Dr. Nathan Pennell, Dr. Muhammed Beg and Ms. Erin Williams discuss improving the time-to-activation of new clinical trials at an NCI-Designated Comprehensive Cancer Center.

Read the article: https://ascopubs.org/doi/full/10.1200/OP.19.00325

TRANSCRIPT

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DR. PENNELL: Welcome to the latest Journal of Oncology Practice podcast brought to you by the ASCO Podcast Network, a collection of nine programs covering a range of educational and scientific content and offering enriching insight into the world of cancer care. You can find all recordings, including this one, at podcast.asco.org.

My name is Dr. Nate Pennell, medical oncologist at the Cleveland Clinic and consultant editor for the JOP. Today, I'd like to talk about clinical trials, specifically the complex process that goes into opening a clinical trial and the surprising amount of time and individual steps that go into what might otherwise seem like a straightforward process. And while we all agree that trials are critically important for patient care and making scientific advances, as a clinical investigator, I can tell you that they can be quite a challenge to open and sometimes take a surprising amount of time and resources, which can be frustrating.

With me today to discuss this topic are Dr. Shaalan Beg, associate professor of medicine in the division of hematology and oncology at the University of Texas Southwestern Cancer Center, and Ms. Erin Williams, associate director of clinical research operations at the Simmons Comprehensive Cancer Center. We'll be discussing their paper, "Improving the Time to Activation of New Clinical Trials at an NCI-Designated Comprehensive Cancer Center," to be published in the November 2019 JOP.

Welcome, Shaalan and Erin, and thank you for joining me on the podcast.

DR. BEG: Thanks for having us.

DR. PENNELL: So can we start off by talking a little bit about what's involved in the clinical trial opening process and why this ends up being such an important issue that leads to projects, like what you describe in your paper?

DR. BEG: Yes. It's a pretty complicated process. And I think I say it a lot, like, how a bill becomes a law. So how does a trial protocol become an open clinical trial available to our patients? So when you have a document which embodies the principles for the clinical trial or the clinical trial protocol, you have a consent form that will be a patient-facing document that the patient sees, which summarizes, in layperson's terms, what the procedures will be for the study. And then these documents have to go through multiple steps of approval within individual institutions.

For example, the institution review board will look at the document in terms of risk management or risk assessment for the institution. Scientific committee will review the scientific integrity and see whether it suits the patients that that specific center is taking care of. And then, in parallel, you have a group of experts who want to see if that trial is something which they can feasibly execute. So hypothetically speaking, if a trial needs treadmill tests, do we have a treadmill to actually do that? So really the rudimentary, sometimes, feasibility questions.

And then, as the studies are becoming more complicated, some of these studies have biomarkers which we want to identify patients for, and we need to test patients before we can find the right patients for the clinical trial. So that entire process is becoming more and more complicated.

DR. PENNELL: That all sounds like it makes perfect sense, but I know a lot of our listeners might be surprised to learn that this entire process from beginning to end can take a long time-- sometimes six months or longer. What are the consequences to an institution of taking a long time to activate a trial?

MS. WILLIAMS: So this is Erin. Well, the consequences can mean our access to clinical trials, right? So it can also mean access for patients to the clinical trials. So both of those things. If we take too long to open the study and a lot of other centers around the country or around the world have a study open-- and specifically, there are a lot of trials that are open internationally, and sometimes it's easier to open trials internationally more quickly-- then our patients lose access to those trials as the spots for enrollment fill up and the study goes closer and closer to its enrollment target.

But in addition, sponsors, industry sponsors, pharmaceutical companies that are bringing trials to their cooperative groups in which we participate-- these are NCI-funded large-cluster groups for phase III clinical trials, we participate with those as well-- they're looking at how long it takes us, as an institution, to activate a new study. And if we start to take longer than most other institutions, they may not favor us for a particular trial to offer that trial to us.

DR. PENNELL: This is such an important process, and I think this is really going to resonate with lots of people who work at centers that open clinical trials. So why don't you take us through the process? So what exactly did you do there?

MS. WILLIAMS: So this is Erin again. We convened a group of stakeholders, along with a leader from our institution's Lean Six Sigma program, to really map out the process. So we convene about four or five hours of a day for everyone to come in. And it didn't just include cancer center stakeholders, but it included stakeholders from our sponsored programs administration office at the institution, our institutional review board, human research protections office, our hospital review committee. We really wanted to gather together all those people who touch the process in some way throughout the course of the time to activation.

And so really with Patrice's help, who is our Lean Six Sigma expert, she really kind of started the process out, and we did kind of what your traditional Lean Six Sigma mapping might look like-- use sticky notes and words on sticky notes, mapping out the process on the long board, and then ultimately creating what the map looks like. And I think what it did was allowed everyone who was in the room to really take a look at the process and how sequential everything came out to look.

