67 – NDA/BLA Submission Process (S5E7)

All right, welcome back to the deep dive. Today,
we're kind of picking up where we left off in
a way. We've been talking a lot about the whole
drug development process. And we've gone through
all these phases. And it feels like we're nearing
the end of this huge story. We're talking about
what happens right after, hopefully, successful
phase three clinical trials. And that is what's
called the NDA, or new drug application. That's
what it is for your more the traditional small
molecule drugs. But for those complex biologic
therapies, those bigger molecules, it's called
the BLA, it's Biologic License Application. So
you followed along with us on this whole journey,
maybe in some previous deep dives, we've talked
about years of just discovery, then preclinical
studies, and then of course we talked about those
large scale phase three trials. So the question
is, You know, what happens after all that, all
that intense work? Yeah, what's next? What happens,
so this NDA or BLA submission, right, this is
that, like, formal request to the FDA. Right.
It's the final hurdle before a drug can actually
become available to patients. Oh, yeah. Sure.
So... You know, you might be thinking, and we're
thinking too, like how do you even begin to take
all that data that's been generated over years,
right, of all this research? How is it the mountain
of data? It's got to be a crazy amount of data
and turn it into something. that regulatory agencies
like the FDA can actually use and review and
go through. So that's our mission today. How
do they even compile all this information? And
what are those key components? And what strategies
do these drug companies employ? What makes for
a successful submission? So we're gonna unpack
all of that today. And we've got a lot of different
expert guides that we're drawing from on drug
development in the regulatory world. I think
it's important to just emphasize just how important
this is, this submission. I mean, you know, you
talked about it. It's that formal request for
market authorization. Right. But it's also the
culmination of everything that's happened before.
I mean, starting with preclinical, you know,
you've got your pharmacology. Right. So that's
like, you know, how it works in the body, how
it interacts with the body. Toxicology, is it
even safe? Right. I mean, can you even give it
to people? And then, you know, just even the
drug formulation. Like, how do you even get the
molecule into the body? So all of that's kind
of... laid out in this application. Right. All
that foundational work. That's right. And then,
of course, then you have the whole development
of the manufacturing process. How are you going
to reliably and safely produce this drug or this
biologic on a commercial scale? You've got to
be able to make a lot of it. And then, yeah,
the clinical trials. I mean, those are huge,
especially those phase three trials. Those pivotal
trials where you're actually putting this drug
or biologic to the test, in real people. Right,
with hundreds or thousands of patients. Yeah,
yeah. Large patient populations. And you've got
to demonstrate beyond a reasonable doubt that
it's safe and that it actually works for what
you say it's going to do. Right. It actually
does what it's supposed to do. So the whole package
is designed to prove that, essentially. Yeah.
So it's safe. It's efficacious. It works. And
it works for the condition it's designed to treat.
That's the key. So you've got this. It sounds
like this huge collection of data. So how does
it actually get sent to the FDA or these other
regulatory agencies? I mean, it's not like they're
reeling in carts of paper anymore. No, no, definitely
not. It's all digital now, which is nice. It's
called the Electronic Common Technical Document.
You'll see that as ECTD a lot. And that's the
global standard. So that's ECTD. Got it. Yeah.
So it's essentially standardized now, all the
data is in the same format. That makes sense.
Which is good. Yeah, I can imagine. Because it
makes it much easier for reviewers to kind of
find the information you're looking for. Right.
When you have that much data, it needs to be
organized. Absolutely. And it sounds like this
ECTD format, it's built around different modules.
It is. So what are those? So the ECTD is based
on guidelines from the International Council
for Harmonization. or ICH. OK. So it's kind of
a global effort to kind of standardize all this,
you know, the technical requirements for registration
of a drug. Got it. So it's a global standard.
Yeah, exactly. So this is how you submit a drug.
Yeah. In the US, in Europe. Pretty much anywhere.
Yeah. Everywhere. And it's divided into five
modules. Five modules. OK. So let's go through
them one by one. Yeah, let's do it. And talk
about what each module contains. So module one,
what is that all about? Module one is really
the administrative stuff. You know, this is where
you're going to have all your application forms,
your cover letter, table of contents. And then
importantly, it also has all the details about
the proposed labeling. You know, like the package
insert that doctors and patients will see. So
it's really kind of the introductory information.
