From phase 1 to phase 3: Scaling radiopharmaceutical trials

Radiopharmaceuticals are a progressively important area of oncology and precision medicine, with a growing number of compounds progressing to later phase development and an expanding range of therapeutic isotopes. While the scientific opportunity is substantial, the operational complexity of these studies is unlike almost any other modality in clinical development. Translating early phase promise into successful pivotal trials requires a strategy that combines high-quality foundational data with robust imaging, dosimetry, logistics, regulatory coordination, and operational consistency at a global scale.

Radiopharmaceutical trials cannot be managed like conventional studies. Success in radiopharmaceutical development depends on creating and maintaining an integrated, scalable system building on high-quality pre-clinical and early phase data.

Why do radiopharmaceutical studies fail to scale?

Early-phase radiopharmaceutical trials are demanding – involving serial dosimetry, intensive imaging, PK assessments, radiation safety procedures, and complex IP workflows for each participant that place significant burden on study teams and sites. Paradoxically, while phase 3 studies often involve fewer procedures per participant, thus simplifying treatment pathways, the operational challenge actually becomes greater. Sponsors must replicate high-quality execution consistently across countries, regulators, hospitals, imaging systems, manufacturing sites, and supply chains.

Many pivotal programmes struggle because key strategic decisions were not addressed early enough during preclinical and phase 1 development. Common weaknesses include:

Inadequate dose justification and escalation strategy
Limited dosimetry and PK evaluation
Insufficient assessment of late toxicity
Underdeveloped imaging companion diagnostic strategy
Manufacturing systems that cannot scale globally
Fragile (or not fully tested) supply chains
Different regulatory alignment across jurisdictions

In radiopharmaceutical development, imaging is inseparable from the therapy itself. It drives dosimetry, endpoint assessment, and companion diagnostics. As a result, imaging charters and standardisation are important as the protocol.

Building a scalable supply chain

Few areas of drug development are as dependent on logistics as radiopharmaceuticals. Trial operations are constrained by isotope half-life, manufacturing locations, transport windows, customs clearance, airport restrictions, radiation licensing, and treatment scheduling.

The operational demands of radiopharmaceutical trials can vary considerably depending on the isotopes, from hours to several days. Any delay in manufacturing, logistics, or participant scheduling can disrupt site operations and planned treatment. A shutdown, or quality incident, may require participant treatment to be postponed, or even cancelled. All facets must therefore function as a single coordinated system.

Successful programmes require:

Reliable isotope access and scalable manufacturing capacity
Regional manufacturing hubs and shipping strategies
Central radio-pharmacies and cold-kit provision
Capacity to match manufacturing output with enrolment pace
Dry-run and mock shipments to troubleshoot transport pathways
Treatment room availability and synchronized dosing schedules

Even seemingly small details, such as formulation stability during customs delays or airport tarmac exposure, can invalidate shipments.

Global regulatory complexity

Global radiopharmaceutical development requires coordination across multiple regulatory layers, including the FDA, EMA, local radiation authorities, ethics committees, and imaging regulators.

Regulators increasingly expect:

Detailed imaging and biodistribution data
Standardised dosimetry models
Robust radiation safety assessment, including organ-absorbed doses
Comprehensive CMC and quality documentation – covering radiotracer purity, sterility, and stability
Companion diagnostic validation, including therapeutic distribution, within theranostic programmes

Project Optimus is an example of evolving FDA expectations around dose optimisation. While the guidance may appear daunting, regulators are often willing to engage flexibly when sponsors present strong scientific rationale, supported by dosimetry and PK data.

At the same time, country-specific requirements continue to evolve. In the US, Radiation Safety Committee approvals frequently precede IRB submission, although some sites integrate these into local IRB processes. Across Europe, requirements for per-participant dosimetry are increasing, with Germany requiring dosimetry for all participants and similar requirements potentially applying in the UK. In Latin America, local customs brokers manage import clearance, making these countries viable options for products with sufficient time between manufacture and administration. In Australia, import licenses should be obtained from the ARPANSA, with EC package review by the site radiologist. Taiwan requires an import license and isotope license to site from the Nuclear Safety Commission and individual protocol review by each site’s radiation safety committee.

Across all regions, ensuring sites hold the licenses needed for therapeutic and dosimetry payloads adds another layer of complexity and can become a rate-limiting factor.

