Pharma has long taken small steps toward phasing out animal testing by using new approach methodologies, such as organ-on-a-chip or AI modeling, instead.
Earlier this year, the FDA reinforced that approach by releasing a roadmap to cut down on animal testing in preclinical safety studies for monoclonal antibodies. The NIH soon followed suit with an initiative to adopt “innovative, human-based science” that limits the use of animals in studies.
But the FDA has lacked guidance for how more drugmakers can replace animals, which has made companies “hesitant” to get fully on board, with many “doing animal experiments in parallel” just in case regulators request them, said Zaher Nahle, senior scientific advisor for Animal Wellness Action and the Center for a Humane Economy.
That has now changed.
Earlier this month, the FDA released draft guidance outlining how drug developers can reduce or eliminate six-month non-human primate toxicity testing in certain monoclonal antibody studies.
In what Nahle described as an “extraordinary” statement, FDA Commissioner Dr. Marty Makary then told the news program “Full Measure” a few days later that the agency is “seeing drug applications come in now where they have an outline for animal testing, and we're telling them, we don't want you to do this animal testing. We don't think it's going to inform us about drug safety. Use computational modeling and other technology instead.”
The draft guidance paired with statements from Makary, should signal to drug developers that “this is not a fluke,” Nahle said.
“This is a guidance that is really practical,” he said. “This is not going to be reversed. You can go ahead and plan your realistic strategy based on this.”
Here are three critical takeaways from the new guidance.
Extremely specific
In addition to being “practical,” Nahle said the guidance is also very specific, applying only to a certain subcategory of monoclonal antibodies called monospecific antibodies. These are usually metabolized in the cell, rather than the liver, and therefore don’t pose as much of a liver injury threat, he said.
“These are therapeutic modalities that have been around for a long time. So we know quite well about how they behave. And that's probably why the FDA chose to start with this class of drugs as the first change for the toxicity assessment,” Nahle said.
The guidance is also limited to long-term, general toxicity studies; excludes oncology studies; and doesn’t address toxicology studies related to multispecific antibodies, conjugated antibodies or antibody constructs.
Nahle called all of this a “reasonable first step” from the FDA.
“Although it's moving aggressively, it's also moving responsibly,” he said.
Going beyond NAMs
In addition to NAMs, the guidance emphasizes the importance of several other weight-of-evidence risk assessments, such as literature examining the potential toxicities associated with the molecular target, or mechanism of action and pharmacology data generated with the monospecific antibody.
“The weight of evidence is the previous information about the target,” Nahle said. “It was important before, but it was not codified in such a manner, in a guidance, to replace animal testing.”
The guidance also supplements specific previous guidance.
“They took the time to list all the other previous important guidance that this one will supplement,” Nahle said, calling this “a big step because any drug company that has been following [that] other guidance before, and established them in their protocol, now must incorporate this particular guidance as well.”
Finally, the draft guidance emphasizes communication between the drug sponsor and the FDA before initiating nonclinical programs.
Clues to what’s next
While this first guidance is currently narrow, it’s likely only the first step and could expand to multispecific antibodies, especially those that metabolize outside the liver, Nahle said.
The guidance also states that for “antibodies that have pharmacological activity similar to humans in both rodent and nonrodent species, general toxicology studies (short- and long-term) conducted in a single rodent species may provide sufficient and appropriate nonclinical data.”
By “reading between the lines,” this part of the guidance could indicate that a future step might require only one rodent study, instead of one rodent study and one larger, non-rodent animal study, Nahle said.
