January 28, 2025 • 19 mins
In this episode, we delve into the fascinating world of pre-clinical drug development—the critical stage where scientists determine whether a drug is safe and effective enough to move to human trials. Often overlooked, this phase lays the groundwork for every new medical breakthrough.
We explore:
- The rigorous pre-clinical studies, including safety pharmacology, toxicology, PK/PD (pharmacokinetics and pharmacodynamics), and genotoxicity testing.
- The role of the Investigational New Drug (IND) application, the gateway to human trials, and its key components like safety data, manufacturing processes, and clinical trial protocols.
- The ethical challenges of animal testing and the promising rise of alternatives like in vitro studies and computer modeling.
- Insights into how biostatistics shapes the understanding of pre-clinical data, ensuring the findings are reliable and meaningful.
Discover how the U.S. Code of Federal Regulations (CFR), Title 21, provides the framework for pre-clinical safety and why this phase is vital in bringing safe, effective drugs to market.
Takeaway Thought: Pre-clinical development may be behind the scenes, but it’s where the journey begins—filled with challenges, innovation, and the hope of life-changing discoveries.
Stay curious, keep learning, and join us as we uncover the meticulous effort behind every medical breakthrough!
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Transcript
Episode Transcript
Available transcripts are automatically generated. Complete accuracy is not guaranteed.
(00:00):
Welcome back.
(00:00):
Looks like we're diving into preclinical development
this time.
You know, that stage where scientists figure out
if a drug is safe and effective enough to even test on people.
Yeah, it's kind of under the radar, but super important.
It's where everything starts.
We're talking safety pharmacology, toxicology,
and of course, that IND, the Investigational New Drug
Application, to get the FDA's OK to move to human trials.
(00:24):
And you sent over some excerpts from the Code
of Federal Regulations, Title 21, right?
The rule book for pharmaceuticals in the US.
So we're going to see how these regulations shape
preclinical development.
Exactly.
Think of Title 21 as like the game board
for developing drugs in the US.
Manufacturing, labeling, preclinical research,
it's all in there.
OK.
So what do these regs tell us about the FDA's approach
(00:46):
to safety in this preclinical stage?
Well, one interesting thing is the FDA's focus on safety
isn't just for drugs.
You sent over part of 21 CFR, part 110, all about sanitation
and food manufacturing.
Right, I was wondering about that one.
Seemed a little out of place.
It might, but it shows you the FDA's mindset.
If they're that strict about food,
imagine how carefully they look at medicine.
(01:08):
That's a good point.
That's a high bar for drug companies.
And what about part 111, dietary supplements?
Similar idea.
Supplements don't have the same testing as drugs,
but the FDA still wants specifications, you know,
for identity, purity, strength, and limits on contamination.
It shows they care about safety for everything,
even stuff that's not regulated as strictly
as pharmaceuticals.
(01:29):
So it's like the CFR is giving us
a peek into the FDA's whole philosophy on keeping
stuff people consume safe.
Absolutely.
OK, now let's get into the core of what you wanted to look at.
Preclinical testing.
That's where 21 CFR, part 312 comes in the part about INDs.
Right, that's the application drug developers need before
even thinking about human trials.
(01:50):
Exactly.
The INDs got to be a really solid document,
making the case for why testing this drug in humans
is safe and scientifically sound.
The FDA will totally reject it if they're not
convinced about safety or the trial design.
I bet that takes a ton of evidence.
What goes into an IND to prove a drug is safe enough?
A lot of it is about preclinical studies.
There are two main types, safety pharmacology and toxicology
(02:13):
studies.
Safety pharmacology looks at how the drug might
affect major organ systems.
Like heart, lungs, brain, that kind of thing.
Exactly.
We got to find any problems early on before even thinking
about giving it to a person.
I see.
So if a drug makes a heartbeat irregularly in an animal,
that's a huge red flag, right?
Absolutely.
It's all about minimizing risk and protecting the people
(02:34):
in those clinical trials.
Now, toxicology studies are the other piece of the puzzle.
They often do dose ranging studies in animals.
Dose ranging, what for?
Well, they want to find two things.
The NOAEL, that's the no observed adverse effect
level, the highest dose without serious toxicity,
and the MTD or maximum tolerated dose.
OK, I see why those are important.
(02:56):
If you're going to test on humans,
you need to know what dose is safe, right?
Right.
That's where NOAEL comes in.
Helps figure out a safe starting dose for human trials.
And the MTD tells you the upper limit
before it gets too toxic.
Makes sense.
But isn't there a problem here?
We're trying to learn if it's safe for humans,
but have to test on animals first.
You've hit a major ethical issue in drug development.
(03:18):
Scientists and regulators are always
trying to balance needing data with animal welfare.
It's a constant debate, but animal testing
is still crucial to avoid potential harm to humans.
