Judith: Welcome to Berry's In the Interim podcast, where we explore the
cutting edge of innovative clinical trial design for the pharmaceutical and
medical industries, and so much more.
Let's dive in.
Scott Berry: Welcome everybody to in the interim, uh, Barry consultants
podcast about all things, science, statistical and clinical trial and medical
sciences of a really cool guest today.
Uh, Mike Krams is our guest today and for everybody's Uh, knowledge, he joined
Berry Consultants in January, but Mike has a, a really interesting history in
clinical trials, drug development, he's been 30 years at multiple pharmaceutical
companies, he's led quantitative sciences departments at these, uh, he's done
innovation everywhere he's been, and now we're thrilled to have him at Berry, but
we talk about innovation, how do we do innovation at in, in drug development.
So Mike, welcome to In the Interim.
Mike Krams: Hi Scott, and hey, you forgot to mention how it all works.
You write a letter to Professor Don Berry, uh, 25 years ago, and think there'll
never be a response, but then there was a response, and the rest is history.
Scott Berry: Yeah.
So, so, so this is a great source of, we, we are celebrating Barry
Consultants 25th anniversary this year.
Uh, we're, we're marketing this and you can see this everywhere,
but we've been working with Mike Krams for well over 25 years.
Um, so I, I'd love to hear a little bit about, and I know much of this, but tell
us about the Aston Stroke trial, which was your first interaction with Don Barry.
Mike Krams: Yes, I was trained as a neurologist and a stroke neurologist.
Um, you know, we, uh, worked in one of the first stroke units in
Germany, uh, before I went to London to do, um, functional brain imaging.
And in that functional brain imaging environment, I learned a lot about being
clever on how to detect a weak signal in functional MRI and PET studies, a
weak signal in a noisy environment.
I learned a lot of statistics.
And then I joined a pharmaceutical R& D, uh, organization.
Um, they were looking for a stroke neurologist with a background
in functional brain imaging, interested in developing acute
ischemic neuroprotectins for stroke.
And so I was made for the job.
And then I looked at what was already happening in that area.
And there were plenty of efforts to create new treatments for
acute ischemic stroke patients.
And one failed after the other.
And, you know, when I, when I started in my career in pharma R& D, I just
came from the Institute of Neurology Functional Brain Imaging Unit.
Um, you know, the sophistication of the, um, of the functional brain
imaging, experimental design and analysis world contrasted with a
world in those days where you spend millions of dollars into having two
groups and doing a t test at the end.
And it was just mind boggling.
And it also was pretty clear that identifying the correct dose and
treatment regimen was a big, big issue when people went from phase 2 to phase 3.
And so, I tried to figure out, you know, if that's the problem, if we are not
very good in learning about the correct dose and treatment regimen to take into
confirmative trials, what needs to change?
And that
Scott Berry: so let's, let's set this up a little bit.
So you've got a, you've got a potential neuro protectant for acute stroke.
You go to a traditional, uh, trial design invariably your statistician is going
to say three doses, 80 patients a dose,
Mike Krams: Uh, maybe more
Scott Berry: two.
Mike Krams: yes, but, but yes, it's, it's, it's like, uh, two or three, uh,
active, uh, treatment arms and a control and pairwise comparisons and that's it.
And, uh, you know, just mind boggling, uh, um, how, um, how, how one can do that
and not think about, uh, alternatives.
And so I, Uh, started educating myself about what else one
could do when I came about.
There were a number of papers that were really well written and the author was
this professor whom I imagined with a long beard and probably would never talk to me.
And the name was Professor Don Barry.
Anyhow, I eventually found the courage to write him a letter
and say, hey, I'm really I'm very impressed with your, uh, papers.
There's this one paper about Bayesian thinking in clinical research and,
you know, it totally resonates with me because as a medic, that's how I function.
What you describe as the Bayesian thinking, that's, that's how, how,
how you work, uh, in medicine.
