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“Weight of Evidence vs Carcinogenicity Testing (Part 1)” with Bruce Pearce

April 18, 2023  •  Podcast  •  Dr. Bruce Pearce and James Taylor
Posted In Other News & Insights, Biologics News & Insights – Biologics Consulting  •  Tagged animal carcinogenicity testing

Insight at Biologics – Episode 8

The ICH has released a new guidance which may allow you to forgo animal carcinogenicity testing in favor of a weight of the evidence argument. We begin our two-part discussion of why this has been added, including the goals of the addendum, on this episode of Insight at Biologics featuring expert Bruce Pearce. And, tune in next time for part 2 to find out how to go about this.


James: Carcinogenicity is the ability of a substance to cause cancer. In the development world, you test for this and the International Council for Harmonization has released a new guidance on that testing. Now, there’s a lot to unpack here. We’re going to talk about it over the next two shows with someone who knows a lot about it. That’s Bruce Pierce, and this is Insight at Biologics.

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Hi there, Bruce. There is a lot here that we need to go over and that’s why we’re gonna have two shows. But before we do that, why don’t we just tell people who Bruce Spears is.

Bruce: Oh. Thank you, James. I will. I’m a classically trained pharmacologist and toxicologist with broad expertise in early and late stage development of small molecules and biologics. 30 years of working in this area contributes to this broad spectrum of experience prior to the 12 years plus tenure at Biologics Consulting. I had a number of positions in both the biotech industry and academia, including as an independent consultant within biotech. 

I was involved in the development of molecules, like hemoglobin based oxygen carriers, used to treat blood loss and in surgery in severe trauma, and was involved in the development of line toxin therapeutics. Rather go on and on here for 10 or 15 minutes, I think the scope and depth of my research and drug development interests are reflected in part in my more than 85 publications, including in peer reviewed journals. 

James: Wow. Wow. So, you are kind of here, there and everywhere. That’s cool. Now talking about, you said you could go on and on about your credentials. The other thing you could go on and on about, and you’re going to have to, cuz that’s what we’re doing here, is this new guidance from the ICH. 

The ICH released a guidance called, let’s make sure I have this correctly, S1B(R1), addendum to S1B testing for carcinogenicity of pharmaceuticals. And if I understand what we’re talking about right, this guidance will allow for the use of a weight of evidence argument instead of the two year rat carcinogenicity study. Now, how can a sponsor take advantage of that, and why should a sponsor take advantage of that? 

Bruce: Okay, thank you for the question. Great question. Before I get started in addressing that two-part question, I just wanted to mention what the reason is for preparing the podcast so soon after this guidance was introduced, it was only introduced in November of last year, and this is because it’s something that sponsors need to be very proactive about in order to take advantage of the opportunity to use, if you correctly identify weight of evidence arguments, in lieu of performing the required two-year carcinogenicity study. 

And I’m gonna repeat this theme again and again, the urgency in terms of paying attention to this and developing a strategy for dealing with carcinogenicity assessment. And the reason this is so important partly is that carcinogenicity assessment studies involve a large number of animals, 600 animals per species that would be tested. They take a long time to perform and to analyze the data, and they’re very expensive. They can range between two and four million dollars. 

In addition to the pivotal studies, the design and the dosing of these studies must be supported based upon the results of other studies, for example, long-term six to nine month toxicology studies and rats to support dosing in the two-year rat studies and generally about a 16 week dose range finding study and wildtype mice are needed to support the proposed rasH2 transgenic mouse study.

In addition to this, the design of these studies should first be reviewed in the justification for dosing, accepted by FDA’s Carcinogenicity 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 can be more than four years. Hence my rationale for agreeing very strongly to begin to work on your strategy for carcinogenicity testing is soon after genome toxicity testing, for example, is completed. 

James: Okay. 

