72 - Post-Approval Commitments and Phase IV (S5E12)

Okay, so today we're going deep on what happens
after a drug gets approved, you know, gets that
stamp of approval from the regulators. Right,
because I think a lot of people don't realize
that... You know the story doesn't just end there
with those clinical trials exactly. It's like
the first hurdle Yeah, yeah, and so we're really
gonna be looking at post approval commitments
and these things called phase four studies and
why this stuff really matters You know for anyone
who takes medication exactly because it's all
about making sure those drugs stay safe Yeah,
and they actually work you know, out there in
the real world with all sorts of different people
taking them. Yeah, not just in that controlled
setting of a, you know, research trial. Right.
So we've got a ton of sources for this deep dive.
Oh, yeah. We've got, you know, the pharmaceutical
development guides and the actual regulatory
documents like the CFR. Yeah, all those rules
and regulations. Yeah, and then even some deeper
dives into pharmacokinetics and how clinical
trials work. The nitty -gritty stuff. So let's
jump in. We know that those first phases, those
phase three and three trials, are super important
for getting a drug approved. Absolutely foundational.
But they're really just the beginning, right?
Yeah, they kind of set the stage for everything
that comes after. OK, so then we move into this
phase four, what's often called post -marketing
surveillance. So what exactly changes when we
hit this phase? Well the focus kind of shifts,
you know, in those early trials it's all about
is this drug safe enough to even test in humans
and then does it actually work better than what
we already have and that kind of thing. Right,
very controlled. Very controlled, yeah. But in
phase four we're looking at the long game, you
know, how safe is this drug over years of use
and does it really deliver on its promise for
a much wider range of people, you know, with
different health conditions and lifestyles and
all that. And this is where we get into those
accelerated approvals, right, which I find super
interesting. Yeah, this is where things can get
a bit more complex. So sometimes a drug gets
approved based on what they call a surrogate
endpoint. So could you break that down for us?
Sure. So think of it like this. Imagine you're
trying to measure if a new teaching method helps
students learn better, the ultimate goal, right?
But instead of directly testing their knowledge
after a year, let's say you just measure how
much time they spend reading each week, hoping
that more reading time will eventually lead to
more knowledge. So it's not a guarantee, it's
just an indicator. Exactly. It's an indicator
that suggests things are moving in the right
direction, but it's not the actual proof. OK.
So how does that apply to drugs? Well, sometimes,
especially for serious diseases like cancer or
certain rare conditions, a drug might get approved
based on something that's likely to predict a
real benefit for the patient, but not the actual
benefit itself. So like if a cancer drug shrinks
a tumor, that's great. But the real question
is, does it actually help people live longer
or have a better quality of life? Precisely.
And that's where phase four comes in big time
with these accelerated approvals, because the
company is required to conduct more studies to
prove that the drug truly delivers those long
term benefits. So it's kind of like getting provisional
approval with a promise to show more evidence
later on. Yeah, a bit like that. OK, so let's
talk about safety after a drug is on the market.
Why is it so important to keep monitoring that?
You know, we've already had all those clinical
trials. Right. So those early trials are crucial,
but they're limited. You know, they involve a
certain number of people studied for a certain
period of time. Right. But once a drug is out
there being used by millions of people with all
sorts of different health backgrounds and taking
other medications, well, you start to see things
that maybe didn't show up in those initial smaller
studies. You're casting a much wider net. Exactly.
You might find rare side effects that only happen
in one in 10 ,000 people or side effects that
take years to develop. Those are things you just
wouldn't catch in a typical phase three trial.
And real -world use is just so different than
a controlled trial, right? People might not always
take the drug exactly as prescribed. Absolutely.
They might miss doses or take it with certain
foods or drinks that interfere with how it's
absorbed or they might have other health conditions
that complicate things. So it's messy. Yeah,
real life is messy. Okay, so when these what
they call adverse events do happen, how is that
information handled? So everything gets documented
really meticulously. What happened? How bad was
it? How long did it last? And most importantly,
was it likely caused by the drug? So it could
detect his case file. Kinda. Yeah, and this lets
researchers and regulators look for patterns.
