112 – Global Regulatory Variations (S8E7)

All right, so welcome to another deep dive. Today
we're going to be talking about something really
crucial, I think, to the entire pharmaceutical
industry. And ultimately, that means it affects
all of us as patients too. Yeah, for sure. It's
about how new drugs, new medicines get developed
and approved around the world. And it all comes
down to regulations. Think of it as a massive
rule book that determines how a scientific discovery
Some of this starts in a lab, actually makes
it to patients who need it. OK, so basically
you're saying it's like the journey a drug takes
from the lab to your medicine cabinet. Exactly.
And what's really interesting is that the rules
of the game, the regulations, aren't the same
everywhere. So today, we're going to look at
some of the key differences in how some of the
biggest regulatory bodies around the world operate.
So you mean like the FDA here in the US, right?
Absolutely. The FDA is a major player. Yeah.
But we'll also be looking at the EMA. That's
the European Medicines Agency. Then you've got
Japan's PMDA and China's NMPA. We're going to
really get into how their approaches to drug
approvals compare and contrast. Wow. OK, so that
sounds like a lot to cover. But I guess the big
question is, like, why does it even matter that
there are these differences, right? I mean, a
drug is a drug, isn't it? Well, that's where
it gets really interesting. You see, while the
ultimate goal is the same, making sure new medicines
are safe and effective for patients, the specific
pathways to get there can vary quite a bit. I
see. It's kind of like, um... Well, imagine trying
to ship a product internationally and every country
has slightly different import rules, safety standards,
labeling requirements. It's the same product,
but the hoops you have to jump through are different
everywhere. Yeah, that's a great analogy. And,
you know, the regulations we're talking about
here, they cover a massive scope. It's not just
about, you know, is the drug effective. It's
about everything from how a drug is manufactured
to how it's labeled, even down to how it's distributed.
And each agency has its own very detailed rulebook
on all of that. So we're talking about really
granular level detail here. I mean, just to get
a sense of the scale of this, like in the US,
the FDA has something like 21 CFR parts, 200
through 299, and those are all dedicated to drug
regulations. So we're talking a lot of rules.
A lot of rules, a lot of nuance. And it's when
you get into those specifics that you really
start to see where the... the key differences
emerge between these agencies. So let's start
by talking about the very beginning of the drug
development process. We're talking pre -clinical
data. OK, so that's basically all the research
that happens before a drug is even tested in
humans, right? Exactly. And a huge part of that
is toxicology studies. Before you can even think
about giving a new drug to a person, you need
to have a very solid understanding of its potential
risks. Right, makes sense. You need to make sure
it's not going to cause any serious harm. And
I remember reading in the material our listener
sent that A common type of preclinical study
is like a 28 -day repeated dose study. Usually
they do this in rodents, sometimes in other animals,
too. Yeah, that's a standard approach. But here's
the thing, even though that general concept is
the same, the specific details, like the specific
animal species they use, how long the study goes
on for, exactly what they're measuring in terms
of toxicity, that can all differ between the
FDA EMA, PMDA, and NMPA. Oh, interesting. So
it's not like there's one universal pre -clinical
playbook that everyone follows. Not exactly.
And it's the same story when it comes to the
CMC information that needs to be included in
an IND. CMC stands for chemistry, manufacturing,
and controls. And basically, this is all about
showing regulators that you really understand
your drug, how to make it consistently. And then
it's going to be of high quality. So you're saying
like you need to prove you can make the same
drug with the same purity and potency every single
time. Precisely. And again, the general principle
is the same everywhere, but the level of detail,
what exactly constitutes proof in the eyes of
the FDA versus the EMA, for example, that might
not be exactly the same in the early stages of
development. Right. I guess in those early phases,
you're still figuring a lot out. So maybe the
the bar. for what's considered enough information
is a bit lower. But as you progress through the
clinical trials, testing the drug in larger groups
of people, regulators naturally want more and
more assurance that the drug is being produced
to a consistent high standard. Exactly. And that
makes sense, right? You're going from small early
studies focused mainly on safety to larger trials
where you're also looking closely at effectiveness
in a wider range of patients. The stakes get
higher as you move along. For sure. And speaking
of those later stage trials, our sources also
mentioned something about bioavailability and
bioequivalence studies. I have to admit I'm not
totally clear on what those are. Sure. So bioavailability
basically refers to how much of a drug actually
gets absorbed into your bloodstream when you
take it. You know, you take a pill, but not all
of it necessarily ends up, you know, actually
active in your body. Some of it might get broken
down before it can be absorbed. Oh, interesting.
So bioavailability is like how much of the drug
actually gets to where it needs to go to do its
job. Exactly. And then you have bioequivalent
studies. These are super important when you're
comparing different versions of the same drug.
