108 – Role of Pharmacovigilance (S8E3)

Welcome back everyone to the deep dive. Today
we're gonna be digging into something that I
think we can all agree is pretty important. Absolutely.
Something that impacts all of our lives when
we need it most. Definitely impacts all of our
lives. When we're sick or when we need some help,
you know. medications, the drugs we take, the
things that help us feel better. And hopefully,
they do help us feel better. Exactly. And that's
what today is all about. It's about how we can
trust that those medications are actually gonna
do what they're supposed to do. And that's where
this whole field of pharmacovigilance comes in.
Yeah, that's a great way to put it. Pharmacovigilance
is all about ensuring that the medicines that
we all rely on are safe and effective. You know,
when you go to the pharmacy and you pick up a
prescription, you want to be confident that that
medicine is going to help you and not cause any
unexpected problems. And that's what pharmacovigilance
is all about. So today we're going to do a deep
dive into this whole world of pharmacovigilance.
We've got a ton of interesting stuff to go through.
We've got everything from the official rule books,
the actual code of federal regulations, Title
21. That's the one that covers food and drugs.
Right. So we'll be taking a look at that. We've
also got some really fascinating scientific articles
that go deep into how drugs are developed and
all the latest research on pharmacovigilance.
So by the end of this deep dive, we want to make
sure you've got a crystal clear picture of what
pharmacovigilance really is, why it's so crucial,
especially after a drug has already gotten approved.
Right. You know, it's already out there in the
world. People are taking it. Why is it still
so important to keep an eye on it? Yeah. And
then, of course, we'll get into the nitty gritty
of how potential safety concerns are spotted
and how they're managed. And, of course, to really
bring it to life, we'll even delve into some
real world examples. Absolutely. So let's start
right at the beginning. Let's get back to basics.
OK. In the simplest terms possible. What exactly
is pharmacovigilance? Okay, so pharmacovigilance
You can think of it as this ongoing safety net
for all the medications that are out there being
used Okay, it's really about keeping a watchful
eye on those drugs and making sure they're still
doing what they're supposed to be doing and they're
not causing any unexpected harm I like that a
safety net. Yeah, so it's like Even after a drug
gets approved, the safety checks don't just stop,
right? No, absolutely not. It's like a continuous
process. Exactly. So can you break down for us
the core activities involved in pharmacovigilance?
What does it actually look like in practice?
Sure. So at its heart, pharmacovigilance boils
down to four key actions. You've got detection.
That's basically spotting any potential problems.
OK. You know, red flags that might pop up with
medication. Then there's assessment. This is
where you really dig in and figure out how serious
the problem is. Got it. Is it a minor side effect
or is it something more concerning? Then you've
got understanding. Okay. So this is about getting
to the bottom of why this problem might be happening
in the first place. Right. And then finally,
and perhaps most importantly, you've got prevention.
Prevention. That's key. Exactly. Because we want
to stop these things from happening in the first
place. Right. Or if they do happen, we want to
limit the damage as much as possible. Exactly.
And it's all about making sure that, you know,
at the end of the day, the benefits of the medicine
are outweighing any potential harm. So we've
talked about how pharmacovigilance kicks in after
a drug is approved. Can you elaborate on why
this post -perpoval monitoring is so essential?
Yeah, this is a crucial point. So you're right,
clinical trials, they are definitely a critical
part of drug development. You have to see if
the drug actually works and if it's safe enough
to use in people. Right. That's the whole point
of clinical trials. Exactly. But the thing is,
clinical trials do have limitations. For one
thing, you're testing on a limited number of
people. And these trials usually only last for
a certain amount of time. Makes sense. So there's
always a chance that some side effects, especially
the really rare ones or the ones that take a
while to show up, they might slip through the
cracks. They might not become apparent until
the drug is out there being used by a much larger
and more diverse group of people. That's a really
good point. It's like, when you think about it,
once a drug is approved, it's kind of like it's
entering this massive real -world clinical trial.
Exactly. You know, it's being used by potentially
millions of people with all sorts of different
health conditions. They might be taking other
medications. They might have different lifestyles,
different diets. And all of these factors can
influence how a drug behaves in their body. So
it's really about understanding how a drug works
in the complexity of the real world, right? Exactly.
Because in clinical trials, you're trying to
control as many variables as possible. OK. But
in the real world, it's just impossible to control
for everything. So you mentioned other medications,
right, that people might be taking. Right. And
this brings us to a really crucial topic, which
is drug. drug interactions, or as you mentioned,
DDIs. Yeah, DDIs. So can you explain to our listeners,
just to recap, what a DDI actually is? Sure.