And so, hey, can we meet and can you perhaps, uh, uh, discuss with us, um,
what one could do to approach this, uh, problem, namely, uh, identifying
the correct dose in a different manner.
And so that's how it all started.
And then, uh, you know, we had, uh, just an amazing time, uh, exploring
the opportunity space for what could be done with fantastic colleagues in
the team and Don, of course, and others Peter Muller and many others Andy Greve,
key person and, you know, over many months we were able to Effectively,
in those days, not exactly invent, but really apply for one of the first times
simulation guided clinical trial design.
And, uh, you know, that the, the explanation that we gave, uh, to our
senior managers was look, the way we currently work is we build an airport.
Um, we then build a plane.
We put peasant passengers on a plane that's never been flown before.
As the plane is traveling, we build another airport where it'll
land, and then it'll land, and by that time, we'll have destroyed
the airport from where we started.
And then we do this over and over again.
And that's how we do clinical research.
How can we do things differently?
And, uh, you know, with Don's help, and Andy Reeve's help,
and other people's help.
Um, we eventually came up with, uh, design that's published and well presented.
Um, where we had, believe it or not, 16, uh, different treatment arms.
And what is called a response adaptive allocation to treatments.
Uh, uh, uh, responding to the data, uh, on, uh, stroke
scores coming in in real time.
So that's how it started.
Nope.
Scott Berry: uh, interestingly that the time it took to do
those simulations and build this.
This is a time where software is not available.
You're custom coding.
This is many months to carry out these simulations.
But even today that trial 16 doses response adaptive randomization the result
of that trial Which has been published was a resounding success in that it
demonstrated clearly the drug didn't work
Mike Krams: it did.
And it did so, there was a futility rule built in, and so it stopped
early for, um, for, for futility.
And so the design did what it was supposed to do, yes.
And, but you mentioned, uh, the time that it took in those days to
fine tune the, uh, Uh, the software that was, uh, handmade, uh, custom
built really to, uh, support this.
And, you know, we were always angry when we had to wait another
two or three weeks before the next iteration of software came in.
Compare this to today, where you have, you know, software packages like facts
or others, where on a push of a button, you can plug in stuff and immediately
get a first sense of how things work.
So, hey, that, but that's, that's how it started.
Yep.
Scott Berry: Yeah.
Yeah.
So, so we now have software that can do those simulations,
can build trials like that.
But in doing that, the hard part may not have been the simulations.
The hard part may not have been the modeling, the response
adaptive randomization.
It helps when you have Peter Mueller, uh, you know, brilliant
scientist, uh, doing all of that.
So I, I want to talk a little bit about bringing change.
You go into a place where it's typically fixed trial designs, enroll this, and come
back and show me the data in three years.
Now you're doing interim's monthly, weekly, response adaptive randomization.
How do you bring change to this industry?
Is it, you know, so that's what I'd like to talk about.
You know, this,
Mike Krams: sure.
And let's, let's just talk in general terms rather than about one
particular trial in one particular pharma R& D environment, because
the general aspects hold true, uh, really, uh, wherever you look.
Overall, Uh, our industry is extremely conservative and people haven't got
a lot of, uh, encouragement to think out of the box and try things that
might perhaps require additional interactions with health authorities,
regulatory scientists, et cetera.
So the going in position is everybody is.
Uh, doing what was done before and, uh, is not that comfortable.
Uh, proposing quite different approaches and the question, of course, is why do
something different if what we are already doing is working, but it's not working.
It's so inefficient.
And so you are asking how to bring about change.
Well, if you are in an environment that is utterly against it and from a top down
perspective, you know, senior management will not allow you to, uh, explore.
Uh, uh, innovative, um, uh, uh, approaches, it's very tough.
So if you want to do this bottom up and you haven't got a champion in a, um, in
a more senior position, it's, it's, you know, uh, my experience tells me I've been
most successful in places where my boss and the boss of my boss were champions
for the idea that we brought forward.
