Recent update to carcinogenicity study guidelines will transform how new drugs are evaluated, and selection of the Taconic Biosciences rasH2™ mouse gold standard test system can dramatically shorten overall drug development timelines
Carcinogenicity testing is a vital step in a small molecule drug compound's journey from concept to market. Guidelines on safety testing strategies for evaluating carcinogenicity along with other risks such as genotoxicity, immunotoxicity, and reproductive toxicity are issued by the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH). These guidelines form the basis for harmonized global pharmaceutical regulatory requirements.ICH guidelines previously required a two-year rodent carcinogenicity study (typically in rats) along with a carcinogenicity assay in a second species, typically done in mice as either a two-year assay with standard mice or a six-month assay in a transgenic mouse model such as rasH2™ mouse. The two-year rat requirement presented several challenges, including spontaneous tumor risk, extended in-life and reporting timelines, and high costs for animal housing, labor, drug material, and histopathological review. Researchers who opted for the six-month rasH2™ mouse study as the second bioassay saw some benefits, but the two-year rat study still slowed time-to-market and increased animal use and study costs.
In the last several years, retrospective data analyses demonstrated that a Weight of Evidence (WoE) approach including an assessment of data from upstream investigative and toxicology studies could reliably predict the outcome of a two-year rat carcinogenicity study in many cases. A further prospective study involving submissions to five drug regulatory agencies confirmed that the outcome of most two-year rat studies was consistent with a WoE evaluation generated prior to the rat study. Based on this sizeable evidence, the ICH issued an addendum to its S1B guidelines in August 2022 that opens the door to omit the two-year rat study and greatly accelerate carcinogenicity testing and the overall drug development timeline for many investigational new drugs.
Updated Guidelines Can Reduce Testing Dramatically
The ICH S1B(R1) Guideline allows for a more integrative approach to assessing a drug's carcinogenicity risk, using a mechanism-based risk assessment starting earlier in the drug development process.This approach uses WoE criteria on a case-by-case basis to inform whether a two-year rat study is likely to add value to a human carcinogenicity risk assessment or if it can be eliminated without jeopardizing patient safety.
These WoE criteria include:
- Target biology and pharmacology
- Secondary pharmacology
- Histopathology from chronic studies
- Hormonal effects
- Genotoxicity
- Immune modulation
The updated guidance has the power to transform drug carcinogenicity testing by significantly reducing overall carcinogenicity assessment timelines and costs. For a compound that receives a two-year rat study waiver, opting to conduct the mouse bioassay on a six-month timeline using the transgenic rasH2™ mouse rather than a two-year timeline in a standard mouse cuts the carcinogenicity evaluation timeframe by 75 percent.
Besides yielding faster answers that can bring novel drugs to market quicker, the six-month rasH2™ mouse bioassay requires fewer animals (supporting the 3Rs principles) and greatly reduces the risk of spontaneous tumors that can lead to false positives.
This change in recommendations also clarifies an appropriate PK-based high dose selection for six-month rasH2™ mouse carcinogenicity studies, further supporting testing in this system. After a review of marketing applications and publications on 53 drugs, it was determined that when high-dose exposures are tolerated in the rasH2™ mouse, there is no benefit to exceeding a 50-fold exposure margin. Given that the lack of a reasonable PK-based high dose endpoint has historically inhibited adoption of the six-month carcinogenicity testing option, updated guidance allowing a PK endpoint of 50-fold plasma exposure ratio (rodent:human) is likely to encourage greater use of the rasH2™ mouse.
The Taconic rasH2™ mouse is a rapid, cost-effective, and sensitive carcinogenicity test system for detecting both nongenotoxic and genotoxic carcinogens. The model exhibits significantly more rapid onset and higher incidence of more malignant tumors after treatment with genotoxic carcinogens compared to wild type controls, with very low incidence of spontaneous tumors at six months. This model has long been the gold standard carcinogenicity test system that investigators choose to evaluate their drug's toxicity, with nearly half of all mouse carcinogenicity studies now conducted using this model. Now, the rasH2™ mouse model will become more widely used as researchers opt for a shorter carcinogenicity evaluation timeline for drugs that no longer require a two-year rat study. This approach could shorten the time required for nonclinical studies and move up New Drug Application (NDA) submission by as much as three years.
In addition to widespread use of the rasH2™ mouse for required safety testing during late-stage drug development, pilot studies are underway to determine the utility of these mice in new molecular tools which could provide key information about carcinogenicity risk further upstream in the drug development process.
Taconic recently explored how the ICH S1B addendum will impact drug development during a webinar presented by Dr. Frank Sistare, assistant professor at the University of North Carolina, former rapporteur for the ICHS1 Carcinogenicity Expert Working Group, and a retired scientific associate vice president within safety assessment at Merck. View the webinar on demand to hear Dr. Sistare's insights.
To learn more about how the rasH2™ mouse test system can greatly speed and improve your carcinogenicity testing, view our product sheet or contact us.