7- Clinical Trial Phases Overview (S1E7)

All right, let's dive into clinical trials. Everyone's
heard of them. But how many of us really know
how they work? Like what goes on behind the scenes
to get a new drug from the lab to, well, to our
medicine cabinet? Yeah, it can seem kind of like
a black box. Right. So that's exactly what we're
going to unpack today. We'll be talking about
phase one, two, and three clinical trials and
how they make sure that new medications are safe
and that they actually work. It's really a journey
with, you know, with a series of very carefully
planned steps. Each one has a very specific purpose.
I like that, a journey. So where does this journey
begin? It starts with phase one trials, also
known as first in human studies. First in human.
That sounds pretty intense. I mean, are these
like brave volunteers or what? Well, they are
kind of pioneers, you could say. A small group
of volunteers, they're usually healthy individuals,
and they're the first people to actually receive
the drug. Wow. So what are researchers looking
for at this stage? Safety. Safety is the primary
focus of phase one. We want to understand how
the drug is tolerated, what kinds of side effects
it might have, and how it moves through the body.
How it's absorbed, distributed, metabolized,
and excreted. All that good stuff. Oh, right.
ADME, right. Absorption, distribution, metabolism,
excretion. Exactly. That's what ADME stands for.
Yep. And understanding that process, the ADME
is absolutely essential for figuring out the
right dose and also for predicting potential
interactions, you know, if someone's taking other
medications at the same time. So phase one is
like a like a first test, right? To make sure
it's safe to move on to bigger trials. Exactly.
We're gathering crucial data on safety before
we can proceed. OK, so let's say the drug passes
this first safety check. What happens next? Then
we move on to phase two. And here the focus shifts.
Now we're looking at efficacy. In other words,
does the drug actually work? Does it do what
it's supposed to do? Right. So now it's not just
about safety, but about whether it actually has
benefits. Yeah. Exactly. And in phase two, the
group of people in the study gets bigger. We
start including patients who actually have the
condition the drug is intended to treat. And
researchers, they carefully evaluate whether
the drug is really having the desired effect.
I'm guessing dosage is a key factor in this phase
two, right? Like, are we giving the right amount?
Absolutely. Phase two is really about refining
the dosage. It's about finding that sweet spot
where the drug is effective, but we're keeping
the side effects as minimal as possible. It sounds
like a real balancing act. So now let's say a
drug makes it through both phase one and phase
two. It's safe and it's effective. What happens
in phase three? Phase three, that's where things
get really serious. We're talking much larger
trials now, hundreds or even thousands of patients.
Wow. So it's like the big leagues now. You could
say that. Phase three, they're designed to confirm
everything we've learned so far about safety,
efficacy, and that optimal dosage we were talking
about. We're also looking at long -term effects.
And how does this drug compare to existing treatments?
OK, so this is like the ultimate test, right?
Before a drug can even be considered for approval.
which uh speaking of approval where does the
fda fit into all of this i mean they're the ones
who give the final Thumbs up or thumbs down,
right? Absolutely. The FDA is involved throughout
the entire process. Oh, so it's not just at the
very end? Nope, not at all. The FDA, they set
all the rules and guidelines for doing clinical
trials in the first place, and then they very
carefully monitor every single step to protect
the people who are volunteering for the trial.
Right, to make sure everything is being done
ethically and all of that. Exactly, and to ensure
that... to ensure that the data that comes out
of these trials is reliable, you know? Makes
sense. Yeah. So they're like the referees, making
sure everyone's playing by the rules. Right.
I like that analogy. Yeah, that's a good way
to put it. Now, what about clinical trials that
happen outside the United States? Yeah, I was
wondering about that. I mean, are there, like,
international standards? There are. And that's
where the ICH guidelines come in. That's the
International Council for Harmonization. OK,
so what do those guidelines do? They basically
set a common standard for how clinical trials
should be conducted. This ensures that the quality
of the data is consistent, regardless of where
in the world the trial is taking place. That
makes a lot of sense. It's kind of like a level
playing field. Exactly. And it means that researchers
from different countries can collaborate and
share data more easily. OK, that makes a lot
of sense. So we've got the FDA keeping an eye
on things in the US, and the ICH providing these
international guidelines. Right. It sounds like
a very, very carefully controlled process. It
is. Ethical considerations are always paramount.
