Introduction: A research site's actual readiness to run an oncology clinical trial hinges on how well its capacity matches the protocol's demands, and this match is established through two related but methodologically distinct approaches: feasibility assessment and protocol complexity assessment. The two are rarely examined together, even though protocol complexity is one of the primary inputs determining whether a site's favourable patient flow actually translates into successful accrual.
Aim: This review aims to systematise the current literature on feasibility assessment and protocol complexity in oncology trials, with emphasis on the Ontario Protocol Assessment Level (OPAL) tool, and to outline its practical significance for assessing research site readiness.
Materials and Methods: An analytical review was conducted of official regulatory documents (FDA, EMA), peer-reviewed literature indexed in PubMed, and professional position statements (ASCO), published between 2011 and 2026.
Results: Existing feasibility assessment tools remain largely static, self-reported and poorly integrated with systematic risk-assessment tools. Protocol complexity, objectively measured through OPAL, shows high inter-rater agreement and a significant correlation with actual research staffing allocation. An independent analysis of protocol amendments confirms that oncology protocols are amended significantly more often than non-oncology ones, and the Tufts CSDD economic analysis shows that the cost of operational delay is highest in Phase III—the phase in which the largest oncology trials are conducted.
Conclusion: Objective measurement of protocol complexity is a methodologically sound tool for resource planning at the research site and for better aligning feasibility assessment with actual operational readiness.
Kurbegov D, Hurley P, Waterhouse DM, Robert NJ, Nowakowski GS, Thompson MA, et al. Recommendations to streamline and standardize clinical trial site feasibility assessments: an ASCO research statement. JCO Oncol Pract. 2021;17(1):41-51. doi:10.1200/OP.20.00821.
McNerney D, Matheus C. The feasibility gap: why strong sites miss study opportunities [Internet]. Applied Clinical Trials Online. 2026 Apr 24. Available from: https://www.appliedclinicaltrialsonline.com/view/feasibility-gap-strong-sites-study-opportunities.
Willigers BJA, Wiesiolek AE, Potter B, Pszczółkowska A, Kristensson C, Presz V, et al. Development of a protocol complexity tool: a framework designed to stimulate discussion and simplify study design. BMC Med Res Methodol. 2025;25:205. doi:10.1186/s12874-025-02652-9.
Smuck B, Bettello P, Berghout K, Hanna T, Kowaleski B, Phippard L, et al. Ontario protocol assessment level: clinical trial complexity rating tool for workload planning in oncology clinical trials. J Oncol Pract. 2011;7(2):80-4. doi:10.1200/JOP.2010.000051.
Napolitano D, Bozzetti M, Caruso R, Guberti M, Frau I, Smuck B, et al. Validation of the Ontario Protocol Assessment Level (OPAL) tool for assessing clinical trial complexity and supporting workforce planning in the Italian clinical research context. Ther Innov Regul Sci. 2026;60(5):1532-41. doi:10.1007/s43441-026-01006-x.
European Medicines Agency. Clinical Trials Regulation (EU) No 536/2014 [Internet]. Amsterdam: EMA. Available from: https://www.ema.europa.eu/en/human-regulatory-overview/research-development/clinical-trials-human-medicines/clinical-trials-regulation.
Botto E, Smith Z, Getz K. New benchmarks on protocol amendment experience in oncology clinical trials. Ther Innov Regul Sci. 2024;58(4):645-54. doi:10.1007/s43441-024-00629-2.
Tufts Center for the Study of Drug Development. Quantifying the value of a day of delay in drug development [Internet]. Boston (MA): Tufts University; 2024 Aug. Available from: https://csdd.tufts.edu/publications/whitepapers.
Bruneau B, Surdam K, Bland A, Krueger A, Wise A, Cotarlan A, et al. Redefining feasibility in clinical trials: collaborative approaches for improved site selection. Contemp Clin Trials Commun. 2024;40:101291. doi:10.1016/j.conctc.2024.101291.
Holmes K, Idris MY, Harvey J, Forney L, Brinton D, Billingslea JM, et al. Prospective evaluation of the adapted Ontario Protocol Assessment Level score for predicting clinical research coordinator workload: an internal validation study. J Clin Transl Res. 2025;11(5):106-12. doi:10.36922/jctr025260032.
Tyson K, Harvey J, Forney L, Brinton D. Resource management and capacity planning for clinical trial sites. J Clin Transl Res. 2024;10(4):229-36. doi:10.36922/jctr.24.00022.
Akpoviroro O, Castagne-Charlotin M, Joyce NP, Malikova MA. Assessment of the relationship between protocol adherence, study complexity and personnel in surgical clinical trials. Ther Innov Regul Sci. 2023;57(4):619-28. doi:10.1007/s43441-023-00506-4.
Markey N, Howitt B, El-Mansouri I, Schwartzenberg C, Kotova O, Meier C. Clinical trials are becoming more complex: a machine learning analysis of data from over 16,000 trials. Sci Rep. 2024;14:3514. doi:10.1038/s41598-024-53211-z.
Nguyen Q, Kästel H, Hees K, Hofner B. The use of complex clinical trials: a regulatory review. Trials. 2026;27:289. doi:10.1186/s13063-026-09674-8.
European Commission. Complex clinical trials: questions and answers [Internet]. Version 2022-05-23. Available from: https://health.ec.europa.eu/system/files/2022-06/medicinal_qa_complex_clinical-trials_en.pdf.
International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use. ICH harmonised guideline: guideline for good clinical practice E6(R3) [Internet]. Step 4 final version. 2025 Jan 6. Available from: https://database.ich.org/sites/default/files/ICH_E6(R3)_Step4_FinalGuideline_2025_0106.pdf.
Peterson JS, Plana D, Bitterman DS, Johnson SB, Aerts HJWL, Kann BH. Growth in eligibility criteria content and failure to accrue among National Cancer Institute-affiliated clinical trials. Cancer Med. 2023;12(4):4715-24. doi:10.1002/cam4.5276.
Hauck CL, Kelechi TJ, Cartmell KB, Mueller M. Trial-level factors affecting accrual and completion of oncology clinical trials: a systematic review. Contemp Clin Trials Commun. 2021;24:100843. doi:10.1016/j.conctc.2021.100843.
Getz K, Smith Z, Kravet M. Protocol design and performance benchmarks by phase and by oncology and rare disease subgroups. Ther Innov Regul Sci. 2023;57(1):49-56. doi:10.1007/s43441-022-00438-5.
Garcia S, Bisen A, Yan J, Xie XJ, Ramalingam S, Schiller JH, et al. Thoracic oncology clinical trial eligibility criteria and requirements continue to increase in number and complexity. J Thorac Oncol. 2017;12(10):1489-95. doi:10.1016/j.jtho.2017.07.020.
Moore DC, Guinigundo AS. Biomarker-driven oncology clinical trials: novel designs in the era of precision medicine. J Adv Pract Oncol. 2023;14(Suppl 1):9-13. doi:10.6004/jadpro.2023.14.3.16.
International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use. ICH E8(R1): general considerations for clinical studies [Internet]. Guidance for industry. Silver Spring (MD): US Food and Drug Administration; 2022 Apr. Available from: https://www.fda.gov/media/157560/download.
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