SNMMI Clinical Trials Network Research Series for Technologists: An Introduction to Conducting Theranostic Clinical Trials

REVIEW OF PROTOCOL MANUALS

Clinical trials must undergo FDA-mandated phases to ensure that investigational radiopharmaceuticals are safe and effective and comply with all the required rules and regulations (3). Additionally, clinical trials approved by an institutional review board or the equivalent are conducted with the trial participants’ written informed consent. Each clinical trial has specific requirements, outlined in the primary protocol, and may include additional manuals such as the technical operations manual, imaging manual, and pharmacy manual. Clinical trials may require the use of FDA-approved radiopharmaceuticals for a nonapproved indication, such as using ⁶⁸Ga-DOTATATE and ¹⁷⁷Lu-DOTATATE for patients with newly diagnosed and recurrent glioblastoma (4). The NMT should review the appropriate trial manuals and identify the specific imaging parameters for the radiopharmaceutical—parameters that may differ from the clinical parameters. NMTs are encouraged to review the relevant sections of all provided manuals from a technical perspective and prepare to adhere to those requirements. Once all the manuals are reviewed, NMTs should advise the principal investigator regarding all preparations needed to conduct the protocol locally. If any potential barriers are identified, the NMT should support the primary investigator in communicating them to the multidisciplinary team and, if necessary, to the protocol sponsor to ensure that they are addressed and that a given study is feasible. Manuals should be reviewed and preparations completed before the site initiation visit and preparations confirmed before the first patient is enrolled. This proactive approach is critical to understanding the protocol requirements and developing a good local process.

Reviewing, comprehending, and correctly applying several manuals’ worth of protocol-specific information and detailed applications require adequate time and focus while developing local logistics with a multidisciplinary team for the clinical trial. Understanding the intricate complexities of a clinical trial is essential, but it can be challenging to recall multiple manuals’ worth of detailed information (5). One approach is to condense the technical requirements of the protocols into a local, site-specific day-of-infusion or day-of-imaging document. This document is not intended to replace sponsor-required documents or manuals but serves as a quick reference for the essential items of which an NMT needs to be aware. This local document may include such items as the subject identification number, cohort or phase the patient is enrolled in, number of therapeutic cycles, dosage amount (weight-based or fixed), administered and residual measurements, radiopharmaceutical-specific dose calibrator dial setting, duration of infusion, infusion timing, biologic sampling protocols (including any testing or storage requirements), requirements for scintigraphic imaging, and postinfusion radiation safety precautions.

The local document may also include contact information for pertinent staff, such as authorized users, medical physicists, electrocardiography staff, phlebotomists, radiation safety specialists, nurses, the primary investigator, referring physicians, study coordinators, statisticians, social workers, blood draw personnel (e.g., arterial lines increasingly need to be placed by interventional radiologists), and nuclear pharmacists or radiochemists at the radiopharmacy or production site.

These items and personnel (6) will vary with the clinical trial requirements and the clinical sites’ needs. As the clinical trial progresses, the data acquired may influence changes to the initial version of the protocol. Therefore, the NMT should be aware of any protocol addendums, memos, or protocol revisions to ensure compliance with the updated trial.

EQUIPMENT QUALIFICATIONS

Nuclear medicine instrumentation, both imaging and nonimaging, is an essential tool in the execution of a radiopharmaceutical clinical trial (7). Nuclear medicine imaging uses devices such as γ-cameras, hybrid PET scanners combined with either a CT scanner (PET/CT) or an MRI scanner (PET/MRI), and hybrid SPECT scanners combined with a CT scanner (SPECT/CT) to produce biodistribution images of the diagnostic radiopharmaceuticals in the body’s internal organs and tissues (8). Diagnostic imaging in a theranostic clinical trial helps with the selection of appropriate patients through confirmation of target expression on an initial scan and verification of radiopharmaceutical treatment response on follow-up scans. Nonimaging nuclear medicine instrumentation, such as dose calibrators, well counters, and ionization survey meters, is essential in supporting a theranostic radiopharmaceutical clinical trial. Nonimaging equipment should be calibrated for each clinical trial. For example, dose calibrators are essential for determining the activity administered to the patient, and well counters are essential for radiation safety and biologic sample counting. After therapeutic administration, ionization meters are routinely used to determine patient exposure rates for determination of and compliance with patient-release criteria.

