The COVID-19 pandemic drove rapid vaccine development, which in turn produced a surge in demand for nonhuman primates (NHPs). Against that pressure, the 3R principles of Replacement, Reduction, and Refinement point the other way: use fewer animals, and use each one better. That expectation is set out in the Guidelines For Lifetime Use Of Nonhuman Primates in Biomedical Research, and nonclinical safety assessment is where it is felt most directly, because the species cannot always be swapped for a smaller one.
For many biopharmaceuticals, oligonucleotides, and gene therapy products, no other non-rodent species is pharmacologically relevant, so the monkey carries the nonclinical safety package. Monkeys also predict human safety and efficacy reasonably well, given how closely their physiology and pharmacokinetics track ours. That combination has led many pharmaceutical companies to reach for monkeys whenever a choice exists, and supply is a constraint in its own right, as summarized under Nonhuman Primate Resources.
When NHP use is necessary for general toxicology studies, several strategies can still lower the number of animals. 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. This does not significantly reduce the number of animals, because the study design must still ensure statistical validity.
- Omitting Control Groups: Using extensive pre-dosing data and historical controls might reduce the need for concurrent control groups. The approach runs into 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
A Toxicology package built on a repeat-dose study in NHPs typically 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. The total number of animals might not significantly decrease, since the number per group should increase to maintain statistical power.
Eliminating Control Groups
Some toxicological endpoints have sufficient pre-dosing data, but eliminating control groups remains difficult because of variability in animal backgrounds and the lack of broad historical control databases. The species and source decisions behind that variability are covered in Selecting The Ideal Non-Human Primate For Toxicology Studies: Cynomolgus Macaque, Rhesus Macaque, And Marmoset.
Eliminating Recovery Groups
Recovery groups can be omitted to reduce NHP usage without compromising data integrity significantly. What a recovery group buys is the ability to separate an effect that persists from one that resolves, so the trade is a reasonable one only when reversibility is not in question.
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, this poses challenges due to their potential for off-target toxicity, which is precisely what an additional dose group is there to expose.
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 minimizing NHP usage on scientific grounds. Alternatives such as dogs or mini-pigs should be considered where feasible, and Opportunities And Challenges Of Mini Pigs As A Nonclinical Large Animal Species sets out what that substitution costs in practice. If short-term toxicology studies show similar results in NHPs and rodents, long-term studies might favor NHPs.
Where NHP toxicology studies are necessary, single-gender use, eliminating control and recovery groups, optimizing dose groups, and combining administration routes can each reduce animal usage. Challenging a traditional design requires thorough communication with regulatory authorities, since innovation and compliance have to be balanced rather than traded.
In summary, reducing the use of nonhuman primates in nonclinical safety assessments matters for ethical, scientific, and economic reasons at once. By adopting strategic approaches and maintaining open dialogue with regulators, the industry can keep animal use to a minimum while still delivering reliable drug safety evaluations.
Keywords: Nonhuman primate, NHP, nonclinical safety assessment, drug development, animal reduction strategies, FDA, pharmaceutical industry