So it's important to have champions.
in senior positions to, to help you achieve this, but then what's
equally important is to clearly articulate the value proposition.
You don't do innovation for innovation's sake, but if there is a way of
convincing the, environment that we work in, that there is a better
decision to be made at an earlier time point in a more efficient manner.
Now we're talking.
And, being able to articulate, clearly understanding the position of the person
at the other side of the table, and bringing along the audience, that's key.
Let me give you some
Scott Berry: So, so, so can I, can I talk about, I think this is so critical,
so we, I, I, you've got experience of this, you know, in development programs,
uh, much more top level than I, so I end up working a lot with teams and we
explore adaptive designs in all of this.
and in, in, even at that level, you've gotta create a champion that's
gonna go up and fight, fight for it.
First of all, you've gotta demonstrate to that person that
what you're doing is better.
They've gotta believe in it.
But I've also found that you need that, uh, a little bit, that that person has
ownership in that what you've created
Mike Krams: Oh, absolutely.
Scott Berry: so that when, when we're doing these sim and so.
The name, the consultant, we don't go in and say you've got to do X
and we're kind of beating them down.
They're not a champion for you.
They don't necessarily believe in it.
They're not going to go and fight for this.
But if you get them to believe what you're doing better, they made the decisions.
You guided them and you showed them the ramifications.
That's why clinical trial simulation is beautiful, by the way.
You can see the ramifications of all that.
They become the champion.
They can go up and say here's why.
And, and, and.
If they're fighting for it, they're, they're champion at that level.
And then what happens above that?
Mike Krams: Yeah, well, you made it so clear that it can't be
that an external party comes and says this is the way it's done.
Drug development is a team sport.
And the way I've experienced this with Don and you and others has been that
you've empowered us to stand up with a proposal that you helped develop, but
you really empower the team on point within the farm R and D organization.
to then carry, uh, the flag and make the points.
And, uh, what, what happens?
So, so you need to, uh, think about who are the key decision makers.
Initially, in, uh, uh, compound development teams,
you have a, uh, team leader.
Uh, you have, uh, a, uh, Uh, program or project manager, you have a therapeutic
area head, you have, uh, functional heads, lots of people who have a say in this.
And often what happens is that even though you may have been successful in
bringing your own team, uh, around to, uh, embracing, uh, innovative idea,
it's enough if just one person somewhere higher up says, Hey, I don't like this.
This, this, this has never been seen before.
I don't think that this will fly.
That's enough to derail it.
And then it's important, uh, not to give up, but to try to understand
what is the motivation of that person to say, um, hey, it won't work.
I'll give you an example.
When, um, we implemented, um, response adaptive dose finding
studies in a broader way.
One of the arguments that we made were, um, it's of value to have
more doses rather than less doses.
Um, and, uh, the person who headed up the Pharmaceutical
Sciences Organization at the time.
They would have ultimately been accountable for making more dose
strengths and enabling that whole many doses rather than a few.
They hated this.
They absolutely hated it.
And then, you know, within learn trials, we proposed something that
proved really, an amazing thing.
We invited the head of the Pharmaceutical Sciences organization to be a silent
observer in the data monitoring committee.
So that person was now able to see firsthand how the information evolved over
time and was sworn to secrecy, obviously, but in the back of their minds, they
were clear on how the trajectory of a particular program was more likely to go.
And of course, that might have implications on, bigger strategic
thinking and some key decisions that might have been in that person's mind.
So to understand where the resi the resistance comes from, taking that very
seriously, but then also finding an opportunity to bring that person into
a position where that person can also, support and champion what we're doing.
And that.
That function ultimately became a big supporter for us, because they understood
that we were more frequently stopping things that shouldn't go forward, and
bringing forward things that should go forward more, more, rapidly.
Scott Berry: Yeah.
Yeah.
Uh, so a little bit.
So the title of this, we've titled this the art and slog of innovation.
