71 - Accelerated Approval & Breakthrough Therapies (S5E11)

You know, we always hear about these new medical
breakthroughs, right? Yeah. And it's so exciting
to think about new treatments, reaching people
who need them as quickly as possible. Yeah. But
the thing is, and you probably know this from
the stuff we've been looking at, that the standard
path for drug development, it's like an ultramarathon.
That's a good way to put it. It's this really
long process Sometimes it can take over a decade
you can and cost just billions and billions of
dollars It really can and just to kind of give
everyone a picture of what that looks like you
basically have several key stages You start with
scientists that you know discovering potential
drug candidates right trying to understand You
know how they might work. Then there's a ton
of testing First in the lab right and then on
animals to see you know, how safe is this? And
if that all looks good, then it moves on to the
clinical trials in humans. Oh, right, yeah. So
many phases. Multiple phases, exactly. And it's
all to evaluate, you know, is it safe and is
it effective? And then finally, you have the
regulatory bodies like the FDA looking at all
of that data and deciding if it's good enough
to approve. Wow. So much work. And even after
approval, there's still monitoring going on.
You're never really done. Makes sense. So you
shared some articles highlighting how urgent
it is for patients, you know, facing these serious
life threatening or really debilitating conditions.
Yeah. And it just it makes you think, right?
Is there a way to speed this whole thing up?
Right. But without. compromising safety and effectiveness
right like are there faster routes than this
whole drug development marathon when time is
just so critical that's exactly what we're diving
into today okay love it our mission is to understand
those alternative pathways okay the accelerated
ones that are designed to you know get promising
treatments to patients faster I like it so we'll
be focusing on two main mechanisms accelerated
approval and breakthrough therapy designation.
We'll also touch a bit on orphan drug designation
as another way to address those really urgent
medical needs. Okay, so let's dive into this
need for speed thing. It might seem obvious,
but I think it's good to really underscore the
human element here. Oh, absolutely. Especially
for the individuals and families you mentioned
in those articles. Right, yeah. Because for someone
who just got diagnosed with an aggressive cancer
or some kind of rapidly progressing neurological
disorder, waiting 10 to 15 years for a new therapy,
that's just not an option. Yeah, that's not feasible.
And every month, every week, even every day can
be so critical. When you're dealing with something
that's life threatening, that standard timeline
just feels like forever. It really is a stark
reality. It is. And there's also that ethical
consideration, like you pointed out in one of
the articles, when a treatment shows promise
early on for a condition that has very limited
options. You could even say no options. There's
a strong argument to try to make it a failure
to the people who desperately need it. as quickly
as possible, but of course, responsibly. Responsibly,
yes. It's all about balancing the desire to get
these potentially life -saving treatments out
there faster with the need to make absolutely
sure they are safe and they are effective. Yeah,
we can't compromise patient well -being for speed.
Exactly. Okay, so this brings us to that first
expedited pathway, accelerated approval. Yes.
What exactly is this and how does it actually
shorten that? really long timeline we talked
about. So accelerated approval is an FDA pathway.
Okay. That's specifically designed to speed up
the availability of drugs for serious conditions.
Okay. And that fill an unmet medical need. Okay.
Think of it like a conditional approval that
happens sooner than usual. Okay, conditional.
Yeah. So what are the conditions? Right. So the
main condition is that this approval is based
on a surrogate endpoint. The surrogate endpoint.
Yeah. And this is a really important concept
to understand. Okay. A surrogate endpoint is
a marker. It could be a lab measurement, something
from a scan, or even a physical sign that doctors
can see. OK. And it's something that we think
is reasonably likely to predict a real benefit
for the patient. So it's not directly measuring.
how the patient feels or how well they're functioning,
or even if they're surviving. Exactly. It's like
something that suggests those benefits are coming.
Exactly. Can you maybe give an example? Sure.
Let's say there's a new drug for a really rare
and very aggressive type of childhood leukemia,
and early studies show that this drug really
lowers the level of cancer cells in the bone
marrow. So that reduction in the cancer cell
count, that could be considered a surrogate endpoint.