So necessary but not perfect.
How do scientists actually take what they learn from animals
and apply it to people?
There must be big differences between species.
Oh, absolutely.
(03:39):
Trying to predict what will happen in humans based
on animals is tough.
That's why they use different tools to get the best
prediction they can.
Like what?
Well, there are PK studies, pharmacokinetic,
to see how a drug is absorbed, spread around, broken down,
and eliminated in different species.
This helps them figure out doses and predict
what might happen in a human.
Like mapping the drug's journey, considering
(04:00):
how each species is different.
Exactly.
Then we got PD studies, pharmacodynamic,
to see how the drug affects the body and how it works.
This helps understand how it works at the cellular level
and how it might interact with the different systems.
So it seems like the safety pharmacology, toxicology, PK,
PD all comes together to give a complete picture of the drug
(04:20):
safety.
That's it.
And all of this has to be documented and explained
super carefully in the IND application.
The FDA folks are going to look at every bit of it
to be sure the preclinical stuff supports
moving to human trials.
But we'll get more into the IND itself next time.
Sounds good.
So we've got the ground rules from the CFR.
We know the types of preclinical studies.
(04:42):
And next, we tackle the IND.
Welcome back.
Let's dig deeper into these preclinical safety studies.
You know, the heart of the IND.
We talked about those main types, safety pharmacology
and toxicology.
But can we break those down more?
What are some specific toxicology studies
they usually do?
Sure thing.
You've got your acute toxicity studies.
Those are kind of like a first look
(05:03):
at how harmful a drug might be.
They give a single dose to the animals
and then watch them for a short time, usually about two weeks.
So what are they looking for in those two weeks?
Mainly, immediate bad effects.
It helps them figure out the severe toxicity dose.
That helps set a safety margin for those first human trials.
So basically, understanding those short term effects.
(05:25):
Gotcha.
But what about long term effects?
I mean, a drug could have subtle effects
you wouldn't see in just two weeks.
You're absolutely right.
And that's where repeated dose toxicity studies come in.
This time, they give the drug to the animals for a longer time.
Could be weeks, even months.
So it's about finding those longer term or cumulative effects
that wouldn't show up in a short study.
(05:45):
Exactly.
These studies can also help find organs
that are particularly sensitive to the drug,
ones that might be more vulnerable to its effects.
Oh, and they can also show if the side effects get worse
with higher doses.
So we've got the acute and repeated dose studies.
And they tell us about the general toxicity.
But what about specific concerns?
Like, could the drug cause cancer?
(06:06):
That's a big one.
We need to look at genotoxicity studies.
Those are all about figuring out if the drug can damage DNA,
the genetic material in cells.
Damage DNA.
That sounds serious.
What's the big worry there?
Well, DNA damage can cause mutations,
which are changes in the genetic code.
And sometimes, those mutations can lead to cancer.
(06:26):
So these genotoxicity studies are
like looking for early warning signs,
seeing if the drug might increase the risk of cancer
down the line.
Exactly.
Researchers use a bunch of different tests
to figure out if a drug might be genotoxic.
Some are done in vitro, meaning in test tubes or petri dishes,
using bacteria or other types of cells.
So they're basically using simpler systems
(06:47):
to see if the drug messes with genes at a cellular level.
Right.
And then there are in vivo tests, which means
they're done in living animals.
Those often involve looking at the animal's bone marrow cells
to see if there's any chromosome damage.
It sounds like they're really trying
to get a complete picture of whether the drug can damage DNA
using both in vitro and in vivo methods.
(07:08):
They are.
And that data is super important for understanding
the long-term risks, even if those risks don't show up
in the short-term toxicity studies.
Now, what about fertility in pregnancy,
effects on the fetus in development?
Those seem pretty crucial before going to human trials.
Absolutely crucial.
Those are called DART studies, developmental and reproductive
(07:31):
toxicity.
They help us understand the risks a drug might
pose to future generations.
So what do those studies look like?
Well, they expose the animals to the drug at different points,
like before conception, during pregnancy,
even while they're nursing.
Then they look at what happens to the reproductive organs,
how the fetus grows, and if there are any birth defects.
Wow.
(07:51):
So they're trying to see how a drug could affect
the whole reproductive process.
That's the goal.
And they're really important for protecting pregnant women
and their babies, who are especially
vulnerable to drug effects.
So all these toxicology studies, acute repeated dose,
genotoxicity, and DART, they're all key parts of figuring out
a drug's safety, right?
They are.
(08:11):
And all that data, along with the safety pharmacology stuff,
makes up the non-clinical pharmacology and toxicology
section of the IND application.
All right.
We touched on the IND a bit last time.
Can we dive into that more now?
I'm curious, what actually goes into putting one
of those applications together?
