The first drugs are beginning to enter human clinical trials with no review of animal research outcomes.
As 2025 wraps up, it is an excellent opportunity to consider the shifts in drug development that happened over the past year. The FDA released its roadmap to reduce animal preclinical testing, the UK released its strategy to replace animals in research, the VQN program to support New Approach Methodologies (NAMs) was launched, the CDC eliminated primate research.
With so much happening, it can be easy to miss other major advances. In October 2025, a workshop described a case study of one of the very first medicines to enter human clinical trials with no animal data included. Although other animal-free drugs have entered the clinic, this case study may be unique in that animal models were available (and potentially applicable) but were chosen not to be included.
Animal models could have been used but they did not need to be.
I had the pleasure of attending that workshop and hope to provide some insights into what I learned and where the future of animal-free research might be headed.
The Australian Advantage: Human Ethics and Animal-Free Research
The workshop “Practical Application of New Approach Methodologies (NAMs) to support First-In-Human (FIH) Clinical Trials” was held at AusBiotech 2025 and was hosted by Bellberry (Australia’s largest Human Research Ethics Committee (HREC) provider) and the Australian Society of Clinical and Experimental Pharmacologists and Toxicologists (ASCEPT). In Australia, certain medicines can bypass direct regulatory review and move directly to clinical trials after review by an independent HREC through the Clinical Trial Notification (CTN) pathway. This is the so-called “Australian Advantage”.
The workshop detailed the preclinical data for a monoclonal antibody targeting a clinically validated inflammatory pathway and the HREC’s ultimate decision to allow the clinical trial to proceed.
Proving Safety Without Animals
First, context is important. In this case, the drug being reviewed was a monoclonal antibody targeting a therapeutic mechanism demonstrated to be clinically safe in previous clinical trials of similar medications. Major risks for monoclonal antibodies include “on-target, off-tissue” binding. This is often broadly associated with therapeutic mechanism. This mechanism, previously demonstrated as safe, substantially reduced this risk.
With this concern largely addressed, the developers deployed NAMs to evaluate other core requirements in preclinical review including safety, characterization, and dose selection. For the purposes of this article, only safety will be evaluated in depth. If you have questions about other considerations, please contact InnovApproach Consulting.
Three primary risk sources were evaluated by NAMs: selectivity, immunogenicity, and cytotoxicity.
- Selectivity is the possibility for an antibody to bind to an unintended target.
- It was assessed by an in vitro “membrane proteome array”, likely the “Membrane Proteome Array™” (MPA). Traditional tissue cross-reactivity (TCR) was also used.
- No off-target binding was observed with the MPA. TCR showed binding equivalent to other medications in this class
- It was said in the meeting that the MPA data were a primary motivating factor in the approval of this submission
- Immunogenicity is the possibility of a substance to cause an unintended immune reaction
- In silico immunogenicity modeling was comparable to clinically validated comparator substances
- Immunogenicity scoring showed low risk of anti-drug antibody formation
- Cytotoxicity describes the possibility of the drug causing local cell death
- In vitro human organoid models of the target tissue were generated
- Even at 500x the anticipated effective concentration, cells remained viable and active
Safety assessment also included in silico and other digital evaluations of pharmacokinetics that demonstrated similar outcomes to comparators. This modeling also demonstrated dose considerations in line with other comparators, boosting confidence.
Ultimately, it was concluded that the proposed protocol demonstrated sufficient safety to move into first-in-human clinical trials.
NAMs and the Future of Animal-Free Research
One of the most important lessons from this case study is how NAMs can build a weight-of-evidence (WoE) demonstrating that a drug is safe in the absence of animal data. The Membrane Proteome Array and other technologies like it are not intended to be 1:1 replacements for animal data. Instead, they are often deployed as a quantitative and technical improvements upon tissue cross-reactivity, which is often poorly predictive of safety outcomes.
However, within a highly specific context, no off-target interaction being detected in conjunction with other therapies targeting this mechanism being historically safe in humans provided high confidence of the safety of this drug. This approach individually teases apart the sources of possible safety risks and evaluates them independently to demonstrate comprehensive safety.
As regulators move further to reduce and replace animals in preclinical studies, the Weight of Evidence of existing data with scientifically relevant and justified NAMs will be a key to their success.
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