So a DDI is basically when one drug can change
how another drug works in your body. It can either
make the other drug more or less effective, or
it can increase the risk of side effects. And
this can happen in a lot of different ways, right?
It can. There are so many different ways that
drugs can interact with each other. It's kind
of amazing that we're able to manage them all.
But some drugs can block certain enzymes in your
body that are responsible for breaking down other
drugs. And this can lead to higher levels of
those other drugs in your system, which can be
dangerous. So are there any specific examples
of drugs that can cause these types of interactions?
Yeah, there are quite a few. Some common culprits
include ketoconazole, which is an anti -fungal
medication, ritonavir, which is used to treat
HIV, and aminoderone, which is a heart rhythm
medication. Got it. These are just a few examples.
But all of these drugs, they can inhibit, they
can block those crucial enzymes that play a role
in metabolizing other medications. And as Wang
discusses in drug... drug interactions and pharmaceutical
development, you know, this inhibition can really
throw things off. And what about the opposite?
Are there drugs that can speed up the breakdown
of other drugs? Yes, absolutely. That can be
just as problematic, right? If a drug gets broken
down too quickly, it might not have a chance
to do its job. And a good example of this is
a drug called carbamazepine, which is used to
treat seizures. Carbamazepine can induce certain
enzymes, kind of give them a boost. And this
can cause other medications to be broken down
much faster than they normally would. So if someone's
taking carbamazepine and another medication that
relies on these enzymes to work properly, that
other medication might not be as effective, right?
Exactly. And that can be a real problem if that
other medication is essential for their health.
And these CYP enzymes, especially the CYP3A4,
is like a major player in metabolizing a ton
of different medications. So when you have something
like carbamazepine inducing that enzyme, it can
affect a lot of different drugs. And that's just
one example. And it's not just other medications
that can complicate the picture, right? Right.
We also have to consider things like food and
diet. Absolutely. And this is another thing that
often gets overlooked in clinical trials, because
in a clinical trial, they're trying to control
everything. Right. Keep it all very standardized.
Exactly. But in the real world, people are eating
all sorts of different things. Right. And some
foods can actually interact with medications.
They can either increase or decrease absorption.
They can affect how the drug is broken down.
So for our listeners out there, if you're ever
unsure about whether a certain food might interact
with your medication, it's always best to check
with your doctor. or your pharmacist, right?
Exactly. And give you the best advice for your
specific situation. Absolutely. It's not worth
taking the risk. And as Marissa Anapal and their
team highlighted in the study, effects of food
on drug absorption, food can really have a significant
impact on how your body takes in a medication.
They pointed out that some drugs are actually
much better absorbed on an empty stomach, while
others need to be taken with food to work properly.
Got it. So it really depends on the specific
drug. But the point is that these are the kind
of details that often only become clear once
a drug is out in the real world and being used
in all sorts of different contexts. So we've
talked a lot about all these complexities and
challenges with post -approval drug monitoring.
With all these factors at play, how would you
sum up the main mission, the ultimate goal of
pharmacovigilance? The core mission of pharmacovigilance
is really all about balancing the benefits and
the risks of every single medication that's out
there on the market. It's about constantly asking
ourselves, does the good that this drug does,
does it still outweigh any potential harm it
might cause? And that balance can shift over
time, right? It can. As we learn more about a
drug. Exactly. New information can come to light.
New risks can emerge. And that's why pharmacovigilance
is so important. It's about continually evaluating
that balance and making sure that we're doing
everything we can to minimize risks and keep
patients safe. So that's the ultimate goal. Minimize
risks, keep patients safe. Exactly. So how does
pharmacovigilance actually work in practice?
How do we spot these potential problems, these
adverse events. We talked about all these people
taking drugs in all sorts of different ways out
there in the real world. Is there some sort of
magic system that flags every single problem?
Well, if only there was a magic system. But unfortunately,
it's not quite that simple. But we do have a
pretty robust system in place. And one of the
most important components of that system is what
we call spontaneous reporting. Spontaneous reporting.
So what exactly does that mean? So spontaneous
reporting is basically when health care professionals
like doctors, pharmacists, nurses, even patients
themselves can report any suspected side effects
or any other problems that they've experienced
after taking a medication. OK, so if I, as a
patient, notice something unusual after taking
a new medication, I can actually report that
to the authorities. Yes, absolutely. And they'll
take that information seriously. They do. And
in fact, it's really important for patients to
do that because, you know, you're the one experiencing
these effects firsthand. Right. You're the one
who knows your own body best. So if something
feels off, don't hesitate to report it. So who
do we report this to? So you can report it directly
to the FDA, the Food and Drug Administration.
