Clinical Trial Start-Up: The Drivers, the Challenges, and What It Really Takes to Get It Right

Clinical trial start-up is one of the most underestimated phases of drug development, and one of the most consequential. In fact, a study’s success is often determined long before the first patient is enrolled.

For complex studies, particularly global Phase 3 programs, the start-up period is where strategic planning, operational discipline, and tight cross-functional collaboration either come together … or fall apart. Sponsors, Clinical Research Organization (CRO) partners, service providers, and investigator sites must operate as a unified team. When they don’t, timelines slip, budgets stretch, and enrollment suffers.

Below, we break down the key drivers of clinical trial start-up, the challenges that frequently stall progress, and what sponsors and CROs can do to build a predictable, efficient start-up process.

1. Site and Country Strategy: Getting the Foundation Right

Everything in start-up builds on the site and country selection plan. Establishing a qualified site list, developing clear site selection criteria, and crafting a targeted feasibility questionnaire are the first major inflection points in any study.

But this process is rarely straightforward.

• Incomplete feasibility responses. Sites often receive questionnaires before a full protocol is available, which leads to missing or non-specific enrollment projections or operational details
• Confidentiality Agreement (CDA) delays. Without executed CDAs, sites can’t access relevant study documents. Master CDAs, when used, streamline this significantly.
• Unnecessary Site Qualification Visits (SQVs). If a site has been audited, monitored, or activated within the past 12 months without performance issues, an SQV can usually be waived, saving time without compromising quality.
• Limited availability of high-performing sites. Especially for emerging sponsors, it’s not always possible to select sites with whom the CRO or Sponsor has a successful track record.
• Operational variability at the investigator level. Staff turnover, competing studies, resource constraints, and inexperience in the indication all contribute to feasibility uncertainty.

Ultimately, the Sponsor makes the final decision on site and country selection. But that decision must be informed by accurate data, realistic enrollment assumptions, and a history of site performance, something too many start-ups still lack.

2. Site Activation: Where Delays Multiply Quickly

Site activation is often the phase where timelines derail. Even when feasibility is strong, activation delays can cascade across the program.

Key barriers include:

• Clinical supplies not on site in time for activation.
• Concurrent protocol amendments, which prevent sites from activating until earlier versions are resolved.
• Inexperienced or understaffed sites requiring additional training or oversight.
• Contract and budget delays, especially when Sponsors or CROs can’t leverage prior Clinical Trial Agreement (CTA) language.
• Slow or complex internal legal reviews at either the site or Sponsor level.

Using common CTA templates, escalating obstacles early, and maintaining a disciplined activation readiness process helps reduce these delays but it requires proactive coordination.
And there’s a human element: extended start-up delays can cause sites to lose interest, shift priorities, or experience changes in standard of care that affect recruitment. That risk is often overlooked.

3. Clinical Trial Insurance: A Hidden Driver of Timeline Risk

Insurance is a mandatory requirement in most global trials and yet it’s frequently one of the least predictable components of start-up.

Challenges often include:

• Missing or incomplete information required for the application.
• Country-specific requirements for indemnification, limits, and documentation.
• Translations that add days or weeks to timelines.
• Lengthy turnaround times from insurers or local brokers.
• Countries that require local insurance brokers, adding another layer of coordination.

When insurance is required for regulatory submission, any delay here pushes the entire program back. Working with an experienced global broker is essential. It prevents issues that derail timelines more often than most Sponsors realize.

4. Clinical Supplies: A Critical Path in Global Studies

Supply chain issues can have a disproportionate impact on study activation and long-term execution.

Common delays include:

• Labeling updates that lag behind protocol changes.
• Regulatory updates that affect packaging or distribution.
• Import license delays, especially in emerging regions.
• Customs holdups that slow shipment to depots or sites.
• Start-up delays that allow IP to expire, requiring relabeling or replacement.

Ensuring depots are adequately stocked, monitoring expiry windows closely, and aligning regulatory and supply timelines early all mitigate these risks.

5. Service Provider Readiness: Ensuring Every Piece Is in Place

Central labs, imaging vendors, electronic Clinical Outcome Assessment (eCOA) providers, and other partners must be fully aligned before activation.

Some of the top issues include:

• Lab kits not being ready on time.
• Caser Report Form (CRF) finalization delays or poorly designed CRFs that require rework.
• Lack of clarity on data flow, reconciliation requirements, or sample logistics.

A delay from a single provider can halt activation across multiple countries. Coordinated vendor management with accountability is non-negotiable.

6. Regulatory and Ethics Approvals: Managing Variability Across Countries

Global studies require precise tracking of each country’s regulatory and ethics committee timelines and those timelines vary dramatically.

Challenges include:

• Infrequent ethics meetings that extend review cycles.
• Slow translation processes for protocols, Investigators Brochures (IBs), and patient materials.
• Sites relying on local ethics committees with long lead times.
• Approval dependencies, where certain submissions cannot occur until other start-up components are complete.
• Country-specific amendments required before first-patient-in.
• Review clocks that pause due to holidays or incomplete documentation.

Regulatory start-up is rarely linear. It’s a deeply interdependent part of the process and misalignment here can ripple across the entire study.

Final Thoughts: Start-Up Is a Discipline — Not a Checklist

Start-up isn’t simply a series of tasks. It’s a discipline grounded in planning, communication, and foresight. It requires scientific understanding, regulatory awareness, operational agility, and an ability to anticipate issues before they surface.

When you get start-up right, you protect timelines, budgets, enrollment, and, most importantly, patients’ access to potentially life-changing therapies.