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: All right.
Welcome everybody.
Back to in the interim, I'm Scott Berry and I'm joined today by my common
partner in crime here, Kurt Veley.
Dr.
Kurt Veley, welcome back to In the Interim.
Kert Viele: Thanks, Scott.
Scott Berry: Boy, you're showing up enough here on the interim, you probably
don't have a whole lot of alpha left.
Kert Viele: I don't, and I'm old too.
I've done a lot of trials.
Who knows?
That's why we gotta hire new people more alpha.
Scott Berry: yeah.
Okay.
That's not our topic for today, but that is, people get a sense of what
our sense of humor is around here.
in the interim, our topic today may sound dry, but it from its guidance
documents, and it's specifically the ICH E20 draft guidance on adaptive designs.
so my wife Tammy, listens to all of these.
she's the one that listens to all of these.
And so we, we have people like Tammy, who's brilliant.
but she doesn't live this every day.
So what is the ICH E20 the International Council for Harmonization.
That's the ICH of technical requirements for pharmaceuticals, for human use.
Kert Viele: That did make it really exciting right there,
Scott Berry: yeah.
Yes it did.
So and the key word of this, I think is harmonization.
And it talks about its mission statement, is bringing together regulatory
authorities and pharmaceutical industry to discuss scientifical, scientific and
technical aspects of drug registration.
And this is really, can they come to a harmonization a, an agreement
on guidelines for clinical trials interacting with regulators.
And an important thing to think about this is harmonization across
regulatory agencies, global.
EMA, PMDA FDA global countries.
And so for something to show up here, it's largely agreed upon
globally about these guidances.
what to add about ICH, the importance of this to some extent.
Kert Viele: So I, you know, I think the.
The important part here is that this is used for potential sponsors,
people who are designing trials.
This is a, essentially a document which is saying, this is, okay,
this is mildly controversial.
This may be more controversial.
nothing in here says you can or can't do anything.
but it's certainly giving.
Here's the kind of issues we worry about.
It provides a structure for how to talk to regulators.
This is essentially it.
It sets up the playing field and essentially says, these are the kind
of things that are always in bounds.
These are the things that are, you're gonna need more discussion.
All of this is vital in when people first walk into the, I know I
have a trial, what should I do?
This kind of documents where it says, you know, here's my options.
This is the set, the field I can play in.
Scott Berry: Okay.
And it says, harmonization is achieved through the development of
ICH guidelines via our process of scientific consensus with regulatory and
industry experts working side by side.
So in, where is this?
In the process?
They wanted to put out a guidance document, an ICH guidance document
on adaptive designs, something.
Barry, you and I have been living in this space of adaptive designs.
Now the FDA has a guidance.
regulatory agencies may have guidance, and now this is an international
harmonization of guidance, in the sense this is draft and they're looking for.
Feedback from the industry on their draft guidance.
So today we are going to dive into what this guidance, this draft guidance
says, the opinion from people who live the life of adaptive designs.
This is what we do and what our viewpoints on this draft guidances.
So that's the topic today.
So Kert what's your overall impression when you read this?
and by, by the way, people can go out and get access to this.
You can read this.
You should, if you're listening to this podcast and you're not, Tammy,
you should go read this draft guidance.
Kert Viele: You should make Tammy read the guidance.
That should be a requirement.
Scott Berry: Yeah.
let me know if you're successful on that.
yeah.
okay.
So the first time you read it, what did you think?
Kert Viele: alright, so this is, first off, this is a
really interesting place to be.
'cause where we are is the public comment period.
So, you know, the natural thing to do is immediately dive into issues.
But, you know, I think the.
The big picture is the first place to start, and by and
large, this is a great document.
this is evidence, you know, a continuation of the FDA, having adaptive guidance,
the EMA, all of these other places.
The fact that we've spent the last 20 years designing these trials, this is now
something that all needs to be formalized.
there's a wealth of experience, you know, hundreds of adaptive trials
out there, probably thousands.
I haven't done any kind of census on this.
but this is a document that basically says adaptive trials are.