You know, is this particular side effect popping
up more often than we'd expect? Is it happening
mostly in people with certain characteristics?
You're connecting the dots. Yeah, and it helps
us understand the drug's safety profile better.
you know, out there in the wild. In the real
world. Exactly. And we talked about dose limiting
toxicities or DLTs in the early phases. Is that
still something to watch out for after a drug
is approved? Oh, yeah, definitely. So in those
early trials, they figure out the maximum dose
someone can tolerate before the side effects
get too bad. Right, finding that sweet spot.
Right. But then once the drug is being used more
widely, we might find that certain groups of
people are more sensitive to it. Maybe people
with kidney problems or older folks. So the maximum
tolerated dose might actually be lower for them.
So it's not just about finding new side effects.
It's about refining our understanding of the
ones we already know about in different populations.
Right. And that can lead to dosage adjustments
or more specific warnings on the drugs label.
OK. So we've talked about safety. Yeah. Let's
switch gears a bit and talk about effectiveness.
Does that also need to be monitored long term?
Oh, absolutely. Because remember, those early
trials are showing how well a drug works in a
very controlled setting, but real life throws
a lot of curveballs. Right. People forget to
take their meds or, you know, life gets in the
way. Exactly. And so these phase four studies
can tell us how well a drug actually works over
months or even years of use in a much broader
and more diverse group of people. And these aren't
just repeat trials, right? They can actually
explore different aspects of how a drug is used.
Right, they might test different dosages or different
lengths of treatment to see what works best.
They might even discover new uses for the drug,
you know, things it was never originally intended
for. So like off -label use kind of thing? Yeah,
sometimes those off -label uses become official.
you know, if enough evidence shows that the drug
is safe and effective for that new purpose. That's
fascinating. So going back to those accelerated
approvals, what happens if those later studies,
the ones meant to confirm the clinical benefit,
don't actually pan out? Yeah, that's a really
important point. If those confirmatory trials
don't show the expected benefit, the regulatory
agencies can actually withdraw the drug's approval
or at least limit its use. So it's not a done
deal? No, it's a continuous process of evaluation.
They're keeping a close eye on it. Absolutely.
And there have been cases, you know, where a
drug was initially approved based on promising
early data, but then later studies showed it
wasn't as effective as we thought, or that the
side effects were more serious than initially
anticipated. So it's a constant reassessment,
even after a drug is already out there being
prescribed. Right, because we're always learning
more. Okay. And what about pharmacokinetics?
I know it's a big word, but basically it's how
the drug moves through the body. Is that still
studied in phase four? Definitely, because, you
know, it's not just about what the drug does,
it's also about how the body handles the drug.
Right, how it breaks it down and gets rid of
it. Exactly, and that can vary a lot from person
to person. You know, your age, your genetics,
other medications you're taking, even your diet
can affect... how your body processes a drug.
So phase four helps us understand those individual
differences and how they might impact the drug's
effectiveness or safety. Right. For example,
we might find that a certain drug is metabolized
much slower in older adults, which means they
might need a lower dose to avoid side effects.
So it's all about fine tuning our understanding
of how the drug behaves in different people.
Exactly. OK, so where does all this data come
from? All this information about safety and effectiveness
in the real world. It sounds like a massive data
collection effort. There are a few main sources.
One is observational studies where researchers
basically watch what happens to people who are
taking the drug in their everyday lives. So not
a controlled experiment, just observing. Right.
It's more like real world data. OK. Then there
are patient registries, which are databases that
track specific groups of patients who are taking
a particular drug. So for example, there might
be a registry for people with rheumatoid arthritis
who are taking a certain biologic medication.
So that's really targeted data on a specific
condition and drug. Exactly. And then, of course,
there are the adverse event reporting systems,
which are ways for health care providers and
patients to report any suspected side effects.
So it's kind of like crowdsourcing safety data.
Yeah, in a way. And the regulatory agencies like
the FDA and EMA, they play a role in all this
too, right? Absolutely. They're the ones collecting
and analyzing all this data, and they also have
the power to take action. Yeah. You know, if
they see any red flags. Right, like requiring
changes to the drug's label or even pulling it
off the market if it turns out to be too risky.
