Empowering Research-Naïve PIs for Complex and Advanced Therapeutic Trials

Clinical Researcher—April 2026 (Volume 40, Issue 2)

INSIGHTS ON INVESTIGATORS

Rachana Kanvinde, MS, SFC, CCRP

 

Complex and advanced therapeutic clinical trials, including those for cell and gene therapy, rare diseases, and precision medicine, are advancing at an unprecedented pace and reshaping therapeutic possibilities for conditions once considered untreatable. However, the success of these studies depends heavily on a capable and adequately trained investigative workforce. One key yet often underdeveloped component of this workforce is the research-naïve principal investigator (PI)—a clinician who possesses the medical expertise required to oversee a study but lacks substantial experience in clinical trial leadership as they enter their first such experience. Providing structured onboarding, education, and ongoing support for these untested PIs is fundamental for strengthening clinical research capacity, ensuring patient safety, and maintaining high-quality study conduct across sites.{1,2}

With the increasing complexity and volume of studies, the demand for qualified investigators continues to grow. The clinical research enterprise cannot rely solely on seasoned PIs, as turnover rates, geographic limitations, and expanding pipelines create ongoing gaps in site readiness. Therefore, empowering research-naïve PIs is not simply an operational consideration but a strategic necessity for sustaining the clinical research ecosystem.

The Expanding Need for New Investigators in Complex and Advanced Therapeutics

While rare disease research highlights these challenges acutely, similar workforce and operational demands exist across complex therapeutic areas such as cell and gene therapy, immuno-oncology, and precision medicine. Rare diseases often affect fewer than 200,000 individuals in the United States, yet collectively impact an estimated 30 million people.{1} Most of these conditions have genetic origins, which has fueled growth in advanced therapeutic approaches such as gene therapy, genome editing, and RNA-based therapeutics. As of 2023, more than 2,000 regenerative medicine and gene therapy programs were in various stages of development, with an increasing number advancing into clinical phases each year.{3}

This rapid expansion has intensified the need for investigators with specialized knowledge, research competency, and operational support. However, many clinicians such as neurologists, hematologists, immunologists, and geneticists with relevant expertise have limited exposure to research roles due to institutional barriers, lack of mentorship, or limited awareness of pathways into PI positions.

Engaging research-naïve PIs expands opportunities for sites to participate in complex research, increases geographic accessibility for patients, diversifies the pool of investigators, and enhances the capacity of the broader research workforce. Without purposeful pathways to develop new investigators, the clinical trial ecosystem risks bottlenecks that limit patient access and slow scientific advancement.

Challenges Commonly Faced by Research-Naïve PIs

Although brand new PIs bring deep clinical expertise to the table, they often encounter predictable challenges as they navigate unfamiliar research responsibilities:

• Regulatory Knowledge Gaps: PIs and their research staff need to understand such regulatory frameworks as the guideline for Good Clinical Practice (GCP) embodied in International Council for Harmonization (ICH) E6(R3) and recognize that adhering to established tenets for human subjects protection requires structured training and reinforcement.{4} Without proper onboarding, research-naïve PIs may face uncertainty in interpreting oversight requirements, managing protocol deviations, or fulfilling safety reporting obligations.
• Operational Complexity: Complex and advanced therapeutic protocols involve intricate logistics, including chain-of-identity and chain-of-custody requirements, specialized laboratory handling, extended long-term follow-up periods, and coordination across multidisciplinary teams. Research-naïve investigators may have limited familiarity with investigational product accountability, courier logistics, environmental monitoring, or cell-processing workflows.{5,6}
  These challenges are often compounded by limited clarity between site management and site oversight responsibilities. While site management encompasses the execution of day-to-day operational activities, site oversight reflects the PI’s accountability for study conduct, participant safety, and data integrity. Without clear role definition, untested PIs may become overextended by operational demands, reducing their ability to maintain effective oversight. Explicitly addressing this distinction during onboarding supports investigator effectiveness and strengthens overall study quality.
  Further discussion of the distinction between site management and site oversight has been explored in a published thought leadership piece addressing oversight responsibilities in complex research environments.{7}
• Limited Research Infrastructure Knowledge: Many clinicians have limited exposure to core research infrastructure, including institutional review boards (IRBs), regulatory coordination processes, research pharmacy operations, and clinical data management systems. Without a foundational understanding of these components, research-naïve PIs may encounter challenges in providing effective study leadership and oversight.
• Lack of Mentorship: Limited access to experienced PIs remains a significant barrier for new investigators. Without mentorship, research-naïve PIs may have reduced confidence in decision-making and limited familiarity with established best practices for regulatory compliance, study oversight, and sponsor engagement.{8}
• Clinical Demands: High clinical workloads and administrative responsibilities can restrict the time clinicians are able to dedicate to research activities. In the absence of strong operational and team-based support, the scope of PI responsibilities may become difficult to manage effectively.

Addressing these barriers proactively is essential to developing a confident and capable generation of investigators equipped to meet the growing demands of complex clinical research.

Strategies to Onboard and Empower Research-Naïve PIs

Effective onboarding and development programs enable untested PIs to transition successfully into research leadership roles.

