8. Weight of Evidence vs Carcinogenicity Testing Part 1, with Bruce Pearce

The ICH has released a guidance which may allow you to forego animal carcinogenicity testing in favor of a weight of the evidence argument. We begin our two-part discussion of why to do that and how to do that with Bruce Pearce.

Episode Transcript

James C. Taylor (00:02):
Carcinogenicity is the ability of a substance to cause
cancer in the development world.
You test for this and the InternationalCouncil for Harmonization has released
a new guidance on that testing.
Now, there's a lot to unpack here.
We're going to talk about itover the next two shows with
someone who knows a lot about it.
That's Bruce Pearce and thisis Insight at Biologics.

(00:33):
Hi there, Bruce.
There is a lot here that weneed to go over and that's why
we're going to have two shows.
But before we do that, why don't wejust tell people who Bruce Pearce is?

Bruce Pearce (00:43):
Oh, well, thank you James.
I will.
I'm a classically trained pharmacologistand toxicologist with broad expertise
in early and late stage developmentof small molecules and biologics.
30 years of working in thisarea contributes to this
broad spectrum of experience.

(01:04):
Prior to the 12 year plus tenure atBiologics Consulting, I had a number
of positions in both biotech industryand academia, including in as an
independent consultant within biotech.
I was involved in the developmentof molecules, like hemoglobin based
oxygen carriers used to treat bloodloss and in surgery and severe trauma,

(01:31):
and was involved in the developmentof botulinum toxin therapeutic.
Rather than go on and on here for10 or 15 minutes, I think the scope
and depth of my research and drugdevelopment interests are reflected in
part in my more than 85 publications,including in peer reviewed journals.

James C. Taylor (01:52):
Wow.
Wow.
So, you are kind of here,there and everywhere.
That's cool.
Now talking about, you said you couldgo on and on about your credentials.
The other thing you could go on andon about, and you're going to have to,
'cause that's what we're doing here,is this new guidance from the I C H.
The I C H released a guidance called(let me make sure I have this correctly)

S1BR1 addendum to S1B (02:13):
Testing for Carcinogenicity of Pharmaceuticals,
and if I understand what we'retalking about right, this guidance
will allow for the use of a weightof evidence argument instead of the
two year rat carcinogenicity study.

(02:34):
Now how can a sponsor takeadvantage of that and why should
a sponsor take advantage of that?

Bruce Pearce (02:40):
Okay, thank you for the question.
Great question before Iget started in addressing.
That two-part question, I just wantedto mention why-- you know, what the
reason is for preparing the podcast sosoon after this guidance was introduced.
It was only introducedin November of last year.
And, uh, this is because it's somethingthat sponsors need to be very proactive

(03:05):
about in order to take advantage of theopportunity to use, if you correctly
identify weight of evidence argumentsin lieu of performing the required
two-year carcinogenicity study.
And I am going to repeat this themeagain and again, the urgency in
terms of paying attention to thisand developing a strategy for dealing

(03:28):
with carcinogenicity assessment.
And the reason this is so important,in part, is that carcinogenicity
assessment studies involve a largenumber of animals, 600 animals
per species that would be tested.
They take a long time toperform and to analyze the data,

(03:49):
and they're very expensive.
They can range betweentwo and 4 million dollars.
In addition to the pivotal studies,the design and the dosing of these
studies must be supported basedupon the results of other studies.
For example, long-term, six to ninemonth toxicology studies in rats to

(04:10):
support dosing in the two year ratstudies and generally about a 16
week dose range finding study andwildtype mice are needed to support the
proposed rasH2 transgenic mouse study.
In addition to this, the design of thesestudies should first be reviewed in the

(04:33):
justification for dosing accepted by FDA'sCarcinogenicity Assessment Committee,
the CAC, before initiating the studies.
These dose range findings studies,of course, add significant time
and cost to the overall program.
Then an aggregate canbe more than four years.

(04:53):
Hence my rationale for I agreeingvery strongly to begin to work on
your strategy for carcinogenicitytesting is soon after genome toxicity
testing, for example, is completed.

James C. Taylor (05:05):
Okay.

Bruce Pearce (05:06):
And once it's clear that carcinogenicity testing will be
acquired for your particular therapeutic.
I wanted to also add, following on theheight of the pandemic and continuing,
even today, the lead times forlong-term toxicology studies can be
up, up to one year, depending on theCRO and this, the factors contributing

(05:32):
to this log jam coming out of thepandemic will resolve going forward.
And that's starting tosee signs of that already.
But right now, proactive planningand scheduling are absolutely
critical for programs to meettheir projected milestones.