One of the biggest impacts that we identified and that we highlighted in the paper is what you really saw was this gap between our scientific review committee submission and the IRB review, and then everything else in the process, because a lot of steps hung on IRB approval and didn't want to move forward, including hospital review, contract execution, things like that, until the IRB had given their stamp of approval, which of course is the review board for patient safety.

So what we tried to do is, immediately, you could kind of see this visible gap in-between the steps, and that really showed us that potentially aligning that scientific committee review with the IRB review and allowing that IRB approval to happen more quickly might trigger some of the other steps.

DR. PENNELL: One of the things that I found really interesting when you were talking about the various steps in the process was when you chose to start the clock, because I know that there is a lot of attention paid to how long it takes to open trials. And, you know, in my experience, I have heard that there are institutions that somewhat game their numbers by not starting their clock to opening until they've actually gotten a lot of steps already done before they do, say, a regulatory submission. And then it looks as though they're opening the trials quite quickly, but they may have already had the protocol for many months ahead of time, working on things ahead of this.

And you guys chose to start from the time you actually receive the regulatory packet and the protocol to start, which makes sense. I mean, that's really when, I think, you, as an investigator, would think the clock would start. But did you ever get any pushback from your leadership or others to starting that early?

DR. BEG: No. I think it's a matter of being consistent with how we report our numbers. Similar to you, we are an NCI-designated center. We report these to our advisory boards and to the NCI in regular intervals.

I think whenever we're measuring numbers and we set metrics for any target, we run the risk of people trying to cut corners and gaming the system to make the number look good. I think that's pretty well-documented in any industry. And our time-to-trial activation has become this shared quality metric across the cancer center, across the institution. And we were worried that it may start being that way, that folks are trying to, "well, should we take out the weekends, those aren't really work days, or how about the time the sponsor has the packet, or--," you know?

And I think, as humans, we all have tendencies to try and come up with ways to make our numbers look better. But the advantage of publishing this to a journal like the JOP with transparency on how we're measuring it, and, you know, I think we had faith that our audience would recognize when our time is-- when our time clock is starting. And there wasn't any pushback.

MS. WILLIAMS: I'll just add to that. The reason why I think it's so important to be transparent with these numbers is because-- being in an administrative role and an operational in a clinical research office for a long time, investigators who are bringing a trial forward for us to activate, the calendar has started as soon as they bring me a trial that they want to open. And if I tell them that a study only took 60 days to open, and their recollection is nothing near what I'm telling them my metric is, then they're not really going to trust what I'm telling them overall. And I think it's important that I recognize, and that we recognize as an operation, that what really matters is that once we get the study, we're starting the process.

It just makes the numbers more useful to you, internally. It makes it more useful to the outside companies or organizations that you're working with. And, you know, even the non-value added time that's not in your control can sometimes-- you can intervene in that. You could potentially escalate things if you haven't heard from a company in a certain period of time. So I completely agree. That makes perfect sense.

DR. PENNELL: So, well, why don't we dig into your results? So what did you find through the mapping process?

DR. BEG: I think one of the issues was how we can move some of the steps that happened in parallel or that happened sequentially to try and make them work in parallel. And like Erin mentioned earlier, just mapping out the process and having the different offices represented on campus that are a couple blocks away from each other really think about how they-- when they start their clocks and why they wait for specific milestones to start a review process was very helpful.

So one of the steps was to really move from a sequential process of scientific review followed by an institution review board review into a process where we move that in parallel to each other. And different centers have grappled with this question in different ways. The way we decided to address this, we didn't want the IRB to be bogged down by a study that wasn't scientifically valid, that may have concerns, or is not novel enough. But we have internal data that our scientific review committee-- and this is published data-- that our scientific review committee very rarely changes the design or the structure of an industry-sponsored clinical trial, for example.

So we decided that we would come up with a process where the IRB will physically review the study at a time after the scientific committee has reviewed the study. If the study is disproved, then it falls off the IRB's docket. But if it's approved, then they will be ready to review it. And we were able to shrink that time from scientific review to IRB quite significantly by modifying that process.

We talked about institutional studies, so studies that our own investigators are developing. Those studies do tend to get more criticism at the scientific review committee. Our committees review them much more closely and have much more impact on those. And we decided to move them forward on a case-by-case basis. So it really required some restructuring.

MS. WILLIAMS: One of the other things that we outlined in the paper, one of the other outcomes, was that our hospital review committee agreed to review the study in parallel with the IRB and in the PRMC review process and just hold their approval until those approvals had been received. And that happened. And if you looked at the individual time to getting that hospital review committee approval immediately following the intervention, it went down significantly.

