Clinical Trial Compliance Challenges and How to Overcome Them

In the fast-paced world of clinical research, regulatory compliance is both a foundation and a frequent stumbling block. From delayed ethics approvals to inconsistent documentation, compliance gaps can derail timelines, compromise data integrity, and undermine participant trust.

At Rubix LS, we see compliance not as a constraint, but as a strategic enabler, when combined with equity and inclusive design, it drives faster approvals, safer trials, and stronger outcomes.

Here’s how to identify and overcome the most common compliance pitfalls in clinical trials.

1. Delayed IRB or Ethics Committee Approvals

The Challenge:

The review and approval processes of Institutional Review Boards (IRBs) or Ethics Committees (ECs) are essential to participant protection and regulatory compliance, yet they frequently become bottlenecks.

Factors include incomplete or late submissions, overlapping contract and budget issues, site-specific IRB reviews for multi-site or international trials, and lack of integration between feasibility/site-selection and IRB processes.

For example, one review of global randomized clinical trials identified regulatory, contracts/budgets, site activation and inefficient processes as key drivers of start-up delays.

Delayed IRB approval not only extends timelines but also raises ethical concerns because patients may have to wait for access to investigational therapies.

Rubix LS Insight:

At Rubix LS, our regulatory strategy and innovation team builds early regulator engagement into the trial-readiness phase, harmonizing documentation across jurisdictions to accelerate submission cycles.

In one global oncology Phase II program, this pre-submission and aligned ethics approach cut IRB hold-ups by ~35 %, enabling first-patient-in six weeks earlier than forecast.

As discussed in our publication Optimizing Clinical Trial Design for Quicker FDA Approval, engaging ethics bodies at the protocol-development stage ensures regulatory alignment, reduces amendments, and sets a transparent compliance roadmap from day one.

How to Overcome It:

• Plan IRB/EC submissions in parallel with contracts/budgets and site feasibility rather than sequentially.

• Use a project timeline with fixed deliverables for ethics submission, expected review time, and contingencies.

• Choose CRO or partner organizations with ethics-review expertise.

• Streamline submission documents: full checklists, templates, translations prepared early.

• Monitor review status weekly, engage with IRB/EC proactively to anticipate queries, and build plan B sites if approval delays exceed thresholds.

2. Non-Representative or Inequitable Patient Recruitment

The Challenge:

Despite decades of discussion, diversity gaps persist. A review analysis revealed that fewer than one in five U.S. trial participants were from Black, Hispanic, or Indigenous backgrounds, despite higher disease prevalence in these groups. The review attributed these gaps to limited researcher diversity, underfunded trial sites in minority communities, and a lack of culturally tailored recruitment strategies, reinforcing that inclusive engagement and accessible trial design are critical to achieving equitable, generalizable outcomes.

Limited representation not only hinders generalizability but also risks non-compliance with FDA’s Diversity Action Plan and FDORA 2022.

Rubix LS Insight

Rubix LS’s Equity-by-Design recruitment framework leverages an 20 M+ patient dataset with 96.9% diverse representation. By integrating AI-driven analytics in the Patient X platform, we improved participant representativeness by more than 25% in oncology and metabolic-disease studies.

As detailed in Redesigning Clinical Trials for Real-World Patient Representation, inclusive recruitment strategies produce more credible data and meet both ethical and regulatory expectations.

How to Overcome It

• Define diversity targets during protocol development.

• Partner with community health centers and advocacy networks.

• Apply AI analytics to identify underrepresented cohorts.

• Track diversity metrics continuously and adjust mid-trial.

  
  

3. Inadequate Site Monitoring and Oversight

The Challenge:

Site monitoring is central to ensuring GCP adherence, patient safety, and data accuracy. However, traditional on-site models often struggle to scale efficiently in decentralized or global studies.

A joint analysis by the U.S. FDA and European Medicines Agency reviewing 55 shared marketing applications between 2009 and 2015 found that both agencies conducted over 430 GCP inspections across 47 countries, with similar timelines and oversight outcomes. The study demonstrated that most clinical investigator inspections occurred outside the agencies’ home regions, underscoring the globalized nature of trial oversight and the growing importance of coordinated, risk-based monitoring strategies.

As decentralized trial models continue to expand, sponsors must adapt oversight frameworks to detect and resolve deviations in real time rather than retrospectively.

Rubix LS Insight

Rubix LS addresses this challenge by applying risk-based monitoring (RBM) integrated with centralized QA dashboards across 45 U.S. and 30 international sites. Our network uses predictive analytics through the Patient X platform to identify anomalies early, achieving a 28% reduction in protocol deviations and 32% faster issue resolution.

As explored in How Decentralized Trials Are Redefining Oversight and Compliance, data-driven monitoring frameworks not only streamline operations but also elevate regulatory readiness and participant protection.

How to Overcome It

• Design monitoring plans around RBM principles, focusing oversight on high-impact endpoints.

• Use centralized dashboards for remote and on-site data review.

• Implement early-warning analytics for deviation trends.

• Conduct continuous CRA training for decentralized-trial risk indicators.

4. Poor Documentation and Audit Readiness

The Challenge:

Documentation remains the backbone of regulatory compliance. Yet, in digital environments, gaps in validation, version control, or audit trails frequently lead to inspection findings. A Journal of Pharmaceutical Innovation (2024) study analyzing FDA enforcement trends found a 43% increase in warning letters issued per 100 inspections between 2019 and 2023, reflecting heightened scrutiny of documentation, data integrity, and audit-trail consistency across regulated studies.