Part of the armament, part of the things that you're meant to be coming
with us and we need to discuss.
So this is all great.
I think the document does a wonderful job of laying out all the issues.
all of the pros and cons of adaptive design.
it talks about various kinds of designs, group sequentials,
enrichment, seamless designs.
it talks about platforms to some degree, although there are other
guidance documents on that.
So this is a thorough, complete document and I think everybody on the
committee should be congratulated.
So this is, you know, we're gonna talk about our, you know, points
where we disagree on occasion, but by and large this is, you know,
95%, you know, this is wonderful.
Scott Berry: So 10 years ago, ICH was silent on adaptive designs and, it doesn't
mean we weren't doing them, but to some extent it's not part of the harmonization.
So I agree.
The existence of this thing is great.
and it says, and we will come to each one of these, but
Bayesian can be confirmatory.
Simulation is important.
Seamless can be confirmatory, enrichment can be confirmatory.
The, the, that, so that, I mean, almost full stop.
We can end the, we can end the podcast and it says all of those things
Kert Viele: Well, it, it says even more than that 'cause it says how to do it.
I mean, there's layouts.
If you do simulation, here's what needs to be in it.
Here are the issues you need to discuss with regulators.
It's not, it limits the surprises and de-risks the process for sponsors
to adapt, adopt these methods.
Scott Berry: Yep.
Yeah.
Okay.
So let's go into, should we go into the various pieces of this?
within it, what was the, what were potential, negatives?
One of, one of the negatives for me when reading it is a little bit of the tone.
to it a little bit.
And, a really good example is back in 2010, the FDA came out with a
draft guidance on adaptive designs, and it was felt to be, challenging.
And they came out with the phrase that some designs are less well understood.
And that phrase, that four word phrase for some people was.
Negative.
Oh, it's less well understood.
You can't do this.
It's a struggle.
It didn't bother me when I read that.
let's make it understood.
You know, that's part of our job sort of thing, in it.
So are there similar things here to perhaps the tone of it in your read that
could be construed to be similar to that?
Less well understood.
Kert Viele: So on the plus side, I think there's less of that.
I think they've, there some of that lesson has been learned.
maybe that lesson is now well understood about how much a document influences.
Practice indirectly.
I think to me, in terms of the language, issues, like things
are very hard or impossible.
you know, things that I know that we've done and we've gotten accepted, I think
are phrased as, oh, this is gonna be incredibly difficult and we know it's not.
So I think that would be valuable to try to get rid of some of that
and to more talk about the issues.
Scott Berry: Yep.
Okay.
Alright, and the other really important thing, I should
touch on the existence of it.
Is there anything this document says you can't do when you're doing
a design of an adaptive trial?
Kert Viele: No, and I mean, we could keep in mind that there's nothing
anywhere that says, I mean, I know more about the FDA's legal basis than
other regulatory agencies, but there's nothing in the law that says you have
to be frequentist versus Bayesian.
There's nothing in the law that says 0.025.
These are all, there are standards that, you know, this is an easier
path than others, but nowhere does anything say no to anything.
Scott Berry: Yep.
which is a really important thing.
We, I don't find this restrictive of at all.
I'm not going to be involved with the design of a trial and alter
it because of what this says.
overall,
Kert Viele: Yeah, I think this is really about where are you on the
adoption cycle for adaptive trials.
If you're on the bleeding edge, this document's probably irrelevant to you.
It doesn't say no, you're gonna stay on the bleeding edge.
This document is an invitation for people a little farther back to go.
Adaptive designs are now stable enough, acceptable enough that another
group of people can hop on board.
Scott Berry: Okay.
So on the grand scheme, this is an intangible summary from you of this
particular document, the original FDA draft guidance document, 2010, I
think it was, I think generally was perceived to be a lot of, caution.
and generally.
the people on the edge of this doing adaptive designs.
It wasn't gonna stop 'em, but it didn't feel like an invitation.
The current full adaptive design guidance by the FDA is almost saying,
you should be doing some of these things.
Some of these things are better and it's gonna supply better ways for us
to make decisions on your treatments.
