60 - Season 4 Recap & Bridging to Later Phases (S4E15)

All right, so diving in again today and, you
know, whenever we hear about a new drug hitting
the market, it feels like this big moment, right?
But the truth is that announcement, that approval
is just the tip of the iceberg. Yeah, I mean,
it's a journey, a really long and complicated
one, bringing a new medicine to patients. It's
a whole process, tons of stages. And at every
single step, there are crucial choices to make,
paths to choose. And it's risky, right? not every
promising idea actually pans out. It's true.
And that's why we're here today for this deep
dive. We're going to zoom in on a really critical
turning point in drug development that shift
from early stage human trials, phase one and
two, to the much bigger, really decisive phase
three studies. That's where the rubber meets
the road. Exactly, and I think what makes this
transition so fascinating is that it's all about
taking those first glimpses of a drug's potential,
the hints we get from those early trials, and
using that information to build the foundation
for these much larger, more complex studies.
It's about taking a calculated leap forward.
We've got so much to unpack, right? I mean, our
sources cover everything from those initial discoveries
in the lab to those first tests in animals, to
the nitty gritty of how clinical trials are designed,
how drugs behave once they're in the human body,
to the role of the big regulatory players like
the FDA and ICH. It's a lot. Yeah, there's a
ton of information to sift through, but our goal
today is Really straightforward. What did we
learn from phase one and two? What are the big
takeaways about a drug's safety and whether it
even has a shot at working? And crucially, how
do these early findings shape the way we design
those pivotal phase three trials? Because in
the end, it all comes down to one thing, making
sure that if and when a new medicine gets approved,
it's both safe and effective for the people who
need it. All right, so let's break it down. Phase
I and phase II, what are the absolute must -knows
coming out of these early trials? Let's start
with safety. In phase I, safety is the top priority,
right? Oh, yeah, absolutely. And before we even
think about giving a drug to a human, there's
a huge amount of work that happens in the lab,
and then in animals. Preclinical toxicology studies,
they're crucial, like a first line of defense.
We're looking for any red flags, any signs that
the drug might be harmful. And some of our sources,
like preclinical toxicology evaluation, really
emphasize this point. If a drug shows major adverse
effects in animals, that's a serious warning.
We have to proceed with extreme caution before
even considering testing it in humans. It's like
our initial risk assessment, trying to anticipate
potential problems before they arise. And these
animal studies also help us figure out a safe
starting dose for those first human trials, right?
Kind of like finding a safe entry point. Yeah,
exactly. Researchers will do what are called
dose finding studies in animals, testing a whole
range of doses to try and pinpoint that sweet
spot, a dose that's likely to be tolerated by
humans while still having the potential to be
effective. It ties directly into the concept
of the dose toxicity curve, which we see pop
up in clinical trial design. Then, in phase I
trials, the main goal is to figure out the safety
profile of the drug. In humans, we're looking
for that maximum tolerated dose, the MTD. This
usually happens in a small group of healthy volunteers,
although sometimes it's done in patients, depending
on the drug and the disease. And we saw it in
preclinical toxicology evaluation. that if unexpected
toxicities do show up, even in those early animal
studies, it can throw a real wrench in the works.
It can mean needing more resources, delaying
the whole development process, sometimes even
bringing things to a complete halt. It's true.
Unexpected toxicity can be a major setback. It
can lead to higher development costs, sometimes
even the termination of a promising drugs development.
It's a tough reality of the process. Absolutely.
So we've talked about the importance of safety
assessments, but another crucial piece of the
puzzle is understanding how a drug behaves once
it's inside the body. That's where we get into
pharmacokinetics, or PK. and pharmacodynamics
or PD, right? It's kind of like mapping out the
drug's journey through the system. Yeah, you
got it. Pharmacokinetics is basically studying
what the body does to the drug. It's about how
the drug gets absorbed into the bloodstream,
how it spreads throughout the body, how it's
broken down, and eventually how it's eliminated.
And we have this handy acronym, ADME, absorption,
distribution, metabolism, and excretion. And
multiple sources hammer home the point that understanding
these ADME processes is absolutely fundamental.
Think about it. A drug that's poorly absorbed,
we say it has low bioavailability, might seem
ineffective in later trials simply because it's
not reaching its target in the body at high enough
concentrations. So we could actually miss out
on a potentially valuable drug just because we
don't fully understand how it's moving through
the body. Exactly. It's a real risk. And that's
why those PK studies are so crucial. They help
us figure out things like how long a drug stays
active in the body and how often it needs to
be given what we call the dosing regimen. Right,
the dosing regimen. And bioavailability, that's
a key part of absorption, right? It's about how
much of the drug actually makes it into the bloodstream
and factors like how well the drug dissolves
its solubility and how easily it can cross -sell
membranes, its permeability. Those are super
important here. We've seen this discussed quite
a bit in our sources. Totally. For drugs that
are taken orally, bioavailability is especially
crucial. You could have a drug that works amazingly
in the lab, but if it's not absorbed well in
the gut, it's not going to be very useful clinically.