Bruce: And once it’s clear that carcinogenicity testing will be acquired for your particular therapeutic, I wanted to also add the following. On the height of the pandemic and continuing even today, the lead times for long-term toxicology studies can be up to one year, depending on the CRO and this, the factors contributing to this log jam coming out of the pandemic will resolve going forward, and that’s starting to see signs of that already. But right now, proactive planning and scheduling are absolutely critical for programs to meet their projected milestones. 

James: All right. Now, this guidance, I have a question about that. Does it apply to both small molecules and biologics?

Bruce: Very good question. Today’s discussion will focus on the requirements for small molecules. Carcinogenicity, bile acids are generally not appropriate for biotechnology derived from pharmaceuticals, biologics. However, product specific assessment of carcinogenetic potential may still be needed depending upon the duration of a clinical dosing, the patient population, the biologic activity, the product. For example, does it have a growth factor that is a effect growth factor, is it immunosuppressive, or is there evidence of carcinogenic potential of other drugs in the same class?

Testing may not be needed if the intended clinical exposure is not greater than three to six months, or the risk of carcinogenicity has been addressed in a weight of evidence approach summarizing the published data in information from other molecules in the class. However, detailed information on the target biology and the mechanism of action in vitro data, data from chronic toxicity and clinical data may be important.

In some cases, the available information can be sufficient to address this without performing additional nonclinical studies. However, the product specific assessment, which you’ll need to do for a biologic of the carcinogenic potential, is used to communicate risk for the molecule, provide input to risk management plan, along with the product labeling, clinical monitoring, post-marketing surveillance, and some combination of these approaches may be needed.

This is something that should be discussed with the review division of FDA responsible for your particular drug to understand what they require to address the issue of carcinogenicity. A more detailed discussion of how carcinogenic potential of biologics may be addressed is beyond the scope of our discussion today. Listeners are directed to ICH S1A and S6 guidances for further information in this regard. 

James: So would you recommend, if not urge, sponsors to address the question of the need and requirements for carcinogenicity testing early in the development program?

Bruce: Yes, exactly. Absolutely. That’s a major point here.

James: All right, so an aspect of this guidance that needs to be looked at as well as the need to perform carcinogenicity testing in two animal species, including the high dose criteria for the most popular transgenic mouse model. Now, what about that? 

Bruce: Yes, so the ICH guidance, ICH S1B guidance was first issued in 1997 and it called for flexibility in considering approaches to address pharmaceutical carcinogenicity testing. But the default test, became that performed two long-term studies, and this evolved into the practice of performing studies in one of several transgenic mouse models plus two year rat study. The ICH S1B guidance also mentions a number of transgenic mouse models that could be considered for shorter term carcinogenicity studies.

However, over the past 20 years, pharmaceutical development experience models other than the rasH2 transgenic mouse is far more limited. But one of the problems associated with this was that the use of the transgenic mouse study is the exposure ratio endpoint used in the animal to human plasma area under the curve determination, used to set the high dose for the rasH2 mouse study similar to what has been set for the two year mouse study. 

And the way this has been resolved and it’s addressed in this addendum is the comprehensive analysis was conducted to assess exposures and outcomes from previous rasH2 transgenic mouse studies, and this is described in section three of this addendum. The results of this analysis indicated that a 50 fold plasma area under the curve exposure ratio is an adequate criteria for high dose selection versus the 25 fold adopted for the rat to your car seat study. Getting back more specifically to your question, James – 

James: Mm-hmm. 

Bruce: – In terms of the evolution of thinking about car seat testing. Dr. Timothy McGovern, the Associate Director of Pharmacology and Toxicology and FDA Center for Drug Evaluation and Research Office, has indicated that changes to this testing paradigm have been sought since its introduction in 1997 to incorporate progress in the science, to reduce the use of the number of animals used in this testing.

Since publication of the original S1B guidance, scientific advances toward elucidation of the mechanism of carcinogenicity, a greater understanding of the limitations of these rodent models, ICH and FDA have concluded recently that two year rat carcinogenicity studies might not add value to assessing human carcinogenicity risk in some cases, and the carcinogenic potential could have been assessed adequately based on, for example, a comprehensive assessment of all the available pharmacological, biological, and toxicological data.