It was almost kind of a kick in the butt, if you will.
So it was moving the swath of people to saying, boy, we better
know what's going on here.
We better do this kind of thing.
That maybe that's the sort of scale of, it, it's very encouraging.
You should be doing this.
It's gonna, it's gonna change the industry to caution and
people are gonna use it as well.
If you read this diet got document, I don't think people want you
to do this kind of thing, where do you find this on that scale?
Kert Viele: This is probably a little closer to 2010, and, but it's
also, you know, a few changes and it moves closer to the other document.
so this is all, this isn't substance.
This is, as you've said, tone.
so, you know, I think in terms of, let's talk about, for
example, a bias discussion.
There's discussions of, oh, if you do this or that, you could
run into biased estimates and on.
and all this is fair to be, I mean, I certainly, unbiased I think is important.
Quality of estimates is important.
I'm not sure unbiased is.
You know, the most important thing in every setting.
But this is a set, this is a situation where, you know, you
could have a tone where, oh, all these horrible things might happen.
But, you know, we respond to FDA and EMA questions on this.
We quantify what the bias is.
It's not that much and things are acceptable, or we
need to make small changes.
So this isn't, it's not a roadblock, it's something to be aware of.
Scott Berry: Yep.
Yep.
Okay.
So let's sort of dive into the various pieces of this.
in terms of adaptive designs, it goes through, different parts of,
different kinds of adaptive trials.
So, by the way, this does make a reference that this is
largely for confirmatory trials.
So we should be thinking this late stage.
There's one, one comment in there that I do.
really not like that.
Says that this guidance is also relevant for early trials, and I think there's
a lot of places that's completely misplaced, that this isn't really guidance
and it doesn't make sense in that.
But, so think about this as phase three trials for registration of this.
So it talks about seamless trials.
What do you think about the discussion it has about seamless trials?
Kert Viele: So you gotta read that two or three times I think.
So the seamless trial discussion, it talks about in some detailed trials
that say, have two doses and you do a dose selection and narrow it down.
It doesn't talk about trials where, you know, what we would
consider the more general seamless.
Where you're combining a phase two dose finding and a phase three confirmatory
trial where you've got lots of doses.
and it, it has a couple really negative statements in there.
I think it says adaptive trial shouldn't be a replacement for
a proper dose finding trial.
you know, I think this is one of my places I really would like to see this changed.
you know, a seamless trial.
The fundamental advantage that we see, and this goes back to, I should
probably give the broader picture.
If you separate these trials, what companies will do is they'll spend
a little bit of time in phase two, so they can move to phase
three as quickly as possible.
When they do that, you're more likely to get the wrong dose
when it's a seamless trial.
You actually spend more time in phase two, you can do the math.
You should spend more time in phase two because you get to use the
data, you make better decisions.
So I would say a seamless two, three trial, not always, we should have a
discussion, but in many cases it's a more proper dose ranging trial and gets
the information that regulators want.
It has more information about what is the right dose.
Scott Berry: Yeah, so they, there's snuck in there some phrases that just
feel sort of cautionary, like saying if you do a seamless two three trial, you
might have to do a proper dose ranging trial as though that's not proper.
so a few words like that go away.
And it's overly, you can do seamless two, three trials.
And I agree that's the part where in, in some sense it also says that
the goal of adaptive designs is to be more efficient and it almost
sort of brings out this aspect that.
It's not be, you're not gonna get better answers.
You're just going to do it with less resources.
And I think you gave a great example of where you actually
get better answers with this.
I'll throw a trial out there where I think this exactly happened.
The Sepsis Act trial was a trial in sepsis.
Faring was the sponsor.
They published a paper on the design.
It was a seamless two three trial with.
Four doses in phase two going to phase three where it picks a single dose
because the data in phase two was going to be included in the final analysis,
and that's what a seamless trial is.
It moves from multiple doses to a single dose, but you can use the data in the
first part in the con confirmation because that data was used in the confirmation.
They made the phase two part larger.
it's actually a trial that because it was larger, it stopped for futility
and didn't go to phase three.
Interesting.