And that's where concepts like the rule of five
come in. Medicinal chemists use these rules to
try and design molecules that are more likely
to be absorbed well. And then there's the whole
issue of how a new drug might interact with other
medications a patient is already taking. we call
these drug interactions, or DDIs. Understanding
how a drug is metabolized, broken down by the
body, is essential for predicting and avoiding
these potential interactions. Absolutely. That's
a huge safety concern. We often focus on the
liver. Specifically, these enzymes called cytochrome
P450 enzymes because they play a big role in
drug metabolism. If we know how a new drug is
metabolized, we can start to predict how it might
interact with other drugs that are processed
by the same enzymes. Now, it's worth mentioning
that for biologics, these protein -based drugs,
we don't usually worry as much about these P450
interactions because biologics tend to be broken
down in different ways. Right. So, different
types of drugs, different considerations. Okay.
So, we've covered what the body does to the drug
that's PK. Now, what about pharmacodynamics,
PD? That's all about what the drug does to the
body, right? It's about its mechanism of action,
how it actually produces its effects. Exactly.
Pharmacodynamic is all about the drug's target
in the body. How does that interaction lead to
a biological response, hopefully a therapeutic
one? Having a clear understanding of the pharmacodynamics
is crucial for designing effective clinical trials
and interpreting the results. For example, knowing
that the drug Trasuzumab, which is also known
as Herceptin, targets a specific protein called
HER2 in certain breast cancers, really helped
researchers design trials to evaluate its effectiveness.
It all ties back to that target, to understanding
the mechanism at play. All right, so Phase I
gives us that vital safety data and those initial
PK insights. Then Phase II starts to give us
some early clues about whether the drug might
actually work in patients and the people who
actually have the condition we're targeting.
That's right. Phase II trials are designed to
look at preliminary efficacy in a specific patient
population, people with the disease the drug
is meant to treat. And researchers often look
at things like the objective response rate, which
tells us what percentage of patients showed a
positive response to the treatment. But we have
to be cautious here. Even if we see some promising
signals, we have to remember that these phase
two trials are smaller. That means there's a
higher risk of getting misleading results, both
false positives and false negatives. So even
those encouraging early signs, they need to be
interpreted carefully. And then we come to the
big shift, the transition to phase three. And
all the knowledge we've gained from those earlier
trials, the safety profile, the PKPD characteristics,
those early hints of efficacy, all of that becomes
the foundation for designing phase three trials.
It's like taking the blueprints from the first
drafts and using them to construct the actual
building. I like that analogy. It's a perfect
way to describe it. The data we collect in Phase
I and II informs almost every aspect of Phase
III trial design. For instance, the safety profile
we've built up helps us decide who can participate
in the Phase III study, who might be excluded
because of potential risks, and what specific
safety measures we need to monitor closely throughout
the trial. And the PKPD data. Well, that's essential
for figuring out the best dose or doses to test.
And the best way to administer the drug in those
larger Phase 3 trials, we're trying to find the
treatment regimen that has the highest chance
of working safely and effectively. Exactly. We
want to strike that balance between safety and
efficacy based on what we've learned in the earlier
phases. And then there's the preliminary efficacy
data from phase two. That data helps us define
the primary and secondary endpoints for phase
three. These are the specific things we'll be
measuring to determine definitively if the drug
provides a real clinically meaningful benefit
to patients. So we're taking those initial clues
and turning them into concrete measurable outcomes
that we can track in those larger trials. but
it feels like. Moving to phase three also introduces
a whole new level of complexity, right? I mean,
it's a much bigger undertaking, isn't it? Oh,
absolutely. Phase three trials are significantly
larger, often involving thousands of patients
across multiple locations, sometimes even different
countries. And with that increase in scale comes
the need for really clear, well -defined eligibility
criteria. We have to be very specific about who
can participate in the study to make sure we're
studying the right group of people, people who
are most likely to benefit from the drug and
who are least likely to experience adverse effects.
So we're really trying to refine the study population
to make sure we're focusing on the patients who
are most likely to respond to the treatment.
And the study design itself has to be incredibly
rigorous. It's about minimizing bias, making
sure that any effect we observe is truly due
to the drug and not some other factor. That's
where things like randomization and blinding
come into play, right? You got it. Randomization
is all about making sure that the groups in our
study, the group getting the new drug and the
group getting the standard treatment or a placebo
are as similar as possible at the start of the
trial. And blinding? Well, that's about preventing
both the patients and the researchers from knowing
who's getting which treatment. That helps reduce
the potential for bias and how the results are
reported and interpreted. It's all about maintaining
objectivity. So we're taking those extra steps
to make sure the data is as reliable as possible.
And it seems like, by the time a drug reaches
phase 3, the stakes are even higher, the expectations
from regulatory agencies like the FDA are even
more stringent. They're looking for rock -solid
evidence of both safety and efficacy before they'll
even consider approving a new drug. It's true.
