JPMA Survey Finds Limited Regulatory Experience with NAMs and Uneven Evidence from Submitted Cases

A Company-Level Snapshot After the FDA Roadmap

The Japan Pharmaceutical Manufacturers Association (JPMA) surveyed member companies about NAMs use following the FDA’s April 2025 roadmap. Published in NAM Journal, the study examines a practical transition: moving from interest in human-relevant methods to generating evidence that can be used in a drug application. Its findings describe company reports and the authors’ policy proposals, rather than new requirements issued by a regulator.

The questionnaire was sent to 57 JPMA member companies and collected responses from 18 July to 1 August 2025. Thirty-four companies replied, a response rate of about 60%; 28 were domestically owned and six overseas-owned. One response was accepted per company. Eleven questions covered research use, regulatory submissions, motivations, barriers and expected regulatory actions, with follow-up questions for companies reporting submission experience.

Eighteen of 34 companies knew about the FDA roadmap but had an undecided or unknown response. Five planned to consider a response and three were already considering one. The survey was conducted roughly three months after the roadmap, so these answers capture an early organizational response rather than the eventual effect of the policy.

Research Activity and Submission Experience Are Different Measures

In a multiple-response question, 15 of 34 companies said they had not conducted NAMs research. Eleven reported use in discovery projects or internal decisions, and eight reported basic research without implementation in internal projects. These categories measure different stages of activity and cannot be added as mutually exclusive company groups.

A dedicated regulatory-submission question identified five companies with experience placing NAMs data in documents such as an Investigator’s Brochure or Common Technical Document; 29 reported no such experience. The follow-up examples covered small molecules and antibodies, with uses ranging from occupational-safety and eye-irritation assessment to evaluating human relevance and antibody-specific hazards.

The working definition included methods that reduce or replace animal use, spanning in vitro, chemical, computational and ex vivo approaches. One reported example was an eye-irritation assay using bovine corneas. The survey therefore brought together several model types and established tests, rather than examining a single generation of human-cell technology.

The Submitted Cases Include Both Useful Signals and False Positives

One company submitted results from a novel cytokine-release assay for an antibody. That method produced a strong positive signal while conventional assays showed no cytokine-release symptoms. Regulatory reviewers asked about the proposed use and clinical relevance. Subsequent work identified nonspecific positive reactions in certain antibody formats, and the company later removed the data from its Investigator’s Brochure.

Another company described an off-target-binding assessment intended to complement animal toxicology where its relevance was limited. The assay detected more binding reactions than expected, requiring additional functional tests for the potential off-target binders. This example separates detecting a binding event from establishing its biological consequence.

The same company reported a different antibody case involving Fc gamma receptors, which mediate activating or inhibitory immune responses. The product’s Fc region interacted with human receptors but not the corresponding mouse or cynomolgus-monkey receptors. Human-cell experiments assessed receptor-associated phosphorylation, B-cell apoptosis and platelet activation, providing evidence for submission to the FDA. These cases show why the specific biological question and species relevance matter alongside the method’s NAMs label.

Respondents Prioritize Clear Evidence Expectations

The most frequently selected motivations were promoting the 3Rs, reported by 25 of 34 companies; evaluating human-specific responses, 24 of 34; and improving clinical relevance or success, 22 of 34. Shorter development and lower cost were also selected, but the survey did not measure whether NAMs had delivered those benefits.

Among the 29 companies without submission experience, 25 identified international guidelines as an enabler, while 21 selected qualification guidance in Japan and 21 individual test guidelines. In the full responding group, 26 of 34 cited lack of harmonized international guidance as a barrier. Twenty-four cited insufficient experience, and 23 uncertainty about required datasets and endpoints. Multiple selections were permitted.

The authors propose clearer qualification expectations, early consultation and a public database of qualified methods, together with international coordination. Qualification here concerns a defined interpretation and use of a drug-development tool; it is broader than simply including one assay result in an application. These are recommendations arising from the survey, not evidence that the proposed systems or an ICH guideline had been adopted.

The study used descriptive counts without hypothesis testing. Its self-reported, membership-based sample may favor companies already interested in NAMs, and local affiliates may have incomplete information about global research. Respondents could also interpret the scope of NAMs differently. The submitted cases provide concrete evidence of how methods were used and questioned, while the survey proportions remain a dated snapshot of these 34 companies.