And so a little bit of that seems like the slog that invariably when
you're doing something different that there's, there's ways this has been
done many times within a pharmaceutical company within the industry.
And there's a lot of copycat doing what the last person did and all that.
And now you're saying, proposing something different and invariably.
10 people are going to give a reason not to as this goes from concept and
development and all of these will stop it if you're not able to combat that
with with information and bring those people along as well that you're not an
enemy that we're making better decisions.
That's a bit of the slog of this innovation aspect of it, uh, from it.
That is just so hard to do it.
Mike Krams: Well, you know, uh, it's actually hard work.
And you need to be at the table where strategic decisions are made.
If you're not there, if you're not present, uh, doing this Um,
from a distant with only punctual interactions is much more difficult.
Um, so being embedded in discussions that lead to better problem solving,
that lead to, uh, creating, uh, resource efficiencies and ultimately that lead to
creating a new fun intellectual culture.
That's a key thing.
Uh, you know, is incredibly rewarding.
But you have to be part of the inner discussion where the
strategic direction is being set.
That's why it's so important not just to look at an individual trial in isolation,
but at the development strategy overall.
And then think.
Within that bigger picture, how do we, um, uh, design the, uh, strategy?
Scott Berry: yeah, it's it's so interesting.
So part of this is.
You hear this.
You need to be at the table.
The question is, how do you get to the table?
You can't just blurt out, I need to be at the table.
That generally doesn't work.
And in our circumstances, as a statistician, we may have a number of
statisticians joining this, we have scenarios where, you know, a client
may say, can you show us the power?
Can you show us this, this, and this?
How you present this is so critical.
And if you pass this to somebody else who then brings it up there, and they're
bringing They present it differently.
They answer questions differently, and it's so much the ability to
see how people react to this and what is what do they need to see?
Is it about time?
Is it about cost?
Is it about another development program that they want to
take these additional shots?
So being able to listen and hear all of this?
And then be able to present exactly what's going to help them make that decision
is the really hard part about this.
And it's earning your way at the table that people think you help them and
you're presenting the right thing and you understand the bigger part.
That's what's harder for us as statisticians.
We're really good at calculating something, but this is the hard
part to earn your way to the table.
Mike Krams: True.
Respect is earned, but I tell you, uh, I have had the privilege to work with so
many, statistical experts and modeling experts and mathematicians who are
absolutely brilliant in articulating clearly in a way that the other, function
that might not be, mathematically inclined still understands, and that
is a necessary condition for it.
Getting, the implementation of innovation guaranteed.
So very good communication skills, but as you pointed out, also very good listening
skills and psychological skills, where does the other party come from, but,
there is also a need for putting your foot down and, making sure that, others
understand what statistical experts do is a contribution to strategic thinking.
It's not just a subservient number crunching activity in
the background, absolutely not.
And insisting that there be that, partnership, between clinical experts,
translational science experts, regulators, and statistical and
others, experts, is, very important.
Yeah.
Scott Berry: my, my words I associate with you and you say
this all the time is imagine.
Um, so, so let me, uh, you know, imagine if we could do the following.
We started this off with, uh, 1990s, a neuroprotectant for acute stroke.
We are now 2025.
We have no neuroprotectant for acute stroke.
We have thrombolytics.
We have endovascular therapy.
That, by the way, is incredibly effective in some patients.
We're still in search for neuroprotectant, uh, in stroke.
Imagine if development would have been different.
Are there neuroprotectants that we missed, that we didn't take shots on goals?
We got the wrong dose.
Now, we're, we're, we're, we as an industry, we're
developing really cool things.
They're out there, but this is a really hard area where in some ways
we haven't made tremendous progress.
And does the development affect that?
Mike Krams: Yes.
So, hey, uh, this is so close to my heart, but it's not
just in acute ischemic stroke.
It's in any, uh, important, uh, disease where there aren't solutions.
Uh, you gave a talk once about statistics and baseball, and it inspired me.