Phase three trials are really the make or break
moment. They're pivotal for getting regulatory
approval. The data we collect in phase three
has to be robust, statistically significant,
and it has to clearly demonstrate that the drug's
benefits outweigh its risks for the intended
patient population. And this whole process, the
way these trials are designed, conducted, everything
is heavily influenced by the guidelines set by
the FDA and ICH. There are specific regulations
that dictate how these trials should be run to
ensure the safety and well -being of the participants.
So it's not just about the science, it's also
about ethical considerations, about patient protection.
And speaking of guidelines, ICHM -3, for example,
that gives us guidance on when we need to do
those non -clinical safety studies in animals
to support clinical trials. It's all part of
building a strong foundation for those human
studies. All right, so we're building this comprehensive
body of evidence and eventually all of this data
is submitted to the regulatory authorities for
review. Can we look at a real -world example
to see how this progression from phase one to
phase 3 actually plays out. Yeah, the development
of Trastuzumab or Herceptin is a really good
example. The early phase 2 study showed some
really promising activity in women with a particular
type of metastatic breast cancer, HER2 -positive
breast cancer, and that early evidence, that
signal of efficacy, was strong enough to justify
moving into those larger, more definitive phase
3 trials. And in those phase 3 trials, the drug
really proved itself. It showed a clear benefit
for those patients, which led to its initial
approval. But what's even more interesting is
that the story didn't end there. Subsequent Phase
3 trials explored Trastuzumab in earlier stages
of breast cancer and in combination with other
therapies, which ultimately expanded its use
and helped even more patients. So those initial
Phase 2 trials, they were like a springboard.
They provided the justification for the investment
and the effort needed for those larger phase
three trials, and ultimately that investment
paid off, benefiting a whole lot of patients.
Exactly. And this idea of using early data to
inform later stage development decisions is seen
even earlier in the process. For example, the
decision to move a compound like Compound 27,
also known as RO 0505082, into clinical trials
was based on a careful analysis of preclinical
data looking at its potency in the lab and an
animal model. models, its PK properties, and
any initial signs of toxicity. That whole package
of preclinical data helped researchers decide
whether it was worth taking the risk and moving
into those first -in -human phase I studies.
It's a step -by -step process, each stage building
upon the last, using the information we gain
to make informed decisions about how to move
forward. Of course, this whole journey takes
place within a very clearly defined regulatory
landscape, right? Oh yeah, absolutely. The FDA,
for example, has specific regulations in place,
like 21 CFR Part 312, which governs what are
called investigational new drug applications,
or INDs. And then there are international guidelines
from ICH, like those related to good clinical
practice, GCP, which set the standards for ethical
conduct in clinical trials and ensure the quality
and reliability of the data we collect. These
regulations and guidelines, they aren't just
arbitrary hurdles. They're there to protect patients
and to make sure that only safe and effective
drugs make it to market. Right, they're there
for a reason. And those OECD GLP guidelines,
those are the good laboratory practice guidelines.
and along with those ICH guidelines, they really
help ensure that those preclinical toxicology
studies are up to par, that they... meet the
standards needed to justify starting clinical
trials in humans. It's all about building a solid
foundation for those human studies. So we've
covered a lot of ground today, really highlighted
the crucial role of those early phase clinical
trials, phase one and two. It's clear that the
knowledge we gain in those early stages about
a drug safety profile, how it interacts with
the body, whether it even shows initial signs
of efficacy, all of that is absolutely essential
for designing and running successful phase three
trials. Couldn't have said it better myself.
Phase I and II, they're like the reconnaissance
missions. They give us the information we need
to make smart choices about which drug candidates
to pursue and how to study them in those later
stage trials. Without a thorough understanding
of the drug's behavior in those early phases,
our chances of success in Phase III would be
a lot slimmer. It's like trying to navigate uncharted
territory without a map. You might stumble upon
something interesting, but you're much more likely
to get lost along the way. And this whole process,
this multi -phase journey, all guided by a well
-defined regulatory framework, it's ultimately
about getting safe and effective therapies to
the people who need them. That's the end goal.
And it really speaks to the scientific rigor
and the commitment to patient well -being that
drives drug development. It's a complex process,
but it's a process with a purpose. So as we wrap
up, I want you to think about something. At the
beginning of this journey, there's so much uncertainty,
so much risk. How do those uncertainties get
addressed as we move through those later phases,
especially in those large scale phase three trials?
What does that tell us about the likelihood of
a drug actually making it from the lab bench
to the pharmacy shelf? It's something to ponder,
something to really dig into. And if you want
to learn more, I definitely encourage you to
check out those FDA and ICH guidelines. They're
publicly available. and they provide a fascinating
glimpse into the rules and regulations that govern
clinical trials. Thanks for joining us for this
deep dive. It's been a pleasure exploring this
with you. Likewise. Always a good time to dig
into the complexities of drug development. Absolutely.
Until next time.