Advancing radiopharmaceuticals in clinical trials: Integrated expertise mitigates risk

Precision oncology radiopharmaceuticals (RPTs) use ligands to target specific proteins on cancer cells and deliver a lethal radioactive payload. First-generation products struggled commercially due to high costs and a lack of infrastructure and expertise. However, second-generation products, especially those with a diagnostic component, called theranostics, are undergoing a renaissance. Theranostics first diagnose and stratify patients with a radiolabelled agent that enables accurate 3D imaging. Then, they deliver a personalized therapeutic dose of the same or a complementary radionuclide that kills cancer cells, resulting in better therapeutic outcomes with fewer off-target side effects for patients.¹ 

The recent surge in RPT development is fueled by multiple factors, including:

Clinical and commercial success. Novartis’s two RPT theranostics—Lutathera for neuroendocrine tumors (approved in 2018) and Pluvicto for prostate cancer (approved in 2022, label expanded in 2025) generated more than $2 billion in net sales in 2024.² 

Advances in isotope production. Better commercial nuclear reactors, cyclotron technology, and laser-based isotope separation have improved supply chain reliability and produced novel isotopes such as alpha-emitting radionuclides.

Expedited regulatory programs. 2024 saw a flood of FDA Fast Track designations for sponsors of investigational RPTs, including Clarity Pharmaceuticals, Perspective Therapeutics, Telix, Abdera Therapeutics, Full-Life Technologies, and Oncoinvent.³  

Multi-target potential. RPTs offer multi-target flexibility—including the choice of isotope, ligand, target, and conjugation—and synergies with existing oncology portfolios, which investors now prefer over precision medicines that target tiny subpopulations of patients. ⁴

Discovery of new targets and antibodies. Recent advances in mass spectrometry and computational proteomics are accelerating the discovery of new cancer antigens, which can be targeted using the high specificity and affinity of novel antibodies and antibody derivatives.⁵ 

Developing an RPT is operationally complex, so sponsors must manage risks at every phase of clinical development and execution. Over the past five years, Parexel has completed more than 20 RPT oncology projects for sponsors, involving more than 2,100 patients at over 600 sites in 20 countries. In this report, we present the insights of our clinical, regulatory, and operational experts into critical aspects of conducting clinical trials with RPTs, including:

1. Feasibility and site selection

2. Patient-guided trial design

3. Regulatory strategy

4. Supply chain and logistics management

1. Feasibility and site selection

Beyond Location and Logistics: Defining RPT Trial Viability

The number of new clinical studies testing diagnostic, therapeutic, and theranostic RPTs in cancer indications has grown steadily since 2019: academic studies increased by 72 percent, and industry-sponsored trials jumped 64 percent.⁶  Venture financing of RPTs more than quintupled in the five years ending in 2023⁷,  and multi-billion-dollar biotech acquisitions dominated RPT M&A news in 2024.⁸

The result is an increasingly crowded R&D landscape. RPT trials are expensive and require close coordination between isotope production, manufacturing, and clinical use, as well as nuclear medicine expertise and equipment. For example, sites must have access to positron emission tomography (PET) and single-photon emission computerized tomography (SPECT) scanners, and gamma counters to measure radiation emitted by radionuclides. 

Feasibility testing and site selection are essential to success in this competitive and complex environment. At Parexel, we use the following strategies to identify optimal RPT trial sites:

• Estimate the impact of radioactive material (RAM) licensing on site timelines.

The timeline for securing the necessary RAM licenses at the site level can be from a month to two years, depending in part on the country (Table 1). Conventional oncology trials have much shorter site activation timelines, and the contrast often surprises RPT sponsors we work with. Further, RAM licensing is not a blanket approval: Different radioligands, distinguished by their emission type (alpha, beta, gamma), often necessitate specific licenses. A site licensed for Actinium-225 (²²⁵Ac) might not automatically be approved for Indium-111 (¹¹¹In), creating a layer of complexity that demands meticulous planning and tracking. 

