30 patients, often times they may have only a dozen patients and so it may take a year or so – a year-18 months to run a trial like that. We will come back to this in more detail but certainly in a Phase I trial we are looking for any signal that the drug is working, that somebody’s M-protein is going down, or they are going into remission, or their pain is going away – that the drug is doing something positive. We are certainly, absolutely looking for signs that the drug is working in a Phase I but really a Phase I trial is designed for safety. It takes a year, a year and a half maybe. But the important conclusion of a Phase I trial is to say, we found a safe dose of this medicine to give to patients with myeloma. Once the Phase I trial is completed, then the drug moves into Phase II.

A Phase II trial is a little bit bigger. It may have 50, 60 patients, it may have up to 100 patients I suppose – it depends on the design and so forth. The big question in a Phase II trial is, does it work? So we know it’s safe and the Phase II trial is “Does it work?” The primary end point of a Phase II trial can be different depending on the circumstances, but a Phase II trial is going to look at response rates or how long a remission lasts or how far an M-protein goes down. It’s going to look for some type of definitive evidence that the drug is working in people. A Phase II trial may take a little bit longer, but it is a bigger study and there are more people involved.

Jenny: About how long do you think they take?

Dr. Benson: That’s a good question. It depends on what their end point is. So if the end point is how many people will respond to this treatment, it could be two years or less if you are just looking at the percentage of people who respond. If they are looking at how long will your remission last, then the trial could take much longer, right? Because if it’s a good drug, and the average length of remission is 3 or 4 or 5 years, it may be an awfully long trial to run. So you have to be a little bit thoughtful in how you design your end points because if the drug really is providing significant benefit, you want to move it along. You don’t want to keep your trial running for the sake of the statistics. You want to get the drug out into patients who are going to benefit from this treatment. We can dive deeper into that if you are interested because it’s a really interesting time in myeloma how you define these end points so you vet the drug, you know what you’re dealing with but on the other hand, if you’ve got something really promising, you want to get it out, you want to move it forward and make it available.

Jenny: Sure, how do you do that?

Dr. Benson: In a Phase II trial, so this is where myeloma is unique, I think. Obviously I’m biased, because I take care of people with this disease every day. Myeloma is unique because we have the M-protein, so in other words we have a biomarker, we have a blood test that we can check and we can know with some confidence right away if the treatment is working or not. Right?  Because if the M-protein is going down that means things are going better, if the M-protein is not going down that means the drug is not doing what we hoped it would do.  So many Phase II trials these days the primary end point is response rate. In other words, how many people are going into remission from this treatment?

Jenny:  Do they look at partial remission or complete remission or both?

Dr. Benson:  Yes, they stratify that. So they will look at overall response rates; so how many people have any evidence of response, and then they will divide that up and say how many people get a complete response, how many people get a partial response, how many people get a minor response.  In a lot of trials these days they will say how many people have stable disease, but their pain is better, their anemia is better, their function is better, their quality of life is better. So they will divide that down into categories after they look at the overall response rate.

That's a really good point, because in myeloma, in some of the treatments that we have now, the progression-free survival, or the length of remission, the duration of response, could be very long.  So if you design your trial to look like that, then you'd have a 6 to 7 year trial on your hands. That is not fast enough. We need to make decisions and keep moving forward. Because of that, a lot of studies will look at response rate as their primary end point.  In other words, they will say how many people are responding, and based on that number that we'll get in a year, we will know whether to take it forward or not.  But then a secondary endpoint, they will go ahead and follow-up on people long term, even after enrollment is done, and even after the study is completed, they will continue to follow people and have data on length of remission eventually, but they won't allow that to hold up progress.

Jenny:   I don't want progress held up as a patient. I want to move right along to Phase III.

Dr. Benson: There is a trial that was reported at ASCO, where the median progression-free survival has not been reached yet and it is coming up on three years.  So, clearly it's working. Why do we have to wait?  Phase I is:  Is it safe?  Phase II trial is:  Does it work?   Phase III is:  A randomized trial.  So this is the first time in the process where randomization happens. What happens in a Phase III trial is the most important question.  The question of a Phase III trial is this:  Is this new drug better than the standard of care?  This is the Phase III study is a trial, where half the people in clinical trial get the new treatment, and half the people get the standard of care. Then you see if the new treatment is better than the standard of care or not. It is the ultimate decision, and it's going head-to-head against the best that we have.  What we're saying is this new treatment really poised to push us forward, or in the long run does it turn out to be the same?

Jenny:  Is it always half and half or can the percentages be split up?

Dr. Benson:  The percentages can be split up.  So if you have a particularly promising drug that has really shown a lot of benefit, they may design their trial so that for every person that gets the standard therapy; two people get the new one.  It could be a 2 to 1 randomization.  The other thing that they do in these studies is if someone is participating and they get randomized the standard of care arm and during the trial they find out that it's looking like the new treatments better, then they have what's called a “crossover”. Typically, what happens in a Phase III trial is you don't wait two or three years to find out the result. The data ethics board and safety board look at the data every month or every 3 months for any sign that one arm is doing better than the other. If they see any sign of that, then they do what is called a "crossover" and everybody would get the treatment that is working better right away. The Phase III trial is really the litmus test for that drug and whether it is going to replace our standard of care or not. Ultimately that decision is up to the FDA. The Phase III trial is the one that helps to inform that decision.

Jenny:  How many people are in a Phase III trial and how long do they take?

Dr. Benson:  In Phase III trials in multiple myeloma there are typically hundreds of patients.  So the big Phase III trials that have been done recently have between 500 and 1,000 patients enrolled. Half of the people are getting the standard treatment and half of the people are getting the new treatment. It varies a little bit by how powerful your new treatment is. So if you have an absolutely smashing sensational new treatment and you're predicting a big difference between the groups, you may not want to put that many people in your study.  Statistically you don't need that much power to show the difference. The sooner you get your answer the better. On the other hand, you can look at trials in breast cancer for example where literally 10,000 women might go on a breast cancer trial in part, because the standard treatments are so good that the incremental treatment of new benefits is a little less. You need to have that many people to show the difference. The other reason is breast cancer is more common, lung cancer is more common, and there are generally more people around to be in the trials.  Generally, in a myeloma Phase III trial there are probably between 500 and 1,000 people involved and the trial itself may take three years or so.

