May 16, 2023 • 27 mins
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 conclude our two-part discussion of why to do that and how to do that with Bruce Pearce.
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Episode Transcript
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James C. Taylor (00:01):
In our previous episode, we were talking with Bruce
Pearce about the new I C H guidance,which allows for using a weight
of evidence argument in place of atwo year rat carcinogenicity study.
But how do you make aweight of evidence argument?
Now, Bruce will talk about that in just amoment, and this is Insight at Biologics.
(00:22):
First, a bit of housekeeping.
If you'd like to know the breadth ofBruce's credentials on this subject,
you can listen to him tell you allof that himself in the first part
of this interview, the previousepisode, or you can email us at
insight@biologicsconsulting.com.
Now, let's get back to it.
What are the specific factors toconsider that are recommended for
(00:43):
incorporation into this integratedW O E argument slash document?
Bruce Pearce (00:50):
Thank you for the question, James.
The weight of evidence integratedapproach, as I said in the previous
podcast, is based on a comprehensiveassessment of the totality of data
relevant to the carcinogenic potentialavailable from public sources and from
(01:11):
the results of relevant drug developmentstudies with a sponsors product.
But what's important are, whatare the factors as you've targeted
to consider in this evaluation?
And these are, in fact, the elements thatshould be addressed as a part of putting
together a weight of evidence argument.
(01:34):
And there are five of them thatI will discuss here briefly.
The first is data that informedcarcinogenetic potential based
on the drug target, the primarypharmacologic mechanism of
action of the parent compound.
And I'll mention here for the firsttime, the major human metabolites.
(01:56):
So if you have a major metaboliteidentified in the metabolism of
your parent compound, this willneed to be assessed as well.
Included in this assessment relatedto the primary drug target is
the distribution of the target.
For example, in rats and humans, isthe target present in the rats that
(02:21):
your pharmacologic agent is acting on?
Is the pharmacologic activityand the potency of the parent
compound, or the major metabolitesif appropriate in these species?
Information from genetically engineeredmodels, human genetic association
(02:41):
studies and cancer gene databases.
This is, the idea of the use ofgene expression biomarkers, genomic
biomarkers to help to understandtumorogenic potential, is something
that's new that's being examined.
In fact, last year in 2022 inToxicological Sciences, a paper was
(03:07):
published, I think it was in April,that discusses this collaboration to
use the genomic tools to better predictcarcinogenic potential, and these kinds of
data can be used to substantially enhancethe weight of evidence or arguments.
James C. Taylor (03:30):
Okay.
Bruce Pearce (03:32):
The other, the other element here in terms of the, the target is,
or the particular class of drug that itbelongs to is the information on other
drugs in the class, which can be very,very important and add substantially to
the weight of evidence arguments one wayor the other in terms of carcinogenic.
(03:54):
The second element that I want to orfactor to consider are the results
from secondary pharmacology screensthat are typically done early on
in the assessment of a candidate.
That inform in terms of drug selectivityfor targets and off-target, especially,
(04:16):
for example, if the drug interacts witha nuclear receptor or biotechnology, or
data from repeat dose toxicology studies.
In fact, there's an emphasis on, asI mentioned before, the six month rat
study to support the two year study.
James C. Taylor (04:36):
Mm-hmm.
Bruce Pearce (04:37):
Including information about plasma exposure, margins, parent drug,
and again, major metastas-- metabolites.
An important element is the histopathologyfindings, the histopathology data,
because in a number of cases you cansee histopathological changes that
(04:59):
suggest effects that have carcinogenicpotential when you don't have
effects on other markers, say hormonelevels or something of the kind.
The third element is evidence ofhormonal perturbation, including
knowledge of the drug target,compensatory endocrine responses.
(05:24):
You may see in this regard weights andgross microscopic changes in endocrine
and reproductive organs from repeat dosetoxicology studies, relevant results
from reproductive toxicology studieswhere hormones playing a preeminent
role in the changes that are occuring.
(05:45):
And findings from rat studies suggestinghormonal perturbation may include, as
I have alluded to, microscopic changes.
These include atrophy, hypertrophy,hyperplasia, biologically significant
endocrine and reproductive organweight changes, factors that can't
(06:07):
be addressed in terms of changesthat may have been contributed
associated with stress as a part ofthe process of the, of the testing.
Such findings are suggestive ofpotential carcinogenetic risk,
and unless investigated for humanrelevance and demonstrated otherwise
(06:29):
are treated that these genomicmodels that are being assessed now
in this collaboration may prove veryimportant in terms of addressing
the human relevance, for example.
And the fourth point to consideris genotoxicity testing.