Recently, we performed a competitive landscape analysis for an emerging biotech company planning a first-in-human trial of an RPT to treat neuroendocrine cancer. We analyzed the more than 350 open and planned RPT trials globally, those with a similar completion date (about 75), and those that would directly compete for the same patients in their target geographies (15). Because the study required that every site have a RAM license for two radioisotopes, we advised them to focus on those with existing certification for the initial dose escalation stage of the study to avoid licensing delays. For the dose expansion stage of the trial, we advised adding sites as they obtained the required radioisotope-specific licenses. This gated strategy mitigates competition at frequently selected sites.

At Parexel, we rely on country-specific strategies to prevent delays caused by RAM licensing. For example, site-based nuclear medicine subcommittees in the United States often require final documentation, such as lab and pharmacy manuals, before they review and approve a trial submission (Table 1). It is critical in these cases to prepare and finalize documents well in advance. In the Netherlands, approval to conduct trials involving radioactive materials (RAM) must be obtained from the Authority for Nuclear Safety and Radiation Protection (ANVS). However, if a site does not have an existing ANVS certification, sponsors can submit an application in parallel to the mandatory EU Clinical Trial Regulation (EU-CTR) filing to ensure no delay to study-start-up timelines.
 

Key to acronyms: CIRB: centralized institutional review board; EC: ethics committee; EU-CTR: European Union Clinical Trial Regulation; IP: investigational product; IRB: institutional review board; RA: radioactive approval (committee names for this function vary by institution); RAM: radioactive material; RPT: radiopharmaceutical.

• Profile sites in advance to confirm RPT capabilities

Careful selection ensures that trial sites have the infrastructure to conduct RPT trials, such as PET and SPECT scanners, radiation therapy facilities, and capabilities for radioligand handling, administration, and disposal. For example, radiation shielded rooms are used to isolate patients during and after they are diagnosed or dosed with RPTs, to allow radioactive elements to decay without harming site staff or patients’ family members. Investigational product (IP) waste containing 225Ac must be stored for 100 days, according to guidelines requiring safe storage for at least ten half-lives (the time it takes for half of the material to decay) of a radioactive element.  

At Parexel, we rely on our Oncology Site Alliance Network—supplemented by real-world data, census data, and AI-enhanced querying—to identify high-performing RPT trial sites with access to the necessary equipment and patients. We use detailed questionnaires to assess site capabilities and populate and update our database. Our inquiries go deeper than standard inquiries, probing the specific models of SPECT machines and the site's experience with handling and analyzing radioactive samples for different emission types. Our alliance members have consistent enrollment metrics and standard start-up documentation; these are crucial for rapid startups in institutions with long contracting timelines.

Our goal in building and curating a site relationship network is to make it as easy as possible to work with Parexel. For a contract research organization (CRO), sites must perceive you as a preferred and trusted partner. When we talk to sites, we are the intermediary between them and trial sponsors. We streamline the dialogue and make it a pleasant experience by having a single point of contact instead of a rotating cast of project personnel.

Academic hospitals and clinics are key components of any site list. A profiling step enables slick and efficient knowledge sharing. Is this site already at capacity? Where do they want to go next? If a site is especially interested in prostate or breast cancer studies, we offer them these studies whenever possible. If they tell us they had payment issues in past trials, we ensure payments are handled efficiently and problems are addressed immediately.

• Prioritize sites with nuclear medicine physicians who can collaborate. 

Our global footprint enables us to understand regional practices, such as the prevalence of nuclear medicine physicians as principal investigators (PIs) in certain European countries. To leverage nuclear physicians in RPT clinical trials requires site-specific knowledge of practice and process. We need to know whether nuclear physicians, radiation oncologists, and medical oncologists work well together at each site. 

The success of RPT trials also depends on the investigators’ expertise and enthusiasm. So we identify PIs who are passionate about the field, overlay our knowledge of the site, relationships, and performance in past studies, and then reach out to engage those who are the best fit. In some cases, expanding the site pool to new regions can accelerate enrollment. For example, South Africa has few experienced RPT sites, but investigator interest is high. Including new sites and regions in early-stage trials, mentoring motivated PIs, and providing training are key.
 