Like, let's say you have a brand name drug and
then a generic version comes along. A bioequivalent
study is designed to show that the generic drug
gets absorbed into the bloodstream in pretty
much the same way and to the same extent as the
brand -name drug. OK, so basically it's about
showing that the generic version is essentially
the same as the original in terms of how your
body handles it. Exactly. And the FDA, as you
know, has issued specific guidance documents
on how to conduct these kinds of studies back
in 2002 and 2003. But the specific details of
what those studies need to look like, what the
acceptance criteria are, that might differ slightly
depending on which regulatory agency we're talking
about. I see. It's like, again, same basic concept,
but potentially slight variations in the exact
requirements. And this brings us, I guess, to
the clinical trials themselves. And our sources
touched on something called non -inferiority
margins, which, to be honest, sounds a bit complicated.
Yeah, it can be a bit tricky. So imagine you're
developing a new drug for, let's say, high blood
pressure. Now, sometimes your goal with that
new drug isn't necessarily to show that it's
drastically better than all the existing treatments
out there. Maybe it's just as good as the existing
options, but it has some other advantages. Maybe
it's easier to take. Maybe it has fewer side
effects. Right. So it's not necessarily superior
in how well it works, but it brings other benefits
to the table. Exactly. And that's where non -inferiority
margins come in. So you design a clinical trial
to show that your new drug is, at the very least,
not significantly worse than the current standard
treatment. And that not significantly worse part,
that's defined by the non -inferiority margin.
And it's like setting a boundary. You say, OK,
the new drug can be a tiny bit less effective
maybe within this specific margin, but it can't
be any worse than that. OK, so it's like a predefined
acceptable range of slightly less effectiveness.
But how do they even decide what that margin
should be? That sounds like a judgment call.
It is a judgment call. And that's where it gets
interesting from a regulatory perspective. The
acceptable non -inferiority margin can differ.
depending on the specific disease you're looking
at, the existing treatments available, and the
overall risk -benefit balance. And different
regulatory agencies might have different opinions
or expectations on what constitutes an acceptable
margin in various situations. So, again, we see
some potential for variation depending on which
agency is evaluating the data. Another area where
I noticed some differences in our sources is
in pediatric drug development. I mean, it makes
sense that kids might respond to drugs differently
than adults, right? So the studies need to be
tailored to them. Absolutely. There's been a
real push in recent years to make sure that new
drugs are properly studied in children. Because
for a long time, a lot of drugs were just approved
for adults and then, you know, doctors had to
kind of guess on the right dosage for kids, which
is obviously not ideal. No, not ideal at all.
So I guess the ethical and scientific importance
of pediatric studies is pretty well recognized
now globally, right? Yes, definitely. But when
you get into the specifics of when exactly these
studies should be done, how they should be designed,
what age groups need to be included, that's where
you can still see some variation between different
countries and regulatory bodies. Right. Because
there are a lot of ethical considerations when
you're talking about research in children. Practically
speaking, conducting these trials can be really
challenging. For sure. So we've seen that there's
a lot of complexity in this regulatory landscape.
It can seem pretty fragmented, honestly. It does.
But I'm guessing there are people trying to bring
some order to this chaos, right? Like some efforts
to harmonize these regulations globally. You
bet. That's where the ICH comes in the International
Council for Harmonization of Technical Requirements
for Registration of Pharmaceuticals for Human
Use. It's a mouthful. But basically, it's a really
important initiative that brings together the
regulatory authorities from the U .S., Europe,
and Japan. And they work together to try and
develop harmonized guidelines for drug development
and approval. Okay, so it's like they're all
trying to get on the same page. and, you know,
agree on common standards. And I think our source
has mentioned something about ICH Q8, which is
focused on pharmaceutical development. What's
that all about? Yeah, Q8 is really interesting.
The main thing about it is that it moves away
from this really rigid... checklist -based approach
to drug development and towards something that's
more science -based and risk -managed. So it's
less about ticking boxes and more about really
understanding the science behind the drug and
its manufacturing process? Precisely. And the
idea is that if you have a deep understanding
of your drug and how it's made, you can better
control the quality and make sure it's safe and
effective for patients. Makes sense to me. And
it sounds like this isn't just theoretical, right?
I remember reading that ICH Q8 has actually been
revised, Q8 R1, I think it was called, to give
more specific guidance on how to put these concepts
into practice. Exactly. Q8 R1 is all about making
these principles actually work in the real world.
But beyond specific guidelines like Q8, the impact
of ICH is even broader. It's really seen as the
starting point for what we now call regulatory
science, you know, this whole field that integrates
pharmacy, medicine, chemistry, engineering, all
these different disciplines. So it's really about
bringing together a lot of different areas of
expertise to make sure that drug development
and regulation are based on the best possible
science. Exactly. But as great as ICH is, you
know, it's not a magic solution that instantly
makes all the differences between regulatory
agencies disappear. There are still some real
challenges when it comes to achieving true global
harmonization. Like what? What are some of the
hurdles they're still facing? Well, one of the
biggest challenges is that different countries
and regions might simply have different scientific
and ethical standards for what's considered acceptable.