Researchers have a big responsibility to protect
the people who volunteer for these trials. And
part of that is making sure that people are fully
informed, right? They know what they're getting
into before they agree to participate. Exactly.
Informed consent is absolutely essential. Potential
participants need to understand the risks, they
need to understand the benefits, the procedures
involved, and their rights as volunteers. It's
critical. Right, so they can make an informed
decision about, you know, whether they want to
participate. Precisely. And they always have
the right to withdraw from a trial at any time
and for any reason. Okay, good. Good to know.
So it sounds like there are a lot of safety measures
in place. There are, and these measures, you
know, they've evolved over time. We've learned
a lot from past experiences and are constantly
trying to make clinical research as safe and
as ethical as possible. So it's an ongoing process.
Wow, I'm really starting to appreciate the complexity
of this whole system. It is complex, but it's
also a testament to, you know, the dedication
of the researchers, the clinicians, the regulators,
and, of course, the volunteers who participate
in these trials. Right. The volunteers are the
real heroes in a lot of ways. Absolutely. And,
you know, it's interesting. People volunteer
for clinical trials for all sorts of reasons.
Yeah. What motivates people to do that? I mean,
it can be a pretty big commitment. It can be.
Some people, they really want to contribute to
scientific advancement. They want to help others.
Some are hoping to access, you know, cutting
edge treatments that aren't available yet to
the general public. Right, right. And for some,
it might be a little of both, I imagine. Absolutely.
But the important thing is that it's a personal
decision. There's no right or wrong answer. You're
right. You're right. It's a very personal decision.
Well, I have to say, I'm already learning so
much from this deep dive. Me too. We've only
just scratched the surface though. I know. I
can't wait to dig deeper. But before we do, something
just occurred to me. We've been talking about
clinical trials as if, you know, every drug kind
of starts from scratch. But is there a whole
lot of research that happens before a drug even
reaches human trials? You're absolutely right.
Before we even get close to testing a drug on
a human, it goes through a ton of testing in
the lab, often in animals as well. We call this
pre -clinical research. So what's happening during
that phase? What are researchers looking for?
Basically, it's about gathering as much information
as we can about the drug's potential safety and
effectiveness. We have to do all that before
we can even think about moving to human trials.
So it's like a dress rehearsal? That's a good
way to put it, yeah. In this phase, we're studying
the drug's mechanism of action, how it affects
cells and tissues, how toxic it might be, and
yes, that ADME process again. Right, the ADME,
how the drug moves through the body. Sounds like
that's super important at every stage of development.
It is, and preclinical research really helps
us decide whether a drug is even worth testing
in humans in the first place. Yeah, I can see
why. It would be irresponsible to just jump into
human testing without really understanding the
potential risks and benefits. Absolutely. And
even with all that preclinical research, there
are still things we don't know. That's why clinical
trials have so many layers of safety measures.
Right. To protect the participants. So it's a
very cautious process, right? Every phase builds
on the one before it. Exactly. And safety and
efficacy are always, always the top priorities.
OK. I think we've laid some good groundwork here.
We're starting to understand the overall structure
and the purpose of clinical trials. We are we've
talked about the different phases From those
first volunteers in phase one all the way to
those huge phase three trials. Yep, and We've
touched on the role of the FDA and the ICH those
regulatory agencies that make sure everything
is done, right? Right. Those are key players
for sure. But you know, I'm sensing that There's
another layer of complexity here. There is. We've
zoomed out to get the big picture, but now I
think it's time to zoom back in and look at some
of the finer details. And one of the most fascinating
things is that we've been talking about this
whole process as if all clinical trials are basically
the same. But that's not really true. There are
all kinds of different types of trials, each
with their own specific purpose and their own
design. OK, now you've got me really curious.
Yeah. Tell me more about these different types
of trials. What are some of the main differences?
Well, for starters, there are interventional
trials and there are observational trials. Interventional
versus observational. What's the difference?
OK, so in interventional trials, think of those
phase one, two, and three trials we were talking
about. Researchers are actually intervening.