Sure.
The IND is like a giant document that
sums up everything the drug developers know
(08:31):
about the drug so far.
It has a bunch of sections, each with its own purpose.
OK.
Walk me through those.
What's usually in an IND?
Well, first, you have the introduction.
It's like a high-level overview.
What's the drug for?
What medical need does it address?
How is it supposed to work in the body?
So it's like setting the stage for the rest
of the application, right?
Exactly.
Gives the FDA reviewers some background
(08:52):
and helps them see why the drug's worth studying
in humans.
OK.
What's next?
Then you have the CMC section, chemistry, manufacturing,
and controls.
This one can be the toughest, technically.
It's all about the drug itself, how it's made,
and how they make sure each batch is good.
So things like the chemical structure, the manufacturing
(09:12):
process, how they ensure consistency and quality.
You got it.
The FDA needs to be sure the drug can
be made consistently and reliably before anyone
takes it.
It's wild to think about all that behind-the-scenes work,
just to make sure a drug is safe and effective before it even
gets to a patient.
Oh, it's a huge process, no doubt.
And then we have the section we've been talking about,
(09:33):
nonclinical pharmacology and toxicology.
All those preclinical studies come together here,
telling the story of the drug's safety.
So all that data from the acute, repeated dose, genotoxicity,
and DART studies, plus the safety pharmacology,
it all gets put together and analyzed here.
Exactly.
The sponsor has to present a clear story,
(09:53):
highlighting the main findings, and explaining
what it all means for the drug's overall safety.
I imagine that's a really important part for the FDA
reviewers.
Oh, definitely.
This is where they really dig into the data
and decide if it's safe enough to start human trials.
OK, we've got the intro, the CMC, and the preclinical study
section.
Anything else in the IND?
The last big part is the clinical protocols.
(10:14):
That's the plan for the first studies in humans,
the phase one trials.
So this is where it gets real.
Preclinical research turns into actual human testing.
It is.
The protocols lay out everything about the planned trials,
the study design, who they'll enroll,
what doses they'll test, how they'll monitor for safety,
and what they'll look at to see if the drug works.
(10:35):
It sounds like a lot of planning goes into these clinical trials.
Absolutely.
And the FDA reviews these protocols very carefully.
They've got to make sure the studies are designed to protect
the people participating and that the data will be reliable.
So the IND is like a roadmap, taking the drug from the lab
to the clinic.
That's a perfect way to put it.
But submitting the IND isn't the end.
(10:55):
The FDA plays a big role, too.
Right, what happens after they get the IND?
Do they just glance at it and give the OK?
Not quite.
A team of FDA scientists and clinicians
review it very carefully.
They look at everything, the preclinical data,
the manufacturing info, and those clinical trial plans.
So they're looking for any problems,
anything that might put the people in the trials at risk.
(11:17):
You got it.
They also think about the potential risks and benefits
of the trials, making sure they're
ethical and scientifically sound.
They've got 30 days to review it.
And if they're happy, the sponsor can start the trials.
But what if the FDA isn't happy?
What happens then?
That's when things can get complicated.
The FDA can put a clinical hold on the IND.
(11:39):
That stops the sponsor from starting the trials
until they fix whatever the FDA is concerned about.
So it's not just a rubber stamp.
The FDA has real power when it comes to drug development.
Absolutely.
They have to protect the public, and they take that really
seriously.
This is all fascinating.
I had no idea how much scrutiny and oversight
goes into drug development.
It's a lot.
And it all begins with those preclinical stutters.
(12:00):
They set the stage for everything else.
Speaking of preclinical studies, I'm
curious about the ethics of animal testing.
We talked about the science, but I know that raises
a lot of ethical questions.
You're right.
It's a complex issue and one that deserves careful thought.
Can you tell me more about the rules and guidelines
for using animals in research?
Sure.
In the US, animal research is governed by federal regulations,
(12:23):
mainly the Animal Welfare Act.
And what does that cover?
It sets standards for how animals used in research
should be cared for and treated.
Everything from their living conditions, cage size,
temperature, food, water, to vet care and managing pain.
So it's about making sure the animals are treated humanely
and that their well-being is a priority.
(12:44):
Exactly.
The goal is to keep any unnecessary pain or distress
to a minimum.
There are also regulations on the types of studies
you can do.
Can you give some examples?
Well, the FDA has good laboratory practices or GLP
guidelines.
These are for making sure non-clinical studies are
high quality, things like keeping good records,
(13:04):
managing data, and making sure the people doing the research
are trained.
So it's not just about the animal's well-being,
but also making sure the research itself is top-notch.
Exactly.
And there's another layer, too.
Before any research using animals can start,
it has to be approved by an Institutional Animal Care and
Use Committee, or IACUC.
What do they do?
