The COVID-19 pandemic has spurred rapid development of vaccines, leading to a surge in demand for nonhuman primates (NHPs). Considering the "3R" principles (Replacement, Reduction, Refinement) in animal research, it is crucial to minimize the use of NHPs in nonclinical safety assessments and to optimize the number of animals used.
For many biopharmaceuticals, oligonucleotides, and gene therapy products, monkeys are the only relevant non-rodent species for nonclinical safety evaluations. Monkeys also play a significant role in predicting human safety and efficacy due to their close physiological and pharmacokinetic similarities to humans. This has led many pharmaceutical companies to favor using monkeys whenever possible.
When it is necessary to use NHPs for general toxicology studies, several strategies can help reduce their use. Teams from the FDA, Eli Lilly, Gilead, Genentech, Seagen, Merck, Roche, Pfizer, Amgen, and Incyte have discussed five key strategies:
- Single-Gender Studies: When a drug targets a single gender, using only that gender in toxicology studies might be considered. However, this does not significantly reduce the number of animals because the study design must ensure statistical validity.
- Omitting Control Groups: Leveraging extensive pre-dosing data and historical controls might reduce the need for concurrent control groups. However, this approach faces challenges, such as variability in animal sources, ages, and solvents used.
- Eliminating Recovery Groups: Not including recovery groups can directly reduce the number of NHPs used.
- Reducing the Number of Dose Groups: For highly targeted biologics with clear mechanisms of action, reducing the number of dose groups from three to two can be considered if preliminary short-term studies show no significant toxicities.
- Combining Different Administration Routes in One Study: When developing biologics for both intravenous (IV) and subcutaneous (SC) administration, combining these routes in a single toxicology study can be efficient. One example design could include a vehicle control (IV+SC), two IV dose groups, and one SC dose group.
Classic Design of NHP Repeat-Dose Toxicity Studies
Typically, a repeat-dose toxicity study in NHPs includes one control group and three dosing groups, each with ten animals (five males and five females), with six animals in the main study group and four in the recovery group. Reducing animal numbers can be achieved by limiting recovery group inclusion to only the control and high-dose groups.
Considerations for Single-Gender Studies
For indications targeting a single gender, single-gender studies are mentioned in ICH M3(R2) guidelines. However, the total number of animals might not significantly decrease since the necessary number per group should increase to maintain statistical power.
Eliminating Control Groups
While some toxicological endpoints have sufficient pre-dosing data, eliminating control groups can be challenging due to variability in animal backgrounds and the lack of comprehensive historical control databases.
Eliminating Recovery Groups
Recovery groups can be omitted to reduce NHP usage without compromising data integrity significantly.
Reducing Dose Groups
For targeted biologics with well-understood mechanisms and safety windows, reducing the number of dose groups can be feasible. For small molecules, however, this poses challenges due to their potential for off-target toxicity.
Combining Administration Routes
For biologics administered both IV and SC, toxicological profiles typically do not differ significantly between routes, allowing combined studies. Another strategy is to evaluate IV toxicity in NHPs and SC local tolerance in rodents or rabbits.
Conclusion
Reducing NHP use aligns with the "3R" principles and can lower drug development costs, but this should not come at the expense of scientific rigor. The FDA and industry discussions emphasize scientifically and reasonably minimizing NHP usage. Alternatives like dogs or mini-pigs should be considered where feasible. If short-term toxicology studies show similar results in NHPs and rodents, long-term studies might favor NHPs.
For cases necessitating NHP toxicology studies, strategies like single-gender use, eliminating control and recovery groups, optimizing dose groups, and combining administration routes can be considered to optimize animal usage. Importantly, challenging traditional designs requires thorough communication with regulatory authorities to balance innovation and compliance.
In summary, reducing the use of nonhuman primates in nonclinical safety assessments is crucial for ethical, scientific, and economic reasons. By adopting strategic approaches and maintaining open dialogue with regulators, the industry can achieve a balance between minimizing animal use and ensuring robust drug safety evaluations.
Keywords: Nonhuman primate, NHP, nonclinical safety assessment, drug development, animal reduction strategies, FDA, pharmaceutical industry
