Position paper to facilitate patient access to radiopharmaceuticals: considerations for a suitable pharmaceutical regulatory framework.

BACKGROUND: Nuclear medicine has made enormous progress in the past decades. However, there are still significant inequalities in patient access among different countries, which could be mitigated by improving access to and availability of radiopharmaceuticals. MAIN BODY: This paper summarises major considerations for a suitable pharmaceutical regulatory framework to facilitate patient access to radiopharmaceuticals. These include the distinct characteristics of radiopharmaceuticals which require dedicated regulations, considering the impact of the variable complexity of radiopharmaceutical preparation, personnel requirements, manufacturing practices and quality assurance, regulatory authority interfaces, communication and training, as well as marketing authorisation procedures to ensure availability of radiopharmaceuticals. Finally, domestic and regional supply to ensure patient access via alternative regulatory pathways, including in-house production of radiopharmaceuticals, is described, and an outlook on regulatory challenges faced by new developments, such as the use of alpha emitters, is provided. CONCLUSIONS: All these considerations are an outcome of a dedicated Technical Meeting organised by the IAEA in 2023 and represent the views and opinions of experts in the field, not those of any regulatory authorities.

A new two-strip TLC method for the quality control of technetium-99m mercaptoacetyl-triglycine (99mTc-MAG3).

BACKGROUND: 99mTc-mercaptoacetyl-triglycine (99mTc-MAG3) has been used for dynamic renal imaging since about 30 years. Free pertechnetate (99mTcO4), colloidal 99mTc ((99mTcO2)n), 99mTc-tartrate (precursor), precomplexes (99mTc-(MAG3)x) and lipophilic 99mTc-MAG2 are the main radiochemical impurities that may occur in the preparation. The total amount of these impurities has to be identified before release of the product for patient administration to guarantee patient safety and good image quality. The European Pharmacopoeia suggests a method based on high-pressure liquid chromatography analysis in combination with a paper chromatography. This analytical method is time consuming, expensive and requires specially trained technicians. As a consequence, it is not widely applied in nuclear medicine radiopharmacies. RESULTS: We developed a simple method for radiochemical purity testing of 99mTc-MAG3. The method is based on thin layer chromatography with two strips to be developed in parallel. Method validation was carried out in comparison to the official methods of the companies and to the European Pharmacopoeia method. It was tested on specificity, accuracy, robustness and precision. CONCLUSION: The proposed method is able to identify and quantify the sum of all impurities occurring in the preparation, respecting the acceptance criteria for the radiochemical purity defined by the official methods. Hydrophilic and lipophilic compounds are identified separately and results are obtained within less than 20 minutes. Our method is simple, cost effective, fast and is suitable for employing dose calibrators or radiometric scanners.

Identification, characterization and suppression of side-products formed during the synthesis of high dose 68Ga-DOTA-TATE.

In the course of the establishment of (68)Ga-DOTA-TATE production for clinical use a shoulder comprising presumably several impurities was observed in the chromatogram of the analytical radio-HPLC. LC-MS/MS results support the hypothesis that some of these radioimpurities are radiolytic oxidation by-products of (68)Ga-DOTA-TATE. A new HPLC method was developed for quality control of (68)Ga-DOTA-TATE. Significant improvement on the radiochemical purity of (68)Ga-DOTA-TATE was achieved by the addition of ascorbic acid or ethanol to the reaction mixture.

Clinical value of a combined multi-phase contrast enhanced DOPA-PET/CT in neuroendocrine tumours with emphasis on the diagnostic CT component.

OBJECTIVE: To assess the clinical value of multi-phase, contrast-enhanced DOPA-PET/CT with emphasis on the diagnostic CT component in patients with neuroendocrine tumours (NET). METHODS: Sixty-five patients with NET underwent DOPA-cePET/CT. The DOPA-PET, multi-phase CT and combined DOPA cePET/CT data were evaluated and diagnostic accuracies compared. The value of ceCT in DOPA cePET/CT concerning lesion detection and therapeutic impact was evaluated. Sensitivities, specificities and accuracies were calculated. Histopathology and clinical follow-up served as the standard of reference. Differences were tested for statistical significance by McNemar's test. RESULTS: In 40 patients metastatic and/or primary tumour lesions were detected. Lesion-based analysis for the DOPA-PET showed sensitivity, specificity and accuracy of 66%, 100% and 67%, for the ceCT data 85%, 71% and 85%, and for the combined DOPA cePET/CT data 97%, 71% and 96%. DOPA cePET/CT was significantly more accurate compared with dual-phase CT (p < 0.05) and PET alone (p < 0.05). Additional lesion detection was based on ceCT in 12 patients; three patients underwent significant therapeutic changes based on the ceCT findings. CONCLUSION: DOPA cePET/CT was significantly more accurate than DOPA-PET alone and ceCT alone. The CT component itself had a diagnostic impact in a small percentage but contributed to the therapeutic strategies in selected patients.