You can also report it to the drug manufacturer.
They have their own systems for collecting these
reports. So those are the two main avenues. And
the FDA, they have a whole system for collecting
and analyzing these reports. They do. What happens
to that information? So they have a huge database
where they collect all of these reports. And
they have teams of scientists who are constantly
analyzing that data, looking for patterns, looking
for signals that might indicate that there's
a problem with a particular drug. OK. So that's
spontaneous reporting. Right. But it's not the
only way that potential safety issues are detected,
right? No, absolutely not. There are other ways.
In addition to spontaneous reporting, we also
have post -marketing surveillance studies. Post
-marketing surveillance studies. So what are
those? So these are studies that are conducted
by pharmaceutical companies after a drug has
already been approved and it's on the market.
Got it. And the goal of these studies is to proactively
look for specific safety signals in larger groups
of patients. They might be looking at a specific
side effect or they might be looking at how the
drug is being used in different populations.
OK. And this can give us a lot more information
than we could ever get from just spontaneous
reports. So it's like a more targeted approach
to safety monitoring. Exactly. And then, of course,
we also have all of the electronic health records
and other real world data sources that are becoming
increasingly valuable for pharmacovigilance.
OK. How does that work? So with electronic health
records, we can now analyze huge amounts of data
on how drugs are being used in the real world.
We can look at things like prescribing patterns.
OK. We can look at patient outcomes. We can see
if there are any correlations between certain
drugs and certain adverse events. And this can
give us a much more comprehensive picture of
a drug's safety profile than we could ever get
from just looking at individual reports. So it's
like using big data to identify potential safety
problems. Exactly. And then let's not forget
about the scientific literature. Right. You know,
scientists are constantly publishing new research
on drugs. Yes. And sometimes those studies will
uncover new safety information that wasn't previously
known. And sometimes we'll even see case reverence
published where a doctor has observed a rare
adverse event in a patient. And while one case
report might not be enough to raise a major alarm,
if you start seeing multiple case reports describing
the same problem, then that can definitely trigger
further investigation. So it's like all of these
different pieces of information coming together
to build a more complete picture. of a drug safety.
Exactly. It's really a multi -pronged approach
to pharmacovigilance. It sounds incredibly comprehensive.
And it highlights just how important it is to
have clear and accurate reporting of all of these
adverse events, right? Oh, absolutely. Accurate
and detailed reporting is the foundation of everything
we do in pharmacovigilance. And I think it's
worth mentioning here. You know, we were talking
about CFR Title 21. Right, the Code of Federal
Regulation. Right. So specifically, Section 203
touches on an interesting point. OK. It's primarily
about drug advertising, but it underscores a
really crucial aspect of pharmacovigilance. OK.
So this section, it focuses on what can be said
in drug advertising about approved uses. Right,
so you can't just make wild claims about what
a drug can do. Exactly. It has to be based on
scientific evidence, right? Right. And approved
by the FDA. Right. So how does that relate to
pharmacovigilance? So while the regulation itself
is about advertising, the implication is that
we're focusing our monitoring on the adverse
events that are associated with those labeled
uses. OK, so we're not really looking at what
happens when people use a drug off label. Right.
We're primarily concerned with what happens when
the drug is used as intended. And that's why
it's so important for health care professionals
to be aware of those labeled uses. Because that's
what they should be prescribing the drug for.
Exactly. And that's what patients should be taking
the drug for. Because if you start using a drug
off label, then you're basically going outside
the bounds of what's been studied and what's
been deemed safe and effective. So that's an
important distinction. We're really focused on
ensuring the safety of drugs when they're used
for their approved indications. Exactly. And
this whole idea of reporting and investigating
adverse events, it often triggers a process called
KPA. PPA. What's that? So KPA stands for Corrective
and Preventive Actions. And as Rodriguez Perez
discusses in KPA for the FDA regulated industry,
this process is really about taking a comprehensive
approach to addressing safety issues. OK. So
it's not just about fixing the immediate problem.
It's about putting measures in place to prevent
it from happening again. So let's say a serious
adverse event is reported, the FDA investigates,
and they find that there's a problem with the
manufacturing process. They'll take steps to
correct that problem, but they'll also implement
new procedures to prevent that problem from happening
again in the future. Exactly. So CAPA is really
a critical part of the overall pharmacovigilance
system. Let's say a potential safety issue has
been detected. OK. You know, whether it's through
spontaneous reporting or one of these other methods
we talked about. Right. What happens next? So
once a potential safety issue is detected, it
triggers a thorough assessment. OK. We need to
figure out, you know, is this a real problem?
