Radiation therapy was first used to treat cancer more than a century ago, and nearly half of all cancer patients still receive it at some point during their treatment.1 Historically, most radiation therapy was given by delivering ionizing beams of radiation from outside the body, but with advances in the field of nuclear medicine, radionuclides are increasingly being used to deliver localized radiation to cancer cells. In this blog, we explore a brief history of radiopharmaceuticals and discuss best practices for planning and executing clinical trials utilizing these novel drugs to treat cancer.
Brief history of radiotherapeutics
Radiopharmaceuticals are a class of drugs that include both diagnostic agents such as contrast agents, molecular imaging probes or tracers and therapeutic agents that treat disease.2 In oncology, diagnostic radiopharmaceuticals have been widely used to detect, diagnose, or stage disease; determine treatment eligibility; or monitor therapeutic response. Therapeutic radiopharmaceuticals, also called radiotherapeutics, are designed with a ligand-linker-radioisotope construct to bind selectively to specific receptors on or within target cells and deliver cytotoxic radioisotopes. A growing area of interest in radiopharmaceuticals is radiotheranostics, which combine a targeted therapeutic with a targeted diagnostic using either the same isotope with multiple emitting capacities or different isotopes to target tumor cells while sparing healthy tissues.
The concept of radiotherapeutics is not new—for example, radioactive iodine has long been used to treat thyroid cancer, with a dramatic impact on outcomes in patients with metastatic disease.3 In the early 2000s, the US Food and Drug Administration (FDA) approved two different radiotherapeutics for relapsed or refractory non-Hodgkin lymphoma, though neither gained significant clinical traction or commercial success. In 2013, the FDA approved radium-223 (Xofigo®) for patients with castration-resistant prostate cancer, symptomatic bone metastases, and no known visceral metastatic disease. Since then, the agency has also approved radiotherapeutics for neuroendocrine tumors, pheochromocytoma and paraganglionoma and mCRPC.4
Over the past decade, the field of radiotherapeutics has seen rapid development, driven mainly by advances in the fields of radioisotope-based therapies, multimodality bioimaging technology, nanotherapeutics, and interventional oncology.2 Further, basic science research into new targets, targeting ligands, linkers, and radioisotopes is expanding opportunities for development. Researchers have also begun to target new indications and early-stage cancers rather than end-stage disease that is refractory to other treatments.2
Key considerations and best practices for radiotherapeutic clinical trials
Despite rapid progress in the field of radiotherapeutics, clinical development challenges remain as the radioactive nature of these products often compounds the complexity inherent in oncology study design and execution. Thus, radiotherapeutic studies require detailed planning and management around regulations, supply chain and logistics, and site and patient selection. At Premier Research, we have translated the lessons learned from our experience in conducting radiotherapeutic trials into best practices for study planning and execution.
Regulatory Considerations
Regulatory requirements for radiotherapeutics vary across countries and jurisdictions. In the US, both the US Food and Drug Administration (FDA) and the Nuclear Regulatory Commission have regulatory oversight of radiotherapeutics and the pathways to market approval are the same as for standard pharmaceuticals. In the EU, radiotherapeutics are regulated under Directive 2001/83/EC and the process of their development and production is regulated by a pool of directives, regulations, guidelines, and guidance documents.5 Member States may also have their own regulatory frameworks and constraints. Understanding this heterogeneity—along with specificities regarding site radioactivity licenses—is essential for designing clinical trials that generate the data necessary to support submission and approval.
Supply Chain and Logistics
There is no one-size-fits-all approach, and each investigational product involves its own set of challenges with respect to the logistics involved in manufacturing, distribution, and administration. For certain products, particularly those with short half-lives, it may be possible for radiolabeling to be performed locally to facilitate timely production and use, mitigating the risk of radioactive decay. With such on site manufacturing, it is critical to ensure that processes are in place to guarantee the quality of the final product.
In addition, limited manufacturing locations, constrained availability of isotopes, their half-life and sources can cause manufacturing bottlenecks. Thus, it is important to have a coordinated scale-up process in place. One of the nuances of using a drug with a relatively short half-life is that the dose administered is dependent upon the time elapsed between the date of manufacture and the date of administration. Delays in product shipment could result in radioactive decay during transit, causing downstream delays in patient treatment due to insufficient active drug. Thus, expedited shipping and tightly coordinated logistics at the site are pivotal for mitigating potential radioactive decay issues.