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2. Patient-guided trial design

Patient-Centric RPT Trials: A Q&A with Parexel experts

Translating radiopharmaceuticals’ (RPTs) promise into benefits and better outcomes for patients hinges on the ability to educate and motivate them to participate in clinical trials. We asked two Parexel experts for insights on how sponsors can address patients’ fears about radiation and other unique patient needs in trial design and execution. Gwyn Bebb serves as Parexel’s Global Therapeutic Area Head for Oncology, and Stacy Hurt is our Chief Patient Officer.

Question: What are patients’ top concerns about radiopharmaceuticals?

Stacy Hurt: Fear of radiation is probably the number one concern I hear from patients. It’s counterintuitive to use radiation to cure cancer. Most RPT trials involve two positron emission tomography (PET) scans, one at the diagnostic stage and another at a follow-up visit. These leave a small amount of radiation in your body. Patients also receive multiple computed tomography (CT) scans, which involve higher doses of radiation than other imaging tests (though the radiation does not stay in the body), and an infusion of a radioactive investigational product. As a cancer survivor who received a PET scan, I understand concerns about radiation. In my case, the higher accuracy of the PET scan, compared to a CT scan, enabled my physicians to re-stage my colon cancer from stage 2-3 to stage 4. Those stages are treated differently, so I began receiving chemotherapy immediately, instead of first undergoing surgery. It saved my life.

Question: How can sponsors reassure patients?

Stacy Hurt: A patient’s concern about radiation is serious and must be addressed with emotional sensitivity and transparency about the risk-benefit ratio. Patients ask: Am I going to get leukemia one day from undergoing these scans? Will I glow with radioactivity after I am dosed in this trial? RPT trials are a new ballgame. Patients will technically be radioactive after dosing, because beta and alpha emitter particles have a local effect. They will need to isolate themselves from site staff and family members for some time. At Parexel, we provide patients with information in understandable language through videos, brochures, and trial websites. Sponsors and CROs must manage patients’ expectations because, after hearing the words “you have cancer” from a physician, patients don’t want any more surprises.

Question: How do RPTs change the patient care pathway?

Gwyn Bebb: Oncologists often don’t consider RPT clinical trials a treatment option, potentially due to a lack of understanding of the logistics. Most assume they must transfer their patient to a nuclear medicine team, and these referrals are not always straightforward. In RPT trials, oncologists and nuclear physicians collaborate to treat patients. Personalized dosimetry (the measurement, calculation, and assessment of the ionizing radiation dose for each patient) complicates treatment planning, necessitating a change to the patient pathway. This is not without precedent. We now have an established tradition of including nuclear physicians in patient care for neuroendocrine tumors and prostate cancer. So we know it can be done, but it’s challenging. 

Question: What does participation look like for patients?

Gwyn Bebb: During trials, patients often need to visit the site for the diagnostic dose, and then return a few days later for the therapeutic dose(s). They then stay in isolated rooms waiting for the radio emissions to decrease to baseline levels. We are currently running a breast cancer trial, and have worked to ensure fluent collaboration between the oncology and nuclear medicine teams to secure a smooth referral route for patients from the oncologist to the nuclear medicine experts, and back again after the treatment period ends. We provided extensive information about the agent’s mechanism of action, expected safety profile, and anticipated level of efficacy (based on preclinical data) to investigators to promote engagement in the study. Sites tell us that the scarce availability of multidisciplinary teams is one of their primary pain points in conducting RPT trials. Integrating RPT education into oncology training and fostering interdisciplinary collaboration takes time and effort.

Question: Can trial materials and support improve patient recruitment?

Stacy Hurt: Sponsors need to simplify complex stories for patients. At Parexel, we map out the site visits and procedures for diagnostic, therapeutic, and theranostic RPT trials using practical, everyday language and graphics. Simplifying intricate scientific details without losing accuracy demands creativity and diverse communication tools. We encourage sponsors to provide comprehensive patient navigation programs to coordinate appointments, arrange transportation, address patients’ everyday concerns, and even extend support to their caregivers. These programs require resources and institutional commitment, but they mean a lot to patients and can boost recruitment and retention. 