Jenny:   So if you add those time-frames up you have one year for the Phase I, then 2-5 years for the Phase II, and then another 3 years for the Phase III, plus your laboratory time-- that adds up to the time-frame you talking about.  How would it be possible to speed that standard process up?  I guess it has to do with enrollment.  If you're having patients enroll and it takes a long time to enroll, that part of it could be sped up.  Are there any other spots besides enrollment that could be sped up?

Dr. Benson:  That is a great question. One of the easy answers is what if we say 5% of people participate, so say 10% of people participated you could conceivably cut that time in half.  Right? If 20% of people participated that would really speed the process up. I think those are things we're trying to do at Ohio State. We have, the last I heard, we had something like 30% of our patients in trials here.  That really helps with getting to answers faster. I think that what is coming in the future is that our ability to design trials more thoughtfully, and what I mean in other words, it is with the science that we have now and the understanding of myeloma that we have now, we can be more deliberate and more creative in the way that we design new treatments. When a drug does come in to a Phase I trial, we could even identify specific patients with myeloma who are most likely to benefit. Conversely, we could identify patients for whom that drug may not work as well. Ultimately, get to a point where these designer drugs, these targeted therapies, are being run in trials that are designed for patients who are most likely going to benefit from those treatments. That would speed up things too.

Jenny:   So let's talk about that process or different approaches to a standard process. I was talking to a researcher who had just finished school. He just made an observation that the current scientific research process hasn't really changed in about 50 years. I don't know if that is true or not. It seems like with newer technologies or different approaches we could really change the way that standard process works.  Of course, we want safety.  We want the evaluation process to be run well. I just think that there has to be a faster way.

You had mentioned to me a New York Times article, written by Clifton Leaf, who was talking about something like you were talking about, talking about the reverse engineering of a clinical trial. Instead of taking one drug and then testing it with patients, taking the patients that are with that subtype of myeloma potentially, and then testing multiple even possibly already FDA approved drugs against that subtype of myeloma.  I thought that was a fascinating approach.  Can you talk a little bit more about that?

Dr. Benson:  Yes.  I think that is a great article by the way. That was in the New York Times a week ago or so. I hope that this is the future of cancer drug development, cancer therapy in myeloma clinical trials specifically. I think that the current paradigm that we have this idea of Phase I, Phase II, Phase III; this was developed decades ago when cancer therapies were all very toxic. If you think about a drug like Melphalan which is a drug we use for stem cell transplants, or a drug like Cyclophosphamide or Doxorubicin - conventional chemotherapy drugs.  These drugs work indiscriminately. In other words, these drugs kill cells that are dividing. That is how they work.  Cancer cells divide. Myeloma cells grow and proliferate and so they present a target for these drugs, and they work kind of like poison. They impair the cell's ability to grow and divide and the cells die. The problem with cytotoxic chemotherapy drugs is any cell that is growing and dividing is going to die as a result. That is why people lose their hair, that's why people have diarrhea. Because your hair is always growing, and the lining of your gut is always growing. While these drugs are busy killing cancer cells they are also busy killing any dividing cell. That's why what they call the therapeutic window, that's why the side effects with conventional chemotherapies are so great.

From that idea emanated this paradigm of Phase I, Phase II, Phase III - that you have to find a safe dose that will be tolerable and then decide whether that drug works or not, and then decide whether it's better than the standard of care. I think things are changing already, I don't think things are about to change. I think the science has moved past that, and now it is up to the clinical trial process to catch up in the evolution. The reason for that is that we know a whole lot more about cancer than we did even 50 years ago, or even 20 years ago, or even 10 years ago.  We know a lot more about the physiology of cancer cells, the metabolism of cancer cells, the genetics of cancer cells, and one of the most important breakthroughs in that process is that we can find targets for treatment.

When I teach at the medical school, I tell the students that it's kind of like when your computer locks up, when your computer freezes. You can get a baseball bat and hit your computer to try and make it work again.  That's very cathartic and it's very comforting and it makes you feel better, but it doesn't fix the computer. The reason is because when you get a blue screen and your computer crashes, and your mouse doesn't work, it's not a problem with the hardware, it's a problem with the software. You can think about cancer as being a bug in the software program.  A mutated gene is like kind of like having a bug in the software of that cell. Hitting it with a baseball bat is like giving it cytotoxic chemotherapy. If you can't fix it, just kill it. In the new era that we've entered, we have clearly entered this era, we can have drugs that work like the Geek Squad. In other words, we have drugs that can go in and find where the problem is in the cell, find where the bug is in the software and fix it. You don't lose your hair, and you don't get diarrhea, because the drug only works on a cancer cell that has that bug in the software.

With these new treatments, the treatment everybody talks about is a drug called Gleevec.  This is a drug for a type of leukemia, it is not a drug for myeloma but it helps to illustrate the principle in CML, in this form of eukemia, there is a very specific mutation in this  form of leukemia that's causes the disease. Before Gleevec, people would get all kinds of chemotherapy that people that may or may not have worked and people who were young enough and strong enough would get a donor stem cell transplant and beyond that there wasn't much you could do about it.  Gleevec was designed basically to target that mutation that was driving the cancer.  In other words, Gleevec was like the fix for the bug in the software.

Jenny:  Is it in that monoclonal antibody group?

Dr. Benson:  Gleevec is actually a small molecule. It is a kinase inhibitor. The legendary result when Gleevec got their approval from the FDA for their Phase I trial. In the Phase I trial of Gleevec, 53 out of 54 patients got a complete remission in 1999. Many of those people are still doing great today. It illustrates the power of a targeted therapy.  If you were to really understand the genetics, that if you really understand the cancer biology, you don't have to hit it with a baseball bat. You can be very creative in your drug design. Then to answer your original question, you can accelerate the drug discovery process and accelerate the speed towards the cure for the disease.

Jenny:  So where does that change come from? If you're changing the process, because you have these more targeted approaches, where does or at what point in that step does it change?

Dr. Benson:  One of the ways that it has changed relatively recently is through what they call the accelerated approval pathway. The FDA back in the 1990s created a new pathway to development for new treatments for a variety of diseases.  It actually came out of all of the research that was being done in HIV and AIDS in the 1990's, where we had this explosion of treatments for HIV. What the accelerated approval pathway does, if the drug has really promising results in the Phase II trial, and it is clearly meeting an otherwise un-met medical need, particularly if it is a particularly rare disease or uncommon condition, the FDA will actually grant approval before the Phase III trial is done and get the drug out as a standard of care even faster.