It's reasonably likely that... lowering the number
of cancer cells is going to lead to some clinical
benefit, like a child living longer or having
a better quality of life. Makes sense. But it
doesn't prove those things right away. Got it.
Yeah. So the FDA might grant accelerated approval
based on this promising surrogate endpoint. Exactly.
And then doctors can prescribe the drug to patients
earlier than if they had to wait for that definitive
proof of survival. Exactly. But it is conditional,
right? It is very much so. What are the drug
company's obligations here? So because that initial
approval hinges on this indirect marker, the
company has to conduct more studies. These are
often called post marketing studies or phase
four studies. And the goal is to confirm that
clinical benefit. So it's like, OK, we see the
potential here. We want to get this to patients
who meet it now. But you absolutely have to prove
it works later. Exactly. And these aren't just
suggestions. Right. If these follow -up studies
don't show that the drug actually provides that
clinical benefit, the FDA can withdraw the accelerated
approval. Wow. Meaning the drug could be taken
off the market. So it's like a safety mechanism.
It is. Absolutely. OK. So accelerated approval
prioritizes getting the drug to people quickly
based on an early indicator. Right. With the
requirement to confirm everything later on. Exactly.
OK. Let's move on to the other pathway you mentioned.
Breakthrough therapy designation. OK. How is
this different from accelerated approval? So
breakthrough therapy designation is another tool.
OK. It's designed to speed up drug development
and review for serious or life threatening conditions.
OK. But it's different from accelerated approval.
in when it's granted and what evidence it's based
on. So with accelerated approval, it's all about
the evidence at the time of potential approval.
Breakthrough therapy designation, a drug can
get this much earlier in development. OK, how
much earlier? It can be granted as early as phase
one or two trials. Wow. Yeah, so phase one, that's
usually focused on safety in a small group of
people. Phase two starts looking at effectiveness
and side effects in a bigger group. And there
are two main criteria for breakthrough therapy
designation. OK. First, the drug has to be for
a serious or life threatening condition. OK.
This is similar to accelerated approval. Right.
But the second thing is that there has to be
preliminary clinical evidence. OK. Showing that
the drug might be a lot better than anything
we have now. OK. So not just a marker that might
predict a benefit. Right. It's like you're seeing
early signs of the actual benefit. Exactly. What
counts as a clinically significant endpoint then?
That depends on the specific disease really.
So for cancer, it could be a statistically significant
increase in how long people survive or a big
reduction in the risk of the cancer coming back
or getting worse. For a chronic illness, it might
be a really noticeable improvement in how people
can function every day or a big drop in how often
they have really bad symptoms. And it's important
that this improvement is a lot better than what
existing treatments can do. What happens when
a drug gets this designation? What are the advantages?
Well, it gets a bunch of benefits, all aimed
at speeding up the journey to patients. The company
gets more guidance from the FDA. on how to design
the rest of the development program. So that
means more meetings with the FDA, direct advice,
and these drugs are eligible for priority review,
which means the FDA tries to review their application
much faster, and they might also be eligible
for fast -track designation, which can speed
up both the development and review. So it's like
the FDA saying, hey, this looks really promising.
We want to help you get this to people quickly
and safely. Exactly. Exactly. You mentioned orphan
drug designation earlier. Right. Can you quickly
explain how that fits in? Sure. So orphan drug
designation, it's meant to encourage the development
of drugs for rare diseases, usually affecting
fewer than 200 ,000 people in the US, or in cases
where the sales of the drug probably won't even
cover the costs of developing it. Oh, wow. So
it's about addressing those unmet needs, but
it does it through incentives. OK. Things like
tax credits, waiving some FDA fees, and even
market exclusivity if the drug gets approved.
It's different from accelerated approval because
it's not about relying on surrogate endpoints
or showing early evidence of improvement like
breakthrough therapy. So it's a separate thing
but it has the same goal of getting treatments
to people who need them. Exactly. Okay so can
we go through a couple of hypothetical scenarios?
Yeah definitely. Just to show how these pathways
might work in the real world. Let's go back to
that childhood leukemia drug. Imagine that in
those early trials, not only does it lower the
cancer cell count, but the kids taking the drug
are actually living longer. Wow, that's amazing.
