Radioisotopes in Medicine: Clinical Applications, Safety, and Regulatory Considerations

1. paź 13, 2025

The robust development of nuclear medicine depends on the availability of radioactive isotopes, some of which are used for diagnostic purposes (e.g., F-18, Tc-99m, I-123), while others are fit for therapy (I-131, Lu-177, Ra-223). However, their huge medical potential goes hand-in-hand with serious challenges in terms of safety, availability, and legislation.

What Are Radioisotopes and How Are They Used in Modern Medicine?

Radioisotopes (radionuclides) are species of chemical elements that undergo radioactive decay. In medicine, radioisotopes are essential for nuclear medicine, including diagnostic (PET, SPECT) and therapeutic procedures. The crucial role of the reliable supply of radioisotopes for public healthcare has been confirmed in the EU and FDA official documents.[1]^,[2]

The medical utility of a particular radioisotope depends on its source and preparation techniques, chemical affinity, half-life and the type of rays it emits, e.g., alpha, beta, gamma or beta-plus. The pharmacological properties of the final radiopharmaceuticals are also affected by ligands bound to the radionuclide atom/ion.

Diagnostic Applications: Commonly Used Radioisotopes in Nuclear Imaging (e.g., Tc-99m, F-18, I-123)

Gamma-emitting radioisotopes are mostly utilized in diagnostic procedures, as g rays cause relatively less damage and are easy to detect by gamma cameras, a.k.a. scintigraphs.

• Fluorine-18 is the most popular radionuclide used in PET scans. It emits positrons (b⁺ radiation). Almost immediately, the annihilation reaction occurs, which produces detectable amounts of gamma radiation.
• Metastable Technetium-99m is a nearly perfect radiotracer for SPECT scanning, as it emits 140.5 keV gamma radiation and has a half-life of ca. 6 hours. Most SPECT scans use Tc-99 m-based radiotracers.
• Radioactive iodine I-123 is the “diagnostic” iodine isotope. It has a half-life of ca. 13 hours and emits the 159 keV gamma rays. Like stable iodine, it accumulates in the thyroid gland, which makes it very suitable for SPECT scans of this particular organ.

Therapeutic Uses: Targeted Radiotherapy with Isotopes like I-131, Lu-177, and Ra-223

Alpha- and beta-radiation make more damage to living tissues than gamma rays, but their range of tissue penetration is much shorter. That is why a and b-emitting isotopes are used mainly in oncology to selectively destroy cancer cells.

• Iodine-131, unlike I-123, emits mostly b radiation and small quantities of g. It is used in the therapy of thyroid malignancies or hyperthyroidism[3]. When administered into the body, it accumulates selectively in the thyroid gland and destroys it. However, I-131 may also be traced by radiation cameras and is very useful in theranostic procedures.
• b-emitting Lutetium-177 is used to treat many types of cancer. For example, the drug Lutathera is registered for the treatment of somatostatin receptor-positive gastroenteropancreatic neuroendocrine tumors in Europe[4] and the USA[5].
• Radium-223 preferentially accumulates in the bones due to its chemical similarity to calcium. Ra-223 emits short-range alpha radiation, which makes it useful to target primary or metastatic bone cancers.[6]

Unique Challenges Associated with the Medical Use of Radioisotopes

Complex safety and efficacy evaluation

Radioisotopes differ from non-radioactive substances, as their activity depends upon both their chemical and nuclear properties. Both aspects must be evaluated jointly in terms of drug stability, safety, and efficacy. Therefore, the CROs must concomitantly observe the guidelines for the development of standard pharmaceuticals[7]^,[8] and the procedures governing the use of radioactive materials.

Global Regulatory Oversight: IAEA, EMA, FDA, and National Competent Authorities

The use of radioisotopes is strictly regulated on many levels. What makes the legislative landscape particularly challenging is its diversity. There are separate legal requirements for the USA and the EU (defined by the CFR & FDA[9] and EMA[10], respectively). The European clinical research of radiopharmaceuticals is regulated by both the EU 536/214 and the Euratom Directives. In the USA, clinical trials must be registered via the full IND (Investigational New Drug) procedure. However, an exception exists for known radiopharmaceuticals used in minimal doses and for diagnostic purposes only, namely the simplified course under the RDRC regulations (21 CFR 361.1). To help the researchers, some global nuclear NGOs (e.g., the IAEA and NEA) have published their own guidelines on radiopharmaceuticals, which are recommended but not legally binding. On top of that, many countries also require separate permissions from the local authorities. Finding a way in the legal maze may be daunting[11]. That is why you need an experienced CRO who knows how to navigate the intertwined regulatory network of nuclear medicine.