Question: How important is transparency in RPT trials?

Stacy Hurt: Transparency is hands down the best approach for patients. For example, radiopharmaceutical extravasations can occur if an RPT diagnostic or therapeutic is erroneously injected into a patient’s tissue during a site visit, missing the intended vein. Extensive extravasation can compromise the quality of diagnostic images or therapy delivery, inadvertently harming patients. However, RPT extravasations do not have to be reported to the patient, which patient advocates argue creates a lack of transparency.  At Parexel, we have found that most patients understand that not all medical procedures go as planned, and, if they are presented with a full and fair disclosure of risks, they can make informed decisions. Early and consistent engagement with patient advocacy groups and transparent communications about clinical research are vital to recruitment and trust.

Question: How can providers impact patient recruitment and retention?

Gwyn Bebb: Oncologists are often the primary care providers for patients considering clinical trials. Training on the principles of RPT therapy helps them communicate effectively and address patient questions accurately. Moreover, when a patient sees their oncologist collaborating well with the nuclear medicine physician, and both deliver a consistent message, they feel more confident about being in the trial. 

Question: What resources do they need to guide patients?

Gwyn Bebb: Supplying physicians with patient-friendly educational resources enhances their ability to guide patients through decision-making. It’s essential to make the underlying science accessible through lay-friendly summaries that avoid technical jargon when explaining isotopes and targeting mechanisms. Interactive tools and videos can visually demonstrate how the radiopharmaceutical seeks out and attacks cancer cells. The focus should always be on the "why" – clearly explaining the rationale behind this therapeutic approach and its potential advantages in their specific situation, such as the "see it and treat it" precision of theranostics.

Well-established success stories, such as radioiodine therapy for hyperthyroidism, can reassure patients of the efficacy of RPTs in a non-cancerous setting. As more data emerges from oncology trials, showcasing positive outcomes builds hope and encourages participation. Emphasizing the "educated patient" concept invites individuals to actively discuss their treatment options and make informed choices based on a clear understanding of the potential benefits.
 

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3. Regulatory strategies

Charting the Regulatory Course for RPT Breakthroughs

Most regulators have limited experience reviewing next-generation radiopharmaceutical (RPT) product submissions, particularly theranostics. Their expertise is primarily in more traditional oncology drugs, which creates uncertainty for RPT sponsors. In light of regulators’ limited knowledge in the field, sponsors must have RPT trial experience and former regulators’ understanding of FDA and EMA processes on their team. At Parexel, we advise sponsors to devise an RPT regulatory strategy that incorporates the following approaches:  

• Prepare for extended reviews involving multiple divisions.

Dual regulatory pathways for drug and radiation safety complicate the review and approval of RPT submissions. For example, at the FDA, both the Office of Oncologic Diseases (OOD) and the Division of Imaging and Radiologic Medicine (DIRM) review new investigational new drug (IND) applications and new drug applications (NDAs). While the EMA handles quality and non-clinical and clinical reviews internally, the FDA involves the Nuclear Regulatory Commission (NRC) for packaging and manufacturing reviews.

The need to consider the viewpoints of multiple divisions impacts timelines for early interactions with the FDA. For example, sponsors should schedule pre-IND and end-of-phase 1 (EOP1) meetings, but they should know that dose optimization and dosimetry plans will be reviewed by both oncology and nuclear medicine regulators, at least in the United States. The data should be submitted as soon as a sponsor has compiled topline results from a trial, because reviews with multiple divisions take longer. In 2025, the FDA is experiencing turmoil due to high- and low-level staffing changes, which may take time for the agency to adjust.

Sponsors must establish a plan for long-term safety monitoring to comprehensively understand and characterize any potential delayed or persistent adverse events (AEs) that may arise following the cessation of treatment. We recommend proposing a minimal follow-up period of 90 days, with adjustments based on emerging data and regulatory feedback. AE monitoring should be robust, especially regarding myelosuppression, and should account for the unique nature of RPTs.  

• Engage with regulators to overcome gaps in formal guidance.

