61 - Phase 3 - Large-Scale Efficacy Trials Overview (S5E1)

So you've sent us some really fascinating stuff
about how new drugs actually get developed and
make their way to patients. And you seem particularly
interested in phase three clinical trials. Oh,
yes. So let's jump right in. When we talk about
these huge phase three trials, what are we really
trying to figure out? And why are they so crucial
in this whole process of drug development? Yeah,
that's a great place to start. All the stuff
that you sent paints a really clear picture,
I think, of just how long and complicated this
whole journey is. And phase three is definitely,
you can't get around it. It's like a make or
break moment for these drug candidates that have
shown some promise. What we really want to do
in this deep dive is break down the core parts
of what phase three is all about. And there are
three big things. One, showing that the drug
really does work in a much bigger group of people.
Two, understanding how it works in all sorts
of different patients, not just one specific
type. And three, we need to look at the safety
of the drug over a longer period of time. If
you really wanna grasp how much evidence is needed
before a new treatment can actually be given
to patients, you gotta understand these three
things. Okay, so let's dive into that first one
you mentioned, large -scale efficacy. What does
that actually mean in the context of a phase
three trial? And how does it build on what we've
already learned in those earlier phases? So you've
got your phase one where it's all about safety
first and foremost. Then you move to phase two
where you're starting to get those early hints
about whether the drug might actually work. But
phase three is where things get really serious.
We're talking way more participants. The main
goal is no longer just hints. we need to know
for sure does this drug really work when you
give it to a wider range of people. Phase two
might give you a glimmer of hope, but phase three
has to provide the proof. It's gotta show how
well the drug performs in a setting that's as
close as possible to how it'll actually be used
in the real world. So it sounds like if the early
phases... are kind of like laying the foundation
and making sure you've got something solid to
build on phase three is when you find out if
the building can withstand a hurricane. Exactly.
That's a great way to put it. This is the trial
that everyone is watching. the researchers, the
regulators, even the doctors and patients who
might one day use this drug, everyone needs to
be convinced that this treatment is the real
deal. So you're putting it to the ultimate test.
Exactly. And a huge part of that is making sure
the people in the trial are a good representation
of the real world. Right, the diverse patient
population idea. Why is that so important in
phase three? Yeah, you sent some stuff about
that. Well, it seems pretty obvious to me you
want to know if a drug is going to work for more
than just a small group of people. Right if your
trial only includes say men of a certain age
and ethnicity How can you be sure it'll be effective
or even safe for women or for people from different
backgrounds? That's exactly it when you include
a wide range of people in your phase three trial
You're considering all sorts of things like their
age their sex their ethnicity even any other
health conditions. They might have this is absolutely
vital. It lets us see if the drug works the same
way across the board. Right, because there could
be differences. Absolutely. You might find that
the treatment works wonders for one group but
is less effective or causes different side effects
in another. If you don't have that diversity
in your trial, you could end up with a drug that
gets approved but doesn't work for everyone.
Or even worse, it's dangerous for some people.
Exactly. That's a real concern. Regulatory bodies
like the FDA are getting more and more strict
about this. They want to see trials that are
truly representative of the people who will be
using the drug. They need that assurance that
the evidence is solid. It reminds me of all the
talk about personalized medicine. I mean, we're
not quite there yet where every treatment is
tailored to your specific genes and all that,
but... This idea of having diverse phase three
trials seems like it's moving us in the right
direction. The more we understand how different
groups of people respond to a drug, the better
we can figure out who's likely to benefit the
most. Exactly. These trials give us so much valuable
information. We may not be able to predict how
each individual will react, but when you have
data from a diverse population, you can make
more informed decisions about treatment options
for different groups of patients. And that leads
to better care. It helps us refine our understanding
of who the drug is really for and where those
potential risks might be hiding. So it's not
just about efficacy. It's also about safety.
And that's another big focus of phase three trials.
Yeah. Right. especially long -term safety. Absolutely.
Phase 3 trials are usually much larger than the
earlier phases and people are on the drug for
a longer period of time. This gives us a much
clearer picture of its safety over the long haul.
You know those side effects that might not show
up right away? The ones that only emerge after
months or even years of taking the drug? Those
are the ones we're really looking for in these
extended studies. And that's important because...
It's crucial because once a drug is approved
people might be taking it for a very long time.
And we need to be absolutely sure that we understand
any potential long -term effects. Right. It's
not just about whether it works in the short
term. It's about making sure it's safe for patients
over the long haul. Exactly. So when you're running
these big long -term studies, what are you actually
measuring? What are the specific things you're
trying to assess? Phase three trials always have
very clear objectives. Usually, These revolve
around what we call endpoints. You've got your
primary endpoint. That's the main result the
study is designed to measure. It's the thing
that tells you if the drug really makes a difference
for patients clinically. So what kind of things
are we talking about? Well, it could be something
like an increase in survival rates, a decrease
in how severe the disease symptoms are, or even
a direct measurement of a biomarker that's important
for that particular disease. Something you can
actually quantify. Exactly. Your source, season
five clinical trials, phase three, and regulatory
approval really hits the nail on the head here.