Selecting the right sites – at scale

Global feasibility assessments for radiopharmaceutical trials are complex and require careful modelling across countries, sites, and operational scenarios. Sponsors must evaluate not just enrolment potential, but also the technical and operational capabilities required to support radiopharmaceutical delivery and complex workflows.

Critical capabilities include:

Nuclear medicine and radiation oncology expertise – trained investigators, physicists, technologists, and pharmacists
Multidisciplinary coordination across nuclear medicine, oncology, radiology, pharmacy, radiation safety, and imaging teams
Nuclear pharmacy and hot lab infrastructure
PET/CT, SPECT/CT, MRI, and advanced imaging capability
Dosimetry and gamma counter capacity
Radiation-safe treatment rooms
Strong referral pathways for participant recruitment
Deep knowledge of potential participant flow

Beyond technical capability and enrolment potential, sites must also be able to coordinate across departments to finalise budgets, ensure appropriate training, maintain prompt data entry, and facilitate the resolution of complex queries.

Not all hospitals are equally equipped for dosimetry or isotope handling; some lack appropriate scanners, collimators, radioactive sample handling capabilities, or operational experience. As a result, successful pivotal trials depend on detailed protocol-specific site profiling and feasibility analyses to identify sites that combine enrolment potential with the technical expertise and operational consistency necessary for global execution.

Coordinating specialist equipment qualification

Equipment qualification can become a major bottleneck if not addressed proactively. Scanner availability for trial qualification, phantom testing, reconstruction validation, and imaging standardisation are all essential to maintaining data integrity across global sites.

Operational success depends on:

Tracer-specific scanner qualification
Standardised imaging acquisition protocols
SOPs governing reconstruction and timing windows
Continuous QC monitoring and retraining
Specialist imaging and radiologic science expertise

The importance of embedding imaging and dosimetry specialists directly within CRO project teams to coordinate communication among vendors, sites, and sponsors cannot be overestimated.

Medical physicists, nuclear medicine technologists, radiologists, and nuclear pharmacists are central to successful execution. Some sponsors and CROs are also bringing dosimetry expertise in-house, to support scientific discussions with regulators and sites.

Protecting endpoint integrity

In radiopharmaceutical studies, variability in imaging interpretation, participant eligibility confirmation, and companion diagnostic alignment can significantly compromise efficacy outcomes.

Key risks include:

Variability between local and central imaging review, which could lead to misclassification of responses or inflated/deflated ORR/PFS
Variability in imaging across sites, leading to reduced comparability and increased noise in response
Delays in central read turnaround, which may cause slower enrolment, protocol deviation, and site frustration
Incorrect eligibility due to inconsistent positivity assessment, potentially diluting the treatment effect
Misalignment between companion diagnostics and the therapeutic programme, which can impact regulatory approval

Central review and imaging rigour must begin in early-phase development. Mandatory blinded independent central review (BICR), standardised imaging charters, central eligibility review before randomisation, continuous imaging QC and site monitoring, and aligning early with regulators on companion diagnostics all support maintaining data quality.

Operational consistency drives pivotal success

Success in radiopharmaceutical programmes depends on decisions made throughout the clinical development pathway. Pivotal trials fail when early phase programmes are not designed from the outset with a foundation for later development and with scalability in mind.

Decisions made during preclinical, phase 1, and phase 2 development – around dosimetry, imaging strategy, manufacturing scalability, supply chain resilience, regulatory alignment, and site capability – shape the operational requirements of later studies.

Operationalising radiopharmaceutical programmes for scale requires far more than simply expanding global enrolment. These programmes demand integrated systems capable of delivering consistent execution across every participant, site, country, imaging platform, and regulatory environment. Imaging integrity, isotope supply, logistics, equipment qualification, endpoint consistency, and technical expertise must function together seamlessly.

As programmes advance toward pivotal development, sponsors and their CRO partners must ensure scalability, technical rigour, and operational detail are adequately addressed. Early investment in infrastructure, specialist expertise, regulatory engagement, and robust operational planning allows sponsors to build radiopharmaceutical programmes capable of generating reliable early data and successfully translating to pivotal global success.

About the author

Dr Lucy Knight is director of project management at PSI. She oversees PSI’s most complex radiopharmaceutical programmes. Dr Knight brings over 20 years of clinical research experience and 167 years of global, full-service project management experience, including the delivery of over 20 studies in various oncology indications and radiopharmaceuticals. In 2021, she received a silver award from PharmaTimes in recognition of her project management skills.