Jenny:  Does myeloma fall into that category?

Dr. Benson:  Absolutely, without a doubt. In fact, the two drugs that have been most recently approved came through the Accelerated Approval Pathway, Carfilzomib and Pomalidomide. Really in the last 10 years the Accelerated Approval Pathway has been dominated by cancer therapies, particularly for uncommon cancers like myeloma.  It represents, relatively speaking, a very important area of unmet medical need. It's a way to keep pace with the scientific discovery too. Drugs like Velcade and Revlimid, and more recently Pomalidomide and Kyprolis, these drugs have gone through an accelerated approval to get out to people faster based on Phase II trial results. They still do the Phase III studies, they still do the Phase IV studies.  The bottom line is people get good treatments faster this way. It does not obviate the need to ask that question still:  "Is this really better than what we have, or not?"  We need to know that ultimately. It's at least a way to get good treatments out to people faster.

Jenny:  It's is a better approach. That is great. So with the different types of trials; going back you helped us understand the phases of the trials.  Can you describe what those different types of trials are and then I have some more general questions about trials.

Dr. Benson:  So describe in more depth each step you mean?

Jenny:  No.  Like the R01 trials or SPORE trials, what's the difference between those trials and do patients need to know about that?

Dr. Benson:  I'm sorry.  Let's talk about who pays for trials. So who pays for all of this?  You know there are estimates it costs anywhere from $800 million to $1 billion to go from an idea in someone's head to a commercialized standard of care. That’s a lot of money. It is compounded by the fact that not all drugs that go through Phase I and Phase II will not make it to Phase III and make it to the market and in fact most drugs don't.  Most drugs fail at one step or another.

Who pays for all this?  One way that these get paid for is through pharmaceutical companies and biotech companies. They will develop a drug in their own laboratories or with their own science. They will act as the sponsor for their own trials. They fund the trials themselves. There are two ways that happens. One way is that a company designs the trial and then works in collaboration with universities and researchers to run the trial. Or the other way that it happens is that someone at a university has an idea, or someone in a cancer center has an idea and it is goes to the company and it is called an investigator initiated trial. Either way, it is the company that is funding the research. That is very common. It is not only common in myeloma, but it is common in all types of cancer and really in all types of health conditions like cardiology, diabetes, and osteoporosis. That is a very common way that trials get paid for. The other way that trials get funded is through the National Cancer Institute.   So the way this works is that every year Congress gets together and they decide on a budget and Health and Human Services gets a budget and The National Institute of Health gets a budget. The National Cancer Institute ends up with a budget. The National Cancer Institute has to decide how much money they are going to allocate to research at the NCI, and how much money they are going to allocate to cancer research across the country.   Investigators, mainly at universities and big cancer centers, can apply and compete for that money to fund their research. In these research programs you can propose and run clinical trials that are actually paid for by NCI dollars.  There are a couple of ways that can happen.  There are different grant mechanisms that you can seek to support clinical research and clinical trials.  Traditionally, the grant mechanism has been really the backbone of cancer research. Medical research in general has been called an RO1 grant.  An RO1 grant is awarded to one person who is an independent investigator in a very specific field who is asking a very specific question. A typical RO1 grant may last between three and five years.  It may be roughly a $1 million of funding, total, maybe more than that, maybe less. You get the idea. It is a 3-5 year grant, it is around $250,000 a year to do your research.  So you can propose to do a clinical trial with that mechanism. Whether or not it is enough money to actually do a trial is debatable, but you can probably do a Phase I  trial that way, you may be able to do a small Phase II trial that way, but I think that model is going away for a couple of reasons. One reason is that there just isn't a lot of money.  The National Cancer Institute does not have a lot of money to fund cancer research. It depends if you see the glass as half full or half empty.  Cancer research funding has absolutely not increased in the last 10 years.  If anything, it has stayed the same, or has gone down if you adjust for inflation.

Jenny:  Yes.  I have read some recent articles about that.  They are saying that it is pretty level or going down.

Dr. Benson:  I think you could say that is level. The fact is that if you apply for an RO1, if you are a cancer researcher and you have a great idea and you want to do a trial, and you apply for an RO1, your chances for getting that award funded today are between 5 and 6% . It is extraordinarily competitive to get an NCI grant.  Traditionally, 20 years ago, your chances would have been 20 or 30% and you could resubmit your grant three times. You could work on criticisms, you could answer questions, and chances are if you had a good idea it would ultimately get funded. These days, that is not the case. Now you are allowed to submit one time and your chances of being funded are between 5 and 6% with that mechanism.

The other general mechanism is to look at collaborative grants. So there are a couple of mechanisms where researchers can work together and do something even bigger, something even greater, synergistically by working together on related projects, or by working together on one project.  One mechanism is called a P01 grant, or what they call a program project grant. This is where a group of researchers come together who have similar complimentary interests and ideas and they propose a programmatic grant where everybody is going to work together towards a common goal.  We have one of these here for example at Ohio State. We have one where 5 or 6 of us researchers work together working on immune treatments for blood cancers and we are all doing our own thing, but the sum of the parts is actually greater than any of the individual parts if that makes sense. In our PO1, I don't know how many trials we have in our PO1, I have two trials in it myself, but there has got to be at least a half-a-dozen trials in there, it is still a five year grant, it is renewable. We actually got ours renewed, it is in our sixth or seventh year now.  Hundreds of patients have been in clinical trials on that mechanism. We have a really cool trial that we can maybe talk about in the next interview that just closed to accrual with some really neat results.

Jenny:  I would like for you to talk about that next time.  I am very excited to hear about it.

Dr. Benson: In a program project grant though the strength lies in the collaboration. Let's bring these researchers together, let's all just acknowledge publicly that one person is not going to cure cancer, that we need to work together, we need to be collaborative, we need to be synergistic.  A program project grant is a way to do that.

The other big collaborative grant is called a SPORE grant ("Specialized Program or Research Excellence"). That is really a very large grant where a number of literally world-class investigators come together and say "We are going to create a specialized center where we just focus on this one disease.  We are going to do trials, basic research, translational stuff, and the lab guys are going to talk to the clinical folks and vice versa.”  A SPORE grant is really the top tier grant from the NCI for collaboration in a particular cancer.

