In short
- Over 90% of oncology clinical trial protocols are amended during their course – therefore it is crucial to practice continuous feasibility to ensure a trial can be conducted successfully, taking into account changes in the real-world situation
- A biopharma sponsor worked with PSI on their landmark oncology phase 3 study of a potentially best-in-class therapeutic agent
- Naturally, there were some challenges – but PSI’s support and adaptability helped to turn these into opportunities:
- Changes in SoC helped recruit a more relevant patient population
- On-time DBL was ensured by keeping the trial database in a “DBL-ready” state for the 6-month period preceding projected DBL
- The trial met enrollment milestones and was delivered according to schedule, supporting the successful FDA approval of the sponsor’s therapy
- Changes to a trial protocol are likely to happen – the adaptability PSI can offer to overcome these challenges is what results in on-time delivery
The need for continuous feasibility in oncology trials
Clinical trials change during the course of their protocol. One study conducted in 2022 on data from 950 protocols and 2188 amendments estimated the mean number of amendments per protocol to be 3.3, with phase 1 and 3 trials having the highest increases in amendments per protocol [1]. In oncology, over 90% of clinical trials had protocol amendments: an average of 4 amendments per trial was reported [2]. Oncology protocols with amendments had significantly lower completion rates (compared with protocols without amendments) [2], impacting both study outcomes and financial forecasts – each protocol amendment can cost >$500,000 [1].
Protocol amendments are often unavoidable. In oncology, the primary causes of protocol amendments are:
- Requests for amendments from regulatory authorities and review boards
- Changing standards of care
- For example, approvals of a new therapy, or updated diagnostic tests impacting eligibility criteria
- Safety monitoring data indicates changes are required
- The design of the trial needs to adapt to real-time readouts
- Responses to real-world events, such as supply chain issues, global pandemics, or unexpected (media) interest in the trial
These factors add complexity to the inherent difficulties of treating patients with terminal diseases.
Given the above complexity, and the inherent difficulties of treating patients with terminal illnesses, continuous feasibility is an important concept in oncology [3]. Evaluating whether and how an oncology trial can be conducted successfully throughout the entirety of the trial’s lifespan at operational, regulatory, site, and patient levels with a forward-facing approach means taking into account evolving requirements and the need to adapt throughout the trial [3].
The challenge
A biopharma sponsor was planning to run a phase 3 oncology trial after receiving positive feedback from the FDA to proceed based on data from an earlier trial. It was crucial that the sponsor could enroll rapidly and effectively, given the changing nature of the oncology landscape.
The sponsor chose PSI based on reputation in pivotal oncology studies. Both the sponsor and PSI were aware that this might be a difficult trial to enroll.
Protocol changes
- During the course of the trial, multiple therapies in the same or similar treatment class were approved, thus amendments were required to prior treatment definitions and control arm considerations. Whilst such potential changes to standards of care were assessed on an ongoing basis by PSI, re-evaluation of the control arms and site viability was streamlined through pre-identification of over 1,000 global sites using PSI’s established oncology network and VISIONAL™ tools
- The changes resulting from these amendments provided a more robust population to evaluate within the trial, and helped to ensure that findings were accurate to the real-world situation. PSI’s scalable resources helped support the several countries where enrollment exceeded expectations
Database challenges
- The trial’s main analysis per the protocol was triggered by a number of central reader-adjudicated PFS events.
- The PSI team implemented a prolonged “DBL-ready” approach for an extended period prior to DBL, to ensure rapid cleaning once the event threshold was hit
- Normally, sites have approximately one week to enter patient data; for the “DBL-ready” state, this had to be considerably faster. PSI worked with the sites to support them, ensuring they didn’t suffer from any added pressure. Eventually, sites in all countries participating in this trial embraced the approach!
- This was in addition to multiple data sweeps for ongoing DSMB reviews, multiple TMF audits, and mock inspections
- Taking the potentially taxing database needs into consideration, DBL was achieved exactly as planned
The outcome
Despite the database cleaning challenges, and the need to adapt the protocol due to changing standards of care, the trial achieved enrollment milestones on time and was delivered as promised. These efforts supported the successful FDA approval of the sponsor’s therapy.
Key takeaways
The rapidly evolving oncology landscape often means trial protocols feasible at study start must change during the study to remain feasible. Planning for this eventuality is a crucial operational, regulatory, and patient- and site-focused strategy, especially in pivotal multi-national studies. Adaptability during the trial to implement the changes, and flexibility to meet sponsor-specific goals, are two things PSI does best to ensure your clinical trial runs on time.
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Abbreviations
DSMB, Data safety monitoring board;
FDA, Food and Drug Administration;
SoC, standard of care;
TMF, Trial master file.
References
1. Getz, K., et al., New Benchmarks on Protocol Amendment Practices, Trends and their Impact on Clinical Trial Performance. Ther Innov Regul Sci, 2024. 58(3): p. 539–548.
2. Botto, E., Smith, Z., and Getz, K., New Benchmarks on Protocol Amendment Experience in Oncology Clinical Trials. Ther Innov Regul Sci, 2024. 58(4): p. 645–654.
3. Moscicka, K., Phillips, J., and Zalud, J., Evolving Feasibility in Oncology: Continuous Assessment for Timely Enrollment. International Biopharmaceutical Industry, 2025. 8(4): p. 62–65.