And in it was, uh, The motion of the time machine to be able to compare
the thing that happened in the past and move seamlessly to the presence
and, and build models around that.
And then I heard your dad, uh, Don Barry, uh, talk about platform trials
and, you know, I've worked in different companies on individual projects.
observing what the competition did.
And it really, at times, drove me nuts how mistakes were reinvented without
comparing notes and working together.
Now Imagine that at the center of the universe was not, an
individual, investigational compound, but the need of the patient.
And imagine that everybody was very keen to get to the right
solution at the earliest time point.
Of course, one would think about how to bring things together.
And what I love to imagine are these integrated research platforms, where
on one hand, on an ongoing basis, You captivate all learnings on how to observe
patients in methodology like studies.
But then you build on top of that the exploration of new
pharmacological entities.
A little bit as is done in platform trials such as iSpy2 or the many others
that have been developed by you guys.
And so I feel So, that is the future.
And, uh, there are some, uh, questions on how to achieve that.
Um, but, hey, uh, that's where we need to go.
Yeah.
Scott Berry: to put in a plug for the STEP platform trial, NIH funded, NINDS
funded that's trying to do exactly this.
Not rebuilding the airplane, airport every time, uh, you know, so this, this is a
fantastic effort and we're seeing much more of this, uh, in platform trials.
So, uh, but I'll come back to the sports things and, you know, I almost.
I interpret things in sports.
I go back to this and a lot of this is very similar.
So, so baseball for years, uh, nobody would do anything different.
The manager, if you did what everybody else did and the team
lost, it was the player's fault.
If you do something innovative and you lose, it's your fault.
If you did something against the grain and all that.
Uh, and it's the same in drug development.
If you do what everybody else did, it's the drug's fault.
But if you do something innovative, maybe it was my fault.
Maybe I did it wrong and all that.
The fascinating thing, of course, in baseball is analytics has
completely changed the game.
And in 15 years, the way the game is played, the way it's
set up, is entirely different.
So, innovation completely changed it, but it's also done that in drug development.
Platform trials, adaptive designs in 15 years.
Now, if you don't do these things, maybe they'll say, Why weren't you doing that?
Why weren't you doing that?
And maybe it's a similar thing.
Mike Krams: you're absolutely right.
We've come a very long way.
And what is so amazing, and that is something that statistical experts
can take a lead in, is the power of simulations to be used as a
tool to bringing people around the table and then playing ping pong
with arguments and saying, Hey, if.
What if, and then you try that out and, uh, and I think the, there's a lot
of openness to, uh, to, uh, innovate.
I want to say this also with experts in regulatory science.
You know, a lot of people say, Oh, regulators don't like it.
It's absolutely not my experience.
My experience is that there have been so incredible interactions with
health authorities that have helped shape on how to go about innovating.
Scott Berry: Yeah, no, I agree completely.
And people don't see 10 trials done like this.
It's not because agencies said you can't do that, but
they're not being brought that.
So I think regulators have have played a huge part, actually, in a lot of the
innovations that's happened in this.
Yep.
But that's that's part of it again.
The slog part of it that when you present this, well, regulators
aren't going to like this.
Well, drug develop, uh, drug supply is not going to like this.
Well, CRO is not going to like this, you know, and that's a bit
of the slog of, uh, and the hard work in doing something different.
Mike Krams: yep, yep.
You know, there's the saying, culture eats strategy for lunch.
But if you, uh, make it a culture to have fun because you are intellectually
challenging each other, and it's not innovation for innovation's sake, but
it's simply the question, what's the best thing in the name of future patients?
Then everything else will follow.
Scott Berry: Yeah, yeah.
Fantastic.
Well, boy, this has been been wonderful.
I'm incredibly excited as as we move forward and part of Berry Consultants,
but it's an incredible look at innovation, the art, and the slog.
Appreciate it very much, Mike.
Mike Krams: Hey, thank you.
Scott Berry: Yeah.
Awesome.
Thanks.