53 - Biomarkers in Phase 2 Trials (S4E8)

All right, welcome everyone to the deep dive.
Today we're gonna be looking at phase two clinical
trials. Yes. Specifically, one of the tools that's
really crucial for figuring out if a drug is
working, and that is biomarkers. Huh? So we've
got a lot of interesting stuff to go over today.
We're going to be drawing from sources that cover
medicinal chemistry, AI and drug development,
pre -clinical studies, how clinical trials are
designed, and we'll even touch on some of the
regulations from the FDA and the ICH. Exactly.
And what we're really going to focus on is this
idea of how biomarkers function within phase
two trials. And I think the best way to think
about it is kind of like an early warning system.
Like, can we use biomarkers to understand if
a drug is hitting the target that it's supposed
to? And even more importantly, are those successes
in hitting that target, are those likely to translate
into real benefits for patients? Right, right.
So by the end of this, what we want to make clear
is just how important biomarkers are for making
phase two trials both informative and efficient.
So efficient. Yeah. OK, so let's just jump right
in. So when a drug is in phase two, how do biomarkers
help us actually see if it's doing what it's
supposed to be doing in the body? Well, at their
most fundamental level, biomarkers are measurable
indicators, right? OK. And this could be anything
from the level of a specific protein in the blood
to the genetic signature of a tumor or even a
change in blood pressure. What we're doing is
we're tracking these markers over the course
of the phase two trial to try and get a much
earlier read on whether the drug is having its
intended activity. And rather than just waiting
to see if the patient actually feels better,
we're trying to look under the hood. so to speak,
really get a window into the mechanism of action
of the drug and how it's interfacing with the
disease process. So it sounds like instead of
relying on whether a patient's symptoms improve
or not, which can sometimes take a while to see
and can be influenced by other factors. Sure,
absolutely. We can look at these more direct
indicators and see if the drug is doing what
we think it should be doing at a biological level.
Yeah, exactly. You know, one of the things our
sources reminded us is that historically in cancer
trials, a key measure of how effective a drug
was is whether or not the tumor shrinks during
phase two. Right. But nowadays, with so many
of these new targeted cancer therapies, we're
paying attention to other things like the rate
of stable disease, meaning is the tumor at least
not growing. OK. Biomarkers could potentially
give us an even earlier and more direct indication
of these effects. You know, sometimes before
we even see changes in tumor size or in the patient's
symptoms. Hmm. That's really interesting. Yeah.
It's kind of like, yeah, we get direct feedback
from the system itself rather than waiting for
the overall outcome. Exactly. Now phase two is
also about figuring out if the drug has a chance
of providing a real clinical benefit later on
in phase three. How do these early changes in
biomarkers help us predict that? Yeah, this is
where things get really interesting. One of the
core objectives of phase two is to really identify
those drugs that have a reasonable chance of
showing a meaningful clinical improvement when
we get to the larger phase three trials. Changes
that we observe in biomarkers during phase two
can serve as these really crucial early signals,
right? Yeah. So for instance, if we see a really
significant and consistent improvement in a biomarker
that we know is closely linked to how a disease
progresses, that strongly suggests that the drug
has the potential to actually alleviate symptoms
or slow down the disease's advancement over the
long term. And this ties into something that
we've talked about before, this idea of surrogate
endpoints. Yes. And how the FDA uses them in
its accelerated approval pathway. While Phase
2 itself doesn't lead to approvals, the data
we gather on these biomarkers can really strengthen
the argument for moving into Phase 3 with a clear
idea of what benefit we expect to see. Exactly.
And while the accelerated approval process hinges
on surrogate endpoints that are reasonably likely
to predict clinical benefit, I think we have
to remember that the foundational work of actually
identifying and validating those potential predictors
often starts all the way back in Phase 2. And
so... You know, the examples that we've talked
about, like using a reduction in viral load for
HIV drugs or using tumor response rates for certain
cancers, those are being used as surrogate markers
later on. But that information really comes from
this early biomarker data that shapes our understanding
throughout the entire drug development journey.