The existing framework of formal regulatory guidelines has not kept pace with scientific advancements in the field. Recently, we systematically analyzed guidance documents from the FDA, NRC, and EMA that cover the clinical development of anticancer RPTs.  We found several key gaps in regulatory guidance for developing theranostics. Current guidelines for in vivo companion diagnostics, especially targeted diagnostic RPTs codeveloped with their therapeutic counterparts, do not align with recent clinical advances. While the FDA provides guidance on the non-clinical aspects of therapeutic RPTs, and the EMA has acknowledged the need for specific clinical guidelines through a published concept paper, neither agency has yet issued formal written guidelines for the clinical development of these agents. The lack of comprehensive, technically relevant guidelines poses challenges for sponsors.

To mitigate these risks, sponsors need to engage with the FDA through early and frequent discussions and correspondence to confirm the acceptability of their clinical development plan, including dose optimization and the validation of novel endpoints specific to theranostic agents. They might also advocate for the agency to issue RPT subsections to future guidance document revisions. We advise sponsors to seek formal scientific advice from the EMA once they have completed dose optimization and are well-prepared to discuss their Phase 3 trial design, rather than engaging earlier in the process. 

• Elevate the science of radiation dosimetry.

Radiation dosimetry is crucial for developing RPTs, especially for safety monitoring and dose determination. Although pharmacokinetic (PK) data are necessary in Phase 1 trials, acquiring them for RPTs can be challenging due to small sample sizes, short drug half-lives, and complex handling procedures. Additionally, relying solely on plasma PK profiles can be misleading, as they only serve as surrogates and do not directly reflect the radiation dose reaching tumors and healthy tissues. To understand this better, mass balance data proves valuable, allowing researchers to monitor the radiopharmaceutical's absorption, distribution, metabolism, and elimination. This broader view aids in interpreting PK data more accurately concerning radiation exposure.

Determining the optimal dosage range for RPTs is complex. Establishing an upper limit is challenging, and there are concerns about underdosing if relying solely on radiation dosimetry. While thresholds from normal organ absorbed dose data in external beam radiotherapy (EBRT) can guide upper limits, their applicability to RPTs is uncertain. Sponsors can propose exceeding these EBRT thresholds in protocol amendments if new patient data supports higher doses. It is vital to remember that high cumulative radiation doses may cause long-term, irreversible adverse effects, requiring extended safety follow-up periods of up to 10 years. Ultimately, defining maximum efficacy and acceptable safety depends on the specific cancer type and available alternative treatments.

• Adhere to Project Optimus for dose optimization.

The FDA's Project Optimus signifies a major change in oncology drug development, prioritizing the identification of the "optimal dose"—the dose yielding maximal efficacy with acceptable safety. This proactive strategy shifts from merely finding an "approvable" dose. The FDA now asks two key questions about dosing: "Can the dose go higher?" and "Can the dose go lower?" Determining this optimal dose is mandatory under Project Optimus, and neglecting it can lead to a clinical hold.

Developing RPTs involves unique considerations aligned with Project Optimus principles, including challenges in obtaining and interpreting PK data, the dose-exposure relationship, and the importance of radiation dosimetry. To reduce uncertainties, and to facilitate agreement on study initiation and the determination of the recommended Phase 2 dose (RP2D), sponsors should gather data for integrated dose-exposure-response analyses and present these to the FDA before and after randomized dose-finding studies. Project Optimus encourages sponsors to investigate a broad range of doses (amount, frequency, duration) to characterize the dose-exposure-response relationship. After dose escalation, the FDA expects well-designed randomized dose-finding studies with more than two dose levels and 20 to 40 patients in each arm.
 

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4. Supply chain and logistics

The Critical Chain: Ensuring Seamless Delivery in RPT Trials

At Parexel, we meet regularly with potential new clients to discuss our approach to running their RPT trials. One way to gauge their experience in the field is by the questions they ask. If their first question concerns logistics, we know they understand the main challenge ahead. 

