Reducing Protocol Deviations in IRD Ophthalmology Trials Through Criticality Checklists and Escalation Pathways

Protocol deviations in inherited retinal disease (IRD) ophthalmology trials represent a multifaceted operational challenge threatening participant safety and primary endpoint data integrity (Getz, 2011; Cilley, 2025). These deviations span imaging acquisition, functional testing, investigational product handling, and visit scheduling. Unlike conventional pharmacological trials, IRD gene therapy involves irreversible surgical interventions where deviations cannot be recovered through repeat visits (Russell, 2017).

This article presents a comprehensive framework for classifying protocol deviation types in IRD trials and identifies strategic intervention points enabling proactive prevention through structured pre-visit preparation and real-time escalation protocols.

The Procedure Criticality Checklist (PCC) system applies risk-based monitoring principles (International Council for Harmonization, 2023) by severity and implementing targeted prevention mechanisms. The framework integrates evidence from surgical safety science (Haynes, 2009), quality-by-design methodology (TransCelerate Biopharma, 2023), IRD trial operations literature (Thompson, 2020).

The framework comprises: (1) a deviation taxonomy, (2) criticality-stratified pre-visit checklists, (3) tiered escalation pathways with predefined decision authorities, and (4) electronic integration mechanisms real-time monitoring.

Implementation is anticipated to reduce preventable deviations, improve data integrity, strengthen regulatory submissions, and accelerate approval timelines for ATMP ophthalmology programs.

This framework addresses a critical gap in IRD trial operations by providing standardized, operationalizable deviation prevention methodology suitable for adoption across national research networks (Igoe, 2024).

advanced therapy medicinal products, clinical trial management systems, deviation taxonomy, inherited retinal disease, procedure criticality checklist, protocol deviations, pre-visit checklists, procedural complexity, quality by design, real-time escalation, risk-based monitoring, risk-based quality management

Chodankar D. (2023). Impact of protocol deviations on the clinical study. Perspectives in clinical research, 14(2), 47–48. https://doi.org/10.4103/picr.picr_69_23

Borchard, A., Schwappach, D. L., Barbir, A., & Bezzola, P. (2012). A systematic review of the effectiveness, compliance, and critical factors for implementation of safety checklists in surgery. Annals of surgery, 256(6), 925–933. https://doi.org/10.1097/SLA.0b013e3182682f27

Thompson, D. A., Iannaccone, A., Ali, R. R., Arshavsky, V. Y., Audo, I., Bainbridge, J. W. B., Besirli, C. G., Birch, D. G., Branham, K. E., Cideciyan, A. V., Daiger, S. P., Dalkara, D., Duncan, J. L., Fahim, A. T., Flannery, J. G., Gattegna, R., Heckenlively, J. R., Heon, E., Jayasundera, K. T., Khan, N. W., … Monaciano Consortium (2020). Advancing Clinical Trials for Inherited Retinal Diseases: Recommendations from the Second Monaciano Symposium. Translational vision science & technology, 9(7), 2. https://doi.org/10.1167/tvst.9.7.2

Daiger, S. P., Sullivan, L. S., & Bowne, S. J. (2013). Genes and mutations causing retinitis pigmentosa. Clinical genetics, 84(2), 132–141. https://doi.org/10.1111/cge.12203

Nuzbrokh, Y., Kassotis, A. S., Ragi, S. D., Jauregui, R., & Tsang, S. H. (2020). Treatment-Emergent Adverse Events in Gene Therapy Trials for Inherited Retinal Diseases: A Narrative Review. Ophthalmology and therapy, 9(4), 709–724. https://doi.org/10.1007/s40123-020-00287-1

European Medicines Agency. (2022). Guideline on quality, non-clinical and clinical aspects of gene therapy medicinal products. EMA/CHMP/BWP/671639/08.

European Medicines Agency. (2023). Guideline on computerised systems and electronic data in clinical trials. EMA/CHMP/ICH/109947/2022.

