Feb 5, 2020
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
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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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