There's a series of studies that aredone that complement the full package
(06:52):
for genotoxicity testing and anyequivocal genotoxicity results that
can't be resolve-- resolved wouldfurther implicate the possible--
the potential for carcinogenic risk.
And finally, fifth, view modulation thatis broad immunosuppression may provide
(07:14):
significant concern for human risk.
James C. Taylor (07:19):
All right, so Bruce, in your view, examination of these
factors that you've just delineated,would that be sufficient support
a weight of evidence argument?
Bruce Pearce (07:29):
Yes, it very well could.
Evaluating these factors may be sufficientto conclude whether or not a two
year rat study would add value to theassessment of human carcinogenic risk.
However, the weight that's attributedto each of these factors may depend
on the nature of the molecule,so it's not so straightforward.
(07:50):
However, one or more weight ofevidence factors may be inconclusive or
indicate a concern for carcinogenicity.
The sponsor can apply investigativeapproaches that could address
the uncertainty or inform humanrelevance of identified risk.
(08:10):
I just want to pause here for a secondand emphasize here again is a situation
where you need time to perform theseother investigative approaches to
be able to address this adequately.
This can't be an afterthought and tryto do this at the end of your program.
James C. Taylor (08:31):
Okay,
so why, why don't you explain a littlebit more about the other investigative
approaches that are appropriate?
Bruce Pearce (08:42):
Yeah, some of the other approaches, may involve other
investigative studies as I've mentioned,or analysis of specimens collected
from prior studies using specialhistochemical stains, for example,
looking for molecular biomarkers, serumhormone levels, immune cell function,
(09:05):
in vitro - in vivo test systems, anddata from emerging technology like the
genomic methods that I've described.
All of these really require someforethought, some looking at these
in retrospect, very difficult to havesamples that you can appropriately
(09:28):
stain, measure the biomarkers and serumhormone levels if you haven't insured
that this was done at the appropriatetiming when these studies were performed.
And also, generated to informhuman mechanistic relevance at
therapeutic doses and exposure.
So I, I, again, it should be, I think,self-evident from this discussion that
(09:54):
to be able to pursue these approaches,you need time and you need foresight
early on to ensure that you'll notmiss the opportunity to collect these
data, both preclinical and clinical.
James C. Taylor (10:08):
All right.
Now, if I recall, there's a differencein the availability of information based
on the type of substance being explored.
For instance, a drug that is a memberof an established class versus a novel
first in class drug that that altershow much information is available.
(10:32):
Yes?
Bruce Pearce (10:33):
That's that-- that's exactly right.
And, and if you are studying a moleculethat has other members of the class,
you can leverage that data to really addsubstantially to your weight of evidence
argument, particularly if carcinogenicityhas been seen among the other members.
That might really be one ofthe primary elements supporting
(10:57):
your conclusion that it's highlylikely that it's carcinogenetic.
But nevertheless, novel drug targets,which you refer to, can be included
in this weight of evidence argument.
The problem is that the bar is higher.
I further evidence that there's nocause of concern regarding the target
(11:21):
biology is needed when there's a lackof other members of this class, or a
lack of precedent, if you will, forthe novel drug that you're study.
And this has been addressedin part, in this addendum.
There is a case, a case study that'sdescribed in the appendix to the
(11:42):
addendum that gives an example of anovel target where a two year study
was not considered to add value.
And the evidence compensatedfor this lack of precedent.
In this example, the cause forcarcinogenic concern was not
identified regarding the drug targetbiology, the compound selectivity.
(12:07):
There's no proliferative changesin any organs or tissues, and
were observed at high multipleexposures in the six month rat study.
The, the results of this were very clean.
This is a particular idyllic example,if you will, but it's actually
(12:30):
drawn from the data from those 45molecules that were studied to assess
the ability of the use of weight ofevidence in lieu of two-year study.
When the weight of evidence assessmentssupports a conclusion that the conduct
of a two-year rat study does not addvalue to the assessment of human risk,
(12:55):
the I C H guidance indicates that thesponsor should seek consultation with
the appropriate regulatory agency in,in accordance with the established
procedures for that particular area.
And they further state that the sponsor,if the sponsor decides to conduct
(13:16):
a two year rat study in accordancewith the S 1 B guidance, there's no
obligation to seek further consultationwith the drug regulatory agency.
But, my opinion is with respect to U SF D A, it is submission of the proposed
protocols for both the RAs mouse,the RAs H two mouse study and the two
(13:41):
year rat carcinogenicity study to theappropriate division for review by the
Carcinogenicity Assessment Committee.
An executive CAC is advisablebefore initiating these studies
and committing two plus milliondollars to performing this study.
