The Extended One Generation Reproductive Toxicity Study (EOGRTS, EU B.56, OECD TG 443) has been the information requirement for reproductive toxicity under the Registration, Evaluation, Authorization, and Restriction of Chemicals (REACH, Annexes IX and X, Section 8.7.3.) since March 2015.
In July 2021, an evaluation of 12 test cases of the Organisation for Economic Cooperation and Development (OECD) 443 study led by the European Chemicals Agency (ECHA) revealed critical issues with study designs that had the potential to compromise data analysis and interpretation.
Recommendations and Impact
Below is an outline of the resulting regulatory recommendations and the subsequent potential impact of these recommendations upon study design that can be taken into account to improve ongoing and future EOGRT studies.
Resulting regulatory advice had an immediate impact upon the design of ongoing and planned OECD 443 studies. Recommendations emphasized selecting the highest possible dose level based upon effects on sexual function and fertility without severe suffering or deaths in parental animals OR to follow the limit test concept. The advice also provided emphasis upon the expectations for histopathology of Cohort 1B animals and intermediate and low dose level groups where applicable criteria were met. Clarity was provided upon required investigations for F2 offspring and immunotoxicity assessment in adults and offspring, along with expectations for adequate documentation of methodology.
A significant recommendation was the provision of clarity regarding the need for 60 offspring/sex/group (representing 3 offspring per sex per litter) to be evaluated for attainment of sexual maturation. As this had not been described implicitly in TG 443 there was the potential for some study design variants to fall short of the numbers required for sexual maturation assessment. For such study design variants, this clarification may have resulted in the need to retain an additional cohort of animals on study until sexual maturation, extending their treatment period and resulting in some additional cost.
The regulatory recommendations do not represent a change in ECHA processes, simply the clarification note summarizes ECHA’s existing policies and expectations. Many of the recommendations bring welcomed clarity with respect to regulatory expectations and address potential ambiguity between TG 443 and Guidance document 151.
Some of the recommendations could impact upon contracted studies in terms of time and potential additional cost, such as the expectation for F2 offspring to undergo the same investigations as F1 offspring on PND 22 which may result in the addition of Thyroid hormone analysis – particularly if F1 breeding is not planned in advance but triggered by in-life study events. Where a study was planned with insufficient offspring taken to sexual maturation the expectation to retain 60 animals per sex per group for sexual maturation assessment could also invoke unplanned additional cost due to additional resource requirements to maintain extra animals on study.
Critical Success Factors
It is published that “Industry sponsors and test laboratories can take these critical issues into account to improve ongoing and future EOGRT studies”. The implementation of the recommendations could result in additional cost, potentially increased report times and scheduling challenges. To combat the unanticipated impacts, we have identified three critical success factors to consider for your next OECD 443 study:
- Experience – it is imperative to partner with a CRO who has experience conducting OECD 443 studies due to their complex logistical nature. Labcorp’s experience of having started over 40 OECD 443 studies in strains of rat commonly used on DART studies and by oral gavage and dietary administration routes underpins our experience and capability to conduct such complex reproductive studies.
- Integrated Study Planning – joined-up study scheduling, in-life conduct and reporting is essential to the smooth running of large and complex DART studies. Labcorp prioritizes effective collaboration of study directors, reproductive toxicologists and operational staff to facilitate teamwork and a understanding of the study objectives and requirements. We compliment this with prompt and informative communication with our customers to minimize risk and substantial setbacks.
- Expertise – Labcorp experts help facilitate study conduct and provide knowledgeable and experienced solutions to unexpected challenges
Labcorp continues to stay ahead of the curve and have put these recommendations into practice. We can offer insights based on past experience supported by 80+ DART animal staff complete with synergies amongst the study team. Learn more about the latest recommendations and our analysis by accessing our webinar.