These endpoints have to be specific, and you
have to be able to measure them. It's not just
about patients saying, I feel a bit better. Right.
You need hard data. And speaking of data, that
source also mentioned something about statistical
hypotheses. How do those come into play in deciding
whether a trial has been successful or not? That's
a great question. So the statistical hypothesis
is basically the framework that researchers use
to analyze all that data they collect and figure
out what it all means. In a lot of phase three
trials, the main goal is to show that this new
treatment is actually better than whatever's
already out there. This could be a placebo, a
sugar pill basically, or it could be the current
standard of care, the best treatment available
right now. Okay, so you're comparing the new
drug to something else. Exactly. And this is
what we call a superiority hypothesis. The researchers
are looking for enough evidence to say, OK, we're
pretty darn sure that this new drug is better
than the control. But sometimes the goal is different.
Sometimes the goal is to show that the new treatment
is at least as good as the existing one. And
why would that be the goal? Well, maybe the new
drug has fewer side effects. Or maybe it's easier
to take, like a pill instead of an injection.
So in those cases, you're not necessarily looking
to be better. You just want to show that you're
not worse. I see. And that's what we call a non
-inferiority hypothesis. Interesting. So there
are different ways to look at the data, depending
on what you're trying to achieve with the new
treatment. Exactly. It all comes down to what's
best for the patient in the end. And to be confident
in the results of these trials, everything has
to be done in a very specific way. Right. Oh,
absolutely. Every single detail of a phase three
trial is carefully planned out and documented
in a protocol. This includes things like who's
eligible to participate, how the treatment is
given, how the data is collected, even how it's
analyzed. Everything is standardized. And why
is that so important? because it minimizes bias
and it ensures that the results are reliable.
By following the same procedures across the board,
researchers can be more confident that any effects
they see are truly due to the drug itself and
not some other variable that wasn't controlled
for. Right. It's all about making sure the data
is clean. Exactly. You need that rigorous structure
to be able to draw meaningful conclusions, especially
when you're dealing with so many participants.
Speaking of which, you know that season five
source we talked about earlier, it mentioned
just how huge some of these three trials can
be. Can you give us a sense of the scale? Oh
yeah, some of these trials enroll hundreds even
thousands of participants. And these participants
are often spread out across multiple research
centers, sometimes even in different countries.
This huge scale is often necessary because sometimes
the difference between the new drug and the existing
one isn't that big. So to be absolutely sure
that the new drug is actually better, you need
a lot of data. You need a lot of people in your
study. And while we're not talking about specific
landmark studies for this deep dive, I'll just
say these large, well -designed phase three trials,
the ones that show positive results, they often
end up changing the way doctors practice medicine.
That makes sense. They can lead to real breakthroughs
in how we treat diseases. Impacting so many lives.
Exactly. And it's important to remember where
all of this fits in the grand scheme of things.
As your source, drug development, from discovery
to market, explains, phase three comes after
years of preclinical research and those earlier
phase one and two trials. It's the final test,
the last hurdle to clear. It's the culmination
of so much work. And if the results are positive,
that's usually what the FDA needs to give the
green light and make the drug available to patients.
So phase three is really the deciding factor.
It's the ultimate proof that a new treatment
is both effective and safe enough for everyone
to use. Well, this has been incredibly helpful
in understanding what phase three trials are
all about. My pleasure. So just to recap for
our listener, these trials are big. They involve
a lot of people from diverse backgrounds, and
they focus on confirming that the drug really
works and that it's safe in the long run. Right.
They have very clear goals, and they rely on
rigorous statistical methods to analyze the data.
And at the end of the day, if a drug makes it
through phase three successfully, that's usually
what paves the way for it to be approved and
made available to patients. Couldn't have said
it better myself. If you want to understand how
modern medicine works, how we know that the treatments
we use are actually effective and safe, then
you need to understand Phase 3 trials. Absolutely.
And with that in mind, here's something for you
to think about, listener. We've talked about
how complex these trials are, how much effort
goes into making sure they include people from
all walks of life. So the question is this. What
do you think are the biggest challenges in making
sure that the results of these trials are not
only scientifically sound, but also a true reflection
of how well the drug will work and how safe it
will be for everyone who needs it. That's something
to ponder, for sure. It's a question that really
gets to the heart of what clinical research is
all about, constantly striving to improve and
make sure that everyone benefits from the latest
advances in medicine. Thanks for joining us for
this deep dive. We'll see you next time. See
you then.