The success of these therapies largely depends on accurate calibration and configuration of the instrumentation and adherence to the recommended quality control procedures. In radiopharmaceutical clinical trials, equipment qualification is essential to confirm that the results obtained are accurate and reliable. Clinical trials involve testing novel investigational drugs or therapies, and the data obtained from these trials are used to evaluate the safety and efficacy of the treatment. Any variability in the imaging results or dosing can lead to incorrect conclusions regarding the safety and efficacy of the treatment. Therefore, it is essential to qualify equipment as part of the clinical trial process.

MULTIDISCIPLINARY TEAM LOGISTICS

Establishing clear roles and responsibilities among a multidisciplinary team is central to a successful clinical trial. Multidisciplinary teams may include a primary investigator, multiple coinvestigators, clinical and data coordinators, NMTs, nurses, advanced practitioners, data specialists, medical physicists or dosimetrists, sponsor-appointed delegates, social workers, radiation safety personnel, statisticians, and authorized users (14). The NMT has unique insight into the technical aspects of radiopharmaceutical imaging and administration that can help bridge knowledge gaps across the multidisciplinary team. Before the first patient is enrolled, it is essential to meet with all multidisciplinary team members and identify which member is responsible for which portions or tasks within the protocol. Effective communication and accounting for these items will help alleviate any uncertainty around each staff member’s responsibility. These established roles and responsibilities must be documented on a protocol-specific delegation log for future reference and clinical trial compliance.

CLINICAL TRIAL ROAD MAP

Developing a locally created protocol-specific road map that outlines critical time points for complex clinical trials helps provide a concise, visual document that allows all members of the team and the patient to see what the protocol requires over time. Clinical road maps should be specific for each protocol and can be segmented to provide a general daily or weekly summary (15). The road map helps team members unfamiliar with nuclear medicine trials to better visualize the sequence of events and the specific protocol timelines. This clear understanding will help ensure that all members account for protocol-required criteria, avoid unnecessary delays, and collect good-quality data.

Therapeutic radiopharmaceuticals tend to be tolerated well by patients compared with systemic chemotherapy, and patients often experience moderately less severe and frequent side effects (16). Although there is always a potential for a reaction during or after infusion of the investigational radiopharmaceutical, identifying investigational product–induced reactions can be difficult because of the limited data available. There needs to be dedicated staff available to monitor the patient and to notify the primary investigator or the authorized user should any reactions occur. A clear and concise plan, for each protocol, details how to counteract minor or severe adverse reactions and is crucial for adequate patient care.

PROTOCOL PLANNING

Before the patient’s scheduled day of investigational radiopharmaceutical infusion, it is recommended that the NMT walk through the patient’s path related to the protocol and ensure that all required aspects of the trial are accounted for. The NMT should take this time to identify that all protocol-qualified equipment is in good operational order and ready for patient use. Performing protocol dry runs with as many front-line team members as possible will help identify areas or items that can be adjusted to simplify or improve workflow processes. Figure 1 provides a general overview for the NMT of the multiple clinical trial aspects to consider when performing a dry run. When paired with the local road map of the clinical trial, dry runs can aid in streamlining detailed tasks and help bring to light any unforeseen circumstances or identify an ambiguous responsibility. With the technical aspects of the protocol accounted for in the dry run, front-line staff can focus on collecting good-quality data while providing optimal patient care.

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FIGURE 1.

Streamlined depiction of common theranostic trial aspects.

DRUG PREPARATION AND DOSAGE MEASUREMENT

The processes for production, delivery, and dispensing of investigational radiopharmaceuticals are subject to a variety of regulations and standards set forth by federal and state agencies and standard-setting organizations including the FDA, the U.S. Nuclear Regulatory Commission, the Department of Transportation, and the U.S. Pharmacopeia (USP). These drugs may be prepared in a variety of ways, including onsite at a cyclotron facility or radiopharmacy or offsite commercially. Although radiopharmaceutical production regulations are beyond the scope of this article, a review of the quality control certificate of analysis and dispensing of the final drug product is pertinent.

On release of the radiopharmaceutical to the clinical site, the production site may send a certificate of analysis outlining the quality control acceptance attributes such as appearance, purity, pH, and bacterial endotoxin results. Other information listed on the certificate of analysis may include drug expiration time, drug activity at calibration time, drug volume, and drug storage requirements. The authorized user and NMT should review all these data on receipt of the radiopharmaceutical and immediately communicate any issues to the trial sponsor or production site. Failure to identify and report drug product issues can lead to patient safety concerns, alteration of the biodistribution of the radiopharmaceutical, or other clinical trial complications.