So we're using biomarkers to see if the drug
is hitting its target and also to see if that's
actually going to translate into benefits for
patients. But this raises a really important
question. How do we know if these biomarkers
are actually giving us reliable information?
Yeah. Which brings us to validation. You got
it. That's a really superb point because for
a biomarker to be truly useful in guiding decisions
and drug development, we need to have a lot of
confidence that we can measure it accurately
and consistently and that it actually genuinely
reflects the biological process or the drug response
that we think it does. This is where the whole
rigorous process of validation really comes into
play. So it's not enough to just notice a change
in something after we give it the drug. We need
to do more than that. Absolutely not. We need
to really thoroughly establish and document several
key aspects of the tests that we use to measure
these biomarkers. So first of all, we need to
make sure that the test is accurate, meaning
that it measures what it's supposed to be measuring.
OK. And then we need to look at the sensitivity
of the test. So that's its ability to detect
even small but potentially important changes.
Gotcha. Specificity is super important too and
that's making sure that the change we're seeing
is truly related to the biological process that
we're interested in and that it's not being influenced
by other factors. Okay. And then finally, we
need to make sure that the test results are reproducible,
meaning that we get consistent results if we
measure the same sample multiple times in different
labs or using different instruments. Right. You
know, these principles are actually very similar
to what we talked about with quality control
and pharmaceutical manufacturing, right? Yeah.
You know, it's absolutely fundamental to generating
trustworthy data. So a validated biomarker is
like a finely tuned instrument. that we can really
rely on to give us an accurate reading of what's
happening. Now, how do researchers actually take
this understanding of biomarkers and incorporate
it into the design of their phase two trials?
Yeah, well this is really where the strategic
power of biomarkers comes into play because they
can be integrated into the actual structure of
a phase two trial in a lot of different ways.
So for instance, biomarker data can be super
valuable in helping researchers determine what's
the optimal dose range for the drug. observing
how different doses impact a specific biomarker,
they can actually pinpoint the range that produces
the desired biological effect without causing
unacceptable side effects. Right. This is a much
more informed approach than just testing out
a few arbitrary doses and seeing what happens.
Right. It's like using the biomarker as a guide
to fine tune the drug's impact. Exactly. And
on top of that, biomarkers can also play a huge
role in patient selection. OK. You know, if we
can identify a biomarker profile that seems to
be predict a better response to the drug, we
can actually design the trial to enroll patients
that specifically have that profile. So it's
almost like personalizing the trial itself. Exactly.
And focusing on the patients that are most likely
to respond. Exactly. And then beyond dose selection
and patient selection, we can also incorporate
biomarkers into what are known as early stopping
rules. OK. So if the biomarker data that's collected
early in the trial shows us that the drug isn't
having the effect that we thought it would have,
or if it's if it indicates some kind of safety
concern based on changes in certain markers,
the trial can be halted early. And this saves
a ton of time and resources. And probably most
importantly, it protects patients from continuing
to receive a treatment that's unlikely to work
or that could potentially be harmful. That makes
a lot of sense. I also remember us talking about
adaptive trial designs. Yes. How do biomarkers
fit into that? Yeah, adaptive trial designs are
a really fascinating area. They basically allow
for pre -planned modifications to the trial protocol
based on data as the trial is going on. So this
could involve adjusting the dose that we're testing
in certain patients. It could mean changing the
number of people that are assigned to different
treatment arms. Or it could even mean selecting
specific subgroups of patients to focus on based
on the early results that we're seeing. And oftentimes,
these adaptations are being guided by the biomarker
data that we're collecting. This flexibility
that adaptive trial designs provide can make
phase two trials even more efficient and increase
the chances of us actually finding a really effective
treatment regimen and the right population of
patients for that treatment. So these all sound
like really powerful applications for biomarkers.