They're giving participants a specific treatment
and then observing what happens. So they're actually
doing something like manipulating a variable
to see what the effect is. Exactly. But in observational
trials, it's different. Researchers are just
observing. They're not intervening at all. They
might be following a group of people over time
to see who develops a certain disease or how
something like lifestyle choices affect health
outcomes. Oh, so it's like watching a natural
experiment unfold. That makes sense. It seems
like those observational trials would be really
useful for things that you just couldn't manipulate
ethically, you know. or practically. You got
it. Like, it wouldn't be ethical to deliberately
expose someone to a harmful substance in a trial,
but you could study a group of people who are
already exposed to it, maybe because of where
they live or work, and compare their health to
people who aren't exposed. Right, right. Okay,
that makes perfect sense. Now, are there different
types of interventional trials too, besides those
phase one, two, and three trials? Absolutely.
We've mostly been talking about trials that...
test new drugs, but there are also trials for
testing new medical devices, new surgical procedures,
even new types of behavioral therapies. Wow,
so it's a lot bigger than just drug development.
Oh, yeah. It's huge. There are trials going on
for, well, for just about every area of health
care you can imagine, like new ways to diagnose
and treat cancer or figuring out which types
of psychotherapy work best. Wow. So many different
research questions. Now you mentioned that trial
design can vary. What are some of the things
that researchers think about when they're designing
a trial? One of the most important things is
randomization. Randomization. That's just like
assigning people to different groups randomly,
right? Like flipping a coin. Well, it is a bit
more complicated than that. Randomization is
really about making sure that everyone in the
trial has an equal chance of ending up in any
of the study groups, whether it's the group that
gets the new treatment or the group that gets
the placebo or the standard treatment. OK, so
it's about making sure the groups are as similar
as possible, except for the treatment they're
getting. Exactly. That way, if we see a difference
in the outcomes between the groups, we can be
pretty confident that it's because of the treatment
and not some other random factor. Right. Right.
It makes sense. Yeah. OK. And what about blinding?
I've heard that term a lot in connection with
clinical trials. What does that mean? Blinding
is another really important technique to make
sure the results are as accurate as possible.
In a single blind trial, the participants don't
know which treatment they're getting. And in
a double blind trial, neither the participants
nor the researchers know who's getting what.
Wait, so even the researchers don't know? Nope.
At least not until after the data has been collected
and analyzed. Wow. I can see why that would be
important. Like if you knew which patients were
getting the new treatment, you might maybe unconsciously
treat them differently or interpret their results
differently. Exactly. Blinding helps make sure
that the data is as objective as possible. It
takes away that potential for bias. Wow. It's
amazing to think about all the thought and care
that goes into designing a really good clinical
trial. It is. And all these elements, randomization,
blinding, and many others, they're essential
for making sure that the data we get is really
reliable. OK. So we've got all these different
types of trials. And we've got researchers using
all these smart design strategies to make sure
that the results are as accurate as possible.
Yeah. But in the end, it all comes down to the
data, right? Absolutely. The data is everything.
It's the foundation of our understanding of new
treatments and how we make decisions about health
care. So how do researchers analyze all that
data? I imagine it can be pretty overwhelming.
It can be massive, yes. And statistical analysis
is critical for making sense of it all. Okay,
I'll be honest. Statistics is not my forte. Can
you give me, like, a simple explanation of how
it's used in this context? Sure. Basically, statistical
analysis helps us figure out whether any differences
we see between the treatment group and the control
group are real. Like, are they big enough that
it's unlikely they just happened by chance? So
it's not just about looking at the numbers. It's
about figuring out what those numbers really
mean. Like, how likely is it that those differences
are actually because of the treatment? Exactly.
Statistical analysis also helps us to estimate,
you know, how much of a difference the treatment
actually makes. So it's about quantifying the
impact, right? Right. Like, how much better did
people do on the new treatment compared to the
old one? Precisely. And those statistical findings,
along with all the safety data, that's what ultimately
determines whether a new treatment is effective
and safe enough to be approved for wider use.
OK, so everything circles back to those two big
goals, safety and efficacy. Exactly, they're
at the heart of everything we do in clinical
research. Well, I have to say, this deep dive
has really opened my eyes to just how complicated
and how rigorous drug development really is.
It's a long journey with all these steps and
careful planning, and it's all about safety and
effectiveness at every single step. It is, and
it might seem like a long and complicated road,
but it's all worth it in the end. Because it
leads to those advancements in health care, the
potential to improve people's lives. Absolutely.