If you go into the interim of where that trial was and you go back
to a small trial, they might have run, they might have jumped and
run a very large phase three trial.
Inappropriately and failed this large phase three trial.
They got better answers by being adaptive in that circumstance.
This isn't, you know, it, there, there are efficiencies, but that's a, that's
an example of a trial where I think you get better answers by being adaptive.
Kert Viele: Well, in a lot of trials like this.
We go, Hey, if I do this one, if I do this in a standard way, I can only
explore three doses if those efficiencies.
We don't always trade them for sample size.
We trade them to answer a more complete question, explore five doses.
Whatever you need to do here.
Scott Berry: Yep.
And if I have to do fixed randomization and I add a dose, it linearly
increases the size of the trial if I do adaptations over there, seamless.
Two three response.
Adaptive randomization.
I might explore more doses.
And we have examples of that as well where Eli Lilly did seven doses
exploring Trulicity, where the original design was three in a fixed trial.
But because of response, adaptive randomization, they could explore
seven, within that circumstance.
So, multiple examples of that.
so I think it's a case where, first of all, they talk about
seamless being confirmatory.
That's great, but there's a few hidden adjectives we would love to see removed.
Okay.
what about Bayesian?
Does it talk about Bayesian in the guidance
Kert Viele: so yes and no.
so I, you know, I have strong opinions about the Bayesian.
I noticed you didn't lead with that.
but anyway, so the Bayesian trial, it is there, there's a section on it.
there's a brief introduction to Bays in general, defines it as
basically updating data with a prior and so on, and then it moves to.
borrowing of external trial data, which going back to the
seamless trial, it's kind of odd.
you know, if you say you can't do seamless, you're saying you can't borrow
in that context, but you could borrow external data into your phase three
trial, but you can't borrow from phase two that was randomized in the same anyway.
It's an odd, it doesn't flow right.
So, but the Bayesian, I just, one thing that's important to
me when you get into borrowing Bayesian is not equal to borrowing.
There are lots of ways to be a frequentist and do borrowing.
we don't tend to do those, so I'm not expert in them, but they exist.
and they certainly do nice things, Bayesians do borrowing, and there's
lots to Bayesian that is not borrowing and that's given short shrift there.
I think there ought to be discussions on hierarchical models for modeling
subgroups, predictive probabilities there, those kind of things.
Should, Bayesian should not only be informative priors, there
are lots of other applications.
Scott Berry: Yep.
Yep.
in that, so gen generally, when you read that section, and by the
way, that's done by others, a lot of times people contact us and say,
we want to do a Bayesian trial.
And what they mean is an adaptive trial in that it's not necessarily driven by.
Bayesian statistical models, in that many of them are, which is why that tying those
things together happened and many times.
I su, I suspect when people come to the agencies about potentially
borrowing, they're probably bringing a Bayesian with them.
And so there's ways in which these things kind of get tied
together, but agree completely.
they're separate topics.
Overall, what was your view of their discussion?
Of base?
Kert Viele: so I thought with the idea that it needs to be expanded for
the bays part, the borrowing part I liked, it has a reasonable discussion.
Of what you need to worry about.
I am not anti type one error, so I am okay with the discussion of that as well.
I think it ought to be there.
I think there's a discussion.
You know, when we go to the agency with these trials, a lot of times
we don't even argue the statistics.
We argue is the data we want to borrow from.
Relevant, and that's certainly in this document.
So I think it says, you know, here are the issues you ought to
discuss, and these are the issues that we've discussed in the past.
And borrowing is sometimes appropriate and sometimes not.
Scott Berry: I thought it was, in some ways I think it's relatively weak.
There's not a lot there.
that's not bad.
in it, again, it's not restrictive in it, it exists, and this is a harmonization.
So some ways this is the factors that largely agreed upon regulatory agencies
globally is that Bess is confirmatory.
I, I mean it's existence in that, that's a really important thing in that, and
it being not overly prescriptive I think is actually pretty good in there.
I thought it was opening, the idea of borrowing is a very.
A reasonable thing, and I think by the way, forecasting forward, that's something
that's gonna be done much more now.
