What Really Slows Oncology Trials: The Decisions Made Before Start-Up

For sponsors, real speed comes from better decisions before execution begins

By Steven Cha; Tanja Obradovic

Executive Summary

In oncology development, speed is often measured by how quickly countries and sites can be activated. But many delays begin earlier, when assumptions about protocol design, eligibility, biomarker strategy, feasibility, and country and site selection go unchallenged.

For sponsors, accelerating development means challenging these assumptions while there is still time to change them. Protocol burden should be treated as an operational risk, feasibility should test whether the clinical strategy can work in real-world settings, and country and site sequencing should reflect patient access, execution capability, and evidence needs. Real speed is not simply faster start-up; it is making better decisions early enough to prevent avoidable delays later.

Key Takeaways

1. Speed starts before site activation. 
Opening sites quickly does not accelerate a trial if the protocol, patient pathway, biomarker strategy, or country plan cannot support enrollment. The decisions made before execution often determine how much time will be lost later.

2. Protocol complexity is an operational risk. 
Avoidable procedures, restrictive eligibility criteria, and unnecessary patient and site burden can narrow the enrollment funnel and increase the risk of amendments and downstream delays.

3. Feasibility should stress-test the clinical strategy. 
Site interest and historical enrollment are not enough. Sponsors need to understand whether sites can actually identify, screen, and enroll the intended patients given testing requirements, referral pathways, competing trials, and operational capacity.

4. Country and site sequencing should support the evidence strategy. 
The fastest countries to activate and the largest academic centers are not always the right first choices. Patient access, biomarker infrastructure, standards of care, site capability, and future regulatory use all need to inform sequencing.

5. Decision gates need the authority to change course. 
Sponsors should define early checkpoints that test whether the original assumptions are holding. When they are not, teams need to act before low enrollment or operational problems become embedded.

Speed Is More Than Site Start-UpMost oncology trial delays do not begin during site start-up. They begin earlier, when optimistic assumptions make it through protocol finalization.

Sponsors often talk about speed as if it means opening sites sooner, pressing sites to enroll more aggressively, or adding countries when recruitment falls behind. Those actions may become necessary, but they are not the same as true acceleration. The programs that move fastest are usually the ones that challenge key assumptions before execution begins.

A trial can activate sites quickly and still lose months because the protocol is too burdensome, the eligibility criteria are too narrow, the biomarker pathway is unrealistic, or the country sequence does not match where patients can actually be identified and treated. Activity may look like progress on a start-up tracker, but it is not progress when it produces low-yield sites, avoidable amendments, or rescue strategies that could have been anticipated.

The better question for sponsors is not, “How fast can we open?” It is, “Which decisions do we need to get right early to avoid losing time later?”

Oncology Enrollment Is Now a Competition for Capacity

Oncology development is operating in a more crowded and less forgiving environment. Recent literature has highlighted persistent under-enrollment and the growing density of recruiting oncology trials, particularly in molecularly defined populations.

That environment changes the meaning of feasibility. A site that appears strong in a database may already be saturated with competing studies. A country that has historically enrolled well may not have the testing infrastructure for a molecularly defined population. A top-tier academic center may have the right investigators but insufficient coordinator capacity. In precision oncology, the bottleneck is often the pathway between diagnosis, molecular testing, referral, consent, and treatment start—not simply biomarker prevalence.

Sponsors should therefore stop treating site activation as the primary measure of speed. The more meaningful measure is whether the first wave of countries and sites can reliably identify, screen, and enroll the intended patients under the protocol as written.

Under-enrollment is not merely a timeline issue. It can change the development path of an asset. A study that cannot identify enough eligible patients may require costly amendments, rescue countries, revised feasibility assumptions, or early closure before generating the evidence needed for the next investment or regulatory decision [1,2].

Protocol Complexity Is a Timeline Risk

Protocol complexity is one of the most predictable sources of downstream delay. Modern oncology studies are necessarily complex; the problem is avoidable complexity—procedures, visits, eligibility restrictions, exploratory endpoints, and data requirements that add burden without improving a development decision.

A 2024 Tufts CSDD analysis found that oncology protocols had a higher prevalence of amendments than non-oncology protocols (91.1% versus 72.1%). Oncology protocols also had a higher average number of amendments, 4.0 versus 3.0. Importantly, oncology protocols with amendments had lower participant completion rates than oncology protocols without amendments [3].

Some amendments are unavoidable: standards of care change, new safety information emerges, and biomarker strategies evolve. Others reflect issues that could have been challenged before protocol approval, including eligibility criteria that exclude too many patients, biopsy schedules that sites cannot support, imaging requirements that exceed local capacity, or exploratory endpoints that add work without influencing the asset’s next decision.

