Improving Transparency in Phase 1 Clinical Trials
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Dr. Shannon Westin and her guests, Dr. Paul Frankel, Dr. Judith Karp, and Dr. Robert Maki discuss how to better inform patients of the risks involved in phase 1 clinical trials.

TRANSCRIPT

Dr. Shannon Westin: Hello, everyone, and welcome to another episode of the Journal of Clinical Oncology After Hours podcast, where we do a deep dive on manuscripts that are published in the Journal of Clinical Oncology. We're so excited to have you all here today. I am your host, Shannon Westin, GYN Oncologist at MD Anderson Cancer Center, and it's my great pleasure to serve as the social media editor of the JCO and the host of this podcast. Today we are going to be discussing a very important manuscript titled “Ethics and Clinical Research: Improving Transparency and Informed Consent in Phase 1 Oncology Trials”). And I'm joined today by several of the authors, as well as one of our editors that helped to review this paper. But before I start, I'll note that none of our authors have any conflicts of interest to disclose. And with that, I'd like to introduce our guests.

First is Dr. Paul Frankel. He's a research professor at the Division of Biostatistics, Department of Computational and Quantitative Medicine, at the City of Hope National Medical Center. Welcome.

Dr. Paul Frankel: Hello and thank you. It's a great honor to be here today.

Dr. Shannon Westin: Also with Dr. Frankel is Dr. Judith Karp, who is Professor Emerita of Oncology and Medicine at the Johns Hopkins University School of Medicine in Baltimore, Maryland. Welcome.

Dr. Judith Karp: Thank you. And I echo exactly what Paul said. Thank you for having me.

Dr. Shannon Westin: And then finally, our esteemed Associate Editor of the JCO, Dr. Robert Maki. He's a professor of hematology and medical oncology, a physician leader in developmental therapeutics, clinical leader of the Sarcoma program at the University of Pennsylvania.

Dr. Robert Maki: Hi, Shannon. Thanks for having me on the program.

Dr. Shannon Westin: Well, it's awesome to have this star-studded group of guests. We are going to try to cover as much details about this important paper as we can in a short period of time. But I encourage you also to check out the JCO to read the paper in full. So first, let's level set. As we start this discussion around phase 1 trials and ethics, maybe, Dr. Mackie, can you start by giving the basics of just phase 1 trials just to make sure everyone's on the same page?

Dr. Robert Maki: Sure, absolutely. Since we have people who are listening from different walks of life, that's for sure. Clinical trials in cancer run anywhere from phase 1, 2 to 3. There are also such things as phase 0 and phase 4 trials. But the primary ones we'll discuss today are phase 1 trials. These are the initial tests, be there a brand-new drug never tested before in people, or it might be testing a new combination of treatments, or it might be looking at an already approved drug or an experimental drug in a new population of patients. Let's say you wanted to take a look at a drug in an elderly population. There aren't any data about that in people who are, let's say, 80 or older, and that would constitute a phase 1 trial. The idea of the trial is to start with low doses of a medication and increase the doses in a systematic way, tracking the side-effects that occur with treatment, and then come to an answer as to how you should move forward with the medication in future trials to determine whether the drug is actually active or not and in which setting. The important point, I guess, in that sense is that a phase 1 trial isn't necessarily looking at whether a drug is useful or not, really just looking at the toxicity of the agent or new combination or new setting overall.

Dr. Judith Karp: If I could add one thing to that, and I think this is something that has evolved—well, it's evolved over the last 30 years, but in terms of practicality and application, it's really over the last 10 years, roughly speaking. It's also, I think, the opportunity to identify potentially informative biomarkers through a series of pharmacodynamic studies. I'm an old leukemia doctor, and so I've had that capability, if you will, with our diseases because they're so accessible. But I think there's been a new emphasis on that over the last decade. And it's an important one because it becomes a tool for stratifying in phase 2 and ultimately for identifying, hopefully, in a prognostic fashion, who is potentially likely to respond versus not. And if it's a versus not, then you go in a different direction once you got a bunch of—or if you're lucky enough to have a bunch of different directions.

Dr. Robert Maki: It's a really important point about looking at so called pharmacokinetic and pharmodynamic markers. How long is the drug staying in the body? What is the body doing to the drug? What is the drug doing to the body? Judith is right on the mark. You can get leukemia cells right out of the body, oftentimes take a look at them directly, whether you're actually hitting the target you think you're hitting. This is a really great place to—and it's often mandatory to get pre- and post-treatment biopsies, even in solid tumor patients, to know if you're actually hitting your target of interest. So, yeah, if you're not achieving that much, then you shouldn't really be moving the drug forward.