It's not always borrowing things we already know about.
Historically, it's a trial of four baskets that I'm prospectively going
into four subsets of disease and I wanna borrow from one subset to another.
I think this is pretty open to that idea as a very reasonable thing to do.
It.
Kert Viele: So I read it as well, and I think here's where it's
worth a little bit more language.
Because part of the language in there on say, bias and estimation
is a little bit at odds with bays.
I mean, to me, working in adaptive trials for the last 15 years or
however it has been, 15 years.
Oh, you're, anyway, it's been 15 years.
The, But anyway, the greatest advantage to bays when you're doing adaptive
trials is the posterior distribution is the posterior distribution.
You don't have to worry about correcting it.
You don't have to worry about what the design is.
You don't need these different, corrections all over the place.
the posterior is the posterior.
The inferences are the inferences, and you are done.
However, from a strict frequentist standpoint, those are.
Biased in some respect, and I think there ought to be some discussion that we
ought to be trying to get good estimates, and especially in adaptive trials, that
should be a focus on mean square error and not necessarily bias is the only thing
or the pre-eminent thing in the world.
Scott Berry: Yeah.
Yep.
agree.
Okay.
you talked about enrichment trials being in there.
anything specifically about enrichment trials?
Kert Viele: I like what's there.
I do think it auto, this is the same with, seamless.
It talked about two doses and not the full seamless, the enrichment
section, it talks about essentially.
Biomarker positive and negative.
And that's the focus.
we do a lot of trials, you know, rare oncology, rare.
Tumor types in oncology where we may look at 10 different cancers
and we wanna borrow among them.
the ROAR trial, for example, was the first pan tumor approval for FDA at least,
where you got a drug that was targeted to anything that had the right mechanism.
the.
The right target for the mechanism to act on.
I do think the enrichment section should talk about those kind of trials, and
this gets into the estimation again, we know if we look at multiple groups, the
highest of the high is biased high, and, you know, hierarchal models to correct
that, that's an important part of this.
Again, getting good estimates, not necessarily unbiased, isn't
necessarily the best estimate.
Scott Berry: Yep.
Yep.
and it tied in this idea.
So we do a lot of adaptive designs where we've been told no by a
regulator because we haven't yet convinced them of type one error.
I mean, this is a red line to some extent that we have had trials
where we know type one error is inflated, and that's been okay too.
So I'm not saying that every single trial is that way, but
that's a very strong thing.
maybe this is a bad thing to say, but I've never, and we supply estimation summaries.
In almost every one of our simulation reports, we look at the behavior of
the estimation, and I don't think we've ever been told no because
of the behavior of the estimation.
Kert Viele: Well, I think in general we want this to, the
shrinkage does reasonable things.
We actually run into the opposite problem where we're, we run a
basket trial, one of the baskets, the drug performs incredibly well.
We shrink it down and we can run into debates over, oh, I don't want the
estimate to be less, Hey, I want to be able to put the big number on there.
But we go, Hey, you know, this is the highest of the high.
It's biased high.
It should come down.
Scott Berry: Yep.
and in some scenarios we know that the estimate of the
highest group's gonna be biased.
I mean, that's the whole role of the particular shrinkage of that.
It does spend a good bit of time on, on two other topics
in the FDA it does as well.
Operational bias and the role of that, the role of blinding and all of that.
What do you think it's dis about?
Its discussion about the implementation, about adaptive designs, ensuring
blinding in those care, those aspects.
Kert Viele: I think those are great.
I think, you know, if I have comments, they're all minor.
it lays out issues.
It talks about communication flows, emphasizes you don't want
data to get to the wrong places.
it discusses what I would consider maybe esoteric topics for Tammy, in terms of.
If a sponsor needs access to certain information, there needs
to be blinded firewalls in place, you know, to make sure it doesn't,
doesn't negatively affect the study.
There's discussions of interim analysis committees.
I think it's very thorough.
I like it a lot.
Scott Berry: Yeah.
Yeah.
I do too.
I, and largely agree with it.
and making sure that's done really well, I think is important for adaptive designs.