A 2025 BMC Medical Research Methodology paper developed a Protocol Complexity Tool spanning operational execution, regulatory oversight, patient burden, site burden, and study design. Its pilot analysis identified associations between protocol complexity and site-activation and enrollment metrics, although further validation is needed [4].

For sponsors, the implication is practical; the protocol is not only a scientific document; it is the operating model for the trial. When that operating model is overloaded, speed becomes expensive later.

Eligibility Criteria Define Enrolment Funnel

Eligibility criteria are designed to protect patient safety and preserve interpretability. Those objectives are essential, but criteria that do not reflect the treated population can quietly undermine both feasibility and generalizability.

A 2026 PLOS Digital Health analysis mapped real-world comorbidity profiles against exclusion criteria from 1,134 lung cancer trials. It found that exclusion patterns varied across racial and ethnic groups [5].

This is both an equity issue and an operational issue. When eligibility criteria exclude large portions of the real-world patient population, the enrollment funnel narrows before a site ever opens. Recruitment performance may then be blamed when the deeper problem is that the protocol describes patients participating sites rarely encounter.

For senior biotech teams, this is where medical, regulatory, operational, and commercial judgment must converge. A narrowly defined population may produce a cleaner early signal, but if it slows enrollment, increases amendments, and limits confidence in applicability, the program may lose more than it gains.

Feasibility Should Be a Stress Test, Not a Survey

Traditional feasibility still relies heavily on questionnaires, historical site performance, investigator estimates, and database-derived patient counts. These inputs are useful, but they are not sufficient for modern oncology development.

A stronger feasibility process asks whether the clinical strategy can survive real-world execution. Can patients be identified at the necessary point in their treatment journey? Is molecular testing routine or exceptional? Is tissue available? Will assay turnaround fit the treatment window? Do proposed sites have access to the right referral networks? Are competing studies targeting the same patient segment? Do sites have sufficient coordinator, pharmacy, imaging, and laboratory capacity?

The Reagan-Udall Foundation’s 2025 oncology Multi-Regional Clinical Trials (MRCT) report highlighted persistent challenges in site activation, start-up timelines, enrollment, staffing, trial complexity, technology burden, and budget negotiations [6].

Feasibility should therefore not be treated as a late-stage confirmation exercise. It should be a disciplined challenge to the protocol, patient pathway, country plan, and site assumptions while meaningful changes are still possible. The most useful output is not a long list of interested sites; it is a defensible explanation of which sites can identify, screen, and enroll the intended patients under the protocol as written.

Country Sequencing Is Now Part of Evidence Strategy

Country selection is sometimes treated primarily as an execution decision: activate familiar geographies first, add rescue countries later, and assume that more sites will solve the problem. In oncology, that approach is increasingly risky.

Country and site sequencing now shape the evidence package itself. The standard of care can vary by region. Biomarker testing availability can differ by country and institution. Tissue pathways may be mature in one geography and fragmented in another. Prior therapy exposure, supportive care, imaging practices, and referral patterns can all affect both enrollment and interpretation.

ICH E17 emphasizes that MRCTs should be planned and designed to increase their acceptability in global regulatory submissions [9]. This is not a technical regulatory point. It is a development strategy point. If a sponsor expects global relevance from a trial, country selection must support more than recruitment volume. It must support data credibility, endpoint interpretation, patient representativeness, and future regulatory use.

Opening the wrong countries quickly is not speed. It is deferred rework.

Where Novotech’s Execution Insight Creates Strategic Value

CRO expertise is most valuable while the protocol and development architecture can still change. A CRO engaged only after protocol finalization may be asked to execute around constraints that are already embedded; engagement at the synopsis or early-protocol stage creates an opportunity to test country roles, patient pathways, site capabilities, biomarker logistics, and operational burden before they become fixed commitments.

Recent Novotech oncology programs illustrate the mechanism. In one first-in-human mRNA immunotherapy program, a phased strategy allowed Australian initiation while regulatory approvals progressed in South Korea and Taiwan. In a separate Phase I/II advanced solid-tumor study, recruitment-focused feasibility, rapid ethics coordination, and investigator-fit site selection enabled first-patient enrollment within one week of site activation and enrollment beyond the original Australian target [10,11, 12].

These results should not be interpreted as universal timeline guarantees. Their value lies in the underlying approach: deliberate country sequencing, therapeutic alignment of investigators and sites, coordinated regulatory execution, and recruitment strategy embedded into feasibility from the outset. That is the distinction between speed as an isolated start-up metric and speed as earlier decision quality.

Sponsors Need Decision Gates Earlier

FDA’s 2024 final guidance on oncology dose optimization reinforces the direction of travel. Sponsors are expected to identify optimized dosages during clinical development before submitting an application for approval [7]. FDA’s 2025 final guidance on enhancing participation in clinical trials also recommends approaches to increase enrollment of representative populations in trials intended to support drug or biologics applications [8].