How serious is it? And what can we do about it?
And this assessment usually involves several
steps. First, we look at how often the adverse
event is happening. OK. Is it a one -off event
or is it something that's being reported multiple
times? Right. Then we look at how serious the
event is. Is it a mild side effect or is it something
that's life -threatening? Got it. And then we
have to assess the evidence linking the event
to the drug. So is it really the drug that's
causing this problem or could it be something
else? Exactly. Because you have to remember,
just because someone takes a drug and then experiences
an adverse event doesn't necessarily mean that
the drug caused the event. Right. There could
be other factors involved. So you have to tease
that out. Exactly. How do you do that? So there
are a lot of different methods that scientists
use to assess causality. But ultimately, it comes
down to weighing all of the evidence and using
our best judgment to determine whether the drug
is likely to be the culprit. OK. So we've looked
at how often the event is happening, how serious
it is, and whether it's really linked to the
drug. What happens next? So once we've got a
pretty good understanding of the potential safety
issue, the next step is to conduct a risk benefit
analysis. Risk -benefit analysis. Yes. So that's
about weighing the risks of the drug against
the benefits. Right. Exactly. And this is where
things can get really tricky, because sometimes
a drug can have serious risks. But if it's the
only effective treatment for a life -threatening
condition, then those risks might be considered
acceptable. So it's not always a black and white
decision. No, it rarely is. It's often a matter
of judgment. Right. And it's a decision that
has to be made on a case -by -case basis. Who
makes that decision? Well, ultimately, it's the
regulatory agencies like the FDA who make the
final decision about whether a drug stays on
the market. Okay. But they rely heavily on the
input of scientists and healthcare professionals
to inform their decision. So what are some of
the actions that can be taken to manage the risks
of a drug? once a potential safety issue has
been identified. Well, there are a range of different
actions that can be taken. And again, the specific
action will depend on the specific drug and the
specific safety issue. But some common actions
include things like changing the drug's label.
OK, so updating the information that comes with
the drug. Exactly. So, for example, they might
add a new warning to the label or they might
add a contraindication. Contraindication? What's
that? A contraindication is basically a statement
that says that this drug should not be used in
people with a certain condition. Okay, so it's
like a hard stop. You shouldn't take this drug
if you have this condition. Exactly. And that's
usually based on some pretty strong evidence
that the drug could be dangerous for people with
that condition. So updating the label is one
option. What else can be done? They might also
make dosage adjustments. OK. So for example,
they might lower the dose of the drug for older
adults or for people with certain health conditions
because those groups might be more sensitive
to the drug's effects. And those changes are
reflected on the label as well, right? Exactly.
So doctors and patients know what the appropriate
dose is. Exactly. Another thing they might do
is restrict who can prescribe or dispense the
drugs. Okay, so limiting access to the drug.
Right. And that's usually done for drugs that
have a high potential for abuse or misuse. Right.
Okay. And then in some cases, they might even
require what's called a REMS. A REMS. What's
that stand for? So REMS stands for risk evaluation
and mitigation strategy. Risk evaluation and
mitigation strategy. Exactly. So it's basically
a plan to minimize the risks of a particular
drug. Exactly. And who develops the REMS? So
the REMS is developed by the drug manufacturer,
and it has to be approved by the FDA. OK. And
it outlines all of the steps that will be taken
to ensure that the drug is used safely. So what
kind of things might be included in a REMS? Well,
it could include things like special training
for prescribers. OK. It could include patient
education materials. OK. It could include requirements
for monitoring patients who are taking the drug.
So it's really a comprehensive plan to ensure
that the drug is used as safely as possible.
Exactly. And then, of course, in the most extreme
cases, the FDA can also withdraw a drug from
the market altogether. And so that's the nuclear
option. It is. And that only happens in very
rare cases, right? It does. But it does happen.
And it usually happens when the risks of the
drug are deemed to outweigh the benefits. So
even after a drug has been approved, it's still
possible for it to be removed from the market
if serious safety concerns emerge. Exactly. Because
at the end of the day, patient safety is the
top priority. And that's really what pharmacovigilance
is all about. And the FDA, they play a really
central role in all of this, right? They do.
They're the ones who are ultimately responsible
for ensuring that drugs are safe and effective.
And they have a whole arsenal of tools at their
disposal to manage the risks of drugs. They do.