So the pharmaceutical industry pays for trials, the NCI pays for trials, and the other place where a lot of funding is coming from these days is philanthropy.  Groups like the American Cancer Society, groups like Leukemia and Lymphoma Society, these philanthropic groups have the same idea. , Investigators have to apply and they have to compete for the money, there are multiple steps for peer review and it is a very competitive process. But the philanthropic groups, like the Leukemia and Lymphoma Society for example, have a very clear mission and a very clear agenda. We want to end blood cancers, whose in?  If you are in, this is a way that you can get funding to do your trial which may not be on the radar of the NCI, or may not be on the radar of drug companies. These days this is a big source of benefit for the research and ultimately for the patients too. This is why we have our own fund raiser here at Ohio State (Pelatonia) that has raised almost $50 million for cancer research.  We have researchers here that are paid for by Pelatonia.

Jenny:  I think it is impressive.  I have a question.  If there is limited funding, and there is this wide kind of swath of different individuals who want to discover different things, or research different things, who is deciding what gets funded and what doesn't?  How does that process work?

Dr. Benson: Great question. Do you have a soap box I can stand on?

Jenny:  Yes, you have an open microphone.

Dr. Benson:  Generally speaking, who decides is a process of peer review. In other words, you come up with your application, you put your best data in there, you put your best ideas, your best support for those ideas, and it is subjected to a peer review process. At the NCI for example, there are study review sections where there might be two dozen of the best researchers in that particular field who come together two or three times a year to review all of the grants. They judge the grants on its individual merits, on the science, on the thinking, on the people who are doing it. They judge the relative merits, and literally say which one is better than the other one. So in the academic realm, in the NCI, and at the philanthropic groups, it is a process of peer review.  Not only which grants hold the most promise, in other words, which trials seem to have the most utilitarian benefit, how many people are going to benefit from this treatment, and what degree of benefit are they going to get?   Frankly, they are also reviewed on their likelihood of success. In other words, have these people done it before? Can we trust them with taxpayer dollars? Can we trust them with literally money that was raised from car washes and lemonade stands?  Not to be dramatic.

Jenny:  Yes, it is true.

Dr. Benson:  Can we trust them with the money to do what they say they are going to do? That is a big part of the decision making too. In pharmaceutical trials, the decisions are often made internally by the physicians and the scientists who work for that company. Ninety-nine point nine percent of the time though, they are made with input from advisory boards where they will call up the researchers who do this for a living and say "Okay, everybody meet in Chicago, because we are going to design a trial together." Or everyone will meet in New York and we are going to sit down and close the door and we are not leaving until we have a trial that is not only promising, but also is going to give us an answer to our question. They have some general similarities. It's getting in a room the best and brightest people we can find and sitting down and chart a course and direction together.

Jenny:  Let me ask a follow-up question first.  I know that the outcome of a lot of clinical trials is publishing.  I think it is a challenge if you are measured on how many papers you are publishing in the industry, and that helps feed into the grants that you are potentially getting, then peer review is a pretty big challenge.  I am outside the industry, so I don't know if all the best ideas are funded and how that works. Maybe you can speak to that as someone inside the industry?

Dr. Benson:  You are spot on Jenny. I just did a talk with some patients in our community here not long ago, I told them to pretend like you are in charge of a pharma company or you are in charge of the NCI.  What projects would you fund?  Before you answer, think about what the alternatives are.  One alternative is you could take some risks. What I mean by that is, if somebody has a completely outside-the-box new idea, new mechanism, new target, new therapy, a totally new approach, and there is not a lot of preliminary data, not a lot of publications, not a lot of experience, but the risk/reward of this is so great, it might be a cure, it might be a long-term durable remission kind of drug, but there is no track record. There is no guarantee that it is going to work. It is what I would call very high risk, very high reward type of study.  The question is:  Would you fund that?  Or would you fund the other option, which is a new treatment that is coming out of a line of research, that is a next generation drug of a class we already have. We know something about the safety of this drug class, we know something about the tolerability, we know something about the efficacy, and this new drug is in the same class, but it is going to provide some incremental benefits. The risk reward is much less, and I tell the students here, if you were playing a baseball game, it would be the difference between a base hit and a home run. You can't fund both. What you have to realize is that people who often hit home runs, also strike out a lot too.  So which one do you fund?  You can't fund both.

Before you answer, the second question is, who are you going to fund?  Are you going to fund a younger investigator who doesn't have a track record or are you going to fund someone who has been doing it for thirty years, whose gotten results? Where is the money going to go?

You can overlap that with again going back to sort of utilitarian ideas.  How can I do for the most benefit for the greatest number of people?  In my view those are the kind of decisions people will face when they are cutting that pie up and saying "We have limited amount of money, limited amount of resources, where are we going to invest?"  Oftentimes, the investment goes to the incremental benefit.

Jenny:  Yes, let's talk about that for a minute.  I would think that you would have a pocket, and I don't know what kind of percentage that invests in incremental innovation, or we have a hypothesis this is going to work, so we are going to fund that, and it is going to be incrementally better.  Patients are going to live a few months longer and that is great. All innovation is good. Right? Then you have this high risk pocket of people who are going to say "I am going to take this already FDA approved drug and see if it works for myeloma.  Or I am going to come up with this really new radical therapy that might work for myeloma.  So when you look at the funding, who falls into those different categories?

Dr. Benson:  This is where the philanthropic groups come in.  I think that (just my opinion, my 2 cents), the really disruptive therapies the ones that have the potential to change practice substantially and significantly, those projects are funded from philanthropic groups. Therapies that will provide an incremental benefit - I don't want to minimize that - there are amazing people in pharma, there are amazing people at the NCI.  I have nothing but respect for people who dedicate their lives that way and they have provided us drugs like Revlamid and Velcade, that have changed the landscape.  The truly the disruptive therapies - Gleevec is a perfect example, we talked about it a few minutes ago - the original work with Gleevec was funded by the Leukemia and Lymphoma Society.  It was something that took a philanthropic group to take a risk like that, just as an example. So, that is my general sense of where funding comes from these. In a lot of ways it is like building a baseball team, you don't want a team of people who hit base hits and no one can hit a home run. You want a mix of all of that in your team. From a birds-eye view, when you look at the whole forest, I think that is what we are trying to shoot for is people who are certainly working on incremental benefits that we can bring to patients quickly. At the same time, you want a core group of people who are willing to think outside the box and really think fundamentally differently than the rest. Ultimately, they are the ones that are going to propose the innovative kind of things that may lead to very sudden changes in treatment.  Part of the problem is this:  We know what we know, but we don't know what we don't know, so if anyone every hears someone stand up and say "We are going to have a cure in 2016", that is dishonest.  That is disingenuous.