The IACUC is an independent group
(13:25):
that oversees all animal care and use at a research place.
It's got scientists, vets, and people from the public.
They look at every research plan involving animals.
They make sure it's necessary that the animals will
be treated well and that they're using the fewest animals
possible.
So the whole system of checks and balances,
regulations, guidelines, and ethical review
(13:45):
to make sure the animals are treated humanely
and the research is done responsibly.
That's it.
It's about balancing the need for scientific progress
with treating animals ethically.
It's tough, but a vital part of drug development.
Now, we talked a lot about getting data
from preclinical studies, but what about analyzing it?
I bet it's not always easy to figure out
what those toxicology and safety pharmacology results mean.
(14:08):
You're right.
Collecting data is one thing.
Understanding it is another.
That's where biostatistics comes in.
Biostatistics.
What's that?
It's basically statistics applied to biology
and medical research.
Biostatisticians are experts at analyzing data
and making sense of it.
So they help researchers understand all those numbers.
They do.
They play a huge role in designing preclinical studies,
(14:29):
analyzing the data, and figuring out
if the results are statistically significant.
Statistically significant.
Meaning what, exactly?
It means the results probably didn't just happen by chance.
It's a way to be sure the findings are solid
and can be trusted.
Makes sense.
So biostatisticians are like quality control for the data
going into the IND.
(14:49):
That's a good way to think about it.
They also help the FDA understand the data
and evaluate the drug's safety.
The FDA wants the data presented clearly
with the right statistical analysis
to back up the conclusions.
So it's not just about throwing numbers at the FDA.
It's about telling a story with the data.
That's it.
The data has to be clear, concise, and convincing.
(15:10):
That's where biostatisticians really come in.
It's amazing how all these different fields, toxicology,
pharmacology, biostatistics, work together
to show a drug is safe.
It takes a whole team, that's for sure.
And it all leads up to that IND application, which
opens the door to human trials.
Well, we covered a lot this time.
Different toxicology studies, the ins and outs
of the IND application, even the ethics of animal research.
(15:33):
It's been a fascinating journey.
It has.
But we're not done yet.
Next time, we'll look at some of the bigger challenges
and debates around preclinical development
and think about the future of drug safety testing.
Sounds intriguing.
I'm ready for the last part of our deep dive.
So we've really gotten into the details
of preclinical development.
The studies, the regulations, the whole IND process.
(15:55):
But I'm wondering, what are some of the big challenges
in this stage, things researchers are still
trying to figure out?
Oh, there are plenty.
One of the biggest is that animal models aren't perfect.
They give us a lot of info, but there's always
some uncertainty when you're trying
to apply that data to humans.
Right.
We're similar to animals, but not exactly the same.
Something that seems safe and effective in, say, a mouse,
(16:17):
might not be the same in a human.
Exactly.
The way different species function, their metabolism,
even how they get diseases, it can all be different.
So it's hard to be totally sure based just on animal studies.
So a drug could look amazing in animals
and then fail in human trials.
Yeah, more often than you'd think.
And the other way around, too.
A drug that might really help people might not
(16:39):
look good in animal studies.
That's tricky.
It makes you wonder how much we can rely on these animal models.
Are they working on ways to make them better, more accurate?
Oh, yeah.
Tons of research going on there, refining the experiments,
improving the animal models, finding better ways
to analyze and understand the data.
So constantly trying to get more out of these studies
and close that gap between animal data
(17:01):
and what happens in humans.
Yep, that's the key.
And there's also a lot of interest in alternatives
to animal testing, like in vitro testing with human cells
and computer modeling.
The in vitro stuff sounds promising,
using actual human cells.
Is that becoming more common in preclinical work?
It is, especially for things like genotoxicity and safety
(17:21):
pharmacology.
Sometimes they give you more relevant data
than animal studies.
But I guess there are limits to in vitro, too.
You can't really mimic the whole human body in a dish.
True.
There's no perfect model, animal, or in vitro.
The key is to use the best tools and know what the limitations
are for each one.
Like putting a puzzle together, using
(17:42):
all these different pieces of evidence, animal studies,
in vitro tests, even computer models,
all to get the clearest picture of a drug's safety.
Great analogy.
And it really shows how important critical thinking
and scientific judgment are through this whole process.
So preclinical development is always changing, then.
Researchers are always looking for better methods
(18:03):
and trying to predict more accurately what
a drug will do in people.
Absolutely.
And as technology gets better, as we learn more
about how the human body works, I
think we'll see even more cool innovations
in preclinical development.
Well, it sounds like we've covered
a lot in this deep dive.
All those preclinical studies, the details of the IND,
even some of the ethical and scientific challenges.
It's been a really interesting look into this world.
(18:25):
It has been.
And hopefully you've got a better grasp
of how important preclinical development is.