You don't want to be in the positionthat after you've spent all of this
(14:03):
time and invested this kind of money,that, that the FDA reviewers inform
you that your study's not acceptable.
So I generally argue that it's alwayssmarter to talk with the division.
And get feedback from thereviewers before you take any
major steps in drug testing.
James C. Taylor (14:24):
Now, I like examples, Bruce.
And so if you would, would yougive us some examples of how these
principles are applied in cases thatcome to each of the conclusions?
Bruce Pearce (14:35):
Yeah, as I, as I mentioned before that there are case studies that
are contained in the add- in the appendixto this addendum, and I talked to you
about the case where it was a novel drugand a novel target, and the conclusion
was that an additional carcinogenicitystudy was not required, and that was case
(15:00):
number four, that case study number four.
Case studies one and two are examplesof pharmaceuticals where the weight
of evidence argument indicated that itwould not add value to the assessment of
human risk and case study number three,described data from weight of evidence
(15:20):
assessment of the carcinogenic potentialwhere the conclusion was uncertain in
there and that situation where a two yearcarcinogenicity study was recommended.
I, I think it's important to understandwhile these examples are taken from
real world data, from the studies thatwere evaluated by this expert working
(15:46):
group, the fact of the matter is itcan't possibly take into consideration
all of the circumstances that wouldoccur with unique, unique drugs.
So this provides guidance but doesn'tcover necessarily all the bases.
James C. Taylor (16:04):
Okay.
All right.
Now, based on what you said, ifall right, let's say I believe that
conducting the two year rat studyis unlikely to contribute to further
understanding of the carcinogenic risk.
What factors should I focus attentionon then when preparing the weight of
evidence document to support that?
Bruce Pearce (16:23):
Yeah, good question.
One of the things that was done in puttingthis addendum together is that the weight
of evidence attributes of a compound thatare more likely to support the conclusion
the results of a two year rat study wouldnot contribute to contribute value to
(16:46):
human carcinogenicity risk assessment.
And I'll, I'll go through theseand I think it helps to clarify.
These, the points to consider that Italked about before in the case of the
target biology, when the target biologyis well characterized, not associated
with cellular pathways known to beinvolved with human cancer development.
(17:12):
These are situations that occurred inthe case of those 45 molecules that were
assessed where there were non mammaliantargets and or the carcinogenicity
data were available with other drugsat the same pharmacologic class.
Two, there were no identified concernsfrom secondary pharmacology points to.
(17:39):
That did not inform anyoff-target potential for their
particular pharmaceutical.
Three, the results of chronic toxicitystudies indicated that there were no
hyperplastic, hypertrophic, atypicalcellular alterations or degenerative
changes without adequate explanationof the pathogenesis or human relevance
(18:06):
indicative of no, or on or off targetpotential for of carcinogenic concern.
Again, this emphasizes the fact that eventhough you may have these observations,
if you can adequately explain themmechanistically and address whether
or not there's any human relevance,it's important to the contribution
(18:33):
to your argument that an additionalstudy to your study is not required.
Number three, no perturbation of endocrineor reproductive organs was observed
or endocrine findings that were notadequately explained with respect to the,
again, the potential for human relevance.
(18:54):
The overall excess assessmentof immunotoxic potential was
concluded to be negative.
And finally, there was no evidence ofimmune modulation or immunotoxicity based
on the repeat dose toxicology studies.
So this review of these factors toconsider give you an indication of
(19:21):
the kinds of findings that would helpyou to make an argument or the nature
of the findings that would help youto make an argument that a two year
rat study would not be required.
James C. Taylor (19:33):
All right, now the, the six months are, excuse me, the
six month RAs H two mouse study.
Can you use that to support a weightof evidence argument, or even in
place of the weight of evidencedocument and the two year study?
Bruce Pearce (19:47):
Yeah.
Thank, thank you, James.
That's a very good question.
The, the results of the RAs H two mousestudy are not required to be included in
the weight of evidence document, but ifthe results of the RAs H two transgenic
mouse study are available, they should bea part of the weight of evidence document.
James C. Taylor (20:08):
Okay.
Bruce Pearce (20:08):
That just in and of itself, that indicates that the data from the
RAs H two transgenic mouse study isnot enough to satisfy the requirement.
You need to provide the weight of evidencecarcinogenicity assessment document
that adequately supports your conclusionof whether or not a study is required.
(20:32):
The other thing I wanted to point out,and this is something that we haven't
touched on yet, is that the RAs Htwo or other mouse study may not be
appropriate, such as when the weight ofevidence assessment strongly argues that
there's no carcinogenic risk to humans.
James C. Taylor (20:51):
Okay.