Dr. Shannon Westin: I agree. And it's so critical because, as we've seen, you know, to your point, Dr. Maki, about the true goals of a phase 1 trial, I think we've done a lot better job of trying to ensure there is efficacy or trying to clarify for whom we are getting efficacy. And I think we all are aware of several drugs that have gotten approvals from an extended so-called phase 1, right? An appropriately selected population. And certainly that's something new over the last five, six, seven years that we've been able to do that. But things like PARP inhibitors in BRCA-mutant populations and TRK fusion inhibitors like Larotrectinib and others in those with NTRK fusions just come to mind kind of quickly. And even more so, we're seeing these focus drugs, right, that are focused on abnormalities in a specific—Exon, like the G12C inhibitors and things like that. So it is interesting to see how drug development is kind of changing in the phase 1 space where we're trying to move that efficacy potentially up earlier and earlier, just to Dr. Karp's point about that biomarker development. So I think it's a really exciting time.

Okay, so the next piece I wanted to just make sure, again, to ensure that we're all on the same page, is these are very common trials, I'd say, and certainly the foundation of drug development. Do one of you want to give an estimate of approximately how many phase 1 trials are ongoing currently and maybe how that's changed over time? Are we seeing more phase 1? Less phase 1? About the same?

Dr. Paul Frankel: Yeah, I can take a look at that. The number of phase 1 studies that are currently accruing patients today in oncology is around 4500, something like that. I think there's 4451 open clinical trials and phase 1 clinical trials in oncology today. If you look at, let's say, in May of this year, there was 4263. So you're seeing it's increasing. But if you want to look at really the increase, you can look at between 2000 and 2010. There were a little bit over 5000 phase 1 clinical trials that had started in that period, that 10-year period. If you look at the next 10-year period, 2010 to 2020, it's over 10,000 that started. So the number of phase 1 clinical trials is very large, and it's increasing at a rapid rate. And these do set, as you mentioned, the foundation for all the studies that subsequently follow.

Dr. Judith Karp: It's very interesting to me that Paul has these numbers in his head. I am not as quantitative as Paul, but we have these increasing numbers of trials, and yet the percentage of patients who go on those trials has not increased at the same rate. There's still that gap where now for children with leukemia—actually, for children with cancers, it's 90%. 90% of those children go on clinical trials. But for adults, it's still around 8 or 10%. It's unfortunate.

Dr. Robert Maki: It's a really good point. There really should be more adults being put on clinical trials. But by the same token, not every adult is appropriate for a clinical trial. Let's say you have—there are things you can do that are clinical trials that aren't treatment either. And if it's data collection or patient-reported outcomes, something that we really don't have a lot of information of in a broad manner, there certainly are clinical trials, even if you're getting standards of care in which patients can be enrolled. So you're certainly speaking to a group of people who espouse and promote clinical research wherever it can be done.

Dr. Paul Frankel: These clinical trials, I think, are often the best opportunity that patients have. And even though we're going to be talking about issues with consent and other issues with regard to phase 1 clinical trials, they still remain the best option for patients in almost every situation, if you can get on them.

Dr. Judith Karp: Yeah. I just think of them as…

Dr. Shannon Westin: Yeah, and I think we could have a whole ‘nother podcast of how to expand an exclusion criteria to allow for those patients, but maybe we'll bookmark that for another episode. Paul, you kind of started mentioning, I think, the last place to level set before we get into a little bit more detail from the paper that you all wrote is from regards to informed consent. Can one of you, or more than one, review the importance and challenges of this process for our listeners?

Dr. Judith Karp: I’ll take a stab at that one. I think the importance of informing a patient, however well we can do it, of what we expect to happen and what we know and what we know we don't know is a very important part of the contract between the physician and the patient. And it's really a partnership, especially for phase 1 trials, where we really know so little. And what we do know is that the patient—these are for treatment trials. We know that there is no therapy widely available for that patient that's going to do that patient any good. So we have to enter into a partnership with the patient to say, “We're going to try something. We know this little bit. We don't know this huge amount.” And so I think that that's really the importance, just ethically, to have the patient be informed. In terms of the challenges, I think that—this is certainly not politically correct, but were I on the receiving end, on the patient end, and somebody gave me a 35-page document to read, I would not for many reasons. In some ways, it's too much information. Most patients are not, by definition, medically sophisticated. That's one. Two, they don't want to read 30 pages. They're either going to sign it, or they're not. And it's confusing. And, yes, you can say to a patient, “Look, take this home, read it, come back in a week, call me in a week,” whatever. There are many instances, certainly in the leukemia field, where you can't do that. You don't have that luxury. So I think that that is a real challenge that we really haven't addressed. And in the good ol’ days when all of us physicians really sat down and talked to the patient, then I think that the challenges were much less. And I think that that's key.