It's a huge part of getting a new drug all the way to market.
I definitely do.
It's amazing how much effort goes
into making sure a drug is safe, even before it
gets anywhere near a patient.
It really shows how dedicated everyone is,
the scientists, the regulators, everyone
(18:46):
working to develop treatments and cures
for all kinds of diseases.
So as you keep learning about pharmaceuticals,
remember preclinical development is where it all starts.
It's full of challenges, things we don't know for sure,
even ethical questions.
But it's also full of hope and the possibility
of discovering something that could change lives.
Thanks for joining us on this deep dive.
(19:07):
Until next time, keep exploring, keep learning,
and keep those good questions coming.
Welcome back.
(00:00):
Looks like we're diving into preclinical development
this time.
You know, that stage where scientists figure out
if a drug is safe and effective enough to even test on people.
Yeah, it's kind of under the radar, but super important.
It's where everything starts.
We're talking safety pharmacology, toxicology,
and of course, that IND, the Investigational New Drug
Application, to get the FDA's OK to move to human trials.
(00:24):
And you sent over some excerpts from the Code
of Federal Regulations, Title 21, right?
The rule book for pharmaceuticals in the US.
So we're going to see how these regulations shape
preclinical development.
Exactly.
Think of Title 21 as like the game board
for developing drugs in the US.
Manufacturing, labeling, preclinical research,
it's all in there.
OK.
So what do these regs tell us about the FDA's approach
(00:46):
to safety in this preclinical stage?
Well, one interesting thing is the FDA's focus on safety
isn't just for drugs.
You sent over part of 21 CFR, part 110, all about sanitation
and food manufacturing.
Right, I was wondering about that one.
Seemed a little out of place.
It might, but it shows you the FDA's mindset.
If they're that strict about food,
imagine how carefully they look at medicine.
(01:08):
That's a good point.
That's a high bar for drug companies.
And what about part 111, dietary supplements?
Similar idea.
Supplements don't have the same testing as drugs,
but the FDA still wants specifications, you know,
for identity, purity, strength, and limits on contamination.
It shows they care about safety for everything,
even stuff that's not regulated as strictly
as pharmaceuticals.
(01:29):
So it's like the CFR is giving us
a peek into the FDA's whole philosophy on keeping
stuff people consume safe.
Absolutely.
OK, now let's get into the core of what you wanted to look at.
Preclinical testing.
That's where 21 CFR, part 312 comes in the part about INDs.
Right, that's the application drug developers need before
even thinking about human trials.
(01:50):
Exactly.
The INDs got to be a really solid document,
making the case for why testing this drug in humans
is safe and scientifically sound.
The FDA will totally reject it if they're not
convinced about safety or the trial design.
I bet that takes a ton of evidence.
What goes into an IND to prove a drug is safe enough?
A lot of it is about preclinical studies.
There are two main types, safety pharmacology and toxicology
(02:13):
studies.
Safety pharmacology looks at how the drug might
affect major organ systems.
Like heart, lungs, brain, that kind of thing.
Exactly.
We got to find any problems early on before even thinking
about giving it to a person.
I see.
So if a drug makes a heartbeat irregularly in an animal,
that's a huge red flag, right?
Absolutely.
It's all about minimizing risk and protecting the people
(02:34):
in those clinical trials.
Now, toxicology studies are the other piece of the puzzle.
They often do dose ranging studies in animals.
Dose ranging, what for?
Well, they want to find two things.
The NOAEL, that's the no observed adverse effect
level, the highest dose without serious toxicity,
and the MTD or maximum tolerated dose.
OK, I see why those are important.
(02:56):
If you're going to test on humans,
you need to know what dose is safe, right?
Right.
That's where NOAEL comes in.
Helps figure out a safe starting dose for human trials.
And the MTD tells you the upper limit
before it gets too toxic.
Makes sense.
But isn't there a problem here?
We're trying to learn if it's safe for humans,
but have to test on animals first.
You've hit a major ethical issue in drug development.
(03:18):
Scientists and regulators are always
trying to balance needing data with animal welfare.
It's a constant debate, but animal testing
is still crucial to avoid potential harm to humans.
So necessary but not perfect.
How do scientists actually take what they learn from animals
and apply it to people?
There must be big differences between species.
Oh, absolutely.
(03:39):
Trying to predict what will happen in humans based
on animals is tough.
That's why they use different tools to get the best
prediction they can.
Like what?
Well, there are PK studies, pharmacokinetic,
to see how a drug is absorbed, spread around, broken down,
and eliminated in different species.
This helps them figure out doses and predict
what might happen in a human.
Like mapping the drug's journey, considering
(04:00):
how each species is different.
Exactly.
Then we got PD studies, pharmacodynamic,
to see how the drug affects the body and how it works.