Key strategies include:

• Structured PI Orientation Programs: Programs should introduce investigators to GCP principles, responsibilities outlined in the Form FDA 1572 from the U.S. Food and Drug Administration, institutional workflows, reporting expectations, and key study milestones. Providing clear guidance early in the onboarding process helps reduce ambiguity and strengthens oversight quality.{9,10}
• Role-Specific Education for Complex and Advanced Therapeutic Research: Research teams should undergo targeted training tailored to the therapeutic modality, for example gene therapy–specific considerations such as vector safety, long-term follow-up, environmental and biosafety requirements, and patient-specific handling procedures. This education helps ensure investigators understand the ethical and operational obligations unique to complex and advanced therapies.{2,6}
• Mentorship and Peer Support: Pairing research-naïve PIs with experienced investigators strengthens competency and facilitates real-world learning. Effective mentorship supports investigator retention, builds confidence, and fosters a culture of shared responsibility and continuous learning.{8}
• Operational Alignment and Support: Research coordinators, regulatory specialists, and pharmacists serve as essential partners to PIs. Clear delegation of responsibilities, regular communication, and shared review of study metrics help research-naïve PIs gain clarity on site workflows, roles, and performance expectations.
• Utilization of Tools and Checklists: Tools such as protocol readiness checklists, safety reporting guides, and workflow diagrams help reduce cognitive burden and promote consistency across study activities. Visual aids are particularly valuable in complex and advanced therapeutic studies, including gene therapy, where processes may differ significantly from traditional clinical trials.
• Continuous Feedback Systems: Regular check-ins and structured feedback help research-naïve PIs identify opportunities for improvement and reinforce existing strengths. Ongoing communication loops support continuous development and sustained alignment with study goals.

Why This Matters for Site Capacity and Workforce Sustainability

Investing in research-naïve PIs contributes directly to the resilience, scalability, and long-term sustainability of the clinical research ecosystem in the following ways:

• Enhanced Patient Access: Expanding the number of qualified PIs increases research opportunities for patients, particularly in geographically underserved and specialty care settings, thereby improving access to clinical trials.{11,12}
• Improved Study Quality: Studies led by well-prepared investigators demonstrate stronger adherence to protocols, fewer deviations, and improved data integrity, supporting overall study quality and regulatory compliance.{13,8}
• Stronger Workforce Pipeline: In the context of a global shortage of experienced investigators, structured onboarding and development of research-naïve PIs helps replenish the investigator workforce and supports the long-term sustainability of clinical research programs.{14,13}
• Readiness for Advanced Modalities: As complex and advanced therapeutic programs including gene therapy continue to expand, sites require investigators who understand the operational, regulatory, and oversight demands of these studies. Empowering research-naïve PIs ensures that sites remain prepared, competitive, and capable of supporting innovative clinical research.{3,6}

Conclusion

Onboarding and empowering research-naïve PIs is a critical strategy for expanding research capacity, improving patient access, and supporting the accelerating demands of complex and advanced therapeutic clinical trials, including rare diseases, gene therapy, and precision medicine research. By investing in structured training, mentorship, and operational infrastructure, organizations can cultivate investigators who demonstrate strong oversight, regulatory accountability, and integrity in clinical conduct.

Preparing the next generation of PIs ensures that the clinical research enterprise remains resilient, sustainable, and capable of delivering innovative therapies to the patients who need them most.

References

1. National Institutes of Health (NIH). 2024. Genetic and Rare Diseases (GARD) Information Center.
2. U.S. Food and Drug Administration (FDA). 2023. Human Gene Therapy for Rare Diseases.
3. Alliance for Regenerative Medicine (ARM). 2023. Sector Report.
4. International Council for Harmonization (ICH). 2023. ICH E6(R3) Guideline.
5. Highfill, et al. 2021. Journal of Gene Medicine.
6. Makhlouf, et al. 2023. Molecular Therapy.
7. Kanvinde R. 2024. Site Management and Oversight Become Must-Haves for Successful Sites. Clinical Leader. https://www.clinicalleader.com/doc/site-management-and-oversight-become-must-haves-for-successful-sites-0001
8. Dombernowsky, et al. 2021. Clinical Trials.
9. Clinical Trials Transformation Initiative (CTTI). 2020. Investigator Qualification Recommendations.
10. Association of Clinical Research Professionals (ACRP). 2022. Workforce Competency Guidelines.
11. National Organization for Rare Disorders (NORD). 2022. Rare Disease Clinical Trial Challenges.
12. Rare Diseases Clinical Research Network. 2023. Access Expansion Report.
13. Getz K, et al. 2020. Applied Clinical Trials.
14. Tufts Center for the Study of Drug Development. 2021. Investigator Turnover Analysis.

Rachana Kanvinde, MS, SFC, CCRP, is a senior clinical research leader with more than 20 years of experience advancing site excellence across complex and advanced therapeutic areas, including rare disease, gene therapy, and oncology. As Director of Clinical Trial Access & Partnerships at Tigerlily Foundation, she leads initiatives that integrate patient advocacy with clinical trial operations to expand access and advance equitable participation in research. A specialist in site oversight, clinical operations governance, and scalable models that align regulatory expectations with real-world execution, she also serves as President of the ACRP Atlanta Area Chapter and contributes to thought leadership on site excellence, accountability, and workforce development.