Dr. Benson: I can tell you honestly that we are further along than yesterday. I can tell you we are a lot further along than we were 5 or 10 years ago, but I can’t tell you where we will be tomorrow until we get there. I think that ultimately, and I don’t mean to keep flipping into analogies, that it’s like running a marathon without a map. You know it’s 26.2 miles and we know what the finish line looks like, we want to cure myeloma, none of that’s in doubt. What is in doubt is do you turn left or right at the next intersection or is there a hill coming up or did we go down a wrong street here? Really the only thing you can control is whether you are going to run or not. You can decide to run or you can decide to give up and beyond that the only thing you can control is how fast you run and that has to do with the funding. The other thing you can control are how many other people are in the race and that’s how many people participate in clinical trials and those are the variable that will get you to the finish line faster.

 Jenny: I agree, but I think there might be one more variable and I don’t know how it’s used in medicine, but my husband is an investor and an entrepreneur so in the environment he’s in, they might have an 80% failure rate in startups, which is kind of the general number. What he is trying to do is figure out how do we focus down and eliminate most of the risk so we can fail early and fail fast. Some of it is in having the accountability. I notice that when we’ve done maybe angel investing or philanthropic investing and then there is no accountability on the other side, there is high predictability that that money will not be used wisely. In science, how does that accountability piece work? Who is accountable and to whom?

Dr. Benson: Good question. So one of the new Phase II trial designs is called a Go/No-Go design. What this trial design does statistically is that it attempts to answer the efficacy question very early in the treatment. Typically what they will do is they will write their trial design to enroll between 9 and 12 patients and if they don’t see X number of responses in that early cohort, they shut the trial down and they don’t continue and they take that money somewhere else. If they do a trial and they enroll 9-12 patients and half of the patients respond, then they expand it to 40 and they go on, so it’s called a two-stage design or a Go/No-Go trial. You are leveraging this really important decision based on your experience in the first group of people. That has helped to weed out the treatments that aren’t that promising right away. For me, though the question just keeps coming back again and again, why did these people respond and these people didn’t? Couldn’t we have predicted something by their disease biology or by the person’s metabolism or by their immune system or by the nature of their disease? Why couldn’t we have predicted this a priori? In other words, why couldn’t have written this study to maximize our response rates right out of the gates rather than have to rely on a Go/No-Go design where you just gave the drug to 5 or 6 people and they didn’t benefit from it? I think we are smarter than that now. We are at a point where we can design trials better in terms of eligibility and circumvent this whole problem.

Going back to accountability, I don’t know that I can speak to pharma accountability. They have the same regulatory accountability that we do both on an ethics side and on a legal and regulatory side for reporting, following patients and ensuring welfare and so forth. We haven’t really talked at all about that, how patients are protected in trials.

Jenny: Go ahead and speak to that.

Dr. Benson: There are multiple steps of accountability with philanthropic dollars and NCI grants, but anyway the same thing holds true for patient welfare, that there are multiple levels of protections built in for patients on trials that deal with foundational concepts about autonomy, beneficence, and acting in a fiduciary manner and responsible manner for the patient and that’s all built in with the review boards and the ethics boards and the data safety monitoring boards. Trials are audited routinely by the FDA, by the sponsor, by the IRB, by internal audits. From a patient welfare standpoint, that’s all taken care of to every degree possible.

Jenny: The reasons a patient may not want to participate or haven’t participated so far – the American Cancer Society listed four reasons. One was just lack of awareness, that they didn’t know the trial was happening. That might be on the clinician’s side to educate their patients about what trials they are running and potential opportunities.

Dr. Benson: Yes, that’s entirely in our lap. That has nothing to do with patients. If a patient is not aware of a trial, that is entirely our fault as their care providers. Part of the challenge with clinical trials is that they take a lot of time. If someone is in a busy practice and they only have 15 minutes to spend with a patient, there may not be time to talk about a trial. All I do is take care of people with myeloma so yes, we are busy and yes, we are always behind. Part of that is because we think this is important, that if it takes a half hour or 45 minutes to talk about a trial and what it is and what it’s like and whether it’s right for you or not, then it’s worth that time investment. It’s a really important thing. This idea that patients aren’t aware, that’s all on us, that’s all on the physicians.

Jenny: Well I know just for me, it would have been fine for me if somebody had talked to me at the clinic about it, not necessarily my myeloma specialist because maybe I can ask follow-up questions for him, but if somebody says, “This is the trial we are running” as my physician’s assistant or something and I just want to let you know about it and give you a little more information about it what it is supposed to do and do the preparatory work, that’s an easy thing to do. Because you are spending plenty of time in the clinic. There is enough wait time to review something like that when you are in the clinic.

Dr. Benson: I agree. We are lucky here with the nurse practitioners we have, the whole team, even the clinic nurses and the PCAs and everybody is on board with this too that trials are important. But I think you are right that the lack of awareness, if it’s not brought up early on in someone’s care, then it kind of fosters sort of a suspicion, well not a suspicion but a question. “Why are we talking about this now, why didn’t we talk about this two years ago if they are so important?” I think there is a lot of mystery around it. You always hear, “I didn’t want mom to be a guinea pig, so I told her not to do the trial.” What does that really mean?  I can tell you that going back to 1992 and getting two doctoral degrees, I’ve never experimented on a guinea pig ever. I don’t know where that analogy even came from.

Jenny: Well, you talked about that at the beginning of our conversation where you were saying it is either the standard of care or something better, so I think at least in myeloma, you don’t really need to worry about that as a patient. You are either going to get the standard of care which is not a cure at this point, so we do need to do something differently if we are going to move things forward.

