The Preclinical Journey: What Must Happen Before Phase I (2/7)
In the previous post, we explored how Sponsors reach the Phase I decision point whether through internal discovery, in-licensing, or acquisition. Now let's dive into what actually happens during those final crucial years before they can submit an IND and begin human testing.
This is the technical bridge between "we have a promising molecule" and "we're ready to dose humans." Understanding this journey transforms how you interpret your Sponsor's behaviour when things don't go according to plan.
The Sacred Threshold: Understanding the IND
Before any drug can be tested in humans in the United States, the Sponsor must file an Investigational New Drug (IND) application with the FDA. This isn't a formality, it's a comprehensive scientific argument that says: "Based on everything we know from preclinical testing, we believe this drug is safe enough to justify human testing, and here's our plan to gather the data we need while protecting patient safety."
The IND package typically includes:
Complete preclinical pharmacology and toxicology data
Manufacturing information and Chemistry, Manufacturing, and Controls (CMC) data
Clinical protocols and investigator information
Previous human experience (if any)
Think of the IND as a gate that separates two worlds: the preclinical world (where everything is animals, cells, and computer models) and the clinical world (where real patients' safety is at stake). Your Sponsor has spent years and millions of dollars earning the right to cross that gate.
The 18-36 Month Gauntlet: What Must Happen
Once a Sponsor has selected their lead compound (the molecule they believe has the best chance of becoming a drug), they enter what I call the IND-enabling studies phase. This typically takes 18-36 months, though it can be longer for complex molecules or challenging therapeutic areas.
Here's what must happen:
Phase 1: Pharmacology Studies (Months 1-6)
Primary Pharmacology: Scientists must definitively demonstrate that the drug does what they think it does. If it's supposed to inhibit a specific enzyme, they need to show it inhibits that enzyme at relevant concentrations. If it's supposed to activate a receptor, they need to show receptor activation.
Secondary Pharmacology: They also need to understand what else the drug does. Does it interact with other biological targets? Could those interactions cause problems? This is about identifying potential off-target effects before they become safety issues in humans.
Pharmacokinetics (PK): How does the body handle this drug? How is it absorbed? How is it distributed to different tissues? How is it metabolized? How is it eliminated? These PK studies are typically done in at least two species (usually rodents and non-rodents).
Why this matters to you: When your Sponsor insists on specific PK sampling timepoints in your Phase I protocol, it's not arbitrary. They're trying to validate (or refute) predictions from these preclinical PK models. Missing those timepoints isn't just a protocol deviation. It's potentially invalidating years of preclinical modeling work.
Phase 2: Toxicology Studies (Months 4-18)
This is the most expensive and time-consuming part of preclinical development. Toxicology studies must be conducted under Good Laboratory Practice (GLP) regulations, which means rigorous quality control, documentation, and regulatory oversight.
Acute Toxicity Studies: What happens when you give animals a single high dose? This helps establish the dose range for longer-term studies.
Repeat-Dose Toxicity Studies: This is the big one. Animals (typically rats and dogs, though sometimes primates for biologics) receive the drug daily for weeks to months. Scientists monitor:
Clinical signs and behaviour
Body weight and food consumption
Clinical pathology (blood chemistry, haematology, urinalysis)
Organ weights
Microscopic examination of tissues
The duration of these studies depends on how long the drug will be given to humans in Phase I:
For single-dose Phase I studies: Minimum 2-week toxicology studies
For repeat-dose Phase I studies up to 2 weeks: Minimum 1-month toxicology studies
For longer Phase I dosing: Typically 3-month or 6-month toxicology studies
Reproductive Toxicology: While not always required before Phase I, sponsors often begin these studies to prepare for Phase II. These studies assess:
Effects on male and female fertility
Effects on embryo-fetal development
Effects on pre- and postnatal development
Genotoxicity Studies: A battery of tests to determine if the drug damages DNA or causes mutations. This is critical safety information that can make or break a development program.
Why this matters to you: When your Sponsor reacts strongly to a protocol amendment that might extend the dosing duration in Phase I, it's because that change could trigger the need for longer (and much more expensive) toxicology studies. A seemingly minor change from "2 weeks of dosing" to "3 weeks of dosing" could require months of additional toxicology work and millions in additional costs.
Phase 3: Formulation Development (Months 6-15)
While toxicology studies are running, formulation scientists are working to develop a dosage form suitable for human use. For Phase I, this might be as simple as a capsule with drug powder, or as complex as an IV infusion with specific stability requirements.
Key challenges:
Stability: Will the formulation remain potent and safe during storage?
Bioavailability: Can the drug be absorbed from this formulation?
Manufacturing feasibility: Can we make this consistently?
Scale-up: Can we manufacture enough for clinical trials (and eventually commercial use)?
Why this matters to you: When your Sponsor has strict drug storage and handling requirements in your Phase I protocol, it's because they spent months optimizing that formulation and know exactly what conditions it requires. Deviations from storage conditions aren't just protocol violations. They potentially invalidate the careful formulation work that made the study possible.
Phase 4: Manufacturing and CMC (Chemistry, Manufacturing, and Controls) (Months 8-18)
Before Phase I can begin, the Sponsor must demonstrate they can manufacture the drug consistently, at the required purity, in sufficient quantity. This involves:
Process Development: Optimizing the manufacturing process for reliability and consistency
Analytical Methods: Developing and validating methods to test the drug's identity, purity, and potency
Stability Studies: Demonstrating the drug remains stable under specified conditions for specified periods
GMP Manufacturing: Producing clinical trial material under Good Manufacturing Practice regulations
For small molecules, this might mean manufacturing a few kilograms of drug substance. For biologics (proteins, antibodies, gene therapies), this means establishing cell culture processes, purification methods, and fill-finish operations. All under GMP.