Much of this increase was linked to fragmented eTMFs, incomplete metadata, and deficiencies in maintaining contemporaneous records, issues that continue to represent a major source of FDA Form 483 observations and inspection citations.

Incomplete documentation doesn’t just delay submissions, it undermines the credibility of the entire study record.

Rubix LS Insight

Rubix LS ensures inspection-readiness through its quality assurance and compliance framework, which integrates validated eCRF and eTMF systems compliant with 21 CFR Part 11 and incorporates automated versioning, access logs, and continuous GCP training.

How to Overcome It

• Adopt validated electronic systems with built-in audit-trail capabilities.

• Automate document versioning and permission controls.

• Conduct quarterly mock audits and close gaps proactively.

• Link documentation performance metrics to team KPIs.

5. Insufficient Training on Evolving Regulations

The Challenge:

Regulatory frameworks are evolving rapidly as ICH E6 (R3), GDPR, decentralized-trial guidance, and real-world-evidence frameworks all demand continual adaptation. An analysis found that inspection findings were linked to inadequate staff training or outdated SOPs, underscoring that human factors remain a leading cause of non-compliance.

The study emphasized that as trials grow more globalized and complex, maintaining quality depends on robust systems defining personnel roles, standardized procedures, and continuous education. To address these gaps, the FDA has advanced initiatives such as risk-based and real-time inspections and partnerships through the Clinical Trials Transformation Initiative to strengthen quality management and oversight across sponsors and CROs.

Without structured, ongoing education, even well-designed studies risk non-compliance.

Rubix LS Insight

Rubix LS fosters structured training programs that embed Good Clinical Practice (GCP), diversity and inclusion awareness, data-privacy standards, and patient-centered design principles into everyday operations. This proactive approach ensures teams remain current with evolving regulations and best practices, significantly reducing training-related errors and improving inspection outcomes.

By encouraging regular feedback and knowledge sharing, Rubix LS demonstrates how a learning-driven compliance culture enhances both operational agility and quality across the clinical research lifecycle.

How to Overcome It

• Implement recurring, role-specific GCP and data-privacy training.

• Extend programs to vendors and partner CROs.

• Link site activation to completion of compliance modules.

• Encourage leadership accountability for continuous learning.

6. Missing or Inadequate Consent Form Translations

The Challenge:

Informed consent is the ethical foundation of every trial. Yet, poor or missing translations remain one of the most common audit findings. Regulators frequently reject data when participants cannot demonstrate understanding. Digital and hybrid consent models add further complexity, requiring validation of comprehension, e-signature traceability, and accessibility for low-literacy populations.

For example, ethics committees recommend back translation of ICFs to ensure meaning is preserved across languages.

Without proper translation workflows, sponsors risk not only regulatory findings but also participant distrust and higher dropout rates.

Rubix LS Insight:

Our decentralized Patient X platform supports e-consent, comprehension checks, and full audit trails. In Global Clinical Trials: How to Navigate Key Federal Compliance Requirements, Rubix LS shows how early language validation and culturally aligned communication improved participant retention and regulator satisfaction.

How to Overcome It

• Use certified life-science translators and back-translation validation.

• Deploy multilingual e-consent systems with audit-trail capture.

• Engage local ethics boards and community representatives for linguistic review.

• Document translation processes and comprehension testing within the Trial Master File, a comprehensive collection of essential documents for a clinical trial that demonstrates compliance with regulations and Good Clinical Practice (GCP).

How to Build Compliance into Success

Before

Too often, compliance is treated as a reactive function, a series of corrective steps taken only after audits, inspection findings, or recruitment challenges arise. This mindset slows progress, inflates costs, and erodes trust among regulators and participants. Without early planning, coordinated partners, or trained teams, trials risk becoming fragmented operations rather than cohesive, quality-driven studies.

After

When compliance is embedded from the start, it becomes a driver of speed, quality, and inclusivity.

• Plan early: Integrate compliance into your project timeline from day one.

• Choose the right partners: Work with CROs that prioritize regulatory alignment and patient inclusion.

• Leverage technology: Use e-consent, eCRF, and monitoring tools for audit-ready documentation.

• Design for diversity: Inclusive recruitment isn’t just ethical, it enhances data relevance.

• Train continuously: Regular GCP and local regulation training keeps teams aligned and confident.

With these principles in place, sponsors transform compliance from an obligation into an operational advantage, accelerating timelines, strengthening data integrity, and ensuring every study reflects the real-world patients it aims to serve.

For a deeper exploration of how proactive regulatory planning drives measurable outcomes, read our companion article, How Regulatory Compliance for Clinical Trials Drives Better Outcomes.

Turning Compliance into a Catalyst

Every compliance challenge, from documentation gaps to inequitable recruitment, is an opportunity to reinforce scientific credibility and operational excellence.

With Rubix LS’s global regulatory expertise, decentralized infrastructure, and AI-integrated patient data covering 20 million + records, sponsors can transform compliance into a measurable differentiator: faster approvals, cleaner data, and more representative outcomes.

Because at Rubix LS, compliance isn’t a checkbox, it’s the compass guiding research toward equity, integrity, and real-world impact.

Partner with us to build trials that are not only compliant, but also inclusive, data-driven, and designed for lasting change.

Let’s redefine what compliant, patient-centered research looks like, together. Contact Rubix LS to start your partnership today.