Dr. Robert Maki: Yeah. I mean, Judith, AML over age 65. You're not going to get most people into remission, and you've got a captive audience because there they are with low counts. And what are you going to do next? We all, in our research, want to follow the Belmont report. We want to respect people. We're looking for studies that offer beneficence, that do no harm. We can't really do no harm a lot of the time, but we can at least minimize harm. And I think it's where the consent process kicks in. And justice, the third tenet of the Belmont report, being sure that we're using well-considered procedures as part of the research. All those are part of those beautiful words that you used, “partnership” and “contract,” that I think are really important in developing that bond with the individual patient who you're going to treat is super critical.

Dr. Judith Karp: Yeah, absolutely. And in some senses, the only real informed consent is if the patient has been through it before.

Dr. Shannon Westin: Right.

Dr. Paul Frankel: So one of the things making it even more challenging, all these challenges exist throughout. And one of the focuses of our paper is that there's been an increasing trend to use designs that specifically target toxicity rather than limit toxicity during the dose finding of the phase 1 study. And so that introduces a whole ‘nother aspect to the consent process. So if you look at those studies, the most common toxicity target, as noted by others, is a 25% DLT rate. And if interpreted directly, that means that these risk-targeting designs, they claim to aim to find the dose where one in four patients are expected to experience a severe or a life-threatening adverse event in the first cycle of therapy, which is usually 28 days. And that's despite dose modifications. And further, most of these designs consider it a positive feature if a large percent of the enrolled patients are treated near the target. Now, whether this is really what the physicians want or not is separate. But one way or the other, what we have noted in our paper is that our collective experience that the actual toxicity target, the targeted risk, whether it's 20%, 25%, or even 33%, is not disclosed to the patient in the initially submitted consent forms that we see. That is a fundamental change in the way we've designed studies, but it requires that we adapt the consent process to this very challenging problem.

Dr. Judith Karp: Along those lines, you're talking about toxicity. Any treatment that targets a non-itchy skin rash has got to be a lot less toxic than a drug that is targeting refractory ovarian cancer or leukemia or what have you. And the disease itself is toxic. So I think there has to be a way to approximate and weigh those toxicities, the toxicity of the treatment versus the toxicity of the disease, because the disease is not benign.

Dr. Shannon Westin: One of my mentors, Dr. Razelle Kurzrock, used to always say, “The worst toxicity is progression of cancer.” And I completely—that's a very wise woman. But I think it's a really good point. And I think, just to kind of summarize what you all were saying, if we're targeting a certain toxicity level, we just need to make sure that patients are aware of that. And many of them might be willing and would probably be willing to take that for that potential benefit and things they might get out of it, but we need to be more transparent on that kind of individual protocol level. Would you say that’s…?

Dr. Paul Frankel: That’s the critical thing is to be transparent about these things. And certainly certain different treatments which have maybe more curative potential, certain types of diseases, they’re going to be more amenable to a higher toxicity threshold. But it depends on the intent of the therapy, and these need to factor into the decision of what's being used, what kind of target and kind of design is being used. That's kind of part of the issue of transparency is once you get that in front of the patient and the physician and they discuss it, you're likely to get people to agree if it's at least a reasonable target.

Dr. Robert Maki: The toxicity targets up from some of these Bayesian designs, oftentimes they're kind of guardrails to ensure there's not too little or too much toxicity on a trial. I think people are using more of the rules-based designs, this risk-targeting design, than the classic three plus three simply from the inability to come up with an adequate dose-escalation scheme using three plus three simply from the fact that you're just looking at the prior three patients. If you look at a lot of the kinase inhibitors that have been approved over time, even when they’re FDA approved, drugs like lenvatinib or cabozantinib, even in the phase 3 trials, patients had to have their dose reduced two times out of three. And it really speaks to something went awry in the development of these agents if they really were looking for a 16% DLT rate in a classical sense, which is what you get from that three-plus-three design, one out of six people. It's pretty crazy that two thirds of people in a larger population need that dose reduction. So perhaps by putting better guardrails with one of these rule-based designs, we’ll actually end up with a schema for treatment of a patient that ends up being more appropriate.

Dr. Judith Karp: It would be very interesting, actually, to examine how often we're wrong. It might be very easy. 100% of the time, I would imagine. But how often the so-called RP2D turns out not to be that. And even with phase 3 trials, you never really know a drug until it's out on the street and thousands and thousands and thousands have been treated with that drug or combination. Paul, maybe that's our next study. What do you think? Nah, I can tell you don't like it.

