Regulatory Focus™ > News Articles > ICH S1 Draft Guidance Calls for Industry to Participate in Rodent Carcinogenicity Study

ICH S1 Draft Guidance Calls for Industry to Participate in Rodent Carcinogenicity Study

Posted 15 March 2013 | By Alexander Gaffney, RAC

The US Food and Drug Administration (FDA) has announced it is in the midst of considering the adoption of the International Conference on Harmonisation's (ICH) Safety (S) 1 guidance on rodent carcinogenicity testing, and is calling for public comment as part of the formal adoption process.


The S1 guidance was first announced as a concept paper in May 2012 following a 2011 publication by industry group PhRMA which found that approximately a third of the results from rodent studies could be predicted using alternate and less time-consuming testing procedures.

Upon further analysis, FDA explained that regulators had found that two types of predictions could be made: "Negative predictions can be made when predictive carcinogenic signals are absent and positive predictions can be made when such signals are present."

In other words, regulators can be sure that some products will cause cancer, and others will not. Rodent studies would not be useful in either case. Another category in which a product is likely to cause cancer in rats, but not in humans, is also noted.

But it's a fourth, "in-between" category of compounds that is unlikely to benefit from the ICH guideline, as they "cannot be predicted with sufficient certainty," FDA added.

The results could have the potential to reduce costs and time-to-market for some pharmaceutical compounds, and an ICH working group proposed a guidance as a way to create a formal, unified method of using the approach.

Drafting a Proposal

With those facts in mind, ICH regulators set about trying to get a guidance document together by first determining its goals.

"The aim of this new topic is to introduce a more comprehensive and integrated approach to addressing the risk of human carcinogenicity of pharmaceuticals, and also to clarify and update, without compromising safety, the criteria for deciding whether the conduct of a two-year rodent carcinogenicity study of a given pharmaceutical would add value to this risk assessment," ICH wrote in a statement at the time.

The overall goal of the guidance was to "help determine whether aspects of a pharmaceutical's pharmacology and toxicology, as currently evaluated in nonclinical programs, can be used to adequately assess the degree of carcinogenic risk short of conducting two-year rodent bioassays," they added.

The working group in charge of the development of the guidance has since released a draft proposal for consultation between the three ICH regions (the EU, US and Japan) as part of its five-step process of guidance harmonization and adoption.

The Guidance

"The goal of this potential change is to introduce a more comprehensive and integrated approach to address the risk of human carcinogenicity of small molecule pharmaceuticals, and to define conditions under which 2-year rodent carcinogenicity studies add value to that assessment," FDA explained in its Federal Register posting.

The guideline notes that two-year rodent studies may not always be required, and that certain pharmacologic and toxicological data could be used to predict the outcomes out the studies, which are used to predict the risk of human carcinogenicity.

"It is hypothesized that consideration of this information can provide sufficient information to conclude that a given pharmaceutical in certain cases presents a negligible risk or, conversely, a likely risk of human carcinogenicity without conducting a 2-year rodent study," FDA added.

If this hypothesis is proven to be true, FDA and other regulators would be able to provide waivers to companies seeking to bypass the two-year rodent studies. A carcinogenicity assessment document would take the place of the rodent data in the regulatory dossier or application.

But that's a big "if."

FDA conceded that the hypothesis still needs to be evaluated, and that evaluation is necessary before the guideline can be completed and adopted. "During this prospective evaluation period, the waiver requests would not to be granted and rather are intended solely for gathering experience and hypothesis testing," FDA added. In other words, companies could do the work to generate a waiver request proposal, but it would be an uncertain investment.

Still, that investment is seen by regulators as being "critical" to the success of the guidance. What remains to be seen, then, is whether companies will comply with the additional work requests. It is also unclear how much time it will take to complete the carcinogenicity assessment document (CAD).

FDA is accepting comments on the draft ICH guidance for 60 days after its publication in the Federal Register, now scheduled for 18 March 2013.

Tags: S1

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