Dr. Benson: I totally agree. That’s a concern too that people will say, well, if I go in this trial, I might get a placebo. Let’s talk about that for a minute. A big part of that is on us too as physicians, that we are not explaining trials properly and we’re not explaining what happens in a trial. Now, we do do trials that have placebos, in fact. Recently, Ohio State led the accrual on the biggest trial in North America for post-transplant maintenance. This was a study that was published in the New England Journal of Medicine a couple years back that showed if you take Revlimid after a transplant, it makes your remission last longer. Half of the people in that study got a placebo and half of them got Revlimid, so why could we do that, why is that ethical? The reason is, is that at the time, the standard of care was do nothing. The standard of care was observation. But if you observe half the people and the other half of the people got a pill, then everyone would know who was on Revlimid and who wasn’t. So the people who got the standard of care, which was observation, got a placebo. That way nobody knew who was on Revlimid and who was on placebo. In a trial like that (that’s really rare) but that’s an example of when we would use a placebo. That’s the only time we would do that, when the standard of care was “do nothing.” There aren’t many times in myeloma when the standard of care is “do nothing.” In most myeloma trials, the standard of care is the best we got and in fact there are some Phase III trials where the new drug is randomized against investigator’s choice, which I think is a great trial design. In other words, you have your drug, your very promising drug, and you randomize it against whatever the doctor wants to give that patient. You think you got something better, give it. That’s the trial design. Then you say is this better than everything anyone else has come up with. I’d like to see more Phase III trials done that way, actually.

Jenny: I think there is a need to explore new opportunities in how the trials are structured or how we choose them or can we work backwards like you were saying and do things more specifically. I think part of it is, too, changing the perception of risk in the medical field because, I used the example of entrepreneurship earlier. It is perfectly acceptable for 80% of startups to fail. We kind of assume that these are new ideas, they are radical ideas that may or may not work, but my husband is trying to narrow it down to a process so it’s not so much risk-taking. I think medical professionals end up taking a reputation hit when you could beat up the idea and not the individual when it comes to medical innovation. Sometimes these visionaries will see this and start working on a protocol and everyone else will say, “They are crazy” and ten years after all the data is out, you find “Oh well, they weren’t so crazy.” I don’t know how to change that perception. Maybe you can take a subset of innovation and drive it through a different structure so you de-risk it as much as possible. I think there is a lot of reservation that comes with people who are incredibly smart, they are in the field and they have all the puzzle pieces that they can put together and they are trapped in this environment sometimes that is very risk averse.

Dr. Benson: I think two things with that. One thing is that we are really lucky at my institution because we have dedicated chemotherapy pharmacists who will counsel patients and we have our nurse practitioners and we have this team philosophy and we really try to engage folks as partners in their disease. We want people to learn, we want people to be involved and really help make decisions and figure out what is best for you because what is best for you may not be what is best for the person in the next room. Having said all that, I think the attraction of standard therapy is that it is standard therapy, so it must be less risky, it must be less toxic, it must be safer and that’s not always true. I think a lot of us take for granted that the standard is safe but then we kind of gloss over, well, there is a risk of blood clots, there is a risk of infection, there is a risk of neuropathy. If you read the informed consent for a trial, there are five pages of “risks” in there. Oftentimes people don’t get an informed consent for standard treatment and they are not fully aware of all the risks of a standard treatment, so it’s not apples and apples. Standard treatments can be have dangers. That’s part of the problem is that maybe doctors just don’t want to talk to patients about the possible bad side effects that inevitably come up in a clinical trial discussion. You have to disclose everything in a trial where it might just be easier and quicker to do a standard treatment and not have to worry about full disclosure maybe. And then you kind of alluded to this earlier – the publication bias – the idea that if a trial doesn’t succeed, it’s not going to get published and people’s careers are on the line, and their reputations are on the line and so forth. Well, I’ve published I don’t know how many negative trials, but what we do with each one is say, “Why didn’t this work the way we thought? Why didn’t it work like it did in the mice and why didn’t it work like it did in the test tube?” We still learn from that. We did a study a few years ago. We gave a treatment that worked, but didn’t work as well as we wanted and we went back and said, “Why? Why didn’t this work? It turned out that all these patients that we had enrolled in the study had a mutation in their immune system that wouldn’t bind the drug. We didn’t even know it existed. You don’t know what you don’t know. But it wasn’t until we said, “What? Why didn’t this work?” and did those correlates and it got published in a good journal, but that’s not the point. The point is we learned something to help us take care of the next patient. Even a negative trial can be beneficial. We talked about this before the phone call started, that there are even studies that have been done in research has been done that people may be more likely to benefit in a trial than if they get standard treatment, actually. Whether it’s because they are getting a new and better treatment, or whether it’s because they are getting better care, is debatable. For sure in a trial you are going to have more people looking at your numbers, more people assessing your quality of life, more people looking at your blood tests, more people looking at your total picture because it’s in a trial – because there is a data safety monitoring board, because there is an ethics board, because there is a research nurse, because there is a statistician, because there is a dedicated pharmacist, because there is someone who is going to call on Wednesday morning and just check in and see how you are doing. You have all these people behind you in a trial that you don’t have with standard therapy.

Jenny: My last question and then I’m going to open it up to caller questions is how can patients best help to speed up the discovery process for a cure through clinical trial participation?

Dr. Benson: The best answer is get involved and ask questions. Be a partner in your care and take the reins and take charge. I tell all my patients this myself. We work in a tertiary referral center. I’ve told many of my patients to get a second opinion. Take a week or two and get a second opinion. There is nothing wrong with that. I think taking charge and getting involved is number one. Step two is learn about trials. Find out what’s out there. There is all kinds of resources online, there are all kinds of resources from the philanthropic groups and when you are talking to your doctor, talk about trials. If they propose a trial for you, ask why. Why is this trial good for me? Why is this trial good right now for me? And then my favorite question – a patient of mine asked me this once, and I thought it was such a wonderful question – “How are the results of this trial going to change your practice?” That’s a great question to ask.

Jenny: It is a great question.

Dr. Benson: Because not all trials are created equal and trials are evaluating different drugs and different approaches and different therapies and different options and I think a great question to ask is, “Hey, you know what? I’m really interested in this trial. Just one question for you. How is this going to change your management? How is this going to change your care?

Dr. Benson: I think it is a phenomenal question to ask, and if you get a good answer, I would think about being in it.

Jenny: That’s a great suggestion and a great question, it really is. I’d like to open it up to questions about clinical trials, so if any of our callers have questions, you can press 1 on your keypad. If you do have a question, you can turn off the sound on your computer so we don’t get the feedback.