Bruce Pearce (20:52):
Even before you do a study like that, or when the data
indicate that only sub-therapeutic andpharmacologically inactive levels of
drug compared to the human exposurescan be achieved in the mouse model.
And finally when Weight of Evidenceassessment indicates that a compound
(21:12):
is likely to be carcinogenic in humans.
So there are a, aside from these elementsthat we've talked about here, there are
other circumstances that could contributeto whether or not performing one of these
studies is going to add any value interms of understanding risk in humans.
James C. Taylor (21:34):
All right.
Now, we have talked about a lot,so much that we filled up two
episodes, but how would you likeboiled it all down for them?
Bruce Pearce (21:42):
Well, there are, there are a couple of things that I, I want
to touch on before we end this ratherthan going through and reviewing all the
elements that we've already talked about.
James C. Taylor (21:53):
All right.
Go ahead.
Bruce Pearce (21:54):
I, I want to touch on first with respect to having a clear
understanding of the testing that willbe required for a particular product.
I encourage companies once they'vedetermined based on the nature of
their product, of course, the clinicalindication, duration of treatment, that
carcinogenicity assessment is required.
(22:16):
And have at least formulated a soundstrategy to satisfy this requirement
to consult with the divisionhandling their particular product.
Again, I'm encouraging early interactionwith F D A, getting feedback from them
in this process and to be thinking aboutthis early on, I also hope that the major
(22:38):
takeaway from this review is that thedevelopment of strategy for addressing
carcinogenicity assessment needs tobegin very early for a number of reasons.
First, it's very likely that the datafrom studies that will be performed during
the development of the clinical testing,which examined the pharmacology and
toxicology of the product would or couldgenerate data important to preparing an
(23:04):
adequate weight of evidence documents.
You want to be asking in real timeif there are any data that could be
obtained in the course of performingthese studies that are potentially
important to weight of evidencedocuments such as tissue staining.
Looking at these biomarkers,as I, I touched on previously,
(23:27):
this takes forethought.
Second, you need early on to assessthe metabolites of the parent
drug or its excipients in the drugformulation to assess whether it
require carcinogenicity testing as well.
Each of these may need to be assessedseparately, including a submission
of weight of evidence documents foreach one of these, the metabolites
(23:50):
that are considered major metabolitesand maybe even the excipients one or
more excipients in your formulation.
So this could add a verysignificant increase in the level of
complexity in the overall program.
It needs to be dealt with early on to puttogether a plan where you can utilize this
(24:11):
weight of evidence argument in lieu ofdoing these two plus million rat study.
You may need to perform specializedstudies or analysis of specimens,
which I touched on before, which almostcertainly will require additional
time and need to be appropriatelydesigned, performed, and analyzed in
the results of analysis in a way thatyou know will be adequate for the F D A.
(24:36):
The ladder may require additionaltype C meeting or meetings with F D A.
Third, it's really too late to waituntil the 11th hour for this to be
an afterthought to address theserequirements and most unfortunate to
find yourself in a situation that atthe end, if you're developing a testing
program, that you need to go back andrepeat a six month toxicology studies
(25:01):
or pursue mechanistic studies to supportyour weight of evidence arguments.
In a situation where you're convinced thata two year study is probably not needed,
but you have to have the data to supportyour position, these studies will require
considerable thought in planning as wellas the time to establish a consensus with
(25:22):
the FDA, including the CarcenogenicityAssessment Committee, the CAC.
Sponsors should plan to establisha dialogue and agreement with F D A
regarding what is necessary to satisfythis requirement and the timing of
submission of study reports, certainlyprior to an NDA or a B L A submission,
(25:44):
and preferably by the time of thepre B L A and pre NDA meetings.
It may be possible also to negotiatepost-marketing commitment for completing
and performing the required studies.
However, waiting to address this or otherissues until the 11th hour will almost
(26:04):
certainly be associated with delays tomarket and losses significant revenue.
So Biologics would like to encouragesponsors to be proactive in addressing
these requirements, particularlytheir strategy for satisfying the
requirement for carcinogenicity testingearly on in their development process.
(26:27):
And my colleagues and I are hereto help shepherd sponsors through
this process so that they avoid thepitfalls discussed above and that
and substantially reducing risk.
James C. Taylor (26:42):
All righty.
Thank you, Bruce.
I appreciate you comingand talking about that.
And as you said, we are availableto help you with this and anything
else in the world of biologicdevelopment and drug development.
So if you'd like to talk tous, just send us an email at
(27:02):
insight@biologicsconsulting.com.
That's insight at BiologicsConsulting all one word dot com.
Thank you again, Bruce.
We'd also 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.
(27:24):
The Insight at Biologicstheme is by Tom Rory Parsons.
I'm James C.
