FDA Phase Out of Animal Test Requirements for Drugs Begins With Biologics

Well before a human receives the first dose of an experimental drug, it’s evaluated in an animal to test for toxicity. Monkeys are often chosen for their genetic similarities to humans, and safe results in this preclinical research can clear the way for a first-in-human trial. Nearly 20 years ago, an antibody drug that showed no toxic effects in monkeys led to an excessive immune response and life-threatening complications in all of the healthy human volunteers who received it. No one died, but these study participants suffered permanent injury.

Subsequent research found a key difference between cynomoglus monkeys and humans in the expression of the receptor targeted by the drug, TGN1412. This monoclonal antibody (mAb), discovered and developed by defunct biotech company TeGenero, still stands as an important biopharmaceutical industry case study demonstrating the limitations of preclinical research. It’s also one of the examples cited by the FDA in announcing a renewed push to bring the testing and review of experimental medicines away from animal testing, turning the focus toward other methods better reflective of humans.

“That tragedy highlighted the limitations of animal models for certain immune-activating mAbs and spurred efforts to develop in vitro assays to better predict human responses,” the FDA said in a document outlining its strategy.

The phase out of animal testing will start with biologic drugs, such as monoclonal antibodies, the FDA said Thursday. In place of this clinical research, the agency encourages drug companies to use alternatives, such as organoids — an artificially grown mass of cells that resembles an organ — and organ-on-a-chip systems that mimic human organs as a way to test a drug’s safety (here’s an example of body-on-a-chip research at the Wake Forest Institute for Regenerative Medicine). Other methods include computer modelling and artificial intelligence to predict a drug’s behavior, simulating how an antibody distributes throughout the body as well as predicting side effects.

The FDA said it expects these changes will roll out over the next three years. Implementation will begin immediately for investigational new drug applications where inclusion of these “New Approach Methodologies,” or NAMS data, is encouraged, the agency said. For efficacy analysis, the FDA will begin using pre-existing, real-world safety data from other countries that have comparable regulatory standards and where a drug has already been studied in humans. In a statement, FDA Commissioner Martin Makary said this approach will enable drugmakers to avoid animal tests of drugs that already have broad human data internationally.

“By leveraging AI-based computational modeling, human organ model-based lab testing, and real-world human data, we can get safer treatments to patients faster and more reliably, while also reducing R&D costs and drug prices,” Markary said.

For drugs that still require animal testing the FDA said interim steps can involve refining those testing methods to reduce the number of animals tested and conduct less severe procedures. On the regulatory front, the FDA said it will update guidelines to allow consideration of data generated by these new methods. For example, companies that submit strong safety data from non-animal tests may receive streamlined review, creating an incentive to invest in these new testing platforms.

In a note sent to investors Friday, Leerink Partners said the FDA announcement “is more public relations than a change in policy.” The firm added that it expects minimal near-term impact on pharmaceutical preclinical testing. Non-animal models are already used for biologic submissions to the agency, while cell and gene therapy companies already use organoid models to test potency, Leerink said. Alternative approaches are reflected in 2023 FDA draft guidance that strongly advises minimal use of animals for these purposes. That guidance followed the FDA Modernization Act 2.0, signed into law in 2022, which authorized alternatives to animal testing to evaluate the safety and efficacy of a drug.

“When monoclonal antibodies are not cross-reactive in animal models, FDA already accepts in vitro data from models like organoids paired with human dose escalation that starts at very low doses,” Leerink said.

Longer term, Leerink said the FDA actions could accelerate innovation in preclinical models and spur change within the agency. That view is shared by a former FDA official who spoke with the firm. The official told Leerink that senior agency leadership focus may be the push necessary to drive conservative FDA toxicologists to change. However, success will likely require funding from Congress and public-private partnerships to collect and analyze data. The former official cautioned that the animal phase-out effort could be set back by any patient deaths associated with a drug tested using a prematurely adopted model.

People for the Ethical Treatment of Animals applauded the FDA announcement. In an emailed statement, PETA Senior Vice President Kathy Guillermo called it a significant step toward meeting the agency’s commitment to replace the use of animals, a goal her organization has worked hard to promote.

“All animal use, including failed vaccine and other testing on monkeys at the federally-funded primate centers, must end, and we are calling on the FDA to further embrace 21st-century science,” she said.

The FDA said it will host a public workshop later this year to discuss the animal testing phase out and gather stakeholder input. The agency also plans to launch a pilot program allowing select monoclonal antibody developers to take a primarily non-animal-based testing strategy in close consultation with the regulator. An accompanying pilot study will inform these policy changes and guidance updates that the FDA is phasing in.

Photo: Erik Veland, via Getty Images