So they, it also discusses a, what we call an adaptive design report.
A report that summarizes and describes in complete detail the
adaptive design and the simulations conducted, around the design.
What did you think about its description of the need for
this, the components of this?
In the ICH.
Kert Viele: I think so this is another one of my sections
I think has really done well.
I think it lays out tons of issues, talks about different scenarios,
has important points like, you know.
Plausible scenarios rather than all scenarios.
So there's the famous example we've talked about in other podcast where
we were asked to simulate when people become immortal under certain
conditions, which I think is, you know, largely a time of time passed.
but this document is in the present, so it does that well.
it has a few throwaway statements in it, I'd say.
I don't know if they're throwaway or not, but it's essentially.
This is impossible to do under certain conditions, and I would prefer that
this gets back to less well understood.
I'm worried about somebody just pointing to that and going, oh, they wrote 10 pages
on this, but they really only meant the one sentence that says this is impossible.
That's the secret code that tells us not to read the other 10 pages
and pay any attention to it.
Sometimes this is hard.
Sometimes the null space is hard to explore and you know, we need
to be transparent about that.
But in a number of cases, you know, a dichotomous response.
You know, look at a grid of probabilities and you've done what you needed to do.
Scott Berry: This is another place if we go back to, there's an ICHE
20 guidance that says simulation for demonstration of type one error is.
re is a thing you can do.
It's a scientifically reasonable thing, and it says it in the ICHE 20.
It's draft.
but that's another place that, looking back over the years, that's
been a controversial thing for years and it was never in the FDA.
The question is this, and now it's in the ICHE 20.
The progress that's been made in this, I, that's another place
we don't want to ignore that.
This is a super positive thing that's in them.
Okay.
there are a couple things that we kind of disagree with that I, and I'll
call them little myths, for example, that I'm not sure are grounded.
Don't do a lot of interims.
You know, there, there are people that have this viewpoint that, oh,
you should only do one interim.
And we get people that tell us, oh, you shouldn't do two interims.
Regulators don't like that.
Now, it doesn't tell you can't do six interims in it.
But it gives this feeling that generally interims are bad.
If you read that statement,
in, in that, and we.
I understand the notion that I, and it's interesting for a long time, and
Don has said this, that if you do one interim, it might actually be something
that supplies a certain amount of information about what's going on.
If you were to, at the other extreme, do interims every day, there's almost
nothing that's ever learned by anybody.
Because it's just continually going on within this.
So it's always a statement I've found odd, and I'm not sure it's actually
real, but it's repeated by people.
So there's a couple things like that, that show up in the document as well.
Kert Viele: and one thing I think we ought to, so things that aren't missed that are
cautionary in this document, I think we ought to be, we ought to make sure we.
Echo.
In this podcast, there's a discussion about there is some limit on how many
adaptations and so on you can do.
Now, we certainly aren't on the side of, you know, hey, three interims as
opposed to one is exceeding the limit.
That's not what we would call the budget, but certainly the
document raises a good point.
If you're talking about a platform trial, the model's changing.
there's different protocols at different sites.
you know, lots of things can be very complex.
We've.
We've at some level experimented with experimenting, and I
think it should be fair.
We've walked at the end of the trial and said, Hey, that was maybe too complex.
It didn't do exactly what we wanted it to do.
but this should be part of the discussion.
I don't think, I don't think anyone should take this as, you know, don't
do two interims or don't do two things.
You know, do a factorial design with early stopping, but don't throw in everything
in the toolbox at once, is fair.
Scott Berry: Yep.
I, and I do think that's fair that touches on another topic that I'm
interested in your viewpoint on this.
It does give the viewpoint that you should justify why you're
doing, say, an adaptive design.
Now, I think some people might take the viewpoint of what
does somebody have to justify?
They're doing a fixed trial.
Why do I have to justify a scientifically credible thing?
What's your take on that general sentiment in the document?
Kert Viele: So I am, I'm in favor of that sentiment in the document.
I do think, You know, if we're talking about non-adaptive trials,
they're easier to implement.
They're usually easier for people to write up to understand.
