Stakeholders ask FDA to expand guidance on streamlining testing of single-target monoclonal antibodies

While the US Food and Drug Administration (FDA) said its recent draft guidance for streamlining testing of single-target monoclonal antibodies does not apply to oncology products, multispecific antibodies, conjugated antibodies, or antibody constructs, drug manufacturers want the agency to apply the guidance to other types of studies.

FDA’s draft guidance outlined approaches to reduce, refine, and replace animal testing for single-target monoclonal antibodies, recommending against using chronic toxicology studies for monoclonal antibodies in non-rodent species lasting longer than 3 months. The agency also provided examples of situations where 3-month toxicology studies or longer may be warranted, and noted that a sponsor should create a weight-of-evidence (WoE) risk assessment for a shorter testing plan (RELATED: FDA guidance would cut back on using monkeys for safety testing of monoclonal antibodies, Regulatory Focus 02 December 2025).

The draft guidance is part of the agency’s roadmap to reduce and eliminate animal testing requirements for drug evaluation (RELATED: FDA, NIH officials look to curb animal testing in drug development, Regulatory Focus, 8 July 2025).

However, stakeholders who responded to a request for public comment on the draft guidance noted that the streamlined nonclinical safety approaches apply not only to single-target monoclonal antibodies but also to multispecific antibodies, conjugated antibodies, and antibody constructs in other therapeutic areas.

In their comment, the Pharmaceutical Research and Manufacturers of America (PhRMA) said the agency should expand the scope of their guidance to include monospecific antibodies and bispecific antibodies, and consider either expanding the guidance to include or releasing separate guidance documents for toxicology studies of multispecific antibodies, conjugated antibodies, and antibody constructs as well as in other therapeutic areas, such as oncology.

“[T]he fundamental characteristics that justify streamlined nonclinical safety studies for monospecific antibodies—including metabolism through protein catabolism and degradation rather than hepatic biotransformation, large molecular size with limited tissue distribution, and target-mediated toxicity—also apply to multispecific antibodies,” PhRMA wrote. “At a minimum, FDA could consider broadening this Draft Guidance to include multispecific antibodies with well-characterized targets or well-characterized mechanisms of action.”

Other stakeholders, including Genentech and the Biotechnology Innovation Organization (BIO), concurred with this recommendation.

Expanding the draft guidance to include these other products and therapeutic areas “would enable sponsors to have a holistic understanding of the FDA’s philosophy on how to streamline nonclinical safety studies, given the same guiding principles across therapeutic areas,” BIO wrote in their comment.

Weight-of-evidence approach

Commenters also sought clarity on FDA’s weight-of-evidence (WoE) risk assessment described in the draft guidance. More specifically, they want more details on how a WoE risk assessment can fit into a product’s overall development program.

“FDA should detail the decision-making process for the WoE risk assessment, clarify how a sponsor should document the WoE risk assessment in regulatory submissions, and provide information about where to include the WoE risk assessment in the Investigational New Drug (IND) applications,” PhRMA wrote.

In their comment, BIO noted that a WoE risk assessment “is relevant across the entire nonclinical safety assessment.”

“[W]e recommend the FDA encourage sponsors to perform a WoE risk assessment first when planning their nonclinical safety assessment strategy,” it said. “In addition, given that the principles outlined in this guidance could be applied for a toxicology study of any duration, it would be helpful to have that reflected throughout the guidance, to avoid the perception that this guidance is solely focused on reducing chronic toxicology studies.”

Prior knowledge

BIO also said it would be useful to know when a sponsor could use prior knowledge in a product’s safety profile, and whether the agency would allow use of a product’s summary basis of approval or existing published literature without a right of reference.

Genentech noted in its comment that the draft guidance does not state whether a sponsor needs to have a right of reference when referring to other monoclonal antibodies.

“[W]e ask that, in the final guidance, the Agency should clarify circumstances wherein sponsors would be able to leverage prior knowledge about the safety profile of a specific target without needing a right of reference,” it wrote.

Other recommendations

Another concern raised by Genentech was that the draft guidance does not state whether streamlined nonclinical safety study durations meet the standard for first-in-human trials and for later clinical trial phases.

“We stress that this clarification is required to avoid the risk that a streamlined nonrodent study of 1 or 3 months—while accepted for an initial IND—might be deemed insufficient by the Agency to support Phase 2 or Phase 3 trials of longer duration in the patient population,” it stated. “This would effectively negate the ‘streamlined’ benefit of the guidance, forcing sponsors back into 6-month nonrodent studies to avoid clinical holds during later-stages of clinical development.”

In its comment, the Humane World Action Fund noted that FDA’s guidance “does not go far enough in requiring early engagement.”

By leaving early engagement to the sponsor, the guidance “risks perpetuating established practices rather than catalyzing the meaningful change which is necessary to meet the ambitions of the Roadmap to make animal testing the exception rather than the norm,” the organization stated.

The Humane World Action Fund recommended that monoclonal antibody safety testing animal studies be subject to Good Laboratory Practice regulations. It also asked that FDA should state clear goals of success, such as expected reductions in the use of non-human primates in animal testing for approvals of monoclonal antibodies.

Furthermore, the Humane World Action Fund suggested that the agency could conduct public webinars to clarify the guidance for sponsors and provide greater transparency about recent monoclonal antibody approvals that relied on animal studies.

“The guidance should provide clear examples of acceptable non-animal methodologies, identify practices that should be avoided, and clarify areas where animal studies are not required,” the Humane World Action Fund wrote. “Greater clarity on these points would immediately reduce unnecessary animal use, and where animal use is deemed necessary, should help reduce suffering and improve welfare.”

Guidance

Stakeholders ask FDA to expand guidance on streamlining testing of single-target monoclonal antibodies

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