Why this matters to you: When your Sponsor has limited clinical trial material available and can't easily make more, it's not because they're being difficult. Manufacturing drug for clinical trials is extraordinarily expensive and time-consuming. Running out of drug means months of delay while they manufacture more and re-qualify that new batch.
Phase 5: Regulatory Strategy and IND Preparation (Months 12-18)
Throughout all the previous phases, regulatory strategists are planning the IND submission and engaging with regulatory agencies when appropriate.
Pre-IND Meetings: Many sponsors request formal meetings with FDA to discuss their development plan, ensure their preclinical program is adequate, and get feedback on their Phase I protocol design.
IND Writing: The IND document itself is hundreds to thousands of pages synthesizing all the preclinical data, manufacturing information, and clinical plans. This is a massive undertaking requiring coordination across multiple departments.
Quality Review: Before submission, everything undergoes quality review to ensure accuracy, consistency, and regulatory compliance.
The Modern Complication: When "Drugs" Aren't Small Molecules
Everything I've described so far is the traditional small molecule pathway. But increasingly, drug development involves biologicsβlarge, complex molecules like antibodies, proteins, or even gene therapies.
Biologics add layers of complexity:
Manufacturing is fundamentally different: You're not synthesizing chemicals; you're growing cells that produce your molecule. Consistency is harder to achieve and maintain.
Immunogenicity is a concern: The body might mount an immune response against these large foreign proteins. Preclinical testing must address this risk.
Delivery is more complex: Most biologics can't be given orally; they require injection or infusion. Some require special formulation buffers or storage conditions (like freezing).
Toxicology may require more relevant species: Testing a human antibody in rats might not be informative because the antibody doesn't bind to the rat version of the target. This sometimes necessitates more expensive studies in non-human primates.
Why this matters to you: When your Sponsor's Phase I study involves a biologic, understand that they've navigated an even more complex preclinical journey than small molecule sponsors. The manufacturing, stability, and regulatory challenges are significantly greater.
What Happens When Something Goes Wrong
Now here's the part that explains so much about Sponsor behavior during Phase I: preclinical findings can derail everything, even after the IND is filed.
During toxicology studies, problems can emerge:
Unexpected organ toxicity that wasn't predicted by earlier studies
Findings that require additional studies to characterise
Results that suggest the safe human dose might be much lower than hoped
When this happens, the Sponsor faces agonizing decisions:
Do we add more studies and delay the IND filing?
Do we lower the starting dose and accept slower Phase I progress?
Do we modify the formulation and repeat toxicology?
Do we abandon this molecule and go back to an earlier backup compound?
Each of these options represents months of delay and millions in costs.
Why this matters to you: When your Phase I Sponsor seems hypersensitive to safety signals, even signals that don't reach the threshold for a Serious Adverse Event (SAE), it's because they remember the preclinical journey. They know that unexpected safety findings can cascade into program delays or terminations. They're not overreacting; they're managing risk informed by experience.
The "Success" That Makes It to Your Desk
When you receive that RFP for a Phase I study, you're seeing a molecule that survived the gauntlet. It's one of the few compounds that made it through all the preclinical studies without fatal flaws. The Sponsor has invested:
18-36 months of preclinical work (on top of the years of discovery work we discussed in the previous post)
$5-15 million in preclinical studies alone (toxicology studies are expensive; GLP non-human primate studies can cost hundreds of thousands of dollars)
Countless hours of scientific expertise across multiple disciplines
Regulatory strategy and planning
Manufacturing development and clinical trial material production
And critically: they've built a scientific story that they've articulated to their board, their investors, and regulatory agencies. That Phase I protocol you're reviewing isn't just a study design. It's the next chapter in a story that's been years in the making.
Practical Application: Before Your Next Protocol Review
Before your next Phase I protocol review meeting, take 15 minutes to research:
What type of molecule is this?
Small molecule or biologic?
New chemical entity or reformulation of known compound?
First-in-human or previously tested in other populations?
What's the preclinical package?
What species were used in toxicology?
How long were the toxicology studies?
What's the No Observed Adverse Effect Level (NOAEL) from animals?
How was the starting dose calculated?
What's the manufacturing situation?
How much clinical trial material is available?
What are the storage requirements?
How long does it take to make more if needed?
Understanding these details helps you:
Ask smarter questions during protocol discussions
Understand why certain protocol elements are non-negotiable
Anticipate which changes would be major (requiring sponsor consultation) vs. minor
Position your recommendations in terms of preclinical implications
Note: This type of scientific literacy, understanding enough preclinical development to be a strategic partner, is what distinguishes senior PMs from those still operating as task executors. It's a skill we specifically develop in clinical research project management mentoring.
The Bridge to Human Testing
The preclinical journey isn't just a regulatory requirement. It's the foundation of safety and scientific rationale that makes human testing ethical and justifiable. When your Sponsor talks about "the IND package" or "preclinical data," they're referring to years of work that earned them the right to test their molecule in humans.
In the next post, we'll explore the actual go/no-go decision moment. When leadership decides whether to invest the next $50-100 million in Phase I. Understanding what factors they're weighing, what data they're reviewing, and what pressures they're managing will give you profound insight into why Phase I isn't "just a small pilot study" to them. It's a major strategic commitment with career-defining implications.