James C. Taylor (05:50):
All right, now the-- this guidance.
I, I have a question about that.
Does it apply to both smallmolecules and biologics?

Bruce Pearce (05:58):
Very good question.
Today's discussion will focus on therequirements for small molecules.
Carcinogenicity, bio acids are generallynot appropriate for biotechnology
derived pharmaceuticals, biologics.
However, product specific assessment ofcarcinogenetic potential may still be

(06:21):
needed depending upon the duration of aclinical dosing, the patient population,
the biologic activity of the product.
For example, does it have, is it a growthfactor that does affect growth factors?
Is it immunosuppressive or is thereevidence of carcinogenic potential
of other drugs in the same class?

(06:42):
Testing may not be needed if the intendedclinical exposure is not greater than
three to six months, or the risk ofcarcinogenicity has been addressed in a
weight of evidence approach summarizingthe published data and information
from other molecules in the class.
However, detailed information on thetarget biology and the mechanism of action

(07:05):
in vitro data, data from chronic toxicityand clinical data may be important.
In some cases, the available informationcan be sufficient to address this without
performing additional nonclinical studies.
However, the product specific assessment,which you'll need to do for a biologic

(07:26):
of the carcinogenic potential is usedto communicate risk for the molecule,
provide input to risk managementplan, along with the product labeling,
clinical monitoring, post-marketingsurveillance, which, and some combination
of these approaches may be needed.

(07:46):
This is something that should bediscussed with the review division of F
D A responsible for your particular drugto, uh, understand what they require to
address the issue of carcinogenicity.
A more detailed discussion of howcarcinogenic potential of biologics
may be addressed is beyond thescope of our discussion today.

(08:09):
And--

James C. Taylor (08:10):
Okay.

Bruce Pearce (08:10):
Listeners are directed to I C H S1A and S6 guidances for
further information in this regard.

James C. Taylor (08:20):
So would you recommend, if not urge sponsors to
address the question of the need andrequirements for carcinogenicity testing
early in the development program?

Bruce Pearce (08:30):
Yes, exactly.
Absolutely.
That's a major point here.

James C. Taylor (08:34):
All right, so now an aspect of this guidance that needs
to be looked at as well is the needto perform carcinogenicity testing
in two animal species, includingthe high dose criteria for the most
popular transgenic mouse model.
Now, what about that?

Bruce Pearce (08:48):
Yes, so, so the, the I C H guidance, I C H S1B guidance was
first issued in 1997 and it called forflexibility in considering approaches to
address pharmaceutical carcinogenicitytesting, but the default has became that
performed two long-term studies, and thisevolved into the practice of performing

(09:14):
studies in one of several transgenicmouse models, plus a two year rat study.
The I C H S1B guidance also mentionsa number of transgenic mouse models
that could be considered for shorterterm carcinogenicity studies.

(09:34):
However, over the past 20 years,pharmaceutical development experience
models other than the rasH2transgenic mouse is far more limited.
But one of the problems associated withthis was that the use of the transgenic
mouse study is the exposure ratioendpoint used in the animal to human

(09:58):
plasma area under the curve determinationused to set the high dose for the rasH2
mouse study similar to what was-- hasbeen set for the two year mouse study.
And the way this has been resolved, andit's addressed in this addendum, is a

(10:19):
comprehensive analysis was conductedto assess exposures and outcomes from
previous rasH2 transgenic mouse studies.
And this is described insection three of this addendum.
The results of this analysis indicatedthat a 50 fold plasma area under the curve
exposure ratio is an adequate criterionfor high dose selection versus the 25 fold

(10:47):
adopted for the rat two-year CAR C study.
Getting back more specificallyto your question, James--

James C. Taylor (10:54):
Mm-hmm.

Bruce Pearce (10:55):
In terms of the evolution of thinking about CAR C testing, Dr.
Timothy McGovern, the Associate Directorof pharmacology and toxicology in
FDA's Center for Drug Evaluation andResearch office, has indicated the
changes to this testing paradigm havebeen sought since its introduction

(11:16):
in 1997, to incorporate progress inthe science, to reduce the use of the
number of animals used in this testing.
Since publication of the originalS1B guidance, scientific advances
toward elucidation of the mechanism ofcarcinogenicity, a greater understanding

(11:37):
of the limitations of these rodentmodels, I C H and F D A have concluded
recently that two year rat carcinogenicitystudies might not add value to human
assessing human carcinogenicity riskin some cases, and the carcinogenic
potential could have, some-- could havebeen assessed adequately, based on,

(12:01):
for example, a comprehensive assessmentof all the available pharmacological,
biological, and toxicological data.