Absolutely. So as we wrap up this first part
of our exploration of clinical trials, I'm wondering,
what's a thought -provoking question our listeners
can think about as they continue to explore this
topic? I think a good one is this, given how
expensive and complex grub development is, how
do we make sure that these new treatments are
actually available and affordable to everyone
who needs them? It's a big question and it needs
some really creative solutions. Yeah, that's
a really important question. Food for thought,
everyone. Thanks for joining us on this first
part of our deep dive into the world of clinical
trials. We'll be back soon with part two. You
know, it's interesting, we've been talking about
this whole process, you know, clinical trials
and all that, but we've been very US -centric,
haven't we? Oh, yeah, you're right. I didn't
even think about that. What about the rest of
the world? Does every country have its own FDA?
Not exactly. Many countries do have their own
regulatory agencies, but they often work together,
you know, to try to streamline things. They try
to harmonize their guidelines. OK, so... a drug
company wouldn't have to go through a completely
different process in every single country. That's
the goal, anyway. And that's where those ICH
guidelines we talked about earlier come in. They're
really important for international cooperation.
They make sure that the data from clinical trials
meets a consistent standard, no matter where
those trials are being done. That makes a lot
of sense. It would be a nightmare if every country
had totally different rules. It would. Harmonizing
the regulations, it really helps to speed up
the development of new treatments and make them
available globally. OK, so we've got this global
network of agencies working together. But what
about the companies that actually develop these
drugs? Where do they fit into all of this? Well,
pharmaceutical companies, they're the ones doing
the heady lifting, right? They're the ones discovering
and developing new drug candidates. They're funding
the research, running the trials. And ultimately,
if everything goes well, They're the ones bringing
the drug to market. So they're kind of like the
orchestra conductors, bringing all the different
pieces together. I like that analogy, yeah. They've
got to pull together a whole team. scientists,
clinicians, statisticians, regulatory experts,
so many different people. It's a big operation
to move a drug through that whole development
pipeline. I can imagine. It sounds like a huge
undertaking. I know you can't give financial
advice or anything. Yeah, right. But just out
of curiosity, from a purely informational standpoint,
what are some of the things that influence a
pharmaceutical company's decision to invest in
a particular drug? That's a good question. Lots
of factors go into it. But a really big one is
the unmet medical need. Is this drug targeting
a serious condition where there aren't a lot
of good treatments? Or maybe no effective treatments
at all? So they're looking to fill those gaps
in healthcare where new treatments are really
desperately needed. Exactly. They're also looking
at the scientific potential of the drug itself.
Does it work in a new way? Is it likely to be
more effective or have fewer side effects than
what's already out there? Right, right. I could
see how that would be a major factor. And of
course, market factors matter too. How many people
could potentially benefit from this drug? What's
the market size? Things like that. Yeah, it makes
sense that you'd have to think about that. It's
a business after all, but I guess it's not just
about profit. Right, right. It's more complicated
than that. It's a balance, you know, they're
trying to advance science They want to address
those unmet medical needs and they also have
to think about the business side of things It's
a balancing act for sure Speaking of advancing
science What are some of the areas of drug development
that you're most excited about right now? Like
what's really cutting edge? Oh, there's so much
exciting stuff happening personalized medicine
is one area that's really taking off that's all
about tailoring treatments to an individual's
unique genetic makeup. Wow, that's futuristic.
It is. We're seeing amazing progress in that
field. Gene therapy is another one that's really
exciting. Scientists are actually modifying genes
to treat or even prevent disease. It's incredible.
It sounds like we're living in a golden age of
medicine. I'm excited to see what the future
holds. OK, we've covered a lot of ground in this
episode. We have. We've explored all those different
phases of clinical trials. We talked about preclinical
research. Yeah. Even touched on the global regulatory
landscape and the role of pharmaceutical companies.
It's been a pretty thorough deep dive. It has.
But you know what? I still feel like there's
a piece of the puzzle missing. Well, what's really
fascinating is, well, what's really fascinating
is that even within those phases we were talking
about, you know, phase one, two and three, there's
still so much variation when it comes to trial
design. I mean, it's not like there's a single
blueprint that everyone follows. OK, so what
are some of the factors that go into designing
a trial? I mean, it seems like there would be
a lot to think about. There is, yeah. Researchers
have to think carefully about a lot of things.