Tracking radioactive investigative products from the time of manufacture to shipping and receipt requires carefully choreographed logistics. To ensure safe, appropriate management of IMPs, it is critical to train site staff and provide clear instructions on communication pathways and timelines for maintaining on-site stock levels.
Site & Patient Considerations
The pool of eligible sites for clinical trials using radiotherapeutics may be smaller than other oncology studies due to the need for licenses to handle radioactive materials and specific site imaging equipment. Moreover, the use of radioactive substances is highly regulated and requires interdisciplinary teams with standardized and efficient protocols.
When assessing site feasibility, it is essential to involve all stakeholders and to understand the flow of IMP, patients, study assessments, and samples at each site. Understanding site-level standard operating procedures—and supplementing them with study-specific processes as necessary—ensures safe handling of radiolabeled products and adherence to the study protocol. Sites should be provided with guidelines and materials for managing IMP supply, storage, preparation and administration and handling any waste products. It may also be prudent to review site activation timelines against projected enrollment rates to ensure alignment.
Radiotherapeutic studies may face recruitment challenges due to public perception and fear of radioactivity. Potential study participants may worry about how the use of radioactive material will affect them and those with whom they interact, including family members, friends, caregivers, and even pets. It is vital to educate patients and address commonly asked questions about radiotherapeutics—including potential impact on reproductive ability—and provide information on how to manage exposure.
Given the limited availability of sites that are equipped to conduct radiotherapeutic studies, clinical trial participants may have to travel long distances for site visits and study assessments. As their bodily fluids may continue to be radioactive following drug administration, they may also have to deal with managing and disposing of waste products. Consequently, sponsors should focus on opportunities to limit patient and caregiver burden and making site visits as efficient as possible.
Imaging and Laboratory Considerations
Imaging is integral to the execution of clinical trials involving radiotherapeutics. Therefore, calibration of all imaging equipment is a prerequisite to scanning the first patient. For studies using central imaging analysis, testing of software compatibility and troubleshooting should be completed prior to site activation to prevent delays. Clear communication pathways should be established to ensure effective management of scan uploading for timely analysis. In addition, image tracking and metric reporting responsibilities should be clearly defined at the outset and ongoing image reconciliation throughout the study is recommended.
There are few central labs with the specialized capabilities required to receive and handle radiolabeled samples. Identifying these labs and implementing processes for shipping and receiving these samples ensures safe, timely handling and processing.
Key Takeaway
Radiotherapeutics are an emerging and expanding class of drugs, especially in oncology. Clinical trials in the realm of radiotherapeutics are complex and require careful coordination and collaboration among interdisciplinary teams. Working with a partner who has experience in radiopharmaceutical studies can help sponsors anticipate and manage risk and plan for study success. With dedicated team members experienced in radiotherapeutic clinical trials, Premier Research can leverage our deep expertise and extensive network of vendors to ensure studies are completed on-time and on-budget, with high quality data, to help innovators bring these breakthrough treatments to the patients who need them.
[1] National Cancer Institute. Radiopharmaceuticals: Radiation Therapy Enters the Molecular Age, October 26, 2020. Available at https://www.cancer.gov/news-events/cancer-currents-blog/2020/radiopharmaceuticals-cancer-radiation-therapy.
[2] USP. FAQs: <825> Radiopharmaceuticals. Available at https://www.usp.org/frequently-asked-questions/radiopharmaceuticals.
[3] Hermann K, et al. Radiotheranostics: a roadmap for future development. Lancet Oncol. 2020;21(3):e146-156.
[4] Cancer Treatment Centers of America. Radiopharmaceuticals designed to take radiation directly to the cancer, May 27, 2021. Available at https://www.cancercenter.com/community/blog/2021/05/radiopharmaceuticals-cancer-treatments.
[5] Decristoforo D, Neels O, Patt M. Emerging radionuclides in a regulatory framework for medicinal products – how do they fit? Front Med. 2021;8:678452.
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