The choice of the right registration path is not always straightforward and may require a deep understanding of the legal, formal and medical nuances of a trial. Learn how we helped our client manage a similar problem.

Case description:

A client was planning to conduct a clinical trial testing a diagnostic radiotracer in the USA. As the tracer was intended solely for diagnostic procedures, the client opted for the shorter registration pathway under the RDRC program (21 CFR 361.1). However, after carefully analyzing the research design, we noticed that the trial included an evaluation of diagnostic efficacy, as well as bioavailability, distribution and dosimetry studies. This raised doubts as to whether the project fell under the 21 CFR 361.1 procedure. We therefore advised our client to consult the FDA regarding the questionable details. After receiving consent, we arranged and attended the consultation, presenting the trial plan and highlighting the uncertainties. The meeting concluded that the RDRC program was not applicable in this case, but that the committee would accept an abbreviated set of preclinical data as sufficient. We assisted our client in drafting and submitting the documentation for the IND procedure. This saved them from the initial rejection that would have occurred had they chosen the wrong procedural course, which would have caused a considerable delay to the project.

Radioisotopes in Clinical Trials: IMP Handling, Dosing, and Pharmacovigilance

Every Investigational Medicinal Product requires the procedures for proper handling, labeling and traceability, known as the IMP Accountability process[12]. The use of radioisotopes makes it even more complex, as the sponsor must account for properly equipped facilities, qualified personnel (including the Radiation Safety Officer), radioactive waste disposal and emergency procedures in place, in line with chemical, medical and radiation safety regulations.

The dosing of a radioisotope-containing IMP is always established according to the ALARA principle (As Low As Practically Achievable). The dosing schedules may be known or yet to be defined. In the latter case, it is the subject of the phase I or II of a clinical trial. In each case, the researchers must account for two sides of the drug activity:

• The pharmacologic properties of the radiopharmaceutical, which are particularly relevant for radiotherapeutics or theranostics (which often require higher doses).
• The biodistribution and radiation doses delivered to the organs calculated by dosimetry methods. This pertains mainly to the diagnostic radiotracers. Pharmacological properties are less relevant here, as the applied doses are usually minuscule.

Adverse effects (AEs) may result from misuse, a mistake in dosing, or an incorrect administration route. Regardless of the reason and severity, every adverse event must be properly handled and reported under pharmacovigilance procedures.[13] In the case of radioactive medicines, AEs may also affect the people living close to the patient, especially pregnant women and small children. Therefore, the pharmacovigilance liability extends to providing safe discharge procedures and comprehensive safety instructions for patients and their families.

Contact us to draft a Pharmacovigilance Agreement for your trial to ensure the safety of your patients and the swift flow of your research.

Manufacturing, Transport, and Storage: Compliance with GMP and Radiation Protection Guidelines

The main challenge in coordinating a radiopharmaceutical trial is securing a reliable chain of supply.[14] By nature, radioisotopes are unstable, so they cannot be stored or stockpiled. Therefore, the secure supply is based on the proximity of the sources (nuclear reactors or cyclotrons) or a reliable delivery system which meets the radiation safety standards (e.g., DOT/49 CFR in the USA; ADR in Europe and Asia; IATA rules for air transport). Sometimes the semi-finished products are transported and final molecules are prepared on-site[15]. Regardless of the option, the GMP procedures[16]^,[17] (e.g., vol. 4 of EudraLex guidelines) must be followed at every step.

Learn how Axcellant’s Nuclear Medicine & Imaging Core Lab expertise helped our client avoid obstacles in a large, multi-site research program.

Case description:

Our client was planning a multicenter clinical trial on a diagnostic radiopharmaceutical. However, at that time, the required radioisotope was only available from one source. Waiting for the manufacturing technology to be transferred to other countries would cause significant delays to the project. We therefore found a compromise to enable the trial to start and ensure its smooth continuation. Our international network of experts identified and selected contract manufacturing organizations (CMOs) that were able to implement the required technologies, and we initiated the procedures. At the same time, we coordinated an emergency supply chain of the radioisotopes from the original source. Transport was organized in full compliance with the Security Guidance on the Carriage of Class 7 Radioactive Material, ensuring just-in-time deliveries to the trial centers. The schedule was synchronized with the patient enrolment rate to avoid any waste or shortages until the secondary local sources were available. Our consultants supervised the entire process continuously to identify and resolve any issues as soon as they arose. Consequently, the client could start the trial without delay while the manufacturing technology transfer was still in progress.

