By Justin Yamashita, MSc. Benchtop, site, CRO: three levels of basic and clinical research, explained without spin.

The receipts for everything Monday and Wednesday claimed.

The deeper dive: trial methodology, mechanisms, and the science behind the story.

In Monday's Root Room track, Iris asked why a room full of human cells gets to stand in for the video she watched. Wednesday named the gap between an understudy's performance and the lead's: 90% of drug candidates that pass animal testing still fail once they reach a human trial. This is where that number comes from, what the FDA is doing about it, and what the law changed in 2022 and what it didn't.

The claim underneath both of this week's earlier pieces is a single sentence from the FDA's own April 2025 roadmap: over 90% of drugs that appear safe and effective in animals do not go on to receive FDA approval in humans, predominantly due to safety and/or efficacy issues. That's not an activist estimate; it's the regulator that approves drugs, describing its own approval record.

FDA attributes the figure to a 2023 peer-reviewed review, Marshall and colleagues, published in Alternative Laboratory Animals, which surveyed the translatability record of animal studies across disease areas. The review's headline conclusion and FDA's summary of it agree: strong performance in an animal model is a weak predictor of what happens in a human body. That is the entire argument for NAMs in one number, and it is worth sitting with rather than skimming past.

FDA's own definition of New-Approach Methodologies (NAMs): innovative testing methods and strategies used to assess the safety, efficacy and quality of drugs, biologics and other FDA-regulated products. In practice that spans several distinct tools, not one. In vitro human-based systems use living human cells or tissue instead of an animal's. Organ-on-a-chip devices are microfluidic systems lined with human cells that reproduce an organ's mechanical and chemical environment, such as breathing motion in a lung-on-a-chip. In silico modeling and AI-powered models simulate how a compound behaves in the body computationally, before any physical test runs. Real-world data draws on existing human health records rather than generating new animal data at all.

None of these individually replaces the full scope of what an animal study currently covers. That is precisely why FDA's own roadmap language is 'weight of evidence,' multiple NAMs used together and compared against each other, not one chip swapped in for one mouse.

The FDA Modernization Act 2.0, Pub. L. 117-328, was signed into law on December 29, 2022. What it did: it removed the federal requirement that new drugs be tested on animals before entering human clinical trials, opening the door for sponsors to submit non-animal evidence instead. What it did not do: ban, restrict or phase out animal testing itself. Animal studies remain fully permitted, and for most drug classes still remain the default sponsors use, because the infrastructure, historical comparison data and regulatory familiarity around them are decades deep. The law changed what is legally required. It did not change what is currently practiced. Reporting and social posts that collapse those two claims into one, 'the FDA banned animal testing,' are describing a law that was not passed.

FDA published a one-year progress report in April 2026 against its own roadmap. Four concrete, checkable items shipped: draft guidance reducing routine nonhuman-primate toxicology testing for monoclonal antibody development from 6 months to 3 months, when 1-month studies combined with NAM data show no concerning signals. Updated guidance moving away from horseshoe-crab-derived endotoxin testing, which by FDA's own estimate could spare more than 1,000,000 animals a year, a separate line item from the 90% approval-failure statistic above and not the same claim. The first AI-based drug development tool formally qualified for use in submissions. And a searchable public database now exists so a sponsor can check, before starting a study, whether a given alternative method will be accepted for that specific question.

None of that is 'no more animal testing.' All of it is real, dated and checkable against FDA's own published record, which is a different category of claim than a video asserting the whole system has already changed.

Tier 1, peer-reviewed: Marshall et al. 2023 (Alternative Laboratory Animals, translatability of animal research). Tier 2, regulatory and legal record: FDA Modernization Act 2.0, Pub. L. 117-328; FDA's Roadmap to Reducing Animal Testing in Preclinical Safety Studies, April 2025; FDA's April 10, 2025 monoclonal antibody announcement; FDA's April 2026 Year 1 progress report; the FDA New Approach Methodologies program page. Tier 3, company or institutional press release: none used in this issue. Tier 4, individual case or self-reported: none used in this issue.

Over 90% of drugs that appear safe and effective in animals do not go on to receive FDA approval in humans, predominantly due to safety and/or efficacy issues: Tier 2, FDA Roadmap, citing Marshall et al. 2023 (Tier 1). FDA Modernization Act 2.0 signed into law December 29, 2022, removed the legal requirement for animal testing before human trials, did not ban animal testing: Tier 2, Pub. L. 117-328. Draft guidance would reduce routine primate mAb toxicology testing from 6 months to 3 months under stated conditions: Tier 2, FDA Year 1 report, April 2026. Guidance moving away from horseshoe-crab-derived endotoxin testing could spare more than 1,000,000 animals a year, FDA's own estimate: Tier 2, FDA Year 1 report. First AI-based drug development tool qualified, and a searchable NAM-acceptance database is live: Tier 2, FDA Year 1 report.

Q4, who funded this, and do they have a stake in the answer? The 90% figure comes from the regulator that approves drugs, describing its own approval failures, and the roadmap built on it commits FDA to reviewing less familiar evidence types, not to a faster or laxer approval path. That is a stake in the opposite direction from the one a suppression story usually assumes.

Q9, what do independent experts with no stake in the outcome say? Marshall and colleagues are academic and animal-welfare-affiliated researchers publishing in a peer-reviewed journal, not a pharmaceutical company or a regulator with an approval record to defend, and FDA cites their independent review rather than an internal FDA study to make its own case. Two parties with different incentives arrive at the same number.

Next issue: who actually gets into a clinical trial, and who is deciding that on the sponsor's side before a patient ever sees a consent form.

These 3 issues give you the foundation for everything in this arc.

Issue 003b: How to evaluate any health claim using the Skeptic's Toolkit. Start here.

Issue 001: Why medical distrust is rational, and what to do with it anyway.

Issue 004: How a drug gets from a lab to your pharmacy. The pipeline in plain language.

All back issues are at RootToRx.com.

1. Marshall LJ, Bailey J, Cassotta M, Herrmann K, Pistollato F. "Poor Translatability of Biomedical Research Using Animals - A Narrative Review." Alternative Laboratory Animals. 2023;51(2):102-135. doi:10.1177/02611929231157756

2. U.S. Food and Drug Administration. "Roadmap to Reducing Animal Testing in Preclinical Safety Studies." April 2025. fda.gov

3. FDA Modernization Act 2.0. Public Law 117-328. Signed December 29, 2022. congress.gov

4. U.S. Food and Drug Administration. Press announcement on phasing out animal testing requirements for monoclonal antibody development. April 10, 2025. fda.gov

5. U.S. Food and Drug Administration. "FDA Achieves Year 1 Goals in Reducing Animal Testing in Drug Development." Press announcement. April 2026. fda.gov

6. U.S. Food and Drug Administration. "New Approach Methodologies (NAMs)." Program page. fda.gov

If this was worth your time, the best thanks is a referral. Series 1 cards are the reward.

New here? Root to Rx runs three pieces a week. Monday you watch a real health claim try to work on someone. Wednesday you get the tools to run it yourself. Thursday you get the full evidence so you can check my work. Written by a clinical researcher, free, at RootToRx.com.

For educational purposes only. Nothing in this newsletter is medical advice. Talk to your doctor before making any health decision.

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Disclosure: Root to Rx is published independently by Open Label Media LLC. Views expressed are personal views of Justin Yamashita and do not represent his employer or any affiliated organization. No employer resources or proprietary information are used. Every claim is sourced from publicly available materials.

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