The Nonclinical

Your IND is rejected before a single human being ever reads it. Not because the science is wrong — because a 10-year-old legacy file was missing a digital tag. In this episode, we break down exactly what goes into the nonclinical sections of an IND, how the 5-module eCTD structure works, and the SEND dataset rules that silently kill submissions before they ever reach a reviewer.Key takeaways:The IND is organized into 5 modules — and the nonclinical program lives primarily in Module 2 (summaries) and Module 4 (study reports and SEND datasets)Module 2.4 (Nonclinical Overview) is written last — after the detailed 2.6 summaries are complete — because it summarizes themEvery toxicology study listed in Module 2 must have an associated study report in Module 4, and vice versa — no orphans allowedSEND datasets are required for almost all tox studies, including nonGLP studies — and a missing SEND dataset triggers automatic rejection before a human reviewer ever sees your dataEven studies run 10 years ago still need at minimum a TS domain to pass validation — age of the study is not an exemptionLinks:My course: The Complete Guide to Nonclinical Development, https://www.nonclinical.academy/Work with Dessi: toxistrategy.comRead the full newsletter issue on LinkedIn: https://the-nonclinical.com/The Nonclinical is hosted by Dessi McEntee, MS, DABT — board-certified toxicologist and Fractional Head of Toxicology. Subscribe to the newsletter on LinkedIn, take the course at nonclinical.academy, or work with Dessi at toxistrategy.com.

Everyone in drug development is talking about New Approach Methodologies — AI, organ-on-a-chip, virtual control animals, in silico modeling. The vision is compelling: fewer animals, faster timelines, better translational data. But where are we actually? In this episode, we cut through the hype and take an honest look at where NAMs stand in nonclinical toxicology today, why the hardest part of the pipeline has been the slowest to change, and what it would actually take to get there.Key takeaways:NAMs are advancing rapidly on either side of nonclinical safety — ADME, in vitro screening, computational modeling — but the GLP tox studies that actually get you to IND have been the slowest to changeThe reason is structural: IND-enabling tox studies are the most expensive, most time-sensitive, and most risk-laden studies in the program — most companies won't experiment thereThe silo problem is real: regulatory safety decisions are made by comparing data within a single study, which makes integrating external datasets architecturally difficultVirtual control animals (Charles River/Sanofi) are one of the only dedicated computational solutions in nonclinical toxicology — and may be proof of concept for what's possibleThe FDA is moving in the right direction on NAMs — but most toxicologists would not submit a full IND without GLP animal studies today, and that's not a failure of imagination, it's a responsibility to patientsLinks:Check out my course: https://www.nonclinical.academy/Data Is Not Strategy on Amazon: https://a.co/d/02xUsV6KWork with Dessi: toxistrategy.comThe Nonclinical is hosted by Dessi McEntee, MS, DABT — board-certified toxicologist and Fractional Head of Toxicology. Subscribe to the newsletter on LinkedIn, take the course at nonclinical.academy, or work with Dessi at toxistrategy.com.

More data should mean less risk. In nonclinical development, that's not always true. In this episode, we explore the concept of data hormesis — the inflection point where accumulating more data stops reducing uncertainty and starts creating it. If your team is running another study because the last one didn't give you the answer you needed, this episode is for you.Key takeaways:Data hormesis is the point where more information stops helping and starts obscuring the path forward — just like a drug that's beneficial at low doses and toxic at high onesEarly in development, data reduce uncertainty. Beyond a certain point, signals compete for attention rather than converging toward resolutionWhen decisions aren't defined early, data accumulation quietly becomes a substitute for judgment rather than a tool to support itThe patterns are recognizable: equivocal findings trigger rework instead of interpretation, borderline results lead to more studies without clarity on what would actually changePrograms that move efficiently to IND aren't the ones with the most data — they're the ones that decided early which risks are acceptable and which questions are worth answering nowData don't create strategy. They make strategy visible.Links:Data Is Not Strategy on Amazon: https://a.co/d/02xUsV6KWork with Dessi: www.toxistrategy.comThe Nonclinical is hosted by Dessi McEntee, MS, DABT — board-certified toxicologist and Fractional Head of Toxicology. Subscribe to the newsletter on LinkedIn, take the course at nonclinical.academy, or work with Dessi at toxistrategy.com.

"No major findings." Three words that instantly lower the blood pressure of every executive in the room — and sometimes, quietly derail a program. In this episode, we unpack why a clean toxicology study can still leave your IND dangerously exposed, what teams consistently get wrong when they see no major findings, and why the absence of a finding is never the end of interpretation — it's where interpretation has to begin.Key takeaways:"No major findings" describes what was not observed — it is not an interpretation of what the study resolvedA clean study still leaves critical questions open: how close was exposure to the clinical range? What assumptions are now baked in about escalation?Once "no major findings" enters the conversation, behavior changes — dose rationales harden, exposure assumptions stop being tested, follow-on studies are designed from reassurance instead of uncertaintyThe consequence doesn't show up in nonclinical — it shows up at IND when you're asked to justify decisions you thought were already madeStrong programs use clean studies as an opportunity to do more thinking, not less — documenting assumptions, defining boundaries, and stating explicitly what would change the program's directionLinks:Data Is Not Strategy on Amazon: https://a.co/d/02xUsV6KWork with Dessi: https://www.toxistrategy.com/The Nonclinical is hosted by Dessi McEntee, MS, DABT — board-certified toxicologist and Fractional Head of Toxicology. Subscribe to the newsletter on LinkedIn, take the course at nonclinical.academy, or work with Dessi at toxistrategy.com.