This helps understand how it works at the cellular level
and how it might interact with the different systems.
So it seems like the safety pharmacology, toxicology, PK,
PD all comes together to give a complete picture of the drug
(04:20):
safety.
That's it.
And all of this has to be documented and explained
super carefully in the IND application.
The FDA folks are going to look at every bit of it
to be sure the preclinical stuff supports
moving to human trials.
But we'll get more into the IND itself next time.
Sounds good.
So we've got the ground rules from the CFR.
We know the types of preclinical studies.
(04:42):
And next, we tackle the IND.
Welcome back.
Let's dig deeper into these preclinical safety studies.
You know, the heart of the IND.
We talked about those main types, safety pharmacology
and toxicology.
But can we break those down more?
What are some specific toxicology studies
they usually do?
Sure thing.
You've got your acute toxicity studies.
Those are kind of like a first look
(05:03):
at how harmful a drug might be.
They give a single dose to the animals
and then watch them for a short time, usually about two weeks.
So what are they looking for in those two weeks?
Mainly, immediate bad effects.
It helps them figure out the severe toxicity dose.
That helps set a safety margin for those first human trials.
So basically, understanding those short term effects.
(05:25):
Gotcha.
But what about long term effects?
I mean, a drug could have subtle effects
you wouldn't see in just two weeks.
You're absolutely right.
And that's where repeated dose toxicity studies come in.
This time, they give the drug to the animals for a longer time.
Could be weeks, even months.
So it's about finding those longer term or cumulative effects
that wouldn't show up in a short study.
(05:45):
Exactly.
These studies can also help find organs
that are particularly sensitive to the drug,
ones that might be more vulnerable to its effects.
Oh, and they can also show if the side effects get worse
with higher doses.
So we've got the acute and repeated dose studies.
And they tell us about the general toxicity.
But what about specific concerns?
Like, could the drug cause cancer?
(06:06):
That's a big one.
We need to look at genotoxicity studies.
Those are all about figuring out if the drug can damage DNA,
the genetic material in cells.
Damage DNA.
That sounds serious.
What's the big worry there?
Well, DNA damage can cause mutations,
which are changes in the genetic code.
And sometimes, those mutations can lead to cancer.
(06:26):
So these genotoxicity studies are
like looking for early warning signs,
seeing if the drug might increase the risk of cancer
down the line.
Exactly.
Researchers use a bunch of different tests
to figure out if a drug might be genotoxic.
Some are done in vitro, meaning in test tubes or petri dishes,
using bacteria or other types of cells.
So they're basically using simpler systems
(06:47):
to see if the drug messes with genes at a cellular level.
Right.
And then there are in vivo tests, which means
they're done in living animals.
Those often involve looking at the animal's bone marrow cells
to see if there's any chromosome damage.
It sounds like they're really trying
to get a complete picture of whether the drug can damage DNA
using both in vitro and in vivo methods.
(07:08):
They are.
And that data is super important for understanding
the long-term risks, even if those risks don't show up
in the short-term toxicity studies.
Now, what about fertility in pregnancy,
effects on the fetus in development?
Those seem pretty crucial before going to human trials.
Absolutely crucial.
Those are called DART studies, developmental and reproductive
(07:31):
toxicity.
They help us understand the risks a drug might
pose to future generations.
So what do those studies look like?
Well, they expose the animals to the drug at different points,
like before conception, during pregnancy,
even while they're nursing.
Then they look at what happens to the reproductive organs,
how the fetus grows, and if there are any birth defects.
Wow.
(07:51):
So they're trying to see how a drug could affect
the whole reproductive process.
That's the goal.
And they're really important for protecting pregnant women
and their babies, who are especially
vulnerable to drug effects.
So all these toxicology studies, acute repeated dose,
genotoxicity, and DART, they're all key parts of figuring out
a drug's safety, right?
They are.
(08:11):
And all that data, along with the safety pharmacology stuff,
makes up the non-clinical pharmacology and toxicology
section of the IND application.
All right.
We touched on the IND a bit last time.
Can we dive into that more now?
I'm curious, what actually goes into putting one
of those applications together?
Sure.
The IND is like a giant document that
sums up everything the drug developers know
(08:31):
about the drug so far.
It has a bunch of sections, each with its own purpose.
OK.
Walk me through those.
What's usually in an IND?
Well, first, you have the introduction.
It's like a high-level overview.
What's the drug for?
What medical need does it address?
How is it supposed to work in the body?
So it's like setting the stage for the rest
of the application, right?
Exactly.
Gives the FDA reviewers some background
(08:52):
and helps them see why the drug's worth studying
in humans.
OK.
What's next?
Then you have the CMC section, chemistry, manufacturing,
and controls.
This one can be the toughest, technically.
