FDA has issued a final guidance, “S1B(R1) Addendum to S1B Testing for Carcinogenicity of Pharmaceuticals; International Council for Harmonization; Guidance for Industry,” which introduces a comprehensive and integrative "weight of evidence" approach to assessing human carcinogenic (or having the potential to cause cancer) risk in drugs. This guidance is part of FDA’s work to reduce the use of animals in research for certain drugs.

The guidance, which is the result of a collaboration between the agency and the International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH), outlines an approach that, in certain cases, could determine that a two-year rat study is not necessary to assess the carcinogenic risk of a drug.

In this CDER Conversation, we speak with Timothy McGovern, PhD, about the guidance and what it means for patients, industry, and other stakeholders in drug development. Tim is the associate director of pharmacology and toxicology in FDA’s Center for Drug Evaluation and Research Office of New Drugs' Immediate Office.

Tim, why did FDA and ICH see a need for this guidance?

At FDA and in CDER, we are looking toward ways to improve safety assessments and reduce animal testing, where it makes sense, without sacrificing the safety of human patients who will eventually use these medications. With this in mind, we have worked to amend the safety guidance on testing for carcinogenicity of pharmaceuticals through collaboration with our partners at ICH and other stakeholders.

To provide some background, the ICH S1 guidances (safety guidances on carcinogenicity studies) were issued in 1995 and 1997 that described a strategy to assess carcinogenic risk of new pharmaceuticals. This strategy called for results from one long-term rodent study and a second short- or long-term supplemental study in another rodent species. The strategy has generally translated to a two-year rat study and either a two-year mouse study or a six-month transgenic (or genetically modified) mouse study.

Changes to the paradigm have been sought since 1997 to incorporate progress in the science. Also in the intervening years, there has been a concerted effort to reduce the use of animal testing in drug development studies.

How did you work to develop the guidance? How did the weight of evidence concept come into play?

A greater understanding of the mechanisms of carcinogenicity, the publication of several retrospective analyses indicating that two-year rat carcinogenicity studies might not add value to human risk assessment in some cases, and our commitment to patient safety, expediting drug development, and animal welfare, led us to consider how to amend the original S1B guidance. Under the ICH umbrella, we participated in an expert working group that examined the retrospective analyses and conducted a prospective study to see if an alternative to the standard two-year rat carcinogenicity study would still adequately assess the carcinogenic risk of a pharmaceutical. We ultimately determined, and have described in the guidance, that a “weight of evidence” approach can provide an adequate assessment of carcinogenic risk in certain cases without using data from a two-year rat study.

In scientific terms, weight of evidence refers to a systematic approach in which investigators look at all relevant evidence to make an assessment or determination. As an analogy, consider a scale. As we place each piece of evidence on the scale, we may eventually reach a tipping point and be able to draw a conclusion.

In this case, some factors included in our weight of evidence assessment include information on the mechanism of action and the toxicological profile of a pharmaceutical, the potential for genetic toxicity, evidence of immune modulation (or change), and evidence of hormonal perturbation. The guidance goes into more detail about these and other factors.

How exactly does the weight of evidence approach work in assessing carcinogenic risk?

Basically, the weight of evidence approach helps us reach one of three conclusions:

• The weight of evidence could show that carcinogenic risk is likely. In this case, a two-year rat study would not add value because we have already determined the high carcinogenic risk.
• The weight of evidence could show that carcinogenic risk is unlikely. In this case, a two-year rat study would also not add value because we have already determined the low carcinogenic risk.
• The weight of evidence could show that carcinogenic risk is uncertain. In this case, a two-year rat study would add value because it could help determine the extent of risk.

How do you think the guidance will help reduce animal testing?

It is hard to say for sure because we are just now implementing the weight of evidence approach. However, our working group’s prospective research study suggested the weight of evidence approach could reduce rat carcinogenicity studies by about 25 percent. I also want to emphasize that this guidance continues to recommend a carcinogenicity study in mice as a component of a carcinogenicity assessment plan. Drug developers would still be responsible for conducting those studies to assess carcinogenic risk. So this guidance is one step in our broader effort to improve assessment of this important safety endpoint and to consider alternatives to animal testing, but we must continue to tread carefully and keep patient safety at top of mind when considering changes in drug development.   

Are there any other items you would like to highlight from the guidance?

Yes. The guidance also introduces the use of a drug exposure-based approach for setting the high dose in the rasH2-Tg mouse model. This approach has been used for two-year studies but not for six-month transgenic studies. We concluded that a 50-fold exposure ratio is an adequate criterion for high-dose selection for this model in addition to the other criteria described in the S1 guidances.