Dr. Shannon Westin: This is kind of getting at what Project Optimus is trying to do, right, is getting away from that idea that we have to get to the max dose and instead look at long-term tolerability. And yeah, Robert, I've given quite a bit of lenvatinib and pembrolizumab in my clinic to patients with recurrent endometrial cancer. You can see that that max dose is not the ideal dose for a lot of patients. Now, there are some patients that tolerate just fine, but 70% grade 3/4 toxicity is legitimate, and making sure we're protecting patients from that is really critical. And I want to cover a few more things before we wrap up. I guess we've talked a little bit about what to do on an individual protocol level. Do you all have some recommendations about what can be done at the research/enterprise level to kind of address the issues that we've been discussing today?

Dr. Paul Frankel: One of the issues is, if you look at, let's say, clinicaltrials.gov, you'll see that there's very few studies that have both a model consent form or the protocol on clinicaltrials.gov. And I think if you look at all the clinical trials, the number that have both, you can count on one hand. So the question is whether or not there's a way to systematically evaluate whether the consent form is appropriate, whether the target is reasonable, that kind of thing. And it's very hard to do when you don't have a way to assess that information in a systematic way. So one thing that can happen is that the registries could require a model consent form where they could ask for it, encourage it, one way or the other. It's just a simple document. The other thing that they can do is make sure that the protocol summaries, if the design uses a DLT targeting method to at least state what the target is in the protocol summary, that would help quite a bit. And then you can go through and see if this is reasonable or if this has been communicated in the consent form in particular. And so that's one thing that can happen on the enterprise level that would help considerably.

Dr. Judith Karp: The only thing I would add to that is that I think a model consent form, a template, is it's surprising that it hasn't been done yet, although, as you say, it's not easy with all of these studies being done by government and pharma and other enterprises. But that has to be modulated for the disease that’s being targeted and for the drug. You can't have the same thing for cell cycle cytotoxic agents and immunotherapy because they're totally disparate. And you can't have the same thing for leukemia and breast cancer. The pathogenesis may be the same, but the phenotyping is not. So that's the only thing I would add.

Dr. Robert Maki: The patient population involved as well can certainly impact that. Greater or poorer performance status, susceptibility to complications, all that figures into that consent form. So it's not an easy thing to prepare, at least in a coherent way that a patient is going to understand, especially, as you were saying there, with a 40-page tome that reads at somewhere between grade levels 11 and 14. How do you expect a patient with, let's say, an 8th or 9th grade reading level to fight their way through that if they really wanted to understand the side-effects. It's kind of like the teacher in the Charlie Brown cartoons: “Wah wah wah wah, wah, wah, wah, sign here.” So there are many challenges.

Dr. Paul Frankel: There's no question that this is a minimum requirement. Having a written consent form is just an absolute minimum. But the conversation that needs to take place, the communication, that's a whole ‘nother level that I think the physicians are better able to address. But it's just the minimum requirement to have something in the document, and it doesn't make the document longer to communicate the targeted risk in some of these studies. There's really no extra effort that's being asked. I mean, the model consents exists. The DLT targeting is stated in the protocol. It's all fairly simple.

Dr. Robert Maki: Yeah, it'd be another line or two, wouldn't it? It's just saying here's what our expected rate of toxicity is. And uploading, whether you're a cooperative group, whether you're an industry, whether it's an investigator-initiated trial, some sort of redacted consent form makes a lot of sense. You may not have to have the grid of activities, which oftentimes is now included in one of these cumbersome documents, but at least the description of the treatment and the toxicity would be at least something everybody could agree to.

Dr. Judith Karp: Yeah, some kind of a precede or a FAQs, frequently asked questions. What is this? Why are we doing this? Very simple.

Dr. Robert Maki: And that's now mandated, I think. They said at NCI, they insist that we have a summary of the trial, and one page or page and a half at the beginning of that long document. That, to me, has been incredibly effective, as have been things like a little drawing of patient and going one randomization and things like that. Simple means can really be powerful, especially on those first two pages before the eyes glaze over.

Dr. Judith Karp: Exactly, yeah, a little CONSORT diagram or something like that, very nice, schema.

Dr. Shannon Westin: This has been a really awesome discussion, and I think the bottom line is we need to increase our transparency. And it seems—I don't know, after this discussion, I feel like it's a pretty straightforward ask. Are there any downsides to being transparent? I know we've already talked a little bit about patient burden and how we don't think that would add much to that piece.