Often, the success or failure of an RPT clinical trial depends on how vendors, CROs, and site staff operate during “the last mile” of delivering the drug to a patient. Did the vendor transporting it from the airport to the site’s loading dock drop it off and drive away? Or did they deliver it directly into the hands of waiting study staff, who rushed it to the appropriate on-site holding facility? Successful “last miles” are only achievable if logistics planning begins months or years in advance. Here are the key components of how we manage supply chains and logistics at Parexel:

• Take an integrated approach to planning.

The consequences of mismanaging a supply chain in RPT trials far exceed those for typical clinical research setbacks. Delays can lead to costly investigational products degrading and becoming unusable, which can jeopardize patient dosing schedules and even compromise the integrity of trial data. Limited production sources make it challenging to ensure a reliable supply of radioisotopes. A traditional clinical trial approach, in which sponsors, CROs, and vendors operate with limited integration, does not work for RPTs.

The intricacies of RPT handling, from specialized packaging and transportation to strict regulatory guidelines and site-specific licensing, demand integrated upfront planning. When products may only be viable for a few hours, minor problems can quickly escalate into logistical nightmares. The tendency to view logistics as transactional, managed through arm's-length vendor relationships, can be particularly detrimental. 

At Parexel, we engage all the relevant stakeholders—including sponsors, clinical operations, feasibility assessment teams, laboratory personnel, regulatory experts, and, most crucially, specialized logistics professionals—to create a cohesive strategy from the start of trial planning. Sacrificing early-stage collaboration and communication in the name of budget can ultimately lead to much greater expenses through delays, errors, and the need for trial rescue efforts. 

This collaborative approach fosters a shared, comprehensive understanding of an investigational product's unique characteristics, including its stability profile, specific handling requirements, and potential logistical choke points. Rather than a sequential, often disjointed handover of responsibilities, we integrate logistical considerations directly into the clinical protocol design and site selection processes.  

• Dedicate a project leader for supply chain logistics.

We assign a supply and logistics project manager to every trial—this role is distinct from and in addition to the trial’s overall project lead. In our experience, the benefits of this approach are significant. This individual assumes end-to-end accountability for the supply chain’s seamless operation and ultimate success. Their responsibilities extend beyond merely coordinating shipments; they include meticulously overseeing every stage, from initial manufacturing release to final delivery and management. This encompasses proactively managing all the involved parties, such as specialized couriers and depot facilities, anticipating potential disruptions like transportation delays or customs clearance issues, and orchestrating effective contingency plans to minimize any impact on the trial timeline and patient experience. 

Supply and logistics project leaders examine each site’s processes for handling radioactive patient samples. For example, will samples need to be drawn in the nuclear medicine department or the oncology unit? Where will they be stored? In addition to vetting site procedures and workflow, supply chain project leaders work to provide sites with appropriate resources (within the on-site pharmacy) for preparing and storing RPTs, if needed. They must also consider what to do if a patient cancels their dosing visit. If possible, sites should be ready to dose another patient on short notice. 

• Simulate dry runs of product shipments.

We organize and execute comprehensive shipment dry runs, with radioactive product labeling, to ensure the materials move through airports and ground transportation systems as they will during the trial. This has proven to be a valuable tool for intricate international trials involving multiple regulatory jurisdictions and transport modalities. These detailed simulations—we recently completed several to Brazil and South Korea—allow us to identify and resolve unforeseen logistical challenges before they negatively impact the actual trial. The supply and logistics project manager also trains site personnel on the RPT’s specific handling, storage, and administration protocols to ensure consistent and compliant execution at each participating center. 

• Show unfailing respect for patients, providers, and site staff.

We respect providers’ and patients’ time and commitment to a trial by taking extraordinary steps to guarantee the timely arrival of IP. By planning in detail and pressure-testing our execution strategies, we reduce the administrative and operational burdens on site study staff. Also, we give patients a more streamlined and predictable experience of trial participation, which minimizes their anxiety and maximizes adherence. 

A reliable supply chain is an ethical and effective means of advancing RPT research. With proper orchestration, the last mile of RPT delivery should be the easiest, most reliable step—a reflection of the comprehensive, end-to-end strategic planning and collaborative execution that preceded it.

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