65 - Managing Adverse Events in Large Trials (S5E5)

So we often talk about those initial clinical
trials, you know, the smaller ones. And it might
seem like after those, it's smooth sailing to
get a new medicine out there. Yeah, you'd think,
right. But when you scale things up, like with
those massive clinical trials involving huge
numbers of patients across a bunch of different
hospitals. Yeah, multi -center trials. Exactly.
Well, making sure everything stays safe. That
becomes a whole different ball game. It really
does. Think about it. Keeping tabs on literally
everything happening at all those different sites.
The chances of something unexpected popping up,
what we call adverse events, just skyrockets.
It's like trying to herd cats, but the cats are
spread out all over the country. More like all
over the world sometimes. But that's what we're
digging into today. Those systems and processes,
all those behind -the -scenes efforts to monitor,
report, and manage anything that goes wrong in
those big multi -center trials. And We've got
some really interesting sources that reveal just
how much work goes into making sure patients
are safe while still getting that crucial data.
You know, the data that tells us if a new treatment
actually works. Right. It's a delicate balance.
Totally. And this isn't just for the doctors
or researchers out there. Anyone who's ever wondered
how new drugs are checked for safety on a large
scale. Or if you're just interested in healthcare
in general, this deep dive will give you a good
look at those safeguards. Absolutely. We're going
to unpack how these adverse events are defined,
how they're tracked, the standardized ways they're
reported, and all those safety checks that happen
throughout the whole process. It's a multi -layered
system, that's for sure. So let's kick things
off with the basics. What exactly are we talking
about when we say adverse event in these trials?
And why does having a large trial make managing
them so much trickier? The Anti -Cancer Drug
Development Guide gives us a pretty clear definition.
They say an adverse event is any unfavorable
symptom, sign, or disease that includes abnormal
lab findings, by the way, that happens around
the same time as the treatment, and that event
may or may not be considered related to the treatment
itself. Okay, so temporally associated. like
they say. Right, so it basically means the event
happened when the treatment was given, but it
doesn't automatically mean the treatment caused
it. It's like a red flag that needs more investigation.
Makes sense. Yeah. Especially when you consider
fields like oncology, right? As the guy points
out, many patients already have a ton of symptoms
because of their cancer. Exactly. Figuring out
if a new symptom is from the cancer getting worse
or a side effect of the experimental drug. That's
like trying to solve a puzzle in the dark. It
really adds another layer of difficulty. And
then you zoom out to these giant trials with
patients from all walks of life receiving treatment
at different medical centers. Yeah, tons of variables.
The challenge of spotting and handling those
potential adverse events just explodes. Well,
absolutely. And I think what's really interesting
here is that judging some of these events can
be pretty subjective, like the guide mentions.
You know, whether a patient says they're super
tired or just a little nauseous. Right. It's
their own perception. And then you have the healthcare
professional evaluating them, who also brings
their own interpretation to the table. So even
if it's the same issue, you might get different
descriptions or severity assessments. And when
you have multiple research teams at different
locations, that potential for things to vary
really highlights the need for some kind of standard,
consistent way of doing things. Couldn't agree
more. And that leads us perfectly to the NCI
Common Toxicity Criteria, or CTC. The CTC. It's
a game changer in terms of standardization. Tell
us a bit more about it. Why is it so important?
So the anti -cancer drug development guide says
the NCI CTC, it was updated to version 2 .0 back
in 1999. It's basically the foundation for how
we standardize toxicity assessment, particularly
in those early phase I trials. So it's like the
rule book. You could say that. Picture it as
the super detailed catalog of almost every adverse
event imaginable. Organized by organ system,
like your heart, your gut, your nervous system,
and broken down by specific clinical situations.