Caller: Dr. Benson, I just want to thank you for your time today. It’s been really good. I have a question regarding your processes and the resources that you have available to you. If you could wave a magic wand and take down one hurdle in your work, what would it be? What would make you be able to do your work faster and get to a cure more quickly?

Dr. Benson: That’s a great question. If I could take down one barrier…I would not take down the regulatory barriers. The process of starting up a trial, it could take you easily six months to open a trial because of all the regulatory reviews, review boards, ethics boards and so forth. I wouldn’t change any of that. That kind of rigor is crucial. I think that one barrier that is being addressed now, certainly in our state in Ohio – I know there are probably 20 or 30 states that have adopted this, but there had been a financial barrier to trial participation in that a lot of insurance companies would not cover clinical trials participation for patients. Now many states have adopted laws to prevent that. This legislation basically says that if somebody has cancer and they want to be in a clinical trial, the insurance companies must let them participate and the rationale is that anything considered to be investigational is considered by the sponsor. All that’s asked in these laws is that the insurance companies pay for the standard of care that patients would get anyway. I can’t tell you how huge that was when that barrier fell because a lot of patients who wanted to be in a trial, wanted to make a difference for themselves and for the next patient in the waiting room, couldn’t do it because their insurance company wouldn’t allow it. We are breaking that barrier down now nationally. In addition to having more people participate, I think we are making a little bit of progress in that, I think we are making a little bit of progress is designing more rational trials as well in terms of matching patients with treatments that are most likely to work. The only other thing I would do is potentially shift more funding into the really paradigm-shifting approaches.

Caller: More big swings?

Dr. Benson: I’m in agreement. These treatments that come out provide incremental benefit, that’s a great backbone, it’s a great place to focus resources, but I think that not only in myeloma and cancer in general, but in medicine in general, when you look at the therapies that have changed practice, that have cured diseases, they kind of came out of the blue. It’s not like they were scheduled, like they were predictable. They were people who were answering really hard questions, who were spending their lives on one really fundamentally difficult question and how they got there was just hard work – doing the experiments and trying and failing and going back to it and trying again. It can be a little demoralizing, right? Because you can go months or you could go years without that breakthrough, but when it happens, everything changes overnight from then on. Gleevec is the perfect example. There are others too we could talk about. If I was an investor and I had money to invest, would I want to take that risk? I don’t know. It makes it hard.

Caller: I also have a little bit of investment experience like Jenny’s husband and I would think you need to get a lot of those swings at one time so you can show some success because one big swing is likely to fail. From a pure political standpoint of getting the support you need, trying to do more than one at a time could be helpful, I think.

Dr. Benson: I do too. For whatever reason, those kind of ideas are the first ones to suffer when you are in an environment of limited means and limited resources. You want to be utilitarian and so that means ultimately looking at incremental benefit. That’s great. I’m not trying to downplay that at all. But I think it’s not great to sacrifice funding that goes into really transformative ideas where 99 out of 100 of them might pan out but the one that does is going to change things literally overnight. I think we can’t forget about that.

Caller: Thank you Dr. Benson on your work on this. I really appreciate you taking my question.

Jenny: Second question, go ahead.

Caller: First of all I want to thank you for very thorough coverage of the subject matter. You started eating up all my questions as I was listening in. I’d like to follow up on the last caller as you are talking about funding the disruptions vs. the incremental. You mentioned that you are looking at the whole forest and you can get lost in that perspective. But if you take the forest analogy, if you don’t plant the seeds you don’t get the trees. As a caregiver, it’s frustrating to listen as you are talking about where most of the investment is going into this incremental innovation, not moving towards a cure, but incremental work. There are limited dollars as I’ve understood, things that are driving cures in a disruptive area. So as patients and caregivers, what could we do to change that paradigm? I think we can donate to organizations that are driving research forward, but is there something else that we could do that is more radical? Maybe that is not a fair question for you. Jenny, maybe you could help answer this but maybe we could do this more radically and drive dollars to areas that have a higher probability of failure but it if works could generate the cure. In a funding continuum, you want to do later stage investments and safer stuff, but if you don’t plant the seeds you don’t get the trees. You have to be able to put some money into the early stage and take that risk. The people who are willing to take a risk are people like us. There are no cures out there so we are willing to make those investments but I don’t see the mechanisms out there to do that, but maybe I am just missing it. What else is out there that we could invest in today to drive that to get these younger doctors that are thinking a little bit differently into the research mix.

Dr. Benson: So you hit it on the head. I don’t know if I could have said things better myself. What can you do? You can write to your governmental representatives with these kind of ideas. You can write to the NCI, you can get involved in (these are just low-hanging fruit) your local Leukemia and Lymphoma society chapter, the American Cancer Society chapter, those are all things you can do. The program we have here, Pelatonia, is a cycling event we have once a year. The vast majority of that money actually goes into seed grants. It’s literally like a 100,000 grant, it’s two years of protected time, but the caveat is, it’s for a transformative idea. In other words, it’s risk capital, right? It’s money that is going to be invested in something that is completely out of the box that has no preliminary data at all but it gives the scientists here two years and 100,000 to ask the first questions if this is really something that should be pursued or not. I know other cancer centers are starting the same idea. Dana Farber has Penn Mass Challenge, the Hutch out in Seattle is starting a similar program, but this idea to preferentially fund really transformative thinking, with the full realization that the failure rate for these is going to be very high. I’m reminded of a study – this was published I think in BMJ, the British Medical Journal probably 10 years ago now, but it was a really interesting study, and it is hard to express, so bear with me. What these researchers did, they were actually social scientists, and they went out in the streets of London and they posed this question to folks out in the public and said “Imagine for a minute that you had an incurable cancer. There were no treatment options left and you were really in dire straits and you had two treatment options. The doctor said that one thing we could do is we could give you supportive care and pain medicines and keep you from suffering. If we choose that route there is a 90% chance that you won’t have any suffering but you probably won’t live more than 3-6 months. The other option is we could admit you to the hospital and we could do this experimental treatment and the chances of having side effects and toxicities and significant problems with this treatment are very high. There is a 70-80% chance you will have really significant problems and you might actually die from this treatment.” The question was, what would the chances of success have to be for you to pick that treatment over supportive care?  When the researchers went out into the general population, and asked this question, most of the people answered that the chances of success would have to be very high for that treatment to work for them to pick it. I don’t remember what it was but it had to be like a 75% chance of the treatment working for them to pick that over supportive care. So the researchers thanked them and then they went to oncology nurses and they asked them the same question. The oncology nurses said that the chances of that treatment working had to be something similar or maybe it was even higher as I remember it may have been like an 80% chance of it working for them to pick it. Then they asked a group of oncologist and their answer was the same, it was 60 or 70% chance of it working. Then the researchers did something very interesting. Then they actually went to patients that were in that boat. They sought out patients who had terminal cancers who had progressed to a point where they had no standard treatment options left and they posed them that question. They asked these people, “What would the chances have to be for this treatment working for you to accept that treatment?” And you know what the patients’ answer was? “One percent.”