The radiopharmaceutical may be released to a clinical site in a pharmacy bulk package (vial) or in a patient-specific syringe. According to USP chapter <825>, all manipulations necessary to transfer the drug to the final container (e.g., syringe or vial) for administration to the clinical trial participant are considered to be dispensing and must follow all applicable criteria outlined in the chapter (17). A thorough understanding of USP chapter <825> is required for dispensing radiopharmaceuticals, especially those that require further manipulation (i.e., transfer of the drug product from the original container to another container for dispensing to the participant). On review of the chapter, each site should identify appropriate spaces and equipment and, when necessary, should train personnel. If the site cannot meet the dispensing requirements to comply with USP chapter <825>, it may desire to partner with an onsite or commercial radiopharmacy to help prepare the radiopharmaceutical for dispensing.

INTRAVENOUS ADMINISTRATION METHODS

The administering NMT and authorized user should carefully choose an infusion method that abides with the needs of the clinical trial, is safe for patient use, adheres to the as-low-as-reasonably-achievable radiation safety principle, and accurately identifies the start and end of a continuous therapeutic infusion. Good-quality theranostic data start with a safe, accurate, and precisely timed intravenous radiopharmaceutical infusion.

IMAGING DOSIMETRY FOR THE NMT

Imaging and biologic sample–based dosimetry can aid with identifying the critical components of theranostic trials, such as radiopharmaceutical localization, targeted lesion residence time, rate of excretion, and estimation of absorbed dose to critical organs (20). Determining the absorbed dose to targeted lesions and the critical organs can be achieved using radiopharmaceuticals that have a designated target for therapy and the ability to be imaged via SPECT/CT or PET/CT. Radionuclides with long physical half-lives, such as ¹⁷⁷Lu,¹³¹I, and ⁶⁷Cu, emit β-particles, which produce an intended therapeutic effect on the neoplastic lesion, but also emit γ-photons suitable for scintigraphic imaging. When linked to a bioconjugate, these radionuclides permit researchers to acquire multiple–time-point scintigraphic images and collect biologic samples over several hours or days after treatment. The NMT is key for acquiring these complex multiday acquisitions that provide valuable quantitative data (21). Through quantitative SPECT/CT or PET/CT acquisitions and pharmacokinetic mapping, medical physicists can analyze the dosimetry data to identify the optimal tumor-to-background ratio and the therapeutic radiopharmaceutical dosage that can safely be administered without causing toxicity to the patient. The ability to perform internal patient dosimetry and estimate the absorbed dose to critical organs is a distinctive attribute of theranostic radiopharmaceuticals (22). Control of the absorbed radiation dose to critical organs, especially bone marrow and kidneys, is vital for the safe and effective use of theranostic radiopharmaceuticals. Imaging and biologic sample collection–based dosimetry can be performed prospectively or retrospectively depending on the clinical trial application.

Before investigational radiopharmaceutical treatment, imaging dosimetry can be performed by administering a diagnostic amount of the therapeutic radiopharmaceutical or a surrogate diagnostic radiopharmaceutical that emits positrons or γ-photons. For example, positron-emitting ⁸⁹Zr nuclide and γ-emitting ¹¹¹In nuclide are often used as diagnostic radioactive elements because of their long physical half-lives of 78.4 and 67.2 h, respectively. The physical half-life of the diagnostic imaging tracer is typically paired with that of the therapeutic radionuclide to provide researchers with the opportunity for multiday dosimetry imaging in pretherapy analysis (23). Determining whether the investigational diagnostic radiopharmaceutical has a high affinity, low affinity, or no binding affinity to the targeted disease provides oncologists with detailed, noninvasive data on biologic distribution. Pretherapy dosimetry imaging provides an overview of the biologic distribution and excretion of the investigational radiopharmaceutical. Pretherapy imaging aids in determining the optimal therapeutic dosage to be administered and can help researchers predict the absorbed dose to the biologic target and critical organs. Finally, exposure-rate measurements of patient or pretherapy dosimetry can be used to estimate the patient-specific effective half-life that can be used in determination of patient-release considerations.

Retrospective dosimetry, which is performed after the patient has received a therapeutic amount of radiopharmaceutical, also has clinical value because it can inform the clinical provider about expected organ doses in subsequent cycles of treatment. For example, performing internal dosimetry after the first of a 4-cycle ¹⁷⁷Lu-DOTATATE regimen can inform on the dose contributions from cycles 2–4. Theranostic radiopharmaceuticals are unique in that the treatment can be imaged, providing a good scintigraphic representation of the biologic distribution and localization of the radiopharmaceutical.