Reach out to Axcellant if you are looking for a reliable CRO partner with in-depth, proven expertise in the field of nuclear medicine, which offers Integrated Digital-Driven Clinical Trial Solutions tailored to the exact needs of your clinical trial.

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[1] https://www.consilium.europa.eu/en/press/press-releases/2024/06/17/radioisotopes-for-medical-use-council-approves-conclusions

[2] https://www.fda.gov/drugs/our-perspective/our-perspective-fdas-role-helping-critical-medical-isotope-meet-sufficient-supply-us-first-time

[3] Wyszomirska A. Iodine-131 for therapy of thyroid diseases. Physical and biological basis. Nucl Med Rev Cent East Eur. 2012 Aug 28;15(2):120-3. PMID: 22936505. https://journals.viamedica.pl/nuclear_medicine_review/article/view/19586

[4]https://www.ema.europa.eu/en/medicines/human/EPAR/lutathera

[5] https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-lutetium-lu-177-dotatate-pediatric-patients-12-years-and-older-gep-nets

[6] Morris MJ, Corey E, Guise TA, Gulley JL, Kevin Kelly W, Quinn DI, Scholz A, Sgouros G. Radium-223 mechanism of action: implications for use in treatment combinations. Nat Rev Urol. 2019 Dec;16(12):745-756. doi: 10.1038/s41585-019-0251-x. Epub 2019 Nov 11. PMID: 31712765; PMCID: PMC7515774. https://pmc.ncbi.nlm.nih.gov/articles/PMC7515774

[7] https://health.ec.europa.eu/medicinal-products/clinical-trials/entry-application-clinical-trials-regulation_en

[8] https://www.fda.gov/patients/drug-development-process/step-3-clinical-research

[9] https://www.fda.gov/drugs/science-and-research-drugs/radioactive-drug-research-committee-rdrc-program

[10] 27 Jan 2022 EMA/CHMP/QWP/545525/2017 Rev. 2; Committee for Medicinal Products for Human Use (CHMP) Guideline on the requirements to the chemical and pharmaceutical quality documentation concerning investigational medicinal products in clinical trials. https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-requirements-chemical-and-pharmaceutical-quality-documentation-concerning-investigational-medicinal-products-clinical-trials-revision-2_en.pdf

[11] Decristoforo C, Neels O, Patt M. Emerging Radionuclides in a Regulatory Framework for Medicinal Products – How Do They Fit? Front Med (Lausanne). 2021 May 28;8:678452. doi: 10.3389/fmed.2021.678452. PMID: 34124109; PMCID: PMC8192700., https://pmc.ncbi.nlm.nih.gov/articles/PMC8192700/#s2

[12] Detailed Commission guidelines on good manufacturing practice for investigational medicinal products for human use, pursuant to the second subparagraph of Article 63(1) of Regulation (EU) No 536/2014, https://health.ec.europa.eu/document/download/a0b206a0-5788-406b-9e20-e0525b16e712_en?filename=guideline_adopted_1_en_act_part1_v3.pdf

[13] Martins S, Jesus Â, Suárez AM. Pharmacovigilance of Radiopharmaceuticals: Challenges and Opportunities. J Pharm Technol. 2024 Oct;40(5):257-259. doi: 10.1177/87551225241266172. Epub 2024 Jul 27. PMID: 39431063; PMCID: PMC11483832.

[14] https://euratom-supply.ec.europa.eu/activities/supply-medical-radioisotopes_en

[15] Hendrikse H, Kiss O, Kunikowska J, Wadsak W, Decristoforo C, Patt M. EANM position on the in-house preparation of radiopharmaceuticals. Eur J Nucl Med Mol Imaging. 2022 Mar;49(4):1095-1098. doi: 10.1007/s00259-022-05694-z. PMID: 35050391. https://pubmed.ncbi.nlm.nih.gov/35050391

[16] EudraLex, The Rules Governing Medicinal Products in the European Union, Volume 4. EU Guidelines to Good Manufacturing Practice. Medicinal Products for Human and Veterinary Use. Annex 3: Manufacture of Radiopharmaceuticals.  https://health.ec.europa.eu/document/download/bf281e1f-4897-469a-ba60-18d867b14a94_en?filename=2008_09_annex3_en.pdf

[17] Decristoforo C, Mikolajczak R, Naidoo C, Lapi S, Haddad F, Schmid DE, Gano L, Köster U, Stora T. To be GMP or not to be- a radionuclide’s question. EJNMMI Radiopharm Chem. 2025 Jul 10;10(1):42. doi: 10.1186/s41181-025-00369-0. PMID: 40637991; PMCID: PMC12246291.