Mikkael A. Sekeres is a professor of medicine and the director of the Leukemia Program at the Cleveland Clinic in Ohio. He frequently writes about healthcare issues on the Well Blog on the New York Times website. Today we are speaking to Dr. Sekeres about the issue of stringent eligibility criteria of most randomized cancer clinical trials.
—Interviewed by Anna Azvolinsky, PhD
OncoTherapy Network: According to most estimates, including the American Cancer Society, the percentage of adult cancer patients that participate in clinical trials is only about 3% to 6%. What are some of the reasons that the proportion of these patients that end up participating in trials is so low?
Dr. Sekeres: There are a variety of reasons why adults don’t participate in clinical trials of cancer therapies. The first and one that we’ll talk about in a second is that a lot of people want to participate in clinical trials, but are excluded from doing so because of eligibility criteria for those studies. We often joke that you have to be an Olympic athlete to make it onto a clinical trial of cancer drugs, but it’s actually no joke. Patients have to be very healthy, have few comorbidities (meaning other illnesses), and have to be at the right stage of their cancer therapy to qualify for a lot of these cancer studies. So, that in it of itself excludes people from participating in these studies, but there are also other societal reasons people don’t participate.
When I talk about what I do for a living, my own mother’s reaction is, “Oh I would never want to be a guinea pig for a clinical trial.” So, that notion that we are experimenting on people has not gone away. Even with my own mother, when I remind her “hey, this is what I do for a living,” it doesn’t sway her opinion of clinical trials.
What a lot of people don’t recognize is that clinical trials are conducted in a number of different phases. So, yes, there are very early-phase studies where we have conducted a lot of these into humans in a safe way where the dose is escalated and where we look for side effects. But most studies are more advanced than that where the drugs have already been used in other people, have shown efficacy, and now are moving to the next stage. So the notion that someone is “a guinea pig” is really for the most part unfounded in these clinical trials.
Finally, there are other reasons people don’t participate. Some of these have to do with insurance. People are concerned that insurance won’t pay for clinical trials. The time involved in participating in a clinical trial, so a lot of trials are offered at major medical centers and if you are like any of my patients, a lot of them come from rural Ohio. It’s frankly intimidating to brave the traffic and drive into Cleveland every day, navigate the large buildings, find a place to park, pay for that parking, and then come in for required lab draw that is required for that study.
And one final reason is that clinical trials were not always conducted ethically. They, unfortunately, have a tragic history of being conducted in vulnerable populations and that notion that clinical trials are taking advantage of people has not gone away. That affects people of specific sociodemographic background and when these folks here about clinical trials, some will say, “I don't want you experimenting on me; I have heard what has happened to others.” So part of the reason that people are not participating in clinical trials is our own fault that we are not designing trials to include the people we should be including. The other part of it is that clinical trials frankly, need a better press agent, they need to recover their image a little bit.
OncoTherapy Network: On the first point you mentioned, the eligibility criteria, are there general trends as far as the eligibility criteria for most cancer drug trials, both early- and late-phase ones?
Dr. Sekeres: So the eligibility for clinical trials, some of them make a lot of sense. And some of them, frankly, don’t make a lot of sense. And I will give you an example. If you have a clinical trial of a drug you want to use on women with breast cancer, one of the eligibility criteria is that the woman has to have breast cancer. Well, of course, that makes complete sense. If you are looking at a drug that you think will work in late-stage breast cancer, then one of the eligibility criteria is that a woman has to have late-stage breast cancer to participate. Again, that makes complete sense. But some of the eligibility criteria don't make a lot of sense. A lot of the eligibility criteria focus on how well a person’s organs are functioning. And let me be specific about that. So for example, an eligibility criterion say that you need to have normal kidney function, normal liver function, and if your lab values are anywhere out of normal then you are excluded from that study. On the one hand, you can see why a clinical trial would specify that. They want to enroll healthy patients so that when you are trying to assess whether a patient is having a side effect of that drug you are not confusing that side effect with something that may be caused by a completely different factor within that person’s body. You wouldn’t want to conclude, for example, in a patient that has heart disease, and goes onto a clinical trial, if that person does experience a heart attack, then that heart attack is definitely from the experimental drug. It may be but it may not be because the person went into that trial with known heart disease. So on the one hand you can see why patients would be excluded from trials if they have medical problems, but on the other hand, if these drugs have already been studied and it’s known that they don't cause liver problems or kidney or heart problems, for example, why exclude patients from that study who have other medical conditions, particularly when the vast majority of patients I treat have other medical conditions.