Whether dosimetry is performed before or after therapeutic administration will be protocol-specific. The NMT needs to allocate sufficient time to identify the detailed requirements of each approach. Investigational radiopharmaceuticals should be measured using the protocol-approved dose calibrator with the established dial setting. Accurate measuring and recording of the total administered radioactivity are crucial to calculating the absorbed organ and tumor dose. Patients should be imaged using the protocol-approved PET/CT or SPECT/CT scanner and using the approved protocol imaging parameters. If multiple–time-point images are a protocol requirement, the NMT needs to acquire the patient images similarly at each time point. Imaging the patient in the same manner at each time point will help reduce any variability in count rate statistics. The NMT is a crucial contributor to collecting dosimetry data, and all efforts to reduce imaging inconsistencies should be made.

RADIATION SAFETY PRECAUTIONS

Regulations are set to limit the amount of radiation to which an individual member of the public can annually be exposed, including exposure from medical procedures. Properly monitoring and managing radiation exposure from patients who have undergone radiopharmaceutical therapies are essential to ensuring the health and safety of patients, caregivers, and health care professionals.

The release of a patient after therapeutic administration involving radioactive materials requires adherence to federal and state regulations, such as proposed revision 2 of Nuclear Regulatory Commission Regulatory Guide 8.39, “Release of Patients Administered Radioactive Material” (24). This guideline outlines the specific procedures that must be followed to ensure the safe release of patients. These procedures include monitoring radiation levels in the patient, documenting the patient’s exposure, and ensuring that the patient’s exposure levels do not exceed regulatory limits.

Per the guideline, licensees are authorized to release individuals who have been administered radiopharmaceuticals if the total effective dose-equivalent to any other individual from exposure to the released individual is not likely to increase by 5 mSv (500 mrem). It requires licensees to provide the discharged radioactive patient with instructions on recommended actions if the total effective dose-equivalent to any other individual is likely to exceed 1 mSv (100 mrem). Furthermore, it may also require the licensees to maintain a record (for 3 y after the date of release, depending on the release conditions and justifications used) of the basis for authorizing the release of an individual.

Calculation of the activities at which patients can be released was based on the method described in report 37 of the National Council on Radiation Protection and Measurements, “Precautions in the Management of Patients Who Have Received Therapeutic Amounts of Radionuclides” (25). The assumptions and conditions for the calculations, such as the occupancy factor, are described. The various options to release a radioactive patient generally fall into 3 categories: release based on administered activity, release based on measured dose rate, and release based on patient-specific dose calculations. The guideline (24) provides tabulated values of activity and dose rates, at 1 m from the patient, below which patients can be released without receiving specific instructions. The guideline offers half-lives and exposure rate constants for a comprehensive list of radionuclides that the licensee can use for patient-specific calculations. Example calculations are also provided.

It is likely that many of the newer radiopharmaceuticals, especially α-therapy, are not yet listed in the precalculated tables. In these scenarios, the formalism described to compute patient-specific calculations would need to be used. Also, there are some limitations present, in that the issues related to fractionated radiopharmaceutical therapy are not considered. For example, DOTATATE standard therapy involves 4 cycles of ¹⁷⁷Lu-DOTATATE and is based on the assumption that the total effective dose-equivalent to any individual is not likely to increase by 5 mSv or 1.25 (=5/4) mSv per cycle. There are no straightforward answers, and there is an opportunity to contribute to the body of knowledge needed to treat patients with radiopharmaceuticals.

β- and α-particles are 2 ionizing radiation types that pose challenges in radiation safety practices. β-particles are high-energy electrons that can penetrate the skin and damage cells. α-particles, conversely, are helium nuclei and are more massive than β-particles. They have low penetration power and can travel only a few centimeters in air and a few microns in human tissue. However, they are highly ionizing and can cause significant damage to cells if they enter the body through inhalation, ingestion, absorption, or open wounds. The management of β- and α-particles in health care settings requires specific safety measures. For example, use of appropriate protective equipment, such as gloves and masks, can prevent inhalation or ingestion of α-particles. Additionally, proper disposal of radioactive waste is critical in preventing the spread of contamination.

Radiation safety practices are crucial in health care, particularly in releasing patients who have undergone therapeutic administrations involving radioactive materials. The as-low-as-reasonably-achievable principle and Nuclear Regulatory Commission Regulatory Guide 8.39 provide guidance on maintaining exposure levels as low as reasonably achievable and ensuring the safe release of patients. By adhering to these safety practices, health care professionals can protect the health and safety of patients and themselves.

DISCLOSURE

S. Cheenu Kappadath has received research support from Sirtex Medical, Boston Scientific, and ABK Biomedical and has served as a consultant for Boston Scientific and Terumo Medical. No other potential conflict of interest relevant to this article was reported.