What's the specific question they're trying to
answer? What are the characteristics of the patients
they're studying? What type of treatment are
they testing? And, you know, the ethical implications
of the research. That's a big one too. So it's
like each trial has to be kind of custom designed
to meet the specific goals of the research. Exactly.
It's like tailoring a suit. And there are a lot
of different types of trial designs out there,
each with its own strengths and weaknesses. OK,
so can you give me some examples? What are some
of the common designs? Sure. One of the most
common designs is called a randomized controlled
trial. We call it an RCT for short. This is kind
of the gold standard for figuring out whether
a new treatment really works. Oh, yeah. RCTs.
I've heard of those. Yeah. And that's where you
randomly assign people to different groups, right?
That's right. You usually have a treatment group.
They get the new intervention and then you have
a control group and they get either a placebo
or the standard treatment, whatever that is.
Right. So the control group is like the baseline.
It helps you see whether the new treatment is
actually doing anything or if people would have
gotten better anyway. Exactly. And by randomly
assigning people to the groups, it makes the
results a lot more reliable. It minimizes bias
because the groups should be pretty similar in
all other respects. Right. Right. That makes
sense. What are some other types of trial designs?
Well, we talked a little about observational
studies earlier. Remember those. They're not
interventional. Researchers are just observing,
watching what happens naturally. Right, like
that example you gave about studying people who
were exposed to a harmful substance in their
environment. Exactly. And then there are a bunch
of other types of interventional trials besides
those phase one, two, and three trials. For example,
you've got pilot studies. They're usually small
scale and they're kind of like a test run. We
gather some preliminary data before we launch
a bigger study. So kind of like dipping your
toe in the water before you jump in the pool.
Yeah, that's a good way to put it. And then you've
got pragmatic trials. They're designed to see
how a treatment works in the real world. They
often have more flexible criteria for who can
participate. And the monitoring isn't as strict
as in a traditional RCT. So it's more like, what
would happen if you actually prescribe this treatment
to patients in your clinic? Right. It gives you
a better sense of how the treatment might perform
in everyday life, where things aren't always
so perfectly controlled. Exactly, and there are
lots of other types of trial designs too, each
with its own purpose and methods. Wow, it's a
whole world of its own. No wonder people get
THDs in clinical trial design. It is a fascinating
field, that's for sure. Okay, so we've talked
about how important it is to design trials carefully,
you know, make sure everything is ethical and
all that, but ultimately it all boils down to
the data, right? What did you find? Did the treatment
work? Absolutely. The data are everything. It's
how we learn about new treatments and how we
make decisions about how to care for patients.
So how do researchers go about analyzing all
that data? I imagine it's a ton of information
to sift through. It can be huge, yeah. And statistics
are super important here. They're what help us
make sense of all that data. Full disclosure.
Statistics and I were not exactly best friends.
Can you break it down for me? Like, how do statistics
work in clinical trials? Sure. Basically, statistics
help us figure out if the differences we see
between, say, the treatment group and the control
group, if those differences are meaningful. Like,
is it unlikely that they just happen by chance?
So it's not just about the numbers themselves,
but about understanding the likelihood that those
numbers reflect a real effect. Exactly. And statistical
analysis also helps us to estimate the magnitude
of the effect, like how much of a difference
did the treatment actually make? Was it a big
difference or a small difference? OK, so it's
about quantifying the impact of the treatment.
Yes, precisely. And those statistical findings,
along with all the safety data, that's what we
use to decide whether a new treatment is effective
and safe enough to be approved and made available
to patients. Right. So it all comes back to those
two key things. Safety. and efficacy. Absolutely.
Those are the two guiding principles of all clinical
research. Well, this has been so insightful.
I feel like I have a much better understanding
now of how this whole process works from that
initial research in the lab all the way to a
drug being approved and available to patients.
Me too. It's a complicated journey, that's for
sure, but it's so important. Absolutely. So before
we wrap up, do you have a final thought provoking
question for our listeners? Something to keep
them thinking about clinical trials. How about
this? With all the amazing advances in technology
that we're seeing, how do you think clinical
trials are going to change in the future? What
new challenges and opportunities might we face?
Ooh, that's a good one. Lots to think about there.
Well, thanks for joining us on this deep dive
into the world of clinical trials. We've learned
so much. Until next time, everyone, stay curious.