47 - Designing Phase 1 Safety Trials (S4E2)

Welcome back everybody for another deep dive.
And you know, today we're really stepping into
some uncharted territory, at least for us. I
think we're gonna be talking about phase one
safety trials. Oh, very exciting. Yeah, you know,
the very first time a new drug is tested in humans.
Right. And we're gonna be talking all about how
these trials are designed to... You know really
make sure that volunteer safety is the absolute
top priority. Yeah safety first Yeah, so we're
gonna dig into things like dosing strategies
ethical considerations and all those really strict
regulations that govern this this super critical
stage of drug development Absolutely, I think
you know it's really fascinating because when
people think about phase one trials They think
about you know is it safe, but there's actually
a lot more to it than that though interesting
Yeah, it's not just about you know is this drug
gonna hurt somebody, but really how does it behave
in the human body? How? How is it absorbed? How
is it broken down? What happens to it? The whole
process. So it's like a whole body experience
for the drug. Exactly. It's getting to know the
drug really intimately. That's a great way to
put it. I think one of the things that always
surprises people is that phase one trials often
use healthy volunteers instead of patients. That's
very true. So let's unpack that a little bit.
Why healthy volunteers when we're talking about,
say, a new cancer drug? Right. It might seem
counterintuitive at first, but it's all about
isolating the effects of the drug. Imagine you're
trying to listen to a really faint signal, and
there's a lot of background noise going on. It's
really hard to make out what that signal is,
so healthy volunteers are kind of like that quiet
room. They provide a cleaner slate so we can
really see what the drug is doing without the
added complexity of a pre -existing disease.
So you're saying like a healthy volunteer is
almost like a baseline, like this is how the
drug acts in a healthy person and then from there
you can kind of extrapolate. Exactly. It's all
about starting with a controlled environment.
Okay, that makes a lot of sense. But how do researchers
figure out what a safe dose is to start with?
That's a great question and it's certainly not
a guessing game. Yeah, you can't just, you know,
pick a number out of a hat. No, there's a lot
of work that goes into it before we even get
to that first human dose. Okay. So researchers
use data from you know, pre -clinical studies,
which are done in animals. Right. And they also
use sophisticated computer modeling techniques.
Wow. To try to predict what a safe stargoyze
would be. So it's like a combination of really
detailed science and then also, like you said,
informed estimations. Precisely. It's like taking
a very calculated first step into uncharted territory.
I like that analogy. And once you have that,
you know, that initial dose, then you go into
what's called dose escalation. Exactly, dose
escalation. So it's a very carefully controlled
process where we gradually increase the dose
that's given to small groups of volunteers and
we're looking for signs of any side effects.
So it's like slowly turning up the volume, you
know, just to see where things start to get a
little bit too loud. I like that analogy. Yeah,
it's finding that sweet spot. the highest dose
that we can give without causing unacceptable
side effects. And that's where we get to the
maximum tolerated dose, the MTD. Exactly. And
that's one of the primary goals of a phase one
trial. It helps inform dosing for later trials
and ensures that patients down the line aren't
exposed to unnecessarily high doses. So it's
really like a safety measure. Absolutely. Safety
is paramount. Absolutely. But how do we know?
How do we ensure that the volunteers themselves
are protected, ethically speaking? Yeah, that's
a really important consideration and this is
where informed consent comes in. Volunteers really
need to fully understand the potential risks
and benefits before they even think about participating.
And it's not just about signing on the dotted
line, right? No, it's not about just checking
a box. It's about a genuine conversation and
understanding between the researchers and the
volunteers. So it's a true dialogue back and
forth. Absolutely. Volunteers need to be able
to ask questions, air their concerns, and just
feel confident that they're making an informed
choice. Right. And that's where I think institutional
review boards, the IRBs, come in, right? Exactly.
I've heard that term before, but I'm not exactly
sure what they do. Yeah. So IRBs are like independent
ethical watchdogs. OK. They're there to protect
the rights and well -being of the volunteers.
Got it. So they carefully review the trial protocol,
which is like the plan for the entire study.
Right. And they make sure that it meets the highest
ethical standards. So they're kind of like a
second set of eyes making sure that everything
is above board. Exactly. And they have the authority
to approve, modify, or even reject a trial protocol
if they have concerns. Oh, wow. So they have
a lot of power. They do. And it's a really important
safeguard to make sure that research is conducted
ethically. That's great. That's really reassuring
to know. And I think it's a good point to maybe
dig into the trial protocol a little bit more,
like what kind of information is actually in
that document. Yeah. So it's basically the instruction
manual for the whole trial. It outlines everything
from who can participate, you know, like inclusion
and exclusion criteria to the dosing schedule,
how we're going to monitor safety. what we're
measuring, which we call endpoints, and how we're
going to analyze the data. So it really is like
a blueprint for the whole study just laid out
in a very meticulous way. Exactly. It's all about
consistency and minimizing risks. And speaking
of minimizing risks, you mentioned adaptive safety
measures. Yes. In the intro, can you talk a little
bit about how those work? Sure. So imagine you're
captaining a ship. through uncharted waters.