It's all about the drug itself, how it's made,
and how they make sure each batch is good.
So things like the chemical structure, the manufacturing
(09:12):
process, how they ensure consistency and quality.
You got it.
The FDA needs to be sure the drug can
be made consistently and reliably before anyone
takes it.
It's wild to think about all that behind-the-scenes work,
just to make sure a drug is safe and effective before it even
gets to a patient.
Oh, it's a huge process, no doubt.
And then we have the section we've been talking about,
(09:33):
nonclinical pharmacology and toxicology.
All those preclinical studies come together here,
telling the story of the drug's safety.
So all that data from the acute, repeated dose, genotoxicity,
and DART studies, plus the safety pharmacology,
it all gets put together and analyzed here.
Exactly.
The sponsor has to present a clear story,
(09:53):
highlighting the main findings, and explaining
what it all means for the drug's overall safety.
I imagine that's a really important part for the FDA
reviewers.
Oh, definitely.
This is where they really dig into the data
and decide if it's safe enough to start human trials.
OK, we've got the intro, the CMC, and the preclinical study
section.
Anything else in the IND?
The last big part is the clinical protocols.
(10:14):
That's the plan for the first studies in humans,
the phase one trials.
So this is where it gets real.
Preclinical research turns into actual human testing.
It is.
The protocols lay out everything about the planned trials,
the study design, who they'll enroll,
what doses they'll test, how they'll monitor for safety,
and what they'll look at to see if the drug works.
(10:35):
It sounds like a lot of planning goes into these clinical trials.
Absolutely.
And the FDA reviews these protocols very carefully.
They've got to make sure the studies are designed to protect
the people participating and that the data will be reliable.
So the IND is like a roadmap, taking the drug from the lab
to the clinic.
That's a perfect way to put it.
But submitting the IND isn't the end.
(10:55):
The FDA plays a big role, too.
Right, what happens after they get the IND?
Do they just glance at it and give the OK?
Not quite.
A team of FDA scientists and clinicians
review it very carefully.
They look at everything, the preclinical data,
the manufacturing info, and those clinical trial plans.
So they're looking for any problems,
anything that might put the people in the trials at risk.
(11:17):
You got it.
They also think about the potential risks and benefits
of the trials, making sure they're
ethical and scientifically sound.
They've got 30 days to review it.
And if they're happy, the sponsor can start the trials.
But what if the FDA isn't happy?
What happens then?
That's when things can get complicated.
The FDA can put a clinical hold on the IND.
(11:39):
That stops the sponsor from starting the trials
until they fix whatever the FDA is concerned about.
So it's not just a rubber stamp.
The FDA has real power when it comes to drug development.
Absolutely.
They have to protect the public, and they take that really
seriously.
This is all fascinating.
I had no idea how much scrutiny and oversight
goes into drug development.
It's a lot.
And it all begins with those preclinical stutters.
(12:00):
They set the stage for everything else.
Speaking of preclinical studies, I'm
curious about the ethics of animal testing.
We talked about the science, but I know that raises
a lot of ethical questions.
You're right.
It's a complex issue and one that deserves careful thought.
Can you tell me more about the rules and guidelines
for using animals in research?
Sure.
In the US, animal research is governed by federal regulations,
(12:23):
mainly the Animal Welfare Act.
And what does that cover?
It sets standards for how animals used in research
should be cared for and treated.
Everything from their living conditions, cage size,
temperature, food, water, to vet care and managing pain.
So it's about making sure the animals are treated humanely
and that their well-being is a priority.
(12:44):
Exactly.
The goal is to keep any unnecessary pain or distress
to a minimum.
There are also regulations on the types of studies
you can do.
Can you give some examples?
Well, the FDA has good laboratory practices or GLP
guidelines.
These are for making sure non-clinical studies are
high quality, things like keeping good records,
(13:04):
managing data, and making sure the people doing the research
are trained.
So it's not just about the animal's well-being,
but also making sure the research itself is top-notch.
Exactly.
And there's another layer, too.
Before any research using animals can start,
it has to be approved by an Institutional Animal Care and
Use Committee, or IACUC.
What do they do?
The IACUC is an independent group
(13:25):
that oversees all animal care and use at a research place.
It's got scientists, vets, and people from the public.
They look at every research plan involving animals.
They make sure it's necessary that the animals will
be treated well and that they're using the fewest animals
possible.
So the whole system of checks and balances,
regulations, guidelines, and ethical review
(13:45):
to make sure the animals are treated humanely
and the research is done responsibly.
That's it.
It's about balancing the need for scientific progress
with treating animals ethically.
It's tough, but a vital part of drug development.
Now, we talked a lot about getting data
from preclinical studies, but what about analyzing it?
I bet it's not always easy to figure out
what those toxicology and safety pharmacology results mean.