So it's way more in depth than just a basic checklist
of potential problems. Oh, way more. It goes
into crazy detail. For every adverse event listed,
the CTC gives you a specific grading scale, usually
from zero to five. Zero basically means no toxicity,
and a grade of five is the worst, you know, life
-threatening stuff. A zero to five, got it. And
here's where it gets really cool. The guide gives
a great example with diarrhea. The way they grade
diarrhea actually changes if a patient has a
colostomy compared to someone who doesn't. Oh,
that makes sense. So for someone without a colostomy,
the grade might be based on how many more times
they're going to the bathroom each day. That
obviously wouldn't work for someone with a colostomy,
so they adjust the criteria. Right. That level
of detail, it ensures that no matter where you
are in the study, everyone's using the same measuring
stick for the same event. It's taking something
that can be pretty subjective. and making it
as objective as possible. Exactly. And I can
see how that would be super important when you're
trying to figure out if an adverse event is actually
linked to the drug being studied. Totally. And
on that note, the CTC also gives you guidelines
on how to assess that relationship, how connected
the event is to the drug. They use specific terms
like clearly related, likely related, possibly
related, and so on. So it's taking the guesswork
out of it. Right. This structured approach helps
everyone, all those investigators at the different
centers, evaluate the cause of an event in the
same way. And the Anti -Cancer Drug Development
Guide stresses that when you scale this up to
multi -center trials, oversight of all the safety
data becomes super important, and there's a lot
of regulatory responsibility that comes into
play. So of all these research centers sending
in data on adverse events, who's ultimately in
charge of keeping track of all that information?
The sponsor of the trial, usually the drug company
or research institution funding the study, they're
the ones holding the reins. According to the
Code of Federal Regulations Title 21 Part 312,
the sponsor has to continuously review and evaluate
the safety data coming in from all the investigators.
And that's throughout the entire study? The whole
thing, yep. Wow, that's a massive undertaking.
What are some of the specific things these sponsors
have to do when it comes to reporting safety
concerns? The regulations are crystal clear on
this. Sponsors are legally obligated to quickly
report anything they find out that suggests a
serious and unexpected risk with the drug to
the FDA. The FDA. Yeah. And that includes any
serious and unexpected adverse events. And this
is crucial if a sponsor at any point concludes
that the drug is just too risky for the people
in the study. Too risky. They have to shut down
any part of the investigation that's causing
that risk. Immediately. Immediately. So like
stop. Pretty much. The regulations say it has
to happen as fast as possible, no later than
five working days after the sponsor makes that
decision. They also have to tell the FDA all
the institutional review boards or IRBs overseeing
the study at each site and every single investigator
involved. Okay, so everyone's in the loop. Plus
they need to make sure any leftover supplies
of the drug are accounted for and handled correctly.
It's a whole process with checks and balances
built in. It's good to know those safety nets
are there. But with potentially hundreds of research
sites sending in data on adverse events, how
do you even begin to make sense of all that information?
It must be a mountain of data. Oh, it is. The
Anti -Cancer Drug Development Guide mentions
that in these large scale trials, you can easily
have hundreds, sometimes even thousands of adverse
events being reported. Thousands. Yeah. So putting
all that data together effectively, that's the
key to really understanding how safe the drug
is overall. The source we have on artificial
intelligence in drug development, it really stresses
how powerful it is to combine different sets
of data. Combine different data sets. It strengthens
our grasp of what's happening clinically, especially
if the data from any single site is limited or
varies a lot. It's like trying to solve a jigsaw
puzzle. Yeah. But the pieces are scattered all
over the place. That's a great way to put it.
And this is where technology like artificial
intelligence is becoming a bigger player. AI
tools have the potential to completely change
how we integrate and analyze these huge amounts
of data in drug development. AI, yeah, it seems
like it's everywhere these days. For good reason.
It lets us be more flexible and go deeper when
analyzing complex data sets. But, and this is
an important point from that same source, AI
isn't meant to replace human researchers. critical
thinking and expertise, still essential. It's
more like AI is a powerful tool that makes them
even better at what they do, helps them spot
patterns and insights that might be hard to see
otherwise. So it's like a super powered assistant
for the researchers. Exactly. You still need
that human element to interpret the findings
and make those crucial safety calls. For sure.
Now we've talked a lot about monitoring and reporting
during the trial itself, but safety surveillance
doesn't stop once a drug gets approved. Right,
it's not like mission accomplished and everyone
goes home. Absolutely not. That's where things
get even more interesting. The principles of
standardized reporting carry over into what we
call the post -market phase through pharmacovigilance
systems. We actually talked about this in our
season five deep dive on clinical trials phase
three and regulatory approval. Oh yeah, I remember
that. Once a drug is available to a much wider
group of patients. Out in the real world. Yeah,
health care professionals and patients themselves
reporting adverse events directly becomes incredibly
important. So it's not just the drug company's
responsibility anymore. Exactly. National agencies
like the FDA in the US, with their MedWatch program,
and the European Medicines Agency, the EMA, with
their Udra Vigilance System, they collect these
reports directly. Directly from doctors and patients.