James: Now, what was the basis for coming to this conclusion? 

Bruce: This is an important question. Yeah, in a nutshell, an international prospective study was conducted under ICH S1. It was issued in 2012. This prospective study compared the results of two year carcinogenicity studies performed on 45 molecules. Two carcinogenicity assessment documents submitted by the sponsors performing these two year studies, that address what the integrated weight of evidence assessment concluded regarding whether or not these two year studies would provide additional valuable evidence, regarding carcinogenic risk to humans.

The findings, following a review of these data by the regulatory members of the ICH expert working group overseeing this evaluation, was that an integrated weight of evidence approach could be used to adequately assess the human carcinogenic risk for certain pharmaceuticals in lieu of conducting the two year rat study in some cases. This new addendum introduces or articulates a comprehensive and integrative approach to assessing human carcinogenic risk of pharmaceuticals in a regulatory document for the first time. 

The goals of the addendum are to expand the testing scheme for assessing human carcinogenic risk by introducing an integrative approaches, keep using the same term, and provides specific weight of evidence criteria guidelines into specific criteria that inform whether or not a two year rat study is likely to add value to human carcinogenicity risk assessment.

The second goal was to encourage a more mechanism-based approach to human carcinogenicity risk assessment of pharmaceuticals, starting earlier in drug development. And this is an important one because this adds to my urgency or to the urgency for sponsors to be looking at this early on because you have opportunities with other experimentation and analysis to contribute to the weight of evidence. And they’re pushing us in this direction. And to reduce the use of animals in accordance to the three R principles, that is, replacement, reduction and refinement. 

James: Mm-hmm. 

Bruce: And to focus on generating more, again, mechanism-based carcinogenicity assessments. And the final one was the one that we touched on before, and that is setting this high dose ratio of area under the curve of exposure in the transgenic mouse versus humans.

James: Okay now, there was something you said a little bit earlier in the conversation, we’re gonna run it back a little bit. You talked about carcinogenic potential could have been adequately based on a comprehensive assessment of all available pharmacological, biological, and toxicological data. So, what did you mean by that? 

Bruce: Yeah. This is the central question in this new addendum, this guidance document. So here toward the end of our first part, let me begin to address that. 

James: Okay. 

Bruce: It essentially means that it may be possible in lieu of performing the two year study in rats that provide a comprehensive integrated weight of evidence document assessing human carcinogenic risk of drugs, which involves integration of the data for specific factors to consider use, and we’ll come back to these factors to consider in part two of this podcast. And using data in the literature as well as data from results obtained with the particular therapeutic agent in question.

They support one of three conclusions: that Carcinogenicity is likely, or two, it’s unlikely, and in both these cases of likely or unlikely, you can argue that a two year rat carcinogenicity study would not add value. And finally, the outcome is uncertain, such that a two year carcinogenicity study would add value to human risk assessment.

In cases where the weight of evidence assessment leads to a conclusion of uncertainty regarding human carcinogenicity potential, the approach described originally in S1B have conducted two long-term carcinogenicity studies over the two year study in rats, and the shorter study in the transgenic mouse model would be the most important strategy.

James: Okay. Now, like you said, You’ve got a lot more to say about this and you’re gonna get to say it, but you’re not gonna get to say it today. But if you’ll stick around, we will conclude this interview and people can hear it on our next episode. But between now and then, if you would like more information from Bruce or from anybody else here at Biologics, just email us at That’s Insight, @ Biologics Consulting, all one word, .com. And also, we’d love it if you’d like, subscribe to, and rate and review our show. 

The executive producer of Insight at Biologics is Chris Kraihansel. This episode was produced and edited by James C. Taylor. The technical supervisor is Jeff Weiss. The Insight at Biologics theme is by Tom Rory Parsons. I’m James C. Taylor. Thank you for joining us and please come back for more insight at biologics.

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