Amar Thyagarajan Ph.D. Senior Product Manager Taconic Biosciences

Proposed Changes to Pharmaceutical Carcinogenicity Testing May Shrink Time-to-Market for New Drugs

Prior to obtaining regulatory approval for use in humans, novel pharmaceutical drugs require extensive safety testing. Guidelines regarding testing strategies are issued by the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH), an agreement established in 1991 between the regulatory authorities in the United States, European Community (EC), and Japan. These guidelines help drug developers evaluate potential human health risks of pharmaceuticals including genotoxicity, immunotoxicity, and reproductive toxicity.

Significant Changes for Carcinogenicity Studies

Carcinogenicity testing of drug candidates, particularly those requiring prolonged use, is an important aspect of drug safety testing.  The carcinogenicity testing paradigm is currently poised for a significant change that could impact the cost and time to market for new drugs. The proposed change involves the testing done on animal models and can cause a change in the testing paradigm to not only reduce cost and time of testing, but also improve the quality of human carcinogenic risk assessment. 

For over 40 years, the two-year rodent bioassay has been the regulatory standard to determine the carcinogenic potential of novel pharmaceuticals. As specified by ICH S1 guidelines, this normally involves two long-term (two-year) rodent carcinogenicity assays: one in rats and a second in mice.

A typical long-term carcinogenicity study requires rodents to be exposed to three different drug doses with a comprehensive whole-body analysis performed for each animal, including toxicology and histopathology. Generally, a minimum of 50 animals per sex and per dose are exposed to a drug for two years to obtain meaningful biological and statistical results. Including the cost of labor, animal housing, and pharmaceutical agent, current cost estimates for a single study exceed $2 million. Added to this is the fact that up to three years can elapse from study initiation to completion of the final report.

This is far from ideal since this timeline may impact clinical trial decisions and/or time to market. Furthermore, spontaneous tumors can arise in certain strains of aging animals, leading to false positives and confounding data interpretation. The length of time, false positives, large numbers of rodents, and associated high costs of performing these assays create barriers to addressing carcinogenic risk relevant to humans and elongate the timeline to authorization for new treatments.

Transgenic Mouse Models—An Important Component of the Proposed Change

An improvement came in the late 1990s when the U.S Food & Drug Administration (FDA) approved the use of short- or medium-term bioassays in transgenic mice such as TSG-p53® and rasH2 to substitute for one of the long-term studies. These transgenic models have two key advantages: They provide a relatively quick readout of tumorigenic response, shortening the duration of studies by around six months, and they have lower false positive rates compared to the traditional rodent assay, yielding information on carcinogenic risks that are relevant to humans.

These advantages can be important for strategic decision making in several ways. For example, early identification of carcinogenic risk can impact clinical trial design, limit patient exposure, and even help inform the early termination of a program, so valuable resources can be allocated elsewhere and used more effectively. Lower false positives can help avoid a positive carcinogenic response that can impact label warning of a drug and affect its market potential.

Significant Reductions in Study Cost and Duration

Since a higher proportion of mice have a carcinogenic response, fewer animals are required per study when using these transgenic models. Typically such a study will require 25 animals per sex, per group— about half the number historically needed, which greatly reduces test costs. Short-term transgenic studies typically will cost from $0.5 to $1 million, and data can be acquired faster. The use of transgenic vs. wild type rodents also can provide insight toward the mechanism of action of the compound being tested.

Proposed Changes to the Carcinogenicity Testing Paradigm

A number of retrospective analyses have examined whether data obtained from short-term studies, such as transgenic mouse studies, could be used to predict the eventual outcome of a long-term carcinogenicity study. Based on these analyses, an ICH S1 expert working group has proposed changes to the carcinogenicity testing guidelines that would potentially eliminate the need for a two-year bioassay if other sufficient data are available that warrants an exemption. These proposed changes are estimated to impact up to 30–40% of pharmaceuticals submitted to regulatory agencies for marketing approval. For compounds where a clear exemption cannot be provided, additional testing may be proposed.

Since existing datasets cannot address some of the proposed changes, a prospective evaluation period has been initiated. Upon completion of the prospective evaluation period, the data obtained will be used to inform any final changes to the proposed guidelines.

In light of proposed changes to testing guidelines, transgenic models have the potential to play a significantly greater role in the carcinogenicity testing process. Short-term transgenic studies could help determine whether a lengthy and costly 2-year rat carcinogenicity study is necessary. If the proposed changes allow this scenario, then choosing the correct animal model for testing will be critical to ensure significant time and millions of dollars are not spent obtaining information that isn’t relevant to assessing human risk or doesn’t add further insights into the safety profile of a drug.

rasH2—An FDA-Approved Mouse Model for Carcinogenicity Testing

Several transgenic mouse models have been used in short-term carcinogenicity assays. Among them, the rasH2 mouse is the most widespread transgenic model used today and has been approved by the FDA for short-term carcinogenicity testing to evaluate genotoxic and non-genotoxic carcinogens. Importantly, contract research organizations have generated comprehensive historical control datasets for this model, which are crucial when it comes to regulatory filing.  

The rasH2 model carries multiple copies of the human homolog of the Harvey rat sarcoma virus (c-Ha-ras, commonly known as HRAS) under the control of its own promoter and enhancer elements. This model has a low incidence of spontaneous tumor formation up to six months of age, and the c-Ha-ras oncogene renders these mice highly susceptible to tumor development following carcinogen exposure. Short-term rasH2 studies have been demonstrated to predict known and likely human carcinogens just as well as conventional two-year mouse bioassays, but with less false positives. Advantages such as these are likely to make the rasH2 and other models like it increasingly important tools for investigators performing short-term carcinogenicity testing.

Proposed changes to the ICH S1 guidance on carcinogenicity testing have the potential to significantly impact the current testing paradigm. Specifically, alternative in vivo models, such as the rasH2 mouse, may play an increasingly important role in meeting the new proposed rodent carcinogenicity testing guidelines. These changes may not only help decrease the cost of drug development of drugs intended for prolonged use, but may also reduce the time to market for these drugs, which can have a dramatic benefit for patients.

Amar Thyagarajan, Ph.D. ([email protected]),  is senior product manager at Taconic Biosciences. 


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