James C. Taylor (12:09):
Now, what was the basis for coming to this conclusion?

Bruce Pearce (12:13):
This is an important question.
Yeah.
In a nutshell, an internationalprospective study was
conducted under I C H S1.
It was, uh, issued in 2012.
This study, this prospectivestudy compared the results of
two year carcinogenicity studiesperformed on 45 molecules.

(12:36):
Two carcinogenicity assessment documentssubmitted by the sponsors performing
these two year studies that addresswhat the integrated weight of evidence
assessment concluded regarding whetheror not these two year studies would
provide additional valuable evidenceregarding carcinogenic risk to humans.

(12:59):
The findings following a review ofthese data by the regulatory members
of the I C H expert working groupoverseeing this evaluation was that an
integrated weight of evidence approachcould be used to adequately assess the
human carcinogenic risk for certainpharmaceuticals in lieu of conducting

(13:22):
the two year rat study in some cases.
This new addendum introduces orarticulates a comprehensive and
integrative approach to assessing humancarcinogenic risk of pharmaceuticals in
a regulatory document for the first time.
The goals of the addendum are to expandthe testing scheme for assessing human

(13:48):
carcinogenic risk by introducing anintegrative approach (as I keep using the
same term) and provides specific weight ofevidence criteria guidelines into specific
criteria that inform whether or not a twoyear rat study is likely to add value to

(14:08):
human carcinogenicity risk assessment.
The second goal was to encouragemore mechanism based approach
to human carcinogenicity riskassessment of pharmaceuticals
starting earlier in drug development.
And this is an important one becausethis adds to my urgency or to the urgency

(14:31):
for sponsors to be looking at this earlyon, because you have opportunities with
other experimentation and analysis tocontribute to the weight of evidence.
And they're pushing us in this direction.
And to reduce the use of animals inaccordance to the three R principles, that
is replacement, reduction, and refinement.

James C. Taylor (14:52):
Mm-hmm.

Bruce Pearce (14:52):
And to focus on generating more, again, mechanism
based carcinogenicity assessments.
And the final one was the one thatwe touched on before, and that is,
Setting this high dose ratio ofarea under the curve of exposure in
the transgenic mouse versus humans.

James C. Taylor (15:14):
Okay.
Now, there was something you said alittle bit earlier in the conversation.
We're gonna run it back a little bit.
You talked about carcinogenicpotential could have been ex--
assessed, excuse me, adequatelybased on a comprehensive assessment
of all available pharmacological,biological, and toxicological data.
So what did you mean by that?

Bruce Pearce (15:38):
Yeah.
This is the central question in this, thisnew addendum, this guidance documents.
Here toward the end of our first parthere, let, let me begin to address that.

James C. Taylor (15:49):
Okay.

Bruce Pearce (15:49):
It essentially means that it may be possible in lieu of
performing the two year study in ratsthat provide a comprehensive integrated
weight of evidence document assessinghuman carcinogenic risk of drugs, which
involves integration of the data forspecific factors to consider use and

(16:11):
we'll come back to these factors toconsider in part two of this podcast.
And using data in the literature as wellas data from results obtained with the
particular therapeutic agent in question,the support, the one of three conclusions
that carcinogenicity is likely.

(16:33):
Or two, it's unlikely.
And in both these cases of likelyor unlikely, you can argue that
a two year rat carcinogenicitystudy would not add value.
And finally, the outcome is uncertain,such that a two year carcinogenicity study
would add value to human risk assessment.

(16:54):
In cases where the weight of evidenceassessment leads to a conclusion
of uncertainty regarding humancarcinogenicity potential, the approach
described originally in S1B haveconducted two long-term carcinogenicity
studies over the the two year studyin rats, and the shorter study in

(17:15):
the transgenic, a mouse model wouldbe the most important strategy.

James C. Taylor (17:21):
Like you said, you've got a lot more to say about this, and
you're going to get to say it, butyou're not going to get to say it today.
But if you'll stick around, we willconclude this interview and people
can hear it on our next episode.
But between now and then, if you wouldlike more information from Bruce or from
anybody else here at Biologics, just emailus at [e-mail].

(17:44):
That's insight at BiologicsConsulting all one word dot com.
And also we'd love it if you'd like,subscribe to, rate, and review our show.
The executive producer of Insightat Biologics is Kris Kraihanzel.
This episode was producedand edited by James C.
Taylor and the technicalsupervisor is Jeff Wease.
The Insight at Biologicstheme is by Tom Rory Parsons.

(18:06):
I am James C.
Taylor.
Thank you for joining us, and pleasecome back for more Insight at Biologics.