Editor’s note: Dr. Hudis hosts the ASCO in Action Podcast, which focuses on policy and practice issues affecting providers and patients. An excerpt of a recent episode is shared below; it has been edited for length and clarity. Listen to the full podcast online or through iTunes or Google Play.
I'm pleased to be joined by Edward S. Kim, MD, chair of the Department of Solid Tumor Oncology at the Levine Cancer Institute, to discuss eligibility criteria for cancer clinical trials. Dr. Kim chaired a joint project conducted by ASCO and Friends of Cancer Research that was aimed at broadening eligibility criteria for cancer clinical trials. The result of this collaboration was a set of comprehensive recommendations that we published as a special series in the Journal of Clinical Oncology just last year.
CH: Can you give a brief introduction into the concept of eligibility criteria? Why do we have them?
EK: In order to test a drug, to see if it is worthy and better than the existing standard therapies or creating a new standard of therapy, we want to make sure to control a lot of variables. We know that each individual has different things that affect them. Some of them are physical. Some of them are mental. Some of them are disease-related. Some of them deal with certain organs that they might have issues with. In order for a clinical trial to give the testing drug the best shot, it's important to set up some parameters to try and test the population of patients that in fact will be representative and allow the effectiveness of that drug to be demonstrated. What does that mean in real-world terms? If we enroll patients into trials who are really sick or who have damaged hearts, or lung function, or kidneys, then we might not be giving the drug a fair representation of its effectiveness because of the different medical issues of the patient population.
That's why you hear some of the quips, "Well, in order to be on a clinical trial, you have to be a triathlete or very fit." And that's not what we want either, because that is also not representative of that real-world patient who is battling cancer.
The eligibility criteria establish parameters in which a patient could enroll into a clinical trial, and those who would not be eligible based on these factors. And those factors usually come from basic things. You have to have the histology of the actual cancer. It makes sense. It should be the same stage. Some trials test early stage; some test later stage. It also needs to include performance status, which can be a somewhat subjective marker. Then they look at organs and see how your bloodwork looks. Then there's drug-specific eligibility criteria. Certain drugs that are being tested also have certain contradictions or interactions. Sometimes we have to test a patient's tissue to see if there is a certain presence of a marker in the tumor that makes the eligibility for the study.
The primary purpose of eligibility criteria is to find a population that is consistent, that allows us to interpret the true effect of a drug or intervention, and thus, for the greater good, get it FDA-approved so that patients outside of the clinical trial can also experience those benefits.
CH: We never want to miss the opportunity to identify the beneficial effects of a drug, and in some cases, selecting the wrong patient population, as you pointed out, might limit our observation. But it raises what has become a very topical issue, often labeled real-world evidence: the fact that in most of the circumstances that we see, the real-world impact of a given approved drug is often measured as less than what was reported in the clinical trials.
One of the challenges that's frequently cited is the low level of participation in clinical research. A common statistic is that around 3% of adults with solid tumors enroll on clinical trials. Do you think that these eligibility criteria, appropriate or not, represent a significant cause of that low level of accrual, or do you think it's mostly other factors?
EK: It is really a travesty that the percentage is that low. The eligibility criteria are, certainly, a major component of why we cannot get patients onto clinical trials. We've all tried to use education and awareness to notify people that there are clinical trials available. You can go to clinicaltrials.gov and find the trial that's right for you and the center that has it close to you and put these maps out there to match people to trials. But that does not take into account eligibility criteria. The trial may be present, it may be near you, you may think you're a candidate, but until you go through the 30 to 50 eligibility criteria and those protocols, that's not the case.
CH: Let’s pivot to solutions. ASCO convened a project on broadening eligibility criteria. We did that with Friends of Cancer Research, and you were obviously a leader in that program. You identified with the group five areas where you thought eligibility criteria could be specifically expanded, where the bar to entry could be lowered. Do you want to talk about what those are and why they were chosen?
EK: We knew we weren't going to transform eligibility criteria overnight, but we wanted to take a first step—a significant step. The one we chose first was brain metastases. This has already begun to start changing, but we felt it was very important to reinforce: there's a good number of patients, 20% to 30%, who show up that have brain disease and brain metastases. For many years, they were automatically excluded from clinical trials because the thought was that their overall prognosis was worse. There's been enough data out there to show that that isn't necessarily the case in all tumor types. Many drugs these days actually have very good penetration into the cerebral spinal fluid or through the blood-brain barrier.
HIV was the next criteria. I remember when I was in medical school, this was a huge new issue and people were concerned. I even had classmates in medical school who stated in a class that they would not treat patients who had HIV. I think that was based in a lot of fear. One of the criteria that you'll usually see in protocols is that any history of HIV is not allowed. What we've seen with the technology and the advances in HIV and antiretrovirals is that patients with HIV are living just as equally well as the general population. This was one that seemed antiquated and definitely needed to be changed.
Minimum age was another area that we looked at. What is it about this magic number of 18? Why is it that a 15- or 16-year-old who has a sarcoma that didn't respond well to standard therapy cannot have access to a trial of a newer agent because they're classified in the pediatric sense?
Organ dysfunction mostly focuses on the liver and the kidneys. There are quite a few exclusion criteria within these protocols that don't allow patients who have some deficits in these, and sometimes that's independent of whether the drug is even metabolized or excreted through the respective organs. We thought it was important to be a little more specific there on the actual drug being tested, the actual dysfunction, and how we're measuring it in patients.
Then, concurrent malignancies. If you had a stage I prostate cancer or a stage I or II breast cancer that's being treated on hormonal therapy, then why should we be excluding those patients who have maybe a higher clear and present danger with a new cancer that may have occurred just because they've had prior cancer?
We stated to people that this was going to be about culture shift. It wasn't going to be about just changing up some eligibility criteria. At the end of the day, I want the new generation of clinicians not to think, "Oh, the patient has brain disease. Brain metastases are probably not eligible but let me check." I want it to be that every patient is eligible, and the only exception is this one little thing. It needs to be more of the glass half-full, and then we find out that these criteria are eliminating people from trials, and not a glass half-empty standpoint.
I love it when questions come up: "What about this criteria? Did you consider this one or that one?" That means people want more, and that's really the change we're looking for.
CH: It's fair to say that this is just beginning to be felt at the clinical interface, reflecting a whole lot of work and thoughtfulness. In the years ahead, many of our participants and listeners will see clinical trials written in a way that reflects this new modernized view. I want to remind everybody that ASCO and Friends of Cancer Research will continue to work to implement the recommendations. They will also be identifying additional opportunities to safely expand eligibility criteria and make trials more inclusive. I like the image you had of the glass half-full rather than half-empty—that the question is not, is my patient eligible, but really, why wouldn't my patient be eligible?
Listen to the full podcast online or through iTunes or Google Play. Read a summary of the ASCO-Friends of Cancer Research recommendations to broaden eligibility for clinical trials, and read the full special series of articles in the Journal of Clinical Oncology.