Radiopharmaceuticals present a distinct set of development and regulatory challenges. These agents can be used for both diagnostic imaging and targeted radiotherapy. They combine radioactive isotopes with pharmaceutical and biological compounds, requiring sponsors to address complex intersections of chemistry, biology, physics, and regulatory science. While the field is growing rapidly, particularly in oncology and neurology, the path from concept to clinical trials to FDA approval for use is far from routine.
Ongoing innovation in radiopharmaceutical product development is driving significant advancements in nuclear medicine, with numerous clinical trials and research initiatives currently underway to improve imaging, therapy, and patient outcomes.
Facet Life Sciences supports radiopharmaceutical product developers through the entire regulatory process. This includes everything from early strategy, nonclinical, and clinical study planning to agency interactions and submission management. If you are preparing to bring a new diagnostic, therapeutic, or diagnostic-therapeutic pair to the US market, here are the key considerations you cannot afford to overlook.
Identifying Efficacy Measures and Standard of Truth for a Diagnostic
Unlike traditional drugs, the efficacy of a diagnostic radiopharmaceutical is often based on how well it visualizes or targets a biological structure. The radioactive molecules must be detectable in imaging studies to accurately assess their performance. This requires careful selection of measurable endpoints. For diagnostic agents, that usually means comparing imaging results against a “truth standard,” a reference method that establishes whether the target condition is truly present.
In practice, establishing a valid standard of truth against which a novel diagnostic imaging agent is evaluated can be challenging. In oncology, histopathology most often serves as the standard of truth, but it is not foolproof. For example, tissue confirmation is not always possible (e.g., most patients are not willing to undergo brain biopsies!), and even when it is possible, it can be inaccurate if the wrong tissue is sampled. Some Sponsors try to use another FDA-approved imaging agent as the standard of truth, but this approach can be problematic in that there are no FDA-approved agents that are 100% sensitive and 100% specific. So, if you don’t get agreement in the results of your imaging agent and the approved agent, is it because your agent doesn’t work, the FDA-approved agent is better, or your agent is better? The issues are equally complex outside cancer indications. For example, it is most common not to have a universally accepted truth standard for diseases like arthritis, depression, anxiety, or addictions. In these situations, regulatory and clinical teams must propose alternative strategies to FDA in order to assess the diagnostic performance or efficacy of the radiopharmaceutical product. This can involve multiple discussions with the Agency until an agreement can be reached.
Fortunately, Facet has a proven track record of success helping diagnostic imaging developers propose standards of truth (or measures of agreement, where no standard of truth exists), to establish efficacy that meet FDA expectations and are meaningful in the context of disease. The faster you can come to an agreement with FDA on your comparator in your clinical trial, the faster you will be able to proceed into the clinic with confidence.
Developing and Implementing an Imaging Charter
FDA expects a formal Imaging Charter for all diagnostic and therapeutic radiopharmaceutical clinical trials. The imaging charter defines the specific details for how imaging will be performed, read, stored, and analyzed.
The charter should specify reader training, image acquisition protocols, image transfer procedures, re-imaging requirements, blinding procedures, and adjudication pathways. It must also anticipate variability across study sites and plan for inter-reader consistency.
If imaging data is not collected and interpreted under controlled (and blinded) conditions, it risks being rejected by FDA as non-credible. Facet works with Sponsors to draft Imaging Charters that are aligned with industry best practices and FDA feedback, ensuring defensible, high-quality imaging data that supports the product’s intended use.
Drug Manufacturing Controls and Stability Requirements
As was discussed in the “Tinker to Treasure” webinar, radiopharmaceutical companies must ensure that their analytical methods and manufacturing processes early in development are ‘suitable for use’. It’s not required to be fully compliant with GMP standards. Early in development, the focus is on proving that the methods and processes are reliable and scalable. However, it’s also critical for the developer to build in quality controls into the process to avoid delays later in development.
Radiopharmaceutical manufacturing must ultimately comply with Current Good Manufacturing Practices (CGMP). Facilities must validate not only the purity and identity of each batch but also the timing of synthesis, labeling, and release.
Stability testing becomes a critical issue. For diagnostic agents with extremely short half-lives (such as 11C-choline), traditional long-term stability studies are impractical. Instead, manufacturers may use an approach that combines batch-to-batch consistency data with well-documented synthesis and decay profiles.
FDA still expects validated methods for assessing purity, radiochemical identity, specific activity, and residual solvents. If the agent is intended for commercial distribution, particularly across state lines, additional requirements often apply with respect to packaging, transport, and expiration dating.
Facet supports sponsors in compiling and submitting the required Chemistry, Manufacturing, and Controls (CMC) documentation, tailored to the specific isotope and dosage form, to support both IND and NDA/BLA packages. This includes guiding development of process validation plans and identifying stability data packages that meet FDA expectations.
Mandatory Labeling of Product Radioactivity
Radiopharmaceutical labels must include clear and accurate information about radioactivity content at a specific time point (often referred to as the “calibration time”), as well as instructions for calculating decay. Accurate labeling is essential because the energy of the emitted photons from the radiolabeled molecule determines the effectiveness of imaging and detection. FDA-mandated information includes:
- The amount of radioactivity per unit volume
- The calibration date and time
- Storage conditions and expiration time
- Safety warnings specific to the isotope
These details are required on both the radiopharmaceutical product container label and the package insert. Labeling errors can lead to increased costs associated with destruction of product, compliance issues, or even delays in approval.
Each product has unique labeling needs tied to the radioactive decay profile, formulation, and clinical use. Facet helps teams tailor their labeling content and format, aligning with FDA regulations and guidances.
Facet Helps Get You To and Through FDA Faster
Bringing a diagnostic, therapeutic, or diagnostic therapeutic pair into the clinic and ultimately to the US market requires more than clinical promise. It demands a development plan that anticipates FDA expectations, avoids common pitfalls, and generates data that is both credible and actionable. Each piece of the development puzzle must align.
With deep experience in diagnostic and therapeutic radiopharmaceutical development, Facet can help you define your regulatory path, engage with FDA strategically, and advance toward approval with greater confidence and speed.
Explore our Radiopharmaceutical Development Services to Learn More
gET sOCIAL