Jenny: Really?

Caller: Wow.

Dr. Benson: I make our medical students here read that study because it’s so illustrative of what people are dealing with in real life, that we can sit here and talk for hours about how trials are done and the statistics and the funding, but when I read that study, it really hit home. My dad had cancer and he was in a clinical trial. I digress, but my point is that I think as a community we need to be more in tune with where our patients are on a daily basis and what they are facing and what their family and loved ones are going through. Like you said, what are the implications of how we allocate our funding and our resources?

Jenny: Excellent. I am going to add another question.

Caller: My name is David and I am a student at the University of Utah. I have a friend who has cancer and I am wondering how I can best help him get into their desired trial, if there is anything I can do for them in that regard?

Dr. Benson: Thanks for listening and thanks for calling. Rather than answering you as a doctor I am going to answer you as a friend of a patient too. One of my best friends has cancer right now and she is being treated here. She doesn’t have myeloma, she has breast cancer actually and is going through pretty aggressive treatment right now and I think that as a friend, the first thing that I would say is be available. Having seen this from both sides, a lot of people get a lot of support, a lot of rally when the diagnosis comes, and then what happens over times is that everybody gets back kind of in their routine and everybody has their own obligations and their own commitments that they have to keep every day and so once the dust dies down, the friends don’t go away, but they kind of go back to their lives again. So I think number is one is just be available. You don’t have to take flowers and things, but just be available. It could be just calling to say hi, just put it on your calendar to be available. I think if you have that kind of relationship with your friend – I don’t know what your relationship with your friend is like – that if you are tight enough to talk about how treatments are going and what they are feeling, how they are dealing with things, then maybe you can take the next step and say “Why are you on that treatment?” “Do you want me to go to a doctor’s visit?” “Did you ask your doctor what your other options are?” “Did your doctor mention anything about trials?” Those are questions that are hard. I think it depends on the relationship and how tight you are with them, but the best piece of advice (and Jenny, I think you could weigh in too obviously) is just be available – carve it out in your week and be available.

Jenny: If you have the relationship, you can help with other things, but we had a family member who had AML, a very severe form of leukemia and so we’ve been through this process multiple times and it is helpful when you are in that panicked state to have somebody else do a lot of the homework for you. It’s very, very helpful for people to get online and do research for you because sometimes when you are taking the drugs and you are in a stressful situation, it’s not a time to start researching drug modalities. It is overwhelming and you kind of shut it out, but if someone can do some of that homework for you and say, I found these three things you may want to look at, I think that is really helpful.

We have one more question:

Caller: my name is Kibet and I have a lot of friends with cancer and in the medical community - my mom is a nurse - and I wanted to talk about some of the issues in the clinical recruitment process. It seems like a lot of patients have large issues with the complexities with clinical trials. I know right now a lot of the trends are moving towards innovation and collaboration. Specifically I know of an organization that wants to change the way clinical trials recruit by giving patients access to data. I just want to know what your views are, Dr. Benson, on a more patient-centered approach to these clinical trials and how these can help the innovation and collaboration process.

Dr. Benson: That’s a great question. Thank you for bringing that up. I would go back to the first principle that we mentioned earlier. I think the doctor and patient need to have a partnership. They have to have a very honest relationship and a very interactive relationship and that takes time to develop. I think you don’t trust somebody when you meet them the first time. You really have to develop a relationship with them. You have to know who their spouse is and what fulfills them and what is important to them in life. That’s the kind of relationship that someone with myeloma needs with their doctor so they can have conversations about trials and about everything in life. When it comes to trials, the same kind of standards hold. The more you know, the better. For a patient to be in a trial, the folks who I take care of here on trials, we talk about everything. We talk about what is going on in the other treatment arms, we talk about toxicities other patients have had, we talk about – here are the last six patients that have gone on this trial (I don’t tell them their names or where they live, but we talk in general) and how they are doing, and if their diseases are similar or different, etc. Personally, I don’t have a problem sharing that with my patients. Programmatically, if you are talking about what can we do as a system to improve things, I think these kind of data sharing ideas are great. Ohio State has a big reputation in experimental therapeutics and in Phase I trials, so a lot of patients who come here, come here specifically because someone somewhere else told them that there is nothing left. We have a lot of patients come to be in a Phase I trial here. Many of them come not for themselves, but because they want to help the next person or because of some very incredible, altruistic drive to make life better for everybody else. These people want to know the results of the trial so we share that at every extent, but what else can you do? You can look at the journals and see what is being published, you can get the synopses from the cancer research meetings (ASH, ASCO) and find out, right up-to-date, how many people are responding and what kind of toxicities are being seen, what kind of sub-types seem to be benefitting the most. I absolutely encourage that. That’s part of the fulfillment a patient gets from being in a trial is knowing you made a difference, that the next person and the next family that has to deal with this is going to be in a better place because of your decision.

Jenny: I agree. Thank you Dr. Benson for joining us today. We’ve kept you awhile but it was great information and I’m glad we covered it. We are very excited to hear from you again on August 16th and look forward to learning more about your research in immunotherapies. If you would like to contact Dr. Benson directly, he is listed in our doctor directory. At the bottom of his listing you will see a place where you can “Send a Message”. That will send an email directly to him and his facility. Thank you again so much for participating with us and we look forward to the coming weeks!

Dr. Benson: It’s a great privilege. Thank you for inviting me on and I look forward to our next one. It will be fun.

Jenny: Thanks for listening to another episode of “Innovation in Myeloma.” Join us for our next interview that connects patients with researchers to drive better outcomes for us all.

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