(14:08):
You're right.
Collecting data is one thing.
Understanding it is another.
That's where biostatistics comes in.
Biostatistics.
What's that?
It's basically statistics applied to biology
and medical research.
Biostatisticians are experts at analyzing data
and making sense of it.
So they help researchers understand all those numbers.
They do.
They play a huge role in designing preclinical studies,
(14:29):
analyzing the data, and figuring out
if the results are statistically significant.
Statistically significant.
Meaning what, exactly?
It means the results probably didn't just happen by chance.
It's a way to be sure the findings are solid
and can be trusted.
Makes sense.
So biostatisticians are like quality control for the data
going into the IND.
(14:49):
That's a good way to think about it.
They also help the FDA understand the data
and evaluate the drug's safety.
The FDA wants the data presented clearly
with the right statistical analysis
to back up the conclusions.
So it's not just about throwing numbers at the FDA.
It's about telling a story with the data.
That's it.
The data has to be clear, concise, and convincing.
(15:10):
That's where biostatisticians really come in.
It's amazing how all these different fields, toxicology,
pharmacology, biostatistics, work together
to show a drug is safe.
It takes a whole team, that's for sure.
And it all leads up to that IND application, which
opens the door to human trials.
Well, we covered a lot this time.
Different toxicology studies, the ins and outs
of the IND application, even the ethics of animal research.
(15:33):
It's been a fascinating journey.
It has.
But we're not done yet.
Next time, we'll look at some of the bigger challenges
and debates around preclinical development
and think about the future of drug safety testing.
Sounds intriguing.
I'm ready for the last part of our deep dive.
So we've really gotten into the details
of preclinical development.
The studies, the regulations, the whole IND process.
(15:55):
But I'm wondering, what are some of the big challenges
in this stage, things researchers are still
trying to figure out?
Oh, there are plenty.
One of the biggest is that animal models aren't perfect.
They give us a lot of info, but there's always
some uncertainty when you're trying
to apply that data to humans.
Right.
We're similar to animals, but not exactly the same.
Something that seems safe and effective in, say, a mouse,
(16:17):
might not be the same in a human.
Exactly.
The way different species function, their metabolism,
even how they get diseases, it can all be different.
So it's hard to be totally sure based just on animal studies.
So a drug could look amazing in animals
and then fail in human trials.
Yeah, more often than you'd think.
And the other way around, too.
A drug that might really help people might not
(16:39):
look good in animal studies.
That's tricky.
It makes you wonder how much we can rely on these animal models.
Are they working on ways to make them better, more accurate?
Oh, yeah.
Tons of research going on there, refining the experiments,
improving the animal models, finding better ways
to analyze and understand the data.
So constantly trying to get more out of these studies
and close that gap between animal data
(17:01):
and what happens in humans.
Yep, that's the key.
And there's also a lot of interest in alternatives
to animal testing, like in vitro testing with human cells
and computer modeling.
The in vitro stuff sounds promising,
using actual human cells.
Is that becoming more common in preclinical work?
It is, especially for things like genotoxicity and safety
(17:21):
pharmacology.
Sometimes they give you more relevant data
than animal studies.
But I guess there are limits to in vitro, too.
You can't really mimic the whole human body in a dish.
True.
There's no perfect model, animal, or in vitro.
The key is to use the best tools and know what the limitations
are for each one.
Like putting a puzzle together, using
(17:42):
all these different pieces of evidence, animal studies,
in vitro tests, even computer models,
all to get the clearest picture of a drug's safety.
Great analogy.
And it really shows how important critical thinking
and scientific judgment are through this whole process.
So preclinical development is always changing, then.
Researchers are always looking for better methods
(18:03):
and trying to predict more accurately what
a drug will do in people.
Absolutely.
And as technology gets better, as we learn more
about how the human body works, I
think we'll see even more cool innovations
in preclinical development.
Well, it sounds like we've covered
a lot in this deep dive.
All those preclinical studies, the details of the IND,
even some of the ethical and scientific challenges.
It's been a really interesting look into this world.
(18:25):
It has been.
And hopefully you've got a better grasp
of how important preclinical development is.
It's a huge part of getting a new drug all the way to market.
I definitely do.
It's amazing how much effort goes
into making sure a drug is safe, even before it
gets anywhere near a patient.
It really shows how dedicated everyone is,
the scientists, the regulators, everyone
(18:46):
working to develop treatments and cures
for all kinds of diseases.
So as you keep learning about pharmaceuticals,
remember preclinical development is where it all starts.
It's full of challenges, things we don't know for sure,
even ethical questions.
But it's also full of hope and the possibility
of discovering something that could change lives.
Thanks for joining us on this deep dive.
(19:07):
Until next time, keep exploring, keep learning,
and keep those good questions coming.
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