Taylor.
Thank you for joining us and pleasecome back for more Insight at Biologics.
In our previous episode, we were talking with Bruce
Pearce about the new I C H guidance,which allows for using a weight
of evidence argument in place of atwo year rat carcinogenicity study.
But how do you make aweight of evidence argument?
Now, Bruce will talk about that in just amoment, and this is Insight at Biologics.
(00:22):
First, a bit of housekeeping.
If you'd like to know the breadth ofBruce's credentials on this subject,
you can listen to him tell you allof that himself in the first part
of this interview, the previousepisode, or you can email us at
insight@biologicsconsulting.com.
Now, let's get back to it.
What are the specific factors toconsider that are recommended for
(00:43):
incorporation into this integratedW O E argument slash document?
Bruce Pearce (00:50):
Thank you for the question, James.
The weight of evidence integratedapproach, as I said in the previous
podcast, is based on a comprehensiveassessment of the totality of data
relevant to the carcinogenic potentialavailable from public sources and from
(01:11):
the results of relevant drug developmentstudies with a sponsors product.
But what's important are, whatare the factors as you've targeted
to consider in this evaluation?
And these are, in fact, the elements thatshould be addressed as a part of putting
together a weight of evidence argument.
(01:34):
And there are five of them thatI will discuss here briefly.
The first is data that informedcarcinogenetic potential based
on the drug target, the primarypharmacologic mechanism of
action of the parent compound.
And I'll mention here for the firsttime, the major human metabolites.
(01:56):
So if you have a major metaboliteidentified in the metabolism of
your parent compound, this willneed to be assessed as well.
Included in this assessment relatedto the primary drug target is
the distribution of the target.
For example, in rats and humans, isthe target present in the rats that
(02:21):
your pharmacologic agent is acting on?
Is the pharmacologic activityand the potency of the parent
compound, or the major metabolitesif appropriate in these species?
Information from genetically engineeredmodels, human genetic association
(02:41):
studies and cancer gene databases.
This is, the idea of the use ofgene expression biomarkers, genomic
biomarkers to help to understandtumorogenic potential, is something
that's new that's being examined.
In fact, last year in 2022 inToxicological Sciences, a paper was
(03:07):
published, I think it was in April,that discusses this collaboration to
use the genomic tools to better predictcarcinogenic potential, and these kinds of
data can be used to substantially enhancethe weight of evidence or arguments.
James C. Taylor (03:30):
Okay.
Bruce Pearce (03:32):
The other, the other element here in terms of the, the target is,
or the particular class of drug that itbelongs to is the information on other
drugs in the class, which can be very,very important and add substantially to
the weight of evidence arguments one wayor the other in terms of carcinogenic.
(03:54):
The second element that I want to orfactor to consider are the results
from secondary pharmacology screensthat are typically done early on
in the assessment of a candidate.
That inform in terms of drug selectivityfor targets and off-target, especially,
(04:16):
for example, if the drug interacts witha nuclear receptor or biotechnology, or
data from repeat dose toxicology studies.
In fact, there's an emphasis on, asI mentioned before, the six month rat
study to support the two year study.
James C. Taylor (04:36):
Mm-hmm.
Bruce Pearce (04:37):
Including information about plasma exposure, margins, parent drug,
and again, major metastas-- metabolites.
An important element is the histopathologyfindings, the histopathology data,
because in a number of cases you cansee histopathological changes that
(04:59):
suggest effects that have carcinogenicpotential when you don't have
effects on other markers, say hormonelevels or something of the kind.
The third element is evidence ofhormonal perturbation, including
knowledge of the drug target,compensatory endocrine responses.
(05:24):
You may see in this regard weights andgross microscopic changes in endocrine
and reproductive organs from repeat dosetoxicology studies, relevant results
from reproductive toxicology studieswhere hormones playing a preeminent
role in the changes that are occuring.
(05:45):
And findings from rat studies suggestinghormonal perturbation may include, as
I have alluded to, microscopic changes.
These include atrophy, hypertrophy,hyperplasia, biologically significant
endocrine and reproductive organweight changes, factors that can't
(06:07):
be addressed in terms of changesthat may have been contributed
associated with stress as a part ofthe process of the, of the testing.
Such findings are suggestive ofpotential carcinogenetic risk,
and unless investigated for humanrelevance and demonstrated otherwise
(06:29):
are treated that these genomicmodels that are being assessed now
in this collaboration may prove veryimportant in terms of addressing
the human relevance, for example.
And the fourth point to consideris genotoxicity testing.
There's a series of studies that aredone that complement the full package
(06:52):
for genotoxicity testing and anyequivocal genotoxicity results that
can't be resolve-- resolved wouldfurther implicate the possible--
the potential for carcinogenic risk.