Right. It's all the paperwork, essentially. Exactly.
Like the cover letter. What about module two?
So module two is going to be your summaries.
So this is kind of like the high level summary
of the whole submission. They don't have to dig
into the data yet. So it's the overview. It's
the overview. So you've got an overall summary
of the drug, the program, the key conclusions.
Then you'll have the clinical summary, specifically
about the clinical trials, non -clinical summary,
which is all your preclinical data, and then
a quality overall summary, which talks about
the manufacturing and the controls. So it's like
the executive summary. Yeah, exactly. For the
FDA. Exactly. OK. So modules one and two, that's
kind of setting the stage. Yeah. And then module
three, we're getting into, I imagine, more of
the details. We are, yeah. So module three is
all about quality. OK. And it's often referred
to as CMC, chemistry, manufacturing, and controls.
And so this is where you get into the the nitty
-gritty of the drug substance, which is the active
ingredient, how it's made, how the drug product,
so that's like the final formulation, is manufactured
and controlled to make sure that it's consistent
and pure. And the regulators look at this really
carefully because manufacturing issues are actually
a major cause of delays. Oh, interesting. And
rejections. Yeah, yeah, so they want to make
sure that you can make it and you can make it
reliably. Exactly, not just like a small batch,
but you can scale So for the drug substance,
you're talking about the structure of the molecule,
all its physiochemical properties. So is it soluble?
Is it stable? The manufacturing process, all
the tests you do to check its purity and how
strong it is, specifications, and then stability
data. So all that's in there. Wow, it's very
detailed. It is very detailed. And then for the
drug product itself, it's the same thing. So
the composition of the drug product, so every
ingredient, even the inactive ingredients, the
manufacturing process for that, all the tests
you do on the product specifications, and then
the container closure, like what you put it in,
and then also stability data for the actual product.
And the sources that we've looked at really emphasize
the importance of process safety in GMP, good
manufacturing practice. So it's really... a well
-defined manufacturing process, and one that's
controlled is critical. Okay, so module three
is like, that's like the recipe in the quality
control manual for the drug? Yeah, pretty much,
pretty much. Okay, and then we move on to module
four, which I imagine is more about, okay, what
does it do in a... Living system. Yeah, exactly.
So that's your non clinical study report. So
this is all your preclinical data So every study
that you did before going into humans and and
this is where you're gonna have both your pharmacology
and your Toxicology, right? Right. So you're
talking about like how it's supposed to work
Yeah, and then also all the studies that are
looking at you know, how safe it is. Exactly.
Exactly So so pharmacology studies, you know,
you're talking about the mechanism of action
So like how does it actually work at a cellular
level, you know, right? Yeah, pharmacokinetics.
So that's like, you know, what the body does
to the drug, how it's absorbed. Right, right.
Like, where does it go in the body and how's
it broken down? Exactly, exactly. How do you
get rid of it? So all of that. And then toxicology
is gonna be, you know, acute toxicity. So that's
like a single dose. What happens? Subchronic,
chronic toxicity. So repeated doses over time.
Okay. Carcinogenicity, does it cause cancer?
Genotoxicity, does it damage your DNA? reproductive
toxicity so a lot of a lot of safety data right
goes into into this module and also you know
one thing I should mention is GLP good laboratory
practice? Right, right. I've heard of GLP, yeah.
So that's regulations that basically ensure the
quality of the data that you're generating for
these non -clinical studies. And the reason that
that's so important is because that helps you
justify the starting dose you use in humans,
and then also any kind of safety monitoring you
need to do during the trials. So it all comes
from this pre -clinical work. So you've got to
understand at least to some degree, what's happening
in animals before you go into people. For sure.
You gotta lay that groundwork. And then the big
one, I'm guessing, is module five. Yeah, module
five. This is the clinical study reports. So
this is often the largest and most important
module of the whole submission. And it's got
all the data. from your clinical trials, so phase
one, phase two, and most importantly, your phase
three trials. Right, where you're actually proving
that the drug does what it's supposed to do in
people. Exactly, exactly. So it's all about proving
efficacy and safety in the intended patient population.
And you know, our sources talk a lot about the
importance of randomized controlled trials, often
blinded, often placebo controlled. So it's really,
you know, you're trying to get good solid data
here to prove that that the drug works and that
it's safe. And what kind of information do you
actually include in these clinical study reports?