What might be OK in one place might be viewed
as way too risky in another. And that reflects
different cultural values, different priorities
in their health care systems, you name it. And
I imagine those kinds of differences can really
lead to bottlenecks in the whole drug development
process, right? Like, if a company has to conduct
a bunch of extra studies just to satisfy different
regulatory requirements in different countries,
that obviously takes more time and costs a lot
more money. Absolutely. And that can delay getting
new treatments to patients who need them. One
specific example of this is in stability testing,
figuring out how long a drug stays good on the
shelf. There are harmonized guidelines for this
through ICH Q1, but because environmental conditions
are so different around the world, some places
are hot and humid, others are cold and dry, the
packaging and storage requirements for a drug
might need to be adjusted for different regions.
Yeah, that makes sense. If a drug has to be shipped
and stored in very different climates, you need
to make sure it doesn't degrade and become ineffective.
Exactly. And then there's the whole issue of
CMC. chemistry, manufacturing, and control side
of things. As a drug moves through the development
process from those initial IND filings to a full
new drug application or NDA, the level of scrutiny
from regulators increases dramatically. So basically,
they need more and more detailed information
about the drug and how it's made as you move
closer to actually getting it approved for sale.
Precisely. And by the time you're submitting
an NDA, the FDA and EIA, for example, they want
a really comprehensive understanding. of your
entire manufacturing process, all the potential
impurities, how you control the quality, everything.
Wow. So it's like climbing a mountain with increasingly
difficult terrain as you go higher. And I guess
the requirements for generic drug approvals as
NDAs are even more stringent. Absolutely. And
one of the things regulators are really focusing
on these days is the potential for genotoxic
impurities. These are substances that could damage
DNA, which is obviously a major concern. Yeah,
I remember reading about the Valsartan recalls
a while back. That was a big case where a contaminant
was found in some blood pressure medications.
Exactly. And that really shook things up in the
industry. Now, regulators expect companies to
be much more proactive about... identifying and
mitigating these kinds of risks in their manufacturing
processes. So we've talked a lot about the the
general challenges of global regulatory variations,
but I'm curious, do you have any like real world
examples of how these differences have played
out in practice? Yeah, so unfortunately the sources
our listeners share today didn't include specific
case studies, but you know, in a typical episode
where we do have those kinds of examples, we
dive into stories of drugs that may be sailed
through approval in one country. that then hit
a roadblock in another because of differing requirements.
Maybe they need to do an extra trial or maybe
they need to collect data for a longer period
of time. And on the flip side, I imagine there
are also examples of where harmonization efforts
have actually worked really well and maybe a
drug was able to get approved in multiple countries
around the same time. Right. And those kinds
of success stories are really encouraging because
they show that it is possible to streamline the
process and make sure patients everywhere can
benefit from new treatments. And speaking of
patients, it's important to remember that this
isn't just a theoretical discussion, right? These
regulatory variations, they have a real impact
on people's lives. Absolutely. From the industry
perspective, these differences can mean higher
costs, longer development timelines, and really
tough decisions about which markets to prioritize.
But for patients, it can mean the difference
between getting access to a life -saving treatment
sooner or having to wait months or even years
longer. And those delays can be incredibly frustrating.
especially if you're dealing with a serious illness.
For sure. So the ultimate goal of all these harmonization
efforts is really to benefit patients, you know,
to make sure that safe and effective treatments
are available to everyone who needs them as quickly
as possible. It's like, we want to make the process
as efficient as possible without cutting any
corners when it comes to safety and effectiveness.
And looking ahead, it's going to be interesting
to see how all the new innovations in drug development,
you know, things like gene therapies and personalized
medicine, how those are going to impact global
regulatory harmonization. Yeah, that's a big
question. It's possible that these new technologies
might initially create more challenges, more
divergence, as regulators try to figure out how
to best evaluate them. But maybe, just maybe,
they could also lead to more globally aligned
approaches in the long run. So it's kind of a
wait -and -see situation, but I think it's safe
to say that the global regulatory landscape for
pharmaceuticals is incredibly complex. You've
got all these different requirements, the ongoing
efforts towards harmonization, the persistent
challenges. It's a lot to keep track of. It definitely
is. But understanding these issues is crucial
because, ultimately, It affects all of us. It
impacts how quickly new drugs are developed,
how much they cost, and when patients can actually
get access to them. All right. So to wrap things
up, here's something for all of you listening
to ponder. Given all this complexity, what do
you think is the single most important step the
pharmaceutical industry and regulators need to
take to achieve true global regulatory harmonization?
It's a tough question, but it's one we're thinking
about. Thanks for joining us for another Deep
Dive. Thanks for having me.