And finally, fifth, view modulation thatis broad immunosuppression may provide
(07:14):
significant concern for human risk.
James C. Taylor (07:19):
All right, so Bruce, in your view, examination of these
factors that you've just delineated,would that be sufficient support
a weight of evidence argument?
Bruce Pearce (07:29):
Yes, it very well could.
Evaluating these factors may be sufficientto conclude whether or not a two
year rat study would add value to theassessment of human carcinogenic risk.
However, the weight that's attributedto each of these factors may depend
on the nature of the molecule,so it's not so straightforward.
(07:50):
However, one or more weight ofevidence factors may be inconclusive or
indicate a concern for carcinogenicity.
The sponsor can apply investigativeapproaches that could address
the uncertainty or inform humanrelevance of identified risk.
(08:10):
I just want to pause here for a secondand emphasize here again is a situation
where you need time to perform theseother investigative approaches to
be able to address this adequately.
This can't be an afterthought and tryto do this at the end of your program.
James C. Taylor (08:31):
Okay,
so why, why don't you explain a littlebit more about the other investigative
approaches that are appropriate?
Bruce Pearce (08:42):
Yeah, some of the other approaches, may involve other
investigative studies as I've mentioned,or analysis of specimens collected
from prior studies using specialhistochemical stains, for example,
looking for molecular biomarkers, serumhormone levels, immune cell function,
(09:05):
in vitro - in vivo test systems, anddata from emerging technology like the
genomic methods that I've described.
All of these really require someforethought, some looking at these
in retrospect, very difficult to havesamples that you can appropriately
(09:28):
stain, measure the biomarkers and serumhormone levels if you haven't insured
that this was done at the appropriatetiming when these studies were performed.
And also, generated to informhuman mechanistic relevance at
therapeutic doses and exposure.
So I, I, again, it should be, I think,self-evident from this discussion that
(09:54):
to be able to pursue these approaches,you need time and you need foresight
early on to ensure that you'll notmiss the opportunity to collect these
data, both preclinical and clinical.
James C. Taylor (10:08):
All right.
Now, if I recall, there's a differencein the availability of information based
on the type of substance being explored.
For instance, a drug that is a memberof an established class versus a novel
first in class drug that that altershow much information is available.
(10:32):
Yes?
Bruce Pearce (10:33):
That's that-- that's exactly right.
And, and if you are studying a moleculethat has other members of the class,
you can leverage that data to really addsubstantially to your weight of evidence
argument, particularly if carcinogenicityhas been seen among the other members.
That might really be one ofthe primary elements supporting
(10:57):
your conclusion that it's highlylikely that it's carcinogenetic.
But nevertheless, novel drug targets,which you refer to, can be included
in this weight of evidence argument.
The problem is that the bar is higher.
I further evidence that there's nocause of concern regarding the target
(11:21):
biology is needed when there's a lackof other members of this class, or a
lack of precedent, if you will, forthe novel drug that you're study.
And this has been addressedin part, in this addendum.
There is a case, a case study that'sdescribed in the appendix to the
(11:42):
addendum that gives an example of anovel target where a two year study
was not considered to add value.
And the evidence compensatedfor this lack of precedent.
In this example, the cause forcarcinogenic concern was not
identified regarding the drug targetbiology, the compound selectivity.
(12:07):
There's no proliferative changesin any organs or tissues, and
were observed at high multipleexposures in the six month rat study.
The, the results of this were very clean.
This is a particular idyllic example,if you will, but it's actually
(12:30):
drawn from the data from those 45molecules that were studied to assess
the ability of the use of weight ofevidence in lieu of two-year study.
When the weight of evidence assessmentssupports a conclusion that the conduct
of a two-year rat study does not addvalue to the assessment of human risk,
(12:55):
the I C H guidance indicates that thesponsor should seek consultation with
the appropriate regulatory agency in,in accordance with the established
procedures for that particular area.
And they further state that the sponsor,if the sponsor decides to conduct
(13:16):
a two year rat study in accordancewith the S 1 B guidance, there's no
obligation to seek further consultationwith the drug regulatory agency.
But, my opinion is with respect to U SF D A, it is submission of the proposed
protocols for both the RAs mouse,the RAs H two mouse study and the two
(13:41):
year rat carcinogenicity study to theappropriate division for review by the
Carcinogenicity Assessment Committee.
An executive CAC is advisablebefore initiating these studies
and committing two plus milliondollars to performing this study.
You don't want to be in the positionthat after you've spent all of this
(14:03):
time and invested this kind of money,that, that the FDA reviewers inform
you that your study's not acceptable.