Getz, Kenneth & Campo, Rafael & Kaitin, Kenneth. (2011). Variability in Protocol Design Complexity by Phase and Therapeutic Area. Drug Information Journal - DRUG INF J. 45. 413-420. 10.1177/009286151104500403.

Haynes, A. B., Weiser, T. G., Berry, W. R., Lipsitz, S. R., Breizat, A. H., Dellinger, E. P., Herbosa, T., Joseph, S., Kibatala, P. L., Lapitan, M. C., Merry, A. F., Moorthy, K., Reznick, R. K., Taylor, B., Gawande, A. A., & Safe Surgery Saves Lives Study Group (2009). A surgical safety checklist to reduce morbidity and mortality in a global population. The New England journal of medicine, 360(5), 491–499. https://doi.org/10.1056/NEJMsa0810119

Igoe, J. M., Lam, B. L., & Gregori, N. Z. (2024). Update on Clinical Trial Endpoints in Gene Therapy Trials for Inherited Retinal Diseases. Journal of clinical medicine, 13(18), 5512. https://doi.org/10.3390/jcm13185512

International Council for Harmonization. (2023). ICH E6(R3) guideline for good clinical practice (GCP). ICH Steering Committee.

Lacy, G. D., Abalem, M. F., Musch, D. C., & Jayasundera, K. T. (2020). Patient-reported outcome measures in inherited retinal degeneration gene therapy trials. Ophthalmic Genetics, 41(1), 1–6. https://doi.org/10.1080/13816810.2020.1731836

Yang, Y., & Dunbar, H. (2021). Clinical Perspectives and Trends: Microperimetry as a Trial Endpoint in Retinal Disease. Ophthalmologica. Journal international d'ophtalmologie. International journal of ophthalmology. Zeitschrift fur Augenheilkunde, 244(5), 418–450. https://doi.org/10.1159/000515148

Cilley, K. N., Kaliaev, A. O., & Malikova, M. A. (2025). Impact of Protocol Amendments, Personnel Experience and Social Determinants of Health on Study Protocol Adherence in Clinical Trials with Combination Products. Therapeutic innovation & regulatory science, 59(6), 1506–1515. https://doi.org/10.1007/s43441-025-00859-y

Russell, S., Bennett, J., Wellman, J. A., Chung, D. C., Yu, Z. F., Tillman, A., Wittes, J., Pappas, J., Elci, O., McCague, S., Cross, D., Marshall, K. A., Walshire, J., Kehoe, T. L., Reichert, H., Davis, M., Raffini, L., George, L. A., Hudson, F. P., Dingfield, L., … Maguire, A. M. (2017). Efficacy and safety of voretigene neparvovec (AAV2-hRPE65v2) in patients with RPE65-mediated inherited retinal dystrophy: a randomised, controlled, open-label, phase 3 trial. Lancet (London, England), 390(10097), 849–860. https://doi.org/10.1016/S0140-6736(17)31868-8

TransCelerate BioPharma. (2023). Protocol deviations initiative: Framework for classification and reporting. TransCelerate BioPharma Working Group Report.

Tuohy, G. P., & Megaw, R. (2021). A Systematic Review and Meta-Analyses of Interventional Clinical Trial Studies for Gene Therapies for the Inherited Retinal Degenerations (IRDs). Biomolecules, 11(5), 760. https://doi.org/10.3390/biom11050760

US Food and Drug Administration. (2023). Oversight of clinical investigations—a risk-based approach to monitoring: Guidance for industry. FDA Center for Drug Evaluation and Research.

Taylor, L. J., Josan, A. S., Stratton, I., Jolly, J. K., & MacLaren, R. E. (2023). A cross-sectional study to assess the clinical utility of modern visual function assessments in patients with inherited retinal disease: a mixed methods observational study protocol. BMC ophthalmology, 23(1), 234. https://doi.org/10.1186/s12886-023-02974-6