And as we've seen from our deep dive into CFR
Title 21, they have a lot of regulations and
guidance documents that lay out the framework
for pharmacovigilance. So let's talk about some
real world examples of how pharmacovigilance
works in practice. You mentioned that we could
draw some insights from OPRND literature. Yes,
absolutely. What kind of examples can we glean
from that? OK, so while we can't disclose any
specific patient information or proprietary data,
we can definitely talk about the types of issues
that often come up in pharmacovigilance and how
they're addressed. And a lot of these issues
are actually discussed in publications from the
FDA's Office of Pharmaceutical Quality Operations,
OPRO, and other related literature. So we can
definitely draw some insights from those sources.
OK, that's perfect. So let's get into some of
these real world inspired examples. OK. What's
the first scenario? So imagine a new drug. that's
been approved, it's on the market, and everything
seemed fine in the clinical trials. But then,
as more and more people start taking the drug...
Doctors start noticing an unexpected increase
in a particular side effect. And it turns out
that this side effect seems to be happening more
often in patients who are also taking a certain
older medication. So it sounds like a drug interaction.
Exactly. And it's one that wasn't detected in
the clinical trials because maybe none of the
patients in the trials happened to be taking
that other medication. OK, that makes sense.
So. In this case, the pharmacovigilance system
would pick up on this pattern of reports, right?
Right. Because doctors are reporting these adverse
events. And then scientists would investigate
the potential link between the two drugs. And
if they find that there's a strong enough link,
then the FDA might decide to take action. They
might update the label of one or both drugs to
warn about the interaction. So that doctors know
to be careful about prescribing those two drugs
together. Exactly. Or they might recommend specific
doses adjustments if the two drugs have to be
used together. Got it. So that's a pretty clear
example of how pharmacovigilance can identify
drug interactions that weren't apparent in the
more controlled setting of a clinical trial.
Right. What's another example? Another scenario
is when a very rare but serious adverse event
is identified after a drug has been on the market
for a while. OK. So this might be something that
didn't show up in the clinical trials because,
again, the trials are limited in terms of the
number of patients and the duration. Right. So
it's only after the drug has been used in a much
larger population for a longer period of time
that these really rare events start to emerge.
So these are events that might only affect, say,
one in 10 ,000 people. Exactly. Exactly, something
like that. Okay. So let's say that this rare
event is a specific type of heart problem. Okay.
And it only happens in a very small percentage
of people who take the drug. Okay. But it's a
serious heart problem. Okay. It can be life threatening.
So how would pharmacovigilance detect something
like that? So as more and more people take the
drug, you'll start to see those spontaneous reports
coming in. Right. Doctors will report these heart
problems to the FDA. And at first, it might just
seem like random events. Right, just background
noise. Exactly. Nothing to worry about. But as
the reports accumulate, the FDA's scientists
will start to see a pattern. OK. And they'll
start to suspect that there might be a link.
between the drug and this heart problem. And
they'll investigate that link. Exactly. What
kind of investigation would they do? So they'll
look at all of the data that they've collected
on the drug. They'll look at the spontaneous
reports. They'll look at any post -marketing
surveillance studies that have been done. They'll
look at any data from electronic health records.
OK. And they'll try to piece together all of
the evidence to see if there's a strong enough
link to warrant taking action. And they might
even conduct their own studies to investigate
the link further. And if they find that there
is a link, what kind of actions could they take?
So they could do a number of things. OK. They
could update the drugs label to warn about the
risk of this heart problem. OK. They could restrict
the use of the drug to certain patients who are
less likely to experience the side effect. OK.
Or in the most extreme cases, they could withdraw
the drug from the market altogether if the risks
are deemed to be too high. So that's how pharmacovigilance
can pick up on really rare events that might
not have been detected in the initial clinical
trials. Exactly. And it's really important because
these rare events can be very serious. Right.
They might not happen very often. Right. But
when they do happen, they can have a devastating
impact. Exactly. OK. So another common situation
is when an adverse event turns out to be more
prevalent or more severe in specific groups of
patients. Okay, so this is about how individuals
can respond differently to the same drug. Exactly.
So for example, a particular side effect might
be more common or more severe in older adults
than in younger adults. Okay. Or it might be
more common in people with certain genetic variations
or in people with certain pre -existing health
conditions. And these differences might not have
been apparent in the clinical trials. Right,
because the trials might not have included enough
people from these specific subgroups to detect
these differences. Got it. But once the drug
is out in the real world and being used by a
much more diverse population, these differences
start to emerge.