As with anything, it takes consent kind of massaging and working with those groups. And some of the offices and the infrastructure around clinical trial changed subsequent after we had our time to activation. And so with any of that change, processes start over, people start looking at things over again, and they decide, well, wait, why are we reviewing this in parallel? Or these other groups of people need to be reviewing this in more detail.

Having said that, as those processes have changed, what we've heard and what we've experienced with those stakeholders in the institution is that their eye is always on the activation timeline. And that if we report to them, hey, this time to review committee approval has kind of gone back up, it's creeped back, and we really need to look at this again, you can see their immediate response is, oh, absolutely, we understand, these are kind of some shifts that we made, but let's get together, let's look at it, we really are hoping to push it back down.

DR. PENNELL: Well, I think that's a great point to point out, that this is not a one-time thing. And whatever changes you institute, you can't just do it once and then expect it to be a permanent change if you don't follow up and ensure that it's still working.

DR. BEG: One of the other things which came up when we were looking at our numbers was to figure out how to staff different positions. And there are some steps of the activation process that are very nuanced, really require special expertise. And an example for that is the coverage analysis evaluation, where a third party independent of the investigator's team decides whether every procedure or blood test or scan gets billed to insurance or is that something that gets billed to the study. So is it a research procedure or is it a standard of care procedure? And in oncology, where philosophically we view research as embedded within standard of care, that can be a pretty tricky determination to make.

So the people who do this come in with a really unique set of expertise from their clinical-- that have clinical expertise and research expertise. And one of the things we noticed was for positions like those and for positions other than that, it's really important to have redundancies in those positions, so if there is staff turnover of any kind, that that process can keep moving forward. Because those are steps that-- it's hard for a consultant to come in and fill in and those people don't really just hang out on campus for us to be able to tap their time and to start processing those studies.

So other than looking at our processes, it did come down to staffing those positions and making sure that we create some redundancies in those positions so that we're not completely dependent on, for example, one person for a task like that.

DR. PENNELL: And that is such an obvious issue that I think maybe a lot of people may be shocked to hear that institution's administrations don't always agree that you need more than one person to do a task. But again, this is really resonating with me personally, because we went through this same issue. And there are so many important things that for some reason there's always just one person who can do it. And if they're out for whatever reason, or they leave and there's staff turnover, things just grind completely to a halt. And so I think that that's a wonderful illustration that hopefully will be convincing.

Did all of this work end up making a difference in your time to opening trials?

MS. WILLIAMS: It is making a difference. We are seeing improvements in certain steps of the process. We've definitely seen an improvement in our time to both scientific committee review approval, our time to IRB approval. Our coverage analysis timeline has been very steady. Our time to activation for our national cooperative group studies has been very stable at around 90 to 100 days, since instituting just kind of these simple-- well, not so simple-- but since instituting this whole process.

Where we still have challenges is in our budgeting and contracting process. However, again, since we've got that institutional buy-in, it was actually our sponsored programs administration office contract director who approached me about two or three months ago and said, you know what, we really need to talk about the workflows between covered analysis, budget negotiation, and contract, because I see things kind of being an issue for us, as far as getting expedited approval and execution of contracts.

So we had another about 2 and 1/2 hour meeting just about a month ago to sit down and go through that workflow and identified, again, a couple of key places where we can bring previously sequential steps into a parallel-step process.

And so once again, I think the take-home of the exercise that we performed is that we have institutional stakeholders who aren't necessarily just waiting to hear from us to figure out how we can do better, but are coming to us and identifying timelines and being able to work together to continue to make those happen.

DR. PENNELL: And it sounds like this has worked very well for your institution. But you point out in your manuscript that a lot of the processes are so unique to individual institutions that it's hard to make blanket recommendations that apply everywhere. So what can other sites who are also worried about their time to activation take from your process?

DR. BEG: I think one message is to know what your internal process is. And I think a lot of folks who are listening to this podcast will admit that at their centers there's no one document that really maps out the entire process. So for us, the process of mapping out the trial activation process was probably the most transformative bit, the rest sort of just fell into place.

DR. PENNELL: Shaalan and Erin, thank you so much for joining me on the podcast today.

DR. BEG: Thank you very much.

MS. WILLIAMS: Thank you.

DR. PENNELL: Until next time, thank you for listening to this Journal of Oncology Practice podcast. If you enjoyed what you heard today, don't forget to give us a rating or a review on Apple Podcasts or wherever you listen. While you're there, be sure to subscribe so you never miss an episode.

JOP's podcasts are just one of ASCO's many podcasts programs. You can find all recordings at podcast.asco.org.

The full text of this paper will be available online at ascopubs.org/journal/jop in November 2019.

This is Dr. Nate Pennell for the Journal of Oncology Practice signing off.

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Improving the Time to Activation of New Clinical Trials at a National Cancer Institute–Designated Comprehensive Cancer Center