Together, these expectations make early oncology development less tolerant of loose assumptions. Dose strategy, eligibility, biomarker planning, patient representativeness, and operational feasibility can no longer be treated as separate workstreams. They interact.

Sponsors should establish operational decision gates before enrollment begins rather than waiting until underperformance becomes structural. Reviews should be tied to meaningful milestones, such as the initial screening experience, completion of the first dose-escalation cohort, first-wave site performance, or readiness to activate secondary countries. They should examine screen-failure reasons, biomarker yield, tissue adequacy, assay turnaround, eligibility performance, referral effectiveness, and whether the original country and site assumptions remain valid.

These checkpoints should have authority. They should be able to pause low-yield sites, redirecting recruitment support, adjusting country sequence, simplifying workflows, or initiating a protocol change before delay becomes embedded.

What Sponsors Should Do Differently

First, involve medical, regulatory, feasibility, and operational expertise at the synopsis stage—not only after the protocol has been finalized.

Second, treat protocol burden as a development risk. Every procedure should have a purpose, every visit should justify its burden, and every exploratory endpoint should be evaluated according to whether it could realistically change a clinical, regulatory, or portfolio decision.

Third, sequence countries and sites according to evidence value rather than familiarity or headline start-up speed. The strongest first countries are not always those with the shortest contracting timelines, and the most productive sites are not always the largest academic institutions.

Fourth, establish predefined decision gates with the authority to act. A program should not wait several months to learn that its biomarker assumptions, eligibility criteria, patient pathway, or country strategy are not working.

The Real Meaning of Speed

Oncology sponsors are under pressure to move quickly. Capital is selective, competition is intense, and patients cannot wait. Yet urgency is not the same as acceleration.

Avoidable delay affects cash runway, investor confidence, partnering leverage, competitive positioning, and the credibility of the next go/no-go decision. A preventable amendment, a country strategy requiring rescue, or a site network that opens without patients not only consumes time; it consumes strategic flexibility.

The fastest oncology programs are not the ones that ask sites to absorb more burden or force a flawed plan through execution. They are the programs that create earlier truth, remove avoidable complexity, and make the hard decisions while there is still time to change course.

Going faster is not about making the start-up tracker look better. It is about preventing the avoidable months that come later: fewer unnecessary amendments, better capital efficiency, stronger go/no-go confidence, and a more credible global evidence package.

For sponsors, that is the real speed advantage. For Novotech, it is where execution insight becomes strategic value.

References

[1] ASCO. “Galleri Early Detection Test May Shift Timing of Cancer Detection.” 2026. (ASCO)

[2] Horgan D, Paulson JN, Loaiza-Bonilla A, et al. “A unified framework for pre-screening and screening tools in oncology clinical trials.” npj Precision Oncology. 2026. (Nature)

[3] Botto E, Smith Z, Getz K. “New Benchmarks on Protocol Amendment Experience in Oncology Clinical Trials.” Therapeutic Innovation & Regulatory Science. 2024. (Springer)

[4] Willigers BJA, Wiesiolek AE, Potter B, et al. “Development of a protocol complexity tool: a framework designed to stimulate discussion and simplify study design.” BMC Medical Research Methodology. 2025. (Springer)

[5] Kim JY, Dirks A, Ford RM, et al. “How exclusion criteria can hinder eligibility for lung cancer studies among different racial and ethnic groups.” PLOS Digital Health. 2026. (PLOS)

[6] Reagan-Udall Foundation for the FDA. “Improving Oncology Multi-Regional Clinical Trials.” 2025. (Reagan-Udall Foundation)

[7] U.S. Food and Drug Administration. “Optimizing the Dosage of Human Prescription Drugs and Biological Products for the Treatment of Oncologic Diseases.” Final Guidance for Industry. 2024. (U.S. Food and Drug Administration)

[8] U.S. Food and Drug Administration. “Enhancing Participation in Clinical Trials — Eligibility Criteria, Enrollment Practices, and Trial Designs.” Final Guidance for Industry. 2025. (U.S. Food and Drug Administration)

[9] International Council for Harmonisation / European Medicines Agency. “ICH Guideline E17 on General Principles for Planning and Design of Multi-Regional Clinical Trials.” (European Medicines Agency (EMA))

[10] Novotech. “APAC: From Trial Site to Global Oncology Launchpad.” 2026. (novotech-cro.com)

[11] Novotech. “Accelerating FIH mRNA Immunotherapy Trials Across APAC.” Case Study. April 20, 2026. (Novotech CRO)

[12] Novotech. “Accelerating Phase I/II Oncology Start-Up and Recruitment in Australia.” Case Study. May 14, 2026. (Novotech CRO)