7 Decisions That Shape Your Path from Preclinical to Clinical

2. Sequence Preclinical Studies to Match Your Program’s Actual Constraints

Each program is developing a uniquely valuable medicine and requires a tailored approach, but Good Laboratory Practice (GLP) preclinical safety studies depend heavily on the therapeutic approach (small molecule, antibody, RNA, viral delivery, etc.). Early activities can de-risk studies before IND-enabling work begins.

Early route scouting to optimize synthesis (for small molecules) or expression optimization (for biologics) can save time and money before preclinical studies begin. Also important is early formulation work that can be impactful when it comes to reaching the doses required in toxicology studies.

Platform-specific de-risking helps too:

• Small molecules: mini-Ames and micronucleus assays can identify or de-risk gene tox concerns
• Antibodies: early investment in developing anti-drug antibody (ADA) assay reagents can accelerate preclinical studies
• Cell and gene therapies: early biodistribution studies can address concerns about specificity of target delivery

Whether studies should run in parallel or sequentially depends on your team’s development priorities. If the only concern is time-to-market, it’s possible to run many studies in parallel. If the main goal is controlling spend, it might make more sense to sequence studies from least to most expensive, though a negative result could affect the program’s viability. Most sponsors leverage a blend of the two. The exact distribution of spend and time risk is individual to the program.

3. Design for Manufacturing Before You Need It

Different sponsors work with very different therapeutic platforms. Small molecule, antibody, cell, RNA, viral delivery, etc., each carries its own manufacturing considerations that small teams can’t always account for in early R&D.

A program can be scientifically sound and still stall, not because the biology failed, but because supply or manufacturing capacity wasn’t ready when the studies needed it. Planning your chemistry, manufacturing, and controls (CMC) strategy and choosing manufacturing partners alongside the biology protects your timeline and makes scale-up smoother.

4. Engage Regulators Earlier Than You Think You Need To

For novel therapies, or novel combinations of therapeutic platforms, early engagement with regulators can make or break the timeline. Since many novel therapies don’t have existing precedent to refer to when addressing questions about CMC specifications, relevant pharmacology and toxicology species, or additional requirements, they can require more frequent collaboration with reviewers. The regulatory bodies involved in progressing your program through approval steps need total clarity on scientific intent and product specifics.

The FDA offers several meeting types to help early programs gain clarity on important milestones. It’s generally a good idea to request a pre-IND meeting to align with reviewers on open questions before the submission. Because a sponsor is usually only granted one pre-IND meeting per program, timing it well matters:

• If the most important open question concerns the toxicology species or approach, schedule the meeting before contracting with a CRO for those studies
• If the most important question concerns the clinical protocol, it may make more sense to schedule the meeting after the toxicology studies or the last IND-enabling study, so it can include topics about the protocol and the completed study results

A successful regulatory affairs strategy starts internally. First, assess what’s unknown about the regulatory approval pathway and where scientific and clinical judgment is needed to weigh risks and benefits to patients. From there, compose a clear, concise briefing book that lays out the proposition and where guidance is still needed. It’s worth thinking about whether a given question is best asked narrowly or left open enough for the FDA to expand on.

To build a data package that validates your science across regulatory bodies and markets, it helps to appeal to International Council for Harmonisation (ICH) guidelines and engage experts who have been involved in programs that opened clinical trials in the geographies relevant to the intended clinical program.

5. Close Data Gaps While They’re Still Small

Some preclinical data gaps become real Phase I holdups later:

• Clearance pathways and metabolites (small molecules): understanding these can justify the toxicology species choice, and later, when an absorption, distribution, metabolism, and excretion (ADME) study is done, can de-risk the possibility of a unique human metabolite or a special population with impaired clearance
• Drug-drug interaction (DDI) risk: understanding the risk and magnitude of DDIs can help programs plan for other Phase I studies that may be needed and flag drugs that shouldn’t be co-administered with the test item

A thorough gap analysis is a holistic assessment of the program. It considers the validity of the target in the indication; the studies done to show target engagement, potency, efficacy, and selectivity; and potential safety liabilities, and it checks whether the ADME data supports achieving therapeutic levels of the intended API in humans by the intended route of administration.

6. Know the Blind Spots in Your Therapeutic Area

Australia, for example, has been extremely forward-thinking regarding precision medicine in oncology. Newly diagnosed cancer patients routinely have their tumors sequenced, and sponsors can access anonymized data to target sites with patients who have tumor mutations of interest.

Central nervous system (CNS) programs benefit from characterizing the extent and duration of CNS exposure after administration. For CNS, renal, and cardiometabolic programs alike, data supporting pharmacokinetics/pharmacodynamics (PK/PD), along with any correlative circulating biomarker, can strengthen the package considerably. Different indications carry characteristic safety liabilities, and having experience with the expanded set of toxicology endpoints associated with each therapeutic area matters.

7. Bring in Outside Expertise Before You Need to Course-Correct

Lean biotech teams don’t always have in-house regulatory or preclinical expertise. Knowing when to bring in outside CRO expertise (early) can support more strategic decisions from lead identification through candidate nomination, IND-enabling studies, and beyond.

All development strategies have a shared goal: bringing innovative therapies to patients as fast as possible. Sponsors that align their preclinical development strategy with their clinical study designs are most likely to build a strong, regulatory-ready data package. Upstream decisions can shape both the regulatory pathway and the clinical approach that follows.

It’s worth noting that Australia doesn’t require an IND to start Phase I work. Even so, the regulatory process in Australia is equally rigorous and follows the same ICH guidelines on preclinical studies required to open a trial, and clinical trials can start quickly there due to more streamlined contracting and clinical startup times. Learn more about the Australian advantage for early-phase trials.

If you’re weighing these decisions for your program, talk to an expert at Avance Clinical. Our ClinicReady team supports your program goals from preclinical planning onward, through regulatory milestones, connecting that work directly into Phase I and Phase II+ under the same team.