If you get into corrections for estimation from a frequentest
standpoint, there are complexities that come with an adaptive trial if
you are going to get exactly the same.
So at the end of the day.
Patients are gonna be treated essentially the same chance they
get a good drug, the same chance they mistakenly get a bad drug.
If all of that's the same, and that includes time, correct, choice of
dose, I mean there's a lot more into it than power and type 1 error.
If those are all the same, definitely go simple.
You need to say, here is the advantage that justifies the
cost of doing an adaptive design.
Often that's in adaptive's favor, but we know, you know, if accruals fast,
not time to be adaptive, for example, there are exceptions to adaptive wins.
Scott Berry: The other part of that, and I'm completely fine with that as
well, there, there's one challenge to it, but one other part is.
we don't decide on a design.
We don't throw in adaptive things because, ooh, it would be cool
to do that, or we're showing off.
We've gone through a sequence of comparisons with the design team.
We've said, here's what you could do with this.
We always start with a fixed design.
Here's a fixed design.
Now we start to add adaptations.
We've done all those comparisons and we've demonstrated the
advantages that this design.
Supplies, in it.
So I think it's a very reasonable thing.
One of the challenges that I've always found with this is we go through this
iteration of the design where we do lots of comparisons to other designs.
And what if we do RAR with different frequency?
What if we don't do it?
And it's hard to present that entire story of comparisons
to regulators of the designs.
We're not running.
So we walk in and we say, this is the design here.
I know it relies upon us to explain some, the value of the things we're
doing on that, but it's a little bit harder at the end of the story
to provide all of that story.
Kert Viele: And we've had confusions where regulators have said back.
essentially they have brought up reasonable issues about designs
we're not proposing because they're often those comparisons.
It can be confusing.
So, you know, it's a cautionary tale to lay those out carefully and make
sure we know what the default is.
Now, I will say on that issue, my pet peeve is the one where it says
Bayesian has to be justified adaptive.
I think there's a cost to being adaptive that needs to be.
Justified in terms of the extra effort, operational bays and
frequentist, that's not the same thing.
This is just two different ways of being inference.
I always call this the animal farm argument of statistical paradigms.
Frequentist is equal, but frequentist is more equal than base.
So this, I don't, I object to that one.
Scott Berry: it's good.
I should have asked you your pet peeve.
You have a pet peeve of ev each episode, so I, okay, good one.
other topics I missed on the guidance
draft guidance.
Kert Viele: I think we've actually done pretty well going through it.
As I said, you know, I think we should come back to the positives here and just
how much of this document we agree with.
I think we agree with virtually everything they say.
You know, you should justify the following aspects.
We agree, you know, these are the pros and cons.
We agree.
it's a lot of the adjectives around it.
That we're, we are reticent of essentially, you know, people who
are involved in regulatory consulting going, this is what this means.
It's, oh, this is the sentence that invalidates the rest of the document.
And we've been through that often enough.
We'd like it to focus on the issues.
Scott Berry: Yep.
Yep.
that the regulators don't think a seamless two three trial is proper.
Kert Viele: Yeah.
Scott Berry: you know, and weird things like that.
So largely, I agree that I think this is, I read this and it was
a little bit of uhoh, you know, what are we gonna get here?
And I thought it was largely a very positive document, in that.
So, congratulations to everybody that worked on it.
I know.
Consensus and harmonization.
Yikes.
in this, and so congratulations to them.
are, is Barry planning to provide a response to this?
They've invited responses.
Are we planning to provide a response?
Kert Viele: Yeah, we're definitely going to provide our own response.
we're also interested, I know other groups are working on responses as well.
we're happy to collaborate on those responses.
so certainly, you know, we are, we're gonna make sure that we, we express
where we would like to make changes.
and I think we've covered a lot of the, our big topics today.
Scott Berry: Yeah.
Yeah.
Brilliant.
Alright, so, thank you Kurt for joining.
Thanks for weighing in on this and here in the interim.
And remember, we're always in the interim of science and life, so here we are.
Thanks Kurt.
Kert Viele: Thank you.