"Our CRO has QA — we're covered." It's one of the most common phrases in biotech, and one of the most dangerous assumptions in nonclinical development. In this episode, we break down the critical difference between CRO QA and sponsor-side oversight, why GLP compliance and regulatory strategy are two completely different things, and what happens when nobody is doing the sponsor's job.Key takeaways:CRO QA ensures the CRO complies with GLP — that's it. It does not ensure your study design supports your regulatory strategyWhen a protocol deviation occurs, CRO QA documents it perfectly — but nobody assesses whether it invalidates your NOAEL or affects your INDBig Pharma has five layers of oversight. Most biotechs have two and hope that's enough — the missing layer is sponsor-side QAReal-time study monitoring with a regulatory lens is what catches problems when you can still fix them, not six months later in the final reportMost biotechs choose to do nothing by default — not because they've evaluated the risk, but because they don't know the gap existsLinks:Data Is Not Strategy on Amazon: https://a.co/d/02xUsV6KWork with Dessi: www.toxistrategy.com The Nonclinical is hosted by Dessi McEntee, MS, DABT — board-certified toxicologist and Fractional Head of Toxicology. Subscribe to the newsletter on LinkedIn, take the course at nonclinical.academy, or work with Dessi at toxistrategy.com.

Most nonclinical teams spend a lot of time thinking about which studies to run. Almost none spend enough time thinking about when. In this episode, we unpack why study sequencing is one of the most consequential — and most consistently underestimated — decisions in IND-enabling development, and walk through the three sequencing mistakes that quietly accumulate risk while looking like efficiency.Key takeaways:Sequencing is an informational problem, not a scheduling problem — and confusing the two is where programs get into troubleRunning a GLP pivotal study before dose range is genuinely established is the most common and most costly sequencing mistakeA clean NOAEL without any adverse effects at the high dose isn't a win — it's a failure to toxicologically characterize your marginsParallel execution without informational overlap isn't a compressed timeline — it's two separate bets running simultaneously with limited ability to course-correctRegulators aren't just evaluating what your data shows — they're evaluating whether your program was designed to answer the right questions in the right orderLinks:Data Is Not Strategy on Amazon: https://a.co/d/0cDYM8vPThe Nonclinical is hosted by Dessi McEntee, MS, DABT — board-certified toxicologist and Fractional Head of Toxicology. Subscribe to the newsletter on LinkedIn, take the course at nonclinical.academy, or work with Dessi at toxistrategy.com.

The science is finished. The data is locked. So why is your IND still weeks away? In this episode, we pull back the curtain on one of the most consistent — and avoidable — sources of delay in nonclinical programs: the gap between data lock and final report delivery. We break down the legacy dual-track CRO workflow that's been quietly adding 8-10 weeks to timelines, and explore the single-track solution that's finally fixing it.Key takeaways:Data lock is not the finish line — sponsors who treat it that way get blindsided every timeThe legacy dual-track system has two separate teams manually handling the same data, sequentially — and it was built for an era that no longer existsManual transcription doesn't just slow things down, it introduces reconciliation risk that can cascade into regulatory rejectionPointCross's single-track process runs report generation and SEND dataset preparation in parallel from a single source of truth — eliminating duplication entirelyFor CROs, slow turnaround is no longer just an operational issue — it's a competitive liabilityThe Nonclinical is hosted by Dessi McEntee, MS, DABT — board-certified toxicologist and Fractional Head of Toxicology. Subscribe to the newsletter on LinkedIn, take the course at nonclinical.academy, or work with Dessi at toxistrategy.com.

Before your drug ever reaches a human, it has to earn its way there — and toxicology is what makes or breaks that journey. In this episode, we break down why the toxicology program is the most critical piece of an IND package, what a well-executed tox program actually looks like, and why seeing toxicity in animals is not a red flag — it's exactly what you want. If you've ever sat in a meeting and wondered where tox fits into the bigger picture, this one's for you.Key takeaways:Drug development has two phases: before and after IND clearance — and tox owns the first oneA tox program with zero findings can actually be a bad sign — it may mean your compound isn't doing anything at allEvery tox program is custom-built to the drug — size, type, mechanism, route, and indication all shape itNOAEL and MTD aren't just acronyms — they're the data points that directly determine your Phase 1 starting doseOnce in the clinic, tox shifts from gatekeeper to tactical support roleLinks:Online Course: www.nonclinical.academyWork with Dessi: www.toxistrategy.comThe Nonclinical is hosted by Dessi McEntee, MS, DABT — board-certified toxicologist and Fractional Head of Toxicology. Subscribe to the newsletter on LinkedIn, take the course at nonclinical.academy, or work with Dessi at toxistrategy.com.