In short
- The FDA approved the first targeted radioligand therapy for the treatment of patients with a progressive metastatic cancer. The approval took just 4 years (from the trial being awarded to PSI as the CRO)
- Challenges with enrollment included:
- Collaborating with individual local nuclear safety agencies to ensure the trial protocol was appropriate for each region
- Adapting to the in-country situation of radioligand production so patients were able to receive their treatment
- Uncovering unknown legislation on nuclear medicine safety, and overcoming the surprise challenges that arose
- Challenges with ongoing patient treatment and monitoring included pivoting doses – following last-minute changes in patient availability – to secure the treatment of available patients
- Radiopharmaceutical trials require intense, time-sensitive collaboration between the sponsor, the site, and the CRO throughout to ensure their success
Radiopharmaceutical trials
Radiopharmaceutical trials, more than many other types of trials, require precise time management. Not only within the critical phase of enrolling and managing patients, and managing their data, but with the investigational product itself. The immense benefit of radiopharmaceutical trials, especially those with a theranostic element, can only be realized by sites (and their different medical professionals across specialties) and sponsors (and their CROs) working in tandem to carefully manage their patients.
Enrolling patients in radiopharmaceutical trials has challenges that differ from country to country. Varying regulations and legislation on nuclear medicine, special import licenses, specific transport and storage authorizations, and handling licenses all pose strategic risks.
The challenge
A large biopharma approached PSI based on reputation to undertake their phase 3 clinical trial of the first targeted theranostic radioligand therapy for the treatment of patients with a progressive, metastatic cancer. It took just 4 years from award to FDA approval. But how was this achieved, and what hurdles were overcome along the way?
The solutions
Site collaboration
In , radiopharmaceutical trials require an additional mandatory authorization from a specific nuclear committee. Given that the industry was still new to radiopharm, the existence of this nuclear committee was a complete unknown until PSI uncovered its existence. The site, the sponsor, and PSI worked together to overcome this obstacle: The first patient in Belgium enrolled two months before the projected enrollment.
Throughout the trial, enrollment was always higher than projected – 99% of study sites worldwide enrolled at least one patient. Overall, the speed at which patients were enrolling in the trial required a new approach to ensure SDV was on time. PSI optimized the study team to allow for additional, and fluid, monitoring visits.
Engaging with regulatory agencies
In France, PSI personally engaged the ASNR (the French agency for nuclear safety) document-by-document to ensure that every critical step was accounted for and was according to the highly specific country legislation. A regional dosimetry sub-study in Germany required extensive discussions with the BFS (the German Federal Office for Radiation Protection) to ensure the protocol was approved and on time. The complexity of German legislation also meant that PSI collaborated with licensed sites to manufacture the kits required for treatment locally, to assist the sponsor.
Flexible coordination
Tackling challenges with enrollment is only part of the story that led to the theranostic’s successful approval. Challenges in the treatment period also required time-sensitive problem-solving, for example, when patients unexpectedly needed to delay or cancel their visit while the dose had already been shipped. In one example, PSI received a late evening notice from a site in Belgium stating that their patient had experienced a serious adverse event and could not receive the treatment planned for the next morning. However, as the dose was already en route to the center, the team determined that the dose could be rerouted to a site in the Netherlands, where another patient was ready to advance their visit and receive the dose instead. PSI promptly instructed the drivers, in the middle of the night on the highway, to change their course and deliver the dose to the Dutch site.
The outcome
Following the award of the trial study to PSI in March, the first site was activated in May. Cohesive collaboration meant that the first patient could be enrolled in June in the US.
The significant demand from patients to participate contributed to the speed of being able to submit for FDA approval, however it was vital to:
- Perform early site engagement
- Maintain pre-existing positive site relationships
- Undertake longitudinal, continuous feasibility planning
- Capitalize on internal expertise
- Collaborate closely with the sponsor, sites, and vendors
The competition among sites to secure slots for patient participation was intense, with long waiting lists and even patients calling from abroad to secure a place in a neighboring country. PSI implemented a screening control system to regulate patient flow. PSI worked with the sponsor to encourage mutual support and information exchange among the sites, acting in the role of a moderator, ensuring open and transparent communication, and establishing clear agreements on slot assignments.
Despite all of the challenges, over 800 patients enrolled, surpassing the sponsor’s recruitment goal ahead of schedule. For post-enrollment continuity, PSI’s data management team worked 24/7 to deliver the data, thus expediting DBL.
Key takeaways
Although the field of nuclear medicine is approaching its 100th birthday, radiopharmaceuticals and theranostics, in their current format, are still relatively new fields (perhaps best defined as beginning with Xofigo for prostate cancer in 2013). More sponsors than ever are researching their application in oncology and beyond: Over 100 radiopharmaceutical trials were planned in 2024 [1, 2]. Success in nuclear medicine trials, beyond efficacy of the theranostic, relies on time-critical problem-solving during the whole trial period to ensure that any new therapy can reach as many patients as soon as possible.
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Abbreviations
, Autorité de sûreté nucléaire et de radioprotection;
BFS, Bundesamt für Strahlenschutz;
CRO, Contract research organization;
DBL, database lock;
FDA, Food and Drug Administration;
SDV, source data verification.
References
1. Weber, W.A., et al., What Is Theranostics? J Nucl Med, 2023. 64(5): p. 669–670.
2. Stoy, D. The State of Radiopharmaceuticals: Growth, Challenges, and What’s Ahead. in Targeted Radiopharmaceuticals Summit. 2025.