Than the kids getting the standard treatment.
Yeah. So that's a clinically significant endpoint
right there, survival. Right. And that, along
with the surrogate endpoint data, might make
the drug a candidate for both breakthrough therapy
designation and later on accelerated approval.
Wow. Based on that surrogate endpoint. But they
still need to confirm the survival benefit in
more studies. OK, that's a great example. What
about an example for breakthrough therapy? So
let's say there's a new drug for a really tough
chronic autoimmune disease. OK. And in phase
two trials, this drug shows much better outcomes
than the current treatments. OK. So maybe patients
are having way less pain. They can do more things
every day. Right. And they have fewer flare ups.
That's huge. Yeah. So these are all clinical
endpoints because they directly reflect how patients
are feeling and functioning. Right. And because
this is suggesting a big improvement over what's
already available, this drug could get that breakthrough
therapy designation. Makes sense. And that would
mean more guidance from the FDA and probably
a faster review. Awesome. Once they have all
the data from the phase three trial. OK. Those
examples were really helpful. Good. But we did
talk about how these acceler - accelerated processes
can't be completely free of drawbacks, what are
some of the risks or limitations? So with accelerated
approval, the big question is whether the surrogate
endpoint actually predicts a meaningful clinical
benefit over time. It has to be reasonably likely.
But it's not a guarantee. Those post -marketing
studies are so important to really validate the
initial promise. And sometimes they don't confirm
the anticipated benefit. And in those cases,
the drug can be pulled from the market. And with
breakthrough therapy designation, even though
it's based on promising early data, that's still
just a small group of patients. It is. And the
drug still has to go through those rigorous phase
three trials in a much bigger group of patients,
to really establish safety and effectiveness,
there's no guarantee that the good results from
earlier trials will hold up in those later studies.
So these expedited pathways are about balancing
the need to provide treatments quickly with the
need for strong evidence. Exactly. It's about
getting promising therapies to patients faster
while still sticking to good science and putting
patient safety first. of this important for our
listeners. Well, if you or someone you care about
is dealing with a serious illness. Yeah. understanding
these pathways can help you understand how new
treatment options might become available. And
if you work in healthcare or the pharmaceutical
industry, it's important to understand how these
things work. And for anyone who's interested
in medical progress, it shows how this whole
system of approving new medicines is always evolving.
It really highlights that it's not a fixed system.
It isn't. It's always adapting. And regulatory
agencies like the FDA, they're always evaluating
and reflecting finding these pathways based on
what they learn and new scientific discovery.
OK, so before we wrap up, could we just go over
the key differences between accelerated approval
and breakthrough therapy designation one last
time. Of course. So accelerated approval, that's
about speeding up access to drugs for serious
conditions where there is a big need. Okay. And
it's based on those surrogate end points that
we think predict clinical benefit. But it requires
those post marketing studies to really confirm
the benefit. Right. And the approval can be taken
away if those studies don't work out. breakthrough
therapy designation that's given much earlier
in the process. And it's based on early evidence
suggesting a substantial improvement over what
we already have. So its goal is to speed up the
whole timeline of development and review. Okay,
so both are meant to get promising treatments
to patients sooner. Uh huh. But they work at
different stages. They do. Use different types
of evidence. Right. And have different requirements.
Exactly. It's all about finding that balance.
It is. Between treating diseases urgently. Uh
huh. And making sure that the new therapies are
safe and effective. Exactly. This has been a
really fascinating look at this whole world of
medical innovation. Yeah. And it leaves me with
a final thought for you all. Okay. As we get
better at identifying those early signs of disease
and treatment response. Yeah. How will our use
of surrogate endpoints in accelerated approval
change? That's a good question. And as we learn
more about different diseases, what does substantial
improvement really mean? Right. How should we
be measuring and evaluating that across so many
different conditions? That's a really important
question. It's complex and always changing. It
is. And that's what makes it so interesting.
It does. Thanks for joining us on this deep dive.
Thanks for having me. It's great having you.
Appreciate it.