So I know that our sources for this deep dive
didn't really have case studies that focused
solely on phase two biomarker use. Sure. But
we can definitely draw some connections to some
of the other stuff we've read, right? Yeah, absolutely.
I mean, you know, we've consistently seen that
in oncology trials, even back in phase two, measuring
tumor size and markers of disease progression,
those are really important end points. And essentially
what they're doing is they're using changes in
these biological indicators as biomarkers to
assess whether or not the drug is doing anything.
You know, another interesting case is imatinib
or Gleevec. You know, that drug actually received
accelerated approval based on its effect on the
number of cancerous cells in the bone marrow.
That's a clear example of a surrogate biomarker.
Now, while the accelerated... approval was obviously
based on data from later stage trials. The strong
signal that the drug was working, you know, that
probably emerged much earlier, probably back
in phase two. You know, showing the potential
of the drug early on. The predictive power of
the biomarker. Yeah, exactly. You know, and we
can also think more broadly about other therapeutic
areas. So in heart failure, researchers are tracking
levels of proteins in the blood that are related
to cardiac function. Or in vaccine development,
phase two studies often involve measuring the
levels of antibodies that are produced after
someone receives a vaccine, which serve as key
biomarkers for whether or not the vaccine is
doing what it's supposed to be doing. So even
without specific case studies, we can definitely
see these underlying principles at play. Now,
to wrap things up, let's touch on the regulatory
side of things. What's the FDA and ICH's stance
on biomarkers in phase two? So regulatory agencies
like the FDA and the ICH, they really emphasize
the importance of well -defined and validated
biomarkers throughout drug development. And phase
two is no exception. Now, our sources didn't
have specific guidelines about biomarker use
in phase two, but the fundamental principles
of scientific rigor, data integrity, and demonstrating
a drug's effect, all of that is central to their
regulations. So when the FDA issues guidance
on drug metabolism or drug interaction, actions,
the data that they're looking for to really understand
how a drug works in the body can be informed
by changes in these biomarkers in phase two.
Exactly. You know, really understanding how a
drug is processed by the body, its metabolic
pathways, its potential to interact with other
medications, all of that relies on having really
reliable data, and biomarkers often provide the
most direct way to get that information. Similarly,
the ICH's E6 guideline on good clinical practice,
which basically sets the international standard
for how we conduct clinical trials, applies to
every single part of a trial, including the collection
and analysis of... marker data. Regulatory bodies
expect that these measurements are conducted
with the same level of rigor and quality control
as any other part of a clinical trial. So even
though we don't have specific guidelines for
phase two biomarkers, the general expectations
for good science and reliable data apply to biomarkers.
Absolutely. You know, the regulatory framework
really just underscores a need for solid evidence
that demonstrates the drug's activity and its
potential to actually provide a benefit. Right.
And well -chosen and validated biomarkers in
phase two are one of the best tools that we have
for building that evidence. Okay, so it sounds
like biomarkers really are the unsung heroes
of phase two trials. They provide this early
insight into whether a drug is working, they
give us clues about its potential to help patients
in the future, and they let us design more efficient
clinical trials. Couldn't have said it better
myself. And all of this relies on good validation.
and understanding the regulatory landscape. Exactly.
So this has been a really insightful deep dive
into the world of biomarkers in phase two. It
really highlights how much planning and measurement
goes into understanding a new medicine even before
it gets to phase three. For sure. Now, as technology
is advancing so fast and our understanding of
biology keeps getting better and better, it makes
you wonder how the types of biomarkers we use
and the way we use them in phase two trials,
how that's all going to change. I mean, could
we see even more sophisticated markers or even
totally new ways of tracking a drug's effects?
It's a fascinating question. And ultimately,
this could lead to faster development of new
therapies. Exactly. That's a really interesting
thought. Yeah. So thanks for joining me for this
deep dive. Thanks for having me.