So I generally argue that it's alwayssmarter to talk with the division.
And get feedback from thereviewers before you take any
major steps in drug testing.
James C. Taylor (14:24):
Now, I like examples, Bruce.
And so if you would, would yougive us some examples of how these
principles are applied in cases thatcome to each of the conclusions?
Bruce Pearce (14:35):
Yeah, as I, as I mentioned before that there are case studies that
are contained in the add- in the appendixto this addendum, and I talked to you
about the case where it was a novel drugand a novel target, and the conclusion
was that an additional carcinogenicitystudy was not required, and that was case
(15:00):
number four, that case study number four.
Case studies one and two are examplesof pharmaceuticals where the weight
of evidence argument indicated that itwould not add value to the assessment of
human risk and case study number three,described data from weight of evidence
(15:20):
assessment of the carcinogenic potentialwhere the conclusion was uncertain in
there and that situation where a two yearcarcinogenicity study was recommended.
I, I think it's important to understandwhile these examples are taken from
real world data, from the studies thatwere evaluated by this expert working
(15:46):
group, the fact of the matter is itcan't possibly take into consideration
all of the circumstances that wouldoccur with unique, unique drugs.
So this provides guidance but doesn'tcover necessarily all the bases.
James C. Taylor (16:04):
Okay.
All right.
Now, based on what you said, ifall right, let's say I believe that
conducting the two year rat studyis unlikely to contribute to further
understanding of the carcinogenic risk.
What factors should I focus attentionon then when preparing the weight of
evidence document to support that?
Bruce Pearce (16:23):
Yeah, good question.
One of the things that was done in puttingthis addendum together is that the weight
of evidence attributes of a compound thatare more likely to support the conclusion
the results of a two year rat study wouldnot contribute to contribute value to
(16:46):
human carcinogenicity risk assessment.
And I'll, I'll go through theseand I think it helps to clarify.
These, the points to consider that Italked about before in the case of the
target biology, when the target biologyis well characterized, not associated
with cellular pathways known to beinvolved with human cancer development.
(17:12):
These are situations that occurred inthe case of those 45 molecules that were
assessed where there were non mammaliantargets and or the carcinogenicity
data were available with other drugsat the same pharmacologic class.
Two, there were no identified concernsfrom secondary pharmacology points to.
(17:39):
That did not inform anyoff-target potential for their
particular pharmaceutical.
Three, the results of chronic toxicitystudies indicated that there were no
hyperplastic, hypertrophic, atypicalcellular alterations or degenerative
changes without adequate explanationof the pathogenesis or human relevance
(18:06):
indicative of no, or on or off targetpotential for of carcinogenic concern.
Again, this emphasizes the fact that eventhough you may have these observations,
if you can adequately explain themmechanistically and address whether
or not there's any human relevance,it's important to the contribution
(18:33):
to your argument that an additionalstudy to your study is not required.
Number three, no perturbation of endocrineor reproductive organs was observed
or endocrine findings that were notadequately explained with respect to the,
again, the potential for human relevance.
(18:54):
The overall excess assessmentof immunotoxic potential was
concluded to be negative.
And finally, there was no evidence ofimmune modulation or immunotoxicity based
on the repeat dose toxicology studies.
So this review of these factors toconsider give you an indication of
(19:21):
the kinds of findings that would helpyou to make an argument or the nature
of the findings that would help youto make an argument that a two year
rat study would not be required.
James C. Taylor (19:33):
All right, now the, the six months are, excuse me, the
six month RAs H two mouse study.
Can you use that to support a weightof evidence argument, or even in
place of the weight of evidencedocument and the two year study?
Bruce Pearce (19:47):
Yeah.
Thank, thank you, James.
That's a very good question.
The, the results of the RAs H two mousestudy are not required to be included in
the weight of evidence document, but ifthe results of the RAs H two transgenic
mouse study are available, they should bea part of the weight of evidence document.
James C. Taylor (20:08):
Okay.
Bruce Pearce (20:08):
That just in and of itself, that indicates that the data from the
RAs H two transgenic mouse study isnot enough to satisfy the requirement.
You need to provide the weight of evidencecarcinogenicity assessment document
that adequately supports your conclusionof whether or not a study is required.
(20:32):
The other thing I wanted to point out,and this is something that we haven't
touched on yet, is that the RAs Htwo or other mouse study may not be
appropriate, such as when the weight ofevidence assessment strongly argues that
there's no carcinogenic risk to humans.
James C. Taylor (20:51):
Okay.
Bruce Pearce (20:52):
Even before you do a study like that, or when the data
indicate that only sub-therapeutic andpharmacologically inactive levels of
drug compared to the human exposurescan be achieved in the mouse model.