You have a plan, you have your charted course,
but you also need to be prepared to adjust based
on the weather or maybe you hit some unexpected
obstacles. So adaptive safety measures are kind
of like those course corrections in the trial.
They're predefined rules that are built into
the protocol that allow us to modify the trial
based on new safety data. Oh, that's interesting.
Yeah. So for example, if we see a certain dose
level is causing some unexpected side effects,
the protocol might say, OK, pause that dose level
or even stop it completely. So it's not just
about rigidly following a plan. It's also about
having that flexibility to really respond to
what the data is telling you. Absolutely. We
want to be responsive and ultimately keep our
volunteers safe. that makes a lot of sense. And
it kind of makes me think about, you know, who
sets the standards for these trials? You know,
who makes sure that everybody's playing by the
rules? Right, well that's where regulatory agencies
come in. So, in the U .S. we have the FDA, the
Food and Drug Administration, and internationally
we have the ICH, the International Council for
Harmonization. Got it. And they set guidelines
that are followed pretty much worldwide. Wow.
For clinical trial conduct. And their main goals
are to ensure safety. scientific rigor, and that
the data we're collecting is accurate. So they're
kind of overseeing this whole process of drug
development and making sure that it's done in
a safe and ethical way? Exactly. Their regulations
cover everything from trial design and data collection
to reporting adverse events and protecting volunteer
confidentiality. It's amazing to me that even
before a drug reaches a human volunteer, There's
this whole ecosystem already in place. Oh, absolutely.
There's so much that happens behind the scenes.
That's wild. Before we even get to that first
human dose. And I know one of those things is
non -clinical safety studies. Yes. So can you
talk a little bit about this? Yeah. So these
are studies that are done in animals before any
human testing can begin. Wow. So even before
a human is involved. You're already doing safety
testing. Yes. We want to gather as much information
as we can to make sure it's safe to move into
humans. Right. So these preclinical studies include
things like toxicology studies. So we look at
the effects of the drug on different organs.
OK. We do safety pharmacology studies to assess
the effects of the drug on things like heart
function and breathing. Right. And we do genotexicity
tests to make sure the drug doesn't damage DNA.
So you're really building up this foundation
of safety data. Exactly. It's like building a
house. You know, you wouldn't build the roof
before the foundation is solid. Right. Right.
That's a good analogy. It's incredible how much
work goes into ensuring the safety of these trials.
I think it really speaks to the commitment to
protecting these volunteers. It does. And I think
it's important to acknowledge, you know, their
willingness to participate is essential for advancing
medical research and bringing new therapies to
those who need them. Absolutely. And speaking
of the volunteers, I think it would be really
fascinating to dive into their motivations a
little bit. Like what makes someone sign up for
a trial knowing that there could be risks and
discomfort involved? Yeah, that's a great question.
So I think that's what we'll talk about after
a quick break. Sounds good. Yeah, it really is
a question that I think gets at the heart of
the human spirit. Why would someone willingly
subject themselves to, you know, potential risks
for the sake of science and the well -being of
others? Yeah, you know, it's got to be altruism.
This desire to help advance medicine and to contribute
to something larger than themselves. Altruism
is definitely a huge factor for a lot of volunteers.
They see it as a chance to make a real difference,
to potentially help future patients who might
benefit from the drug being tested. Yeah. It's
a very selfless motivation. Yeah, it really is.
It's inspiring to think that people are willing
to put themselves on the line like that. But
let's be honest, there's also a financial incentive.
Right. Financial compensation is often provided
to volunteers. And these trials can be pretty
time consuming and demanding. They involve multiple
visits, medical procedures, sometimes even overnight
stays. So it's only fair to compensate people
for their time and effort. Right. And I think
it's not just about the compensation itself.
It's also acknowledging that. participating in
a trial can sometimes mean travel expenses, lost
wages, maybe child care costs, things like that.
Absolutely right. It's important to consider
the whole picture. And for some volunteers, that
financial compensation might be the deciding
factor in their ability to participate. Right.
So it's not always a black and white situation.
It could be a combination of altruism and these
financial considerations. Exactly. Each individual
has their own unique set of motivations. And
for some people, you know, the financial aspect
might be secondary to their desire to really
contribute to science. Yeah. And for others,
it might be the primary driver. And, you know,
there's no judgment either way. Yeah, it's just
a reminder that even within this really scientific
setting, human behavior is really complex. Absolutely.
It's never straightforward. Yeah. And I think
beyond altruism and financial incentives, there
could be other personal motivations at play.