Yep. This gives a much broader, more real -world
picture of how safe the drug is when it's being
used routinely. And just like during trials,
drug companies have strict rules about reporting
serious and unexpected adverse events they hear
about to these agencies. Fast. From any source.
Right, any source. And they usually have something
like 15 days to report serious events that aren't
already on the drugs label. Wow, 15 days. That's
moving quickly. It is. And on top of these immediate
reports, they also have to file these big comprehensive
reports. They're called Periodic Safety Update
Reports, or PSURs, or in the US, Periodic Benefit
Risk Evaluation Reports, PDR years. They basically
summarize all the adverse events reported during
a certain time period, plus any new safety findings.
How often do they have to file those? It depends.
Often every six months in the beginning, after
approval, then annually. Regulatory agencies
go through these reports with a fine -toothed
comb to keep assessing the drug's safety over
time. So what happens if they spot new risks
or safety concerns during these reviews? They
can step in and make changes to how the drug
is used or described. Could be anything from
adding warnings to of the label, restricting
who can use it, sending out dear doctor letters
to healthcare providers about new safety info.
So those letters are like a heads up to doctors.
Yeah, basically. And in really serious cases,
they can even temporarily pull the drug off the
market if they think the risks outweigh the benefits.
So they're not messing around. No. You also mentioned
something called active surveillance. How does
that fit into all this post -market safety stuff?
Active surveillance, it's like an extra layer
of monitoring. Instead of waiting for reports
from doctors and patients, systems like the FDA's
Sentinel Initiative take a more proactive approach.
They use huge electronic healthcare databases
and insurance claims data to actively search
for potential safety red flags. So they're not
just waiting for things to come to them. Right,
like they might track if there's a spike in a
specific condition, like a certain type of heart
problem in people who recently started taking
a new drug, all by analyzing these massive data
sets. That's incredible. It's a way to catch
potential safety problems that might slip through
the cracks with just passive reporting. Because
let's face it, not every adverse event gets reported.
Right. Some people might not even realize they
need to report something. Exactly. So active
surveillance uses real -world data to back up
the info from clinical trials and those direct
reports. Before we wrap up, I wanted to touch
on one more safety measure from the Anti -Cancer
Drug Development Guide. Exclusion criteria in
clinical trials. How do those help keep patients
safe? Oh, exclusion criteria. Those are super
important. Basically, they're a set of characteristics
that disqualify someone from participating in
a specific trial. So it's about who's allowed
in and who's not. Right. And it's a safety measure
right from the start. It helps avoid including
people who might be more likely to have adverse
events or who might not handle the treatment
well. The guide gives an example from oncology
trials about previous chemo treatment. There's
usually a required waiting period like four weeks
or even six weeks if they had certain types of
chemo before they can join a new trial. So they
have to be fully recovered from the previous
treatment. Yeah, and make sure they've had enough
time to bounce back from any lingering side effects
before being given the new drug. Otherwise, it'd
be hard to tell what's causing it. new problems
like is it the new drug or a leftover effects
from the old treatment exactly and the guide
also points out that a lot of early phase studies
have a waiting period usually at least two weeks
for any meds that might interact with the study
drug interact like clash with each other yeah
like if they both need the same enzyme in the
body to be broken down it's all about being proactive
and minimizing the risk of those unexpected interactions
and potentially making the side effects worse
so yeah exclusion criteria are about carefully
choosing who gets into the study to minimize
risks from day one. This has been such a fascinating
look into how adverse events are managed in these
huge clinical trials. It's clear that there are
all these systems and processes working together
to make patient safety the top priority. I agree.
It's impressive. We've covered so much. We talk
about what adverse events are and how tricky
they can be to spot in these large studies. Right.
And how important the NCI CTC is in standardizing
things. And then there's the whole layered approach
to safety in trials involving multiple centers,
the power of data integration, and how safety
monitoring continues long after a drug's approved.
We even touched on those upfront safety measures,
the exclusion criteria. It really highlights
that keeping new medicine safe in these big clinical
trials isn't just a one time thing. It's an ongoing
commitment throughout the whole process. A constant
balancing act between getting solid data and
protecting the patients who volunteer for these
studies. Couldn't have said it better myself.
And thinking about all this, you know, the monitoring,
the standardized tools, how data analysis is
getting more advanced all the time. It really
makes you think about how confident we can be
in the safety of the medicines that end up being
prescribed by our doctors. to ponder. It really
is.