Exactly. And remember, those post -marketing
commitments we talked about earlier, those are
often a condition of approval. You know, the
company has to agree to conduct certain studies
or collect certain data to keep their drug on
the market. So it's not just a one -time approval.
It's an ongoing process. Right. It's a partnership
between the company, the regulators, and the
health care community to make sure drugs are
used safely and effectively. We also saw this
term dossier. What exactly is that? So a dossier
is basically a giant file that contains all the
information about a drug It includes all the
preclinical data the results from the clinical
trials and then it keeps getting updated with
all the post marketing data So it's like the
drugs permanent record. Yeah, it's everything
we know about the drug in one place Okay, so
we've talked about how safety and effectiveness
are monitored after a drug is approved? Yeah.
What about the regulatory side of things? Do
the agencies stay involved? Oh, absolutely. They're
constantly monitoring the data that's coming
in, and they have the power to take action if
needed. And what kind of actions can they take?
Well, they can do a few things. They might require
the drug company to change the label, add new
warnings or precautions, or they might ask them
to conduct additional studies to address specific
safety concerns. So they can kind of steer the
ship. Yeah. And in more serious cases, if the
risks start to outweigh the benefits, they can
even restrict the drugs use or withdraw it from
the market altogether. So it's a powerful tool
to protect public health. It really is. Now,
what about those special cases, like orphan drugs
and over -the -counter medications? Does post
-market surveillance apply to them, too? Absolutely.
So, orphan drugs are those drugs that are developed
to treat rare diseases, and they often get special
incentives like market exclusivity to encourage
companies to invest in them. Makes sense because
it's a smaller market. Right. But even though
they have this exclusivity period, they're still
subject to the same post -market surveillance
requirements as any other drug. So, safety is
still paramount. Absolutely. And with over the
counter drugs, the FDA still plays a role in
making sure they're safe and effective. But those
don't go through the same rigorous approval process
as prescription drugs. Right. Not necessarily.
Some OTC drugs are marketed under a monograph,
which is like a recipe book for that type of
drug. It lays out the acceptable ingredients,
the dosages, the labeling requirements, and so
on. So it's kind of like a pre -approved formula?
Yeah. But the FDA can still take action if a
company deviates from the monograph or if there
are new safety concerns that emerge. So it's
not a free -for -all? No. There's still oversight
to protect consumers. OK, so it sounds like this
whole post -approval process is really a crucial
safety net. It really is. It ensures that we're
constantly learning more about drugs as they're
used in the real world and that we're taking
steps to keep them as safe and effective as possible.
So to wrap things up. What are the key takeaways
you want our listeners to remember about post
-approval commitments and phase four studies?
Well, I think the main point is that drug development
doesn't end when a drug hits the market. You
know, phase four and all those post -market activities
are a vital part of the process. It's about continuous
monitoring? Exactly. We're always learning more.
And that knowledge helps us make sure that the
benefits of a drug truly outweigh the risks for
patients in the long run. And for you, our listener,
understanding this phase gives you a much more
complete picture of the entire drug life cycle.
You know, it's not just about those early trials.
It's about what happens after a drug is out there
being used by millions of people. Right. And
it highlights the importance of ongoing research
and surveillance to keep medications safe and
effective. And it makes you realize. How much
data is out there, you know, from all these different
sources? It's a huge amount of information. And
it makes you wonder how we can use that data
even more effectively to improve patient care.
Definitely. Like imagine if we could use artificial
intelligence to analyze all that data and spot
potential safety issues much earlier or to personalize
drug treatments based on a patient's individual
characteristics. That's a fascinating thought.
You know, using data to make medicine even safer
and more effective for everyone. It's an exciting
possibility and something to definitely think
about as we move forward in this era of big data
and personalized medicine. Definitely lots to
ponder. Absolutely. Thanks for joining us today
on the Deep Dive. It was a pleasure. And we'll
see you next time for another Deep Dive into
the world of drug development. See you then.