Right. Some volunteers are just really curious
about the research process. Oh, interesting.
They want to understand how clinical trials work,
how drugs are developed. They want to learn more
about their own bodies, maybe even be a part
of cutting edge medical advancements. So they
have this kind of desire to explore the unknown.
Right, they want to be on the frontier of discovery.
I love that. And then I think for some people,
it's even more personal. If we're talking about
trials for serious or life -threatening conditions,
some volunteers might be hoping to access a potentially
beneficial treatment earlier than they would
otherwise, even if it's still experimental. Yeah,
that's a really important point. difficult reality
to acknowledge, you know, these volunteers might
be driven by hope or even a sense of desperation.
Right. So it's crucial that they're fully informed
about the potential risks and benefits and that
their expectations are managed realistically.
Right. And that kind of brings us back to informed
consent, making sure that volunteers really understand
what they're getting into, both the potential
upsides and the potential downsides. Absolutely.
It's the foundation of ethical research. Yeah.
And it's a reminder that even within, you know,
this highly structured scientific process like
a clinical trial, the human element is always
there. Always, and it's complex. Yeah, it's about
understanding not just the science, but the people
involved, their motivations, their hopes, their
fear. You said it perfectly. It's about seeing
the whole person and approaching their participation
with sensitivity and respect. Well said. So we've
really gone deep today. We've explored the design
of these Phase 1 safety trials, from dose escalation
and adaptive safety measures to the role of regulatory
agencies and IRBs. We've covered a lot of ground.
Yeah. And we've delved into the motivations of
the volunteers themselves, recognizing that it's
often a mix of altruism, financial considerations,
scientific curiosity, and personal hopes. And
I think we've highlighted how important it is
to consider the human element throughout the
entire process. Absolutely. And as we wrap up
this part of our deep dive, I'm kind of curious
about the emotional impact on the volunteers.
What kind of support do they receive during the
trial? How do they cope with all the uncertainty
and the potential potential risks. Those are
great questions and I think, you know, they deserve
further exploration. Yeah, I think it's an essential
aspect of, you know, doing research responsibly.
Absolutely. Ensuring the well -being of these
volunteers both physically and emotionally has
to be a top priority. So how do we make sure
they're supported? Well, it all starts with communication.
It's about building a connection, right? Not
just, you know, seeing them as a subject in a
study. Exactly. It's about fostering trust. Mutual
respect. Researchers need to be approachable,
willing to answer questions honestly and address
any concerns the volunteers have. It really is
a two -way street. Yeah, so it's not just about,
you know, giving them information. It's about
creating a space for Right, and you know, it
goes beyond just the researchers. A lot of trial
sites have, you know, dedicated staff nurses,
social workers, things like that, who are trained
to provide emotional support and guidance. Oh,
wow. They're there to help the volunteers, you
know, navigate the challenges of the trial, cope
with any anxiety or stress they might be feeling.
This is like a built -in support system, right?
Yeah, exactly. People they can turn to if they're
feeling overwhelmed or, you know, just need someone
to talk to. And I imagine... You know, in some
cases, support groups or peer networks could
be really valuable, too. Oh, absolutely. Connecting
with others who have gone through similar experiences,
you know, can create that sense of community
and shared understanding. Yeah, there's something
so powerful about knowing you're not alone, right?
Exactly. And these support networks can provide
practical advice, emotional support, and just
a safe space to share their feelings and experiences
without judgment. It's so interesting to me how
this aspect of support, you know, this human
connection. can be just as important as the medical
monitoring. It really does highlight the importance
of treating volunteers as partners in the research
process. Their contributions are invaluable and
their well -being should be a top priority. So
well said. And as we wrap up this deep dive,
I just want to kind of circle back to what we've
learned about designing these phase one safety
trials. It's a meticulous process with safety
at the forefront of every decision, but there's
also this really profound human element that
we can't overlook. Right, from the rigorous protocols
and oversight by regulatory agencies to the careful
selection of volunteers, the emphasis on informed
consent, these trials are really designed to
minimize risks and gather solid safety data.
We've seen how crucial it is to provide that
ongoing support for the volunteers, recognizing
that their participation is so much more than
just taking a drug. Absolutely. It's about acknowledging
their courage, their commitment to advancing
medical science, and just ensuring their well
-being throughout the entire process. Yeah. It's
a good reminder that progress in medicine isn't
just about data and molecules. It's also about
empathy and compassion and the incredible individuals
who make these trials possible. I couldn't agree
more. Well, this has been such a fascinating
conversation. I feel like I've learned so much
about phase one safety trials. Thank you so much
for joining me today. It's been my pleasure.
And to all of our listeners, thank you for joining
us on this deep dive into the world of Phase
I safety trials. Until next time, keep exploring,
keep learning, and keep diving deep.