Transporters involved in the hepatic uptake of (99m)Tc-mebrofenin and indocyanine green.

BACKGROUND & AIMS: (99m)Tc-mebrofenin hepatobiliary scintigraphy (HBS) and the indocyanine green (ICG) clearance test are used for the assessment of hepatic function before and after liver surgery. The hepatic uptake of (99m)Tc-mebrofenin and ICG is considered similar to the uptake of organic anions such as bilirubin and bile acids. Little is known about hepatic uptake mechanisms of both compounds and recent evidence suggests that the hepatic transporters for ICG and (99m)Tc-mebrofenin are distinct. The aim of this study was to identify the specific human hepatic transporters of (99m)Tc-mebrofenin and ICG. METHODS: The uptake of (99m)Tc-mebrofenin was investigated in cRNA-injected Xenopus laevis oocytes expressing human OATP1B1, OATP1B3, OATP2B1, or NTCP. Chinese hamster ovary (CHO) cells stably expressing OATP1B1, OATP1B3, OATP2B1, or NTCP were used as a mammalian expression system. ICG transport into CHO cells was additionally imaged with confocal microscopy. RESULTS: We demonstrated that OATP1B1 and OATP1B3 are involved in the transport of (99m)Tc-mebrofenin. OATP1B1 showed an approximately 1.5-fold higher affinity for (99m)Tc-mebrofenin compared to OATP1B3. ICG is transported by OATP1B3 and NTCP. CONCLUSIONS: The transporter specificity of (99m)Tc-mebrofenin and ICG partially overlaps as both compounds are transported by OATP1B3. (99m)Tc-mebrofenin is also taken up by OATP1B1, whereas ICG is additionally transported by NTCP.

18F-fluoride PET/CT for detection of sacroiliitis in ankylosing spondylitis.

PURPOSE: The aim of this study was to evaluate the performance of (18)F-fluoride-PET/CT (PET/CT) for the diagnosis of sacroiliac joint (SIJ) arthritis in patients with active ankylosing spondylitis (AS). METHODS: Included in the study were 15 patients with AS according to the modified New York criteria (AS group) and with active disease and 13 patients with mechanical low back pain (MLBP; control group) who were investigated with whole-body (18)F-fluoride PET/CT. The ratio of the uptake in the SIJ and that in the sacrum (SIJ/S) was calculated for every joint. RESULTS: The mean SIJ/S ratio of 30 quantified joints in the AS group was 1.66 (range 1.10-3.07) with PET/CT, and the mean SIJ/S ratio of 26 quantified joints in the MLBP group was 1.12 (range 0.71-1.52). The area under the receiver operating characteristic curve for SIJ arthritis was 0.84. With plain radiography as a the gold standard and taking an SIJ/S ratio of >1.3 as the threshold, the sensitivity, specificity and accuracy on a per patient basis were 80%, 77% and 79%, respectively. On a per SIJ basis, the greatest sensitivity (94%) was found in grade 3 sacroiliitis (n = 16). CONCLUSION: Our results suggest that quantitative (18)F-fluoride PET/CT may play a role in the diagnosis of sacroiliitis in active AS and is an alternative to conventional bone scintigraphy in times of molybdenum shortage.

Therapeutic impact of [(18)F]fluoride positron-emission tomography/computed tomography on patients with unclear foot pain.

PURPOSE: To evaluate the therapeutic impact of [(18)F]fluoride positron-emission tomography/computed tomography ([(18)F]fluoride PET/CT) imaging on patients with unclear foot pain. METHODS: Twenty-eight patients were prospectively included in this study. Therapeutic management was defined by two experienced dedicated foot surgeons before and after [(18)F]fluoride PET/CT imaging. Twenty-six patients underwent cross-sectional imaging [CT, magnetic resonance (MR)] prior to PET/CT. A retrospective analysis of the magnetic resonance imaging (MRI) diagnoses was performed when a therapy change occurred after PET/CT imaging. RESULTS: In 13/28 (46%) patients therapeutic management was changed due to PET/CT results. Management changes occurred in patients with the following diagnoses: os trigonum syndrome; sinus tarsi syndrome; os tibiale externum syndrome; osteoarthritis of several joints; non-consolidated fragments; calcaneo-navicular coalition; plantar fasciitis; insertional tendinopathy; suggestion of periostitis; neoarticulations between metatarsal bones. Os trigonum, os tibiale externum, subtalar osteoarthritis