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👀 The Read
The Guidance Isn't the Whole Answer
The calls that make or break a program are the ones the guidance doesn't spell out.
Ask ten teams how to handle a tricky nonclinical question, and most will start the same way: what does the guidance say?
It's the right first move. ICH and FDA guidances are the backbone of every program. But the guidance tells you what's required. It doesn't tell you what's smart for your molecule. And the gap between those two is where programs get made or broken.
Here’s some examples:
1. ICH S9 says you don't need genotox before first-in-human. Most oncology programs run it anyway. For anticancer drugs in advanced cancer, S9 doesn't consider genotoxicity studies essential to support clinical trials. The logic made sense when the guidance was written: patients with advanced cancer had little time, and a long-term risk like a secondary tumor mattered less. But patients are living longer now. Drugs move into earlier lines of therapy and into combinations. A mutagenic signal you didn't look for becomes a much bigger problem when your patients are around for years. So a lot of teams run at least an Ames before FIH. It's cheap, it's fast, and it means you aren't learning about a genotox liability halfway through the clinic.
2. M3(R2) says human-only metabolites need coverage by Phase III. Your Pre-IND data may force the decision now. If a human metabolite is above 10% of total drug-related exposure and disproportionately higher than in your tox species, M3(R2) expects it covered — in time to support Phase III. On paper, that's later. In practice, if your early metabolism data shows the gap, you have to decide now whether to change species, test the metabolite directly, or build a plan you can defend. Waiting until the guidance says you must is how a manageable gap turns into a timeline problem.
In both, the guidance isn't wrong. It just wasn't written for your molecule, your indication, and your timeline. What fills that gap is judgment: knowing the options, how a reviewer is likely to see each one, and writing a rationale you can defend.
The guidance tells you where the lines are. Knowing what to do when your program sits between them is a different problem entirely.
The Misconception: If it's not in the guidance, there's no answer.
The Correction: Guidance sets the minimum, not the strategy. The answer comes from judgment, built on knowing why each guidance says what it says. Build your nonclinical program on the needs of your molecule, not the desires of the guidances.
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