OncoTherapy Network: At the recent American Society of Hematology meeting that was held in December, you and your colleagues presented an abstract held in December that compared outcomes of leukemia patients that were eligible and ineligible for Southwest Oncology Group (SWOG) leukemia clinical trials. Can you talk about the reason for doing such an analysis and what you and your colleagues found?
Dr. Sekeres: Absolutely. We recently published an article in the journal Leukemia, looking at eligibility criteria for clinical trials, conducted in patients who have cancers of the blood or bone marrow. We looked at 97 studies that were randomized and involved over 40,000 patients over a 5-year period. We went through all of the drugs being studied and determined what their known side effects were based on previous research done with the drugs. We then looked at the eligibility criteria and said, ok, do these line up with the known side effects of these drugs and as it turns out, they didn’t at all. So it looked as though the eligibility criteria were unnecessarily restrictive for patients who had other medical conditions that affected for example, the liver, the kidneys, and the heart. We then looked at the actual side effects of these drugs that occurred on all of these studies to see if they lined up with the exclusion criteria of these drugs and it turns out that they did not line up at all. So for example, the expected rates of toxicities involving the heart, the kidneys, and the liver were much lower than what we would have expected based on the exclusion criteria. So, from the set of research we did, we concluded that the eligibility criteria for randomized studies in cancers of the blood and bone marrow were unnecessarily restricted.
We then took it to the next step and we wondered what would happen to patients who were supposed to be ineligible for studies who were actually treated on those studies. So we focused on one of the National Cancer Institute cooperative groups. There are three large cooperative groups that study cancers across the United States and this is a mandate from the National Cancer Institute, for cancer centers to work together to find better treatments for rare cancers. In this case, we focused on leukemia and trials conducted through the Southwest Oncology Group and we are a member of the Southwest Oncology Group. We looked at 13 trials conducted in leukemia since 2005 and involving almost 2,400 patients. What we were able to identify were patients who were found after the fact to be ineligible for those studies, so they were enrolled and everyone thought they were eligible, but then in a quality assessment afterwards, whoops, these folks were not eligible for these studies. And there are a variety of reasons people are not eligible for studies. We are not talking major stuff like patients were treated for the wrong disease. But what we found is that patients should have been excluded because they got a test that was out of window for the study. So a patient was supposed to have gotten a bone marrow biopsy within 30 days of starting on a study and they may have gotten the bone marrow biopsy within 40 days so it was outside of the window of when they were supposed to undergo that screening test. When we looked at these ineligible patients treated on these studies and compared them to the patients who were eligible, what we found is that these “ineligible patients” had the exact same rates of side effects from the drugs and the exact same efficacy to the drugs as the patients who were eligible. So in other words, these patients who should not have been included on the study based on eligibility criteria actually did just as well as those who were eligible and again we concluded that the eligibility criteria were unnecessarily restrictive.
OncoTherapy Network: So based on this and other studies, do you see any paths of how to improve clinical trial eligibility criteria and in turn, the proportion of cancer patients that participate in clinical trials?
Dr. Sekeres: This is a part of the Joe Biden’s Moonshot initiative, which fell into the 21st Century Cures Act that just got signed into law by President Obama. One of the focal points of trying to advance cancer care and move us quicker to a cure for cancer is patient participation in clinical trials. So they have identified the idea that yes, this is a problem, not enough adults in the United States are participating in clinical trials. So that is a first step, a national recognition that this is a problem.
A second step is including real-world arms on clinical trials. So, yes, study of a drug for approval by the FDA is going to be restricted in the people they enroll onto that study, whether we like it or not. But the FDA has been exploring requiring an additional arm to those studies of real-world patients, patients who have heart disease or liver disease or kidney disease who really represent the types of patients we treat everyday, to also include them on these studies and to see if the drug works just as well in them, and also if they experience the same rates of side effects as people who don’t have these other side effects to the drug. And I think this is absolutely critical because we are often disappointed by the efficacy we see to the drugs in our own practices compared to what was reported in a study that led to a drug’s approval. We need to know for sure that these drugs work just as well in the patients we are actually seeing everyday and whether those patients are able to tolerate those drugs—that those drugs are safe just as they were determined to be for the patients enrolled on a clinical trial. It is that not enough patients are participating in clinical trials.
OncoTherapy Network: Thank you so much for joining us today, Dr. Sekeres.
Dr. Sekeres: Thank you so much for the opportunity.