Dr. Judith Karp: The fear that might exist, that, “Oh, my God, if we really tell them what we're going to do, they're not going to do it. They're going to say no.” I don't think that's realistic. I think patients, especially for phase 1, we're dealing with a population of people for whom there is not a reliable, effective therapy available. These patients know that. Many times they've been through rounds and rounds of chemotherapy or immunotherapy or surgery already. So many patients say, “Just give it to me, and I'll sign it.” And you say, “No, no, no, you must read it.” So they say, “Okay, I'll read it. Where do I sign?”

Dr. Robert Maki: Done. Exactly. But it's a really important point that I'd also like to highlight, that phase 1 trials aren't just for the patients with performance status 3, very sick. You can certainly impose those earlier in a patient's course, especially in situations where there is not a randomized trial, for example, showing evidence of survival benefit. Short of that, I tend to be more aggressive about putting patients in earlier lines on phase 1 trials simply because it provides more options for them.

Dr. Judith Karp: Yes, and I think a good example, as you had brought up, Robert, earlier, the older patient with AML, maybe a myelodysplasia-related AML. There are lots of things you can do, but none of them work. And so is it an opportunity to look at improving the hypomethylating agents where you get a 25% response rate, not much in terms of complete remission, and a year survival, maybe a year and a half survival. Can you improve on that if you add a drug that interrupts the survival pathway targeting BCL? Can you do that? The answer has been yes, but the only way to get there is to do the phase 1 trial initially and then move up the trial schema.

Dr. Robert Maki: To your question, Shannon, though, the administrative burden is a small one. It’s uploading a document, adding a little bit more to a consent form. It should not be a deal breaker, I would think.

Dr. Paul Frankel: There's plenty of burdens on the research team. We certainly don't want to increase that at all, and I don't think this does. One of the questions you mentioned are the downsides of transparency, but some of the upsides also: by having the physicians have more discussion with the patient on some of these issues in a more transparent and lay language, I think, increases the understanding between the physician and the patient. And the physician can take that back to the statistician who's designing the study with the physician and say, “Hey, maybe we need to reconsider this.” There's some upsides in a variety of ways. Transparency and discussion are only going to be improving the ultimate product. And we certainly don't want to find drug doses that end up being a program drug death or unnecessarily hurting patients. Either one are totally unnecessary and unacceptable.

Dr. Shannon Westin: Well, great. I think you've made a very clear call to action. I think the last question is how do we get this done besides raising awareness and just kind of setting the bar, right? Because I know, coming from my standpoint as a clinical trialist, it's not something we think to put into the informed consent as we've transitioned to this more risk-targeting type of trial, which I think, as you mentioned, is becoming much more common and over, like, the three plus three and things like that. How do we implement this? Too big of a question? You’re like, “You tell me.”

Dr. Judith Karp: We, as physicians, have removed ourselves from patients in so many ways. And how do you get it done? You sit down with the patient. And listen, I'm no saint, and none of us are saints, and we all have other things that we have to do, and there are—you know, we're pressed for time and this and that the other. But much of this, yes, full transparency, you have a 20%, a 25% chance of having a dire consequence. That doesn't mean that you will. If you do, it's 100% in you, right? But there's got to be a communication part that goes with it. That's personal. You can't just do it on paper. You need to do it on paper, but you gotta do it with people, too.

Dr. Robert Maki: And the discussion point around potential toxicity, all of the visits, extra visits you might have to make, what extra work you might have to go through, versus, let's say, supportive care only if you are at that point. That is an incredibly important point to make to patients, that you really have exhausted many therapies. Is it best just to go with supportive care for whatever time is left? Because this certainly is rolling the dice. You're going to have some side-effects. And what's the chance of benefit in a phase 1 trial? I think that it's higher now these days, simply from the ability of immunotherapy to intervene on so many different diseases. For example, our success rate is higher than the 5% that's quoted previously, but it's not a home run in any case. And we don't want to take away hope, but we also don't want to give false hope. And I think with Paul's paper and your paper have really pointed out how important it is to have that discussion around the degree of toxicity you might have to expect.

Dr. Judith Karp: Absolutely. Absolutely.

Dr. Shannon Westin: Well, great. I just want to thank you all for such a lively discussion. I learned a ton, and I hope that our listeners did, too. I do want to remind our listeners to check out this paper, “Ethics and Clinical Research: Improving Transparency and Informed Consent in Phase 1 Oncology Trials,” published in the JCO. And also check out other episodes of the JCO After Hours podcast to learn more. So thank you all again and have a wonderful day.

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