And finally when Weight of Evidenceassessment indicates that a compound
(21:12):
is likely to be carcinogenic in humans.
So there are a, aside from these elementsthat we've talked about here, there are
other circumstances that could contributeto whether or not performing one of these
studies is going to add any value interms of understanding risk in humans.
James C. Taylor (21:34):
All right.
Now, we have talked about a lot,so much that we filled up two
episodes, but how would you likeboiled it all down for them?
Bruce Pearce (21:42):
Well, there are, there are a couple of things that I, I want
to touch on before we end this ratherthan going through and reviewing all the
elements that we've already talked about.
James C. Taylor (21:53):
All right.
Go ahead.
Bruce Pearce (21:54):
I, I want to touch on first with respect to having a clear
understanding of the testing that willbe required for a particular product.
I encourage companies once they'vedetermined based on the nature of
their product, of course, the clinicalindication, duration of treatment, that
carcinogenicity assessment is required.
(22:16):
And have at least formulated a soundstrategy to satisfy this requirement
to consult with the divisionhandling their particular product.
Again, I'm encouraging early interactionwith F D A, getting feedback from them
in this process and to be thinking aboutthis early on, I also hope that the major
(22:38):
takeaway from this review is that thedevelopment of strategy for addressing
carcinogenicity assessment needs tobegin very early for a number of reasons.
First, it's very likely that the datafrom studies that will be performed during
the development of the clinical testing,which examined the pharmacology and
toxicology of the product would or couldgenerate data important to preparing an
(23:04):
adequate weight of evidence documents.
You want to be asking in real timeif there are any data that could be
obtained in the course of performingthese studies that are potentially
important to weight of evidencedocuments such as tissue staining.
Looking at these biomarkers,as I, I touched on previously,
(23:27):
this takes forethought.
Second, you need early on to assessthe metabolites of the parent
drug or its excipients in the drugformulation to assess whether it
require carcinogenicity testing as well.
Each of these may need to be assessedseparately, including a submission
of weight of evidence documents foreach one of these, the metabolites
(23:50):
that are considered major metabolitesand maybe even the excipients one or
more excipients in your formulation.
So this could add a verysignificant increase in the level of
complexity in the overall program.
It needs to be dealt with early on to puttogether a plan where you can utilize this
(24:11):
weight of evidence argument in lieu ofdoing these two plus million rat study.
You may need to perform specializedstudies or analysis of specimens,
which I touched on before, which almostcertainly will require additional
time and need to be appropriatelydesigned, performed, and analyzed in
the results of analysis in a way thatyou know will be adequate for the F D A.
(24:36):
The ladder may require additionaltype C meeting or meetings with F D A.
Third, it's really too late to waituntil the 11th hour for this to be
an afterthought to address theserequirements and most unfortunate to
find yourself in a situation that atthe end, if you're developing a testing
program, that you need to go back andrepeat a six month toxicology studies
(25:01):
or pursue mechanistic studies to supportyour weight of evidence arguments.
In a situation where you're convinced thata two year study is probably not needed,
but you have to have the data to supportyour position, these studies will require
considerable thought in planning as wellas the time to establish a consensus with
(25:22):
the FDA, including the CarcenogenicityAssessment Committee, the CAC.
Sponsors should plan to establisha dialogue and agreement with F D A
regarding what is necessary to satisfythis requirement and the timing of
submission of study reports, certainlyprior to an NDA or a B L A submission,
(25:44):
and preferably by the time of thepre B L A and pre NDA meetings.
It may be possible also to negotiatepost-marketing commitment for completing
and performing the required studies.
However, waiting to address this or otherissues until the 11th hour will almost
(26:04):
certainly be associated with delays tomarket and losses significant revenue.
So Biologics would like to encouragesponsors to be proactive in addressing
these requirements, particularlytheir strategy for satisfying the
requirement for carcinogenicity testingearly on in their development process.
(26:27):
And my colleagues and I are hereto help shepherd sponsors through
this process so that they avoid thepitfalls discussed above and that
and substantially reducing risk.
James C. Taylor (26:42):
All righty.
Thank you, Bruce.
I appreciate you comingand talking about that.
And as you said, we are availableto help you with this and anything
else in the world of biologicdevelopment and drug development.
So if you'd like to talk tous, just send us an email at
(27:02):
insight@biologicsconsulting.com.
That's insight at BiologicsConsulting all one word dot com.
Thank you again, Bruce.
We'd also 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.
(27:24):
The Insight at Biologicstheme is by Tom Rory Parsons.
I'm James C.
Taylor.
Thank you for joining us and pleasecome back for more Insight at Biologics.
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