Oh, there's tons in there. So you're going to
have your protocol. So that's how you designed
and ran the study, your statistical analysis
plan, so how you're going to analyze the data,
your data listings. So that's just basically
all the data you collected, summaries of the
individual patient data. And then for phase three
trials, the primary endpoint is really important,
because that's the main outcome the trial was
designed to measure. So you really want to make
sure that that shows a benefit. Yeah, that's
the thing that you're measuring to prove that
the drug works. Exactly, exactly. Okay, so now
you have all this data. It's all nicely organized
into this ECTD format. What happens next? I mean,
what are the timelines like? Well, putting together
an NDA or a BLA, it's a huge job. Yeah. And it
can take a long time, even after the phase three
trials are done. So you've got to make sure everything's
complete, accurate, it's all in the right format.
So there's a lot of very careful attention to
detail required at this stage. Yeah, it makes
sense. It sounds like, though, that you don't
have to wait until every single thing is done.
You don't. No, and actually, for certain drugs
that get special designations like Fast Track,
the FDA might actually let you do what's called
a rolling review. So as sections are done, you
can just submit them. OK. So you could just submit
it piecemeal. Exactly. Yeah. So that can really
speed things up because the FDA can start looking
at it. Right. They can get started earlier. Exactly.
Yeah. OK. So that makes sense. And are there
any other kind of proactive things companies
do to kind of make sure this goes smoothly? Oh,
yeah. They'll often have meetings. with the regulatory
agencies. So for example, you might have like
a pre -NDA or pre -BLA meeting where you're talking
to the FDA and you're kind of going over your
plan and answering any questions they might have.
So you're making sure everyone's on the same
page. Right, you're trying to get ahead of anything,
yeah. Exactly. Okay. And so it's not just about
having all the data, it's also about understanding
the guidelines. Absolutely, yeah. You gotta know
the rules. Right. So things like ICH guidelines,
you know, we talked about E6, good clinical practice,
E9, statistical principles. Right. You gotta
make sure your submission meets all those. If
you don't, you know, it can cause delays or even
rejections. Right, right. So it's really important
to know, you know, what the rules are. So even
if you have a good drug, you know, you have positive
phase three trials. Right. It still sounds like
this whole process can be really complicated.
Yeah, it's definitely not always straightforward.
Are there any like common pitfalls? Yeah or challenges
that companies need to be aware of? Yeah, so
even if your data looks good You know, you might
have some safety signals that pop up that you
didn't see during the trials. And the FDA is
going to look at that really carefully. They're
going to want to make sure that the efficacy
you showed actually translates to a benefit for
patients. And then, of course, CMC, the manufacturing,
is super important. They want to make sure that
you can actually make the drug consistently into
a high standard. So that module three is really
important. Module three, yeah, super important.
And then, you know, sometimes, you know, the
FDA might come and say, hey, we have some questions.
We need some more information. Right. Can you
do another study? Or can you analyze your data
this way? Right, right. So there's often back
and forth. It's not just like you submit it and
then you're done. Right. So you have to be prepared.
You've got to be prepared, yeah. To answer questions
and maybe even do more work. Yeah, definitely.
OK. So it sounds like this NDA BLA submission
process. Yeah. It's incredibly rigorous. It's
tough. Yeah. It's challenging. You're basically
taking all this research. Yeah. and you're turning
it into this formal request to be able to market
this drug. And each module really tells a part
of that story. It's all about demonstrating the
drug's safety and how well it works and convincing
the regulators that it's worth approving. Right,
yeah. And I think for our listeners, those of
you who are following along, this whole process
is, it gives you a sense of... just what goes
into getting a drug approved. It's a long run.
And to market. For sure. And how a new medicine
actually comes to be. It's pretty remarkable
when you think about it. You start from scratch.
You have an idea. You go through all these phases.
You collect all this data. And then finally,
you submit this huge document. And hopefully,
it gets approved. And it can help people. Right.
It's a huge endeavor. It is. It's a huge endeavor.
Well, this has been a really fascinating deep
dive into this critical part of drug development.
And hopefully, this has made you a little bit
more curious about maybe some of the ICH guidelines
or different regulatory pathways in different
parts of the world. Yeah, for sure. So yeah,
there's always more to learn. So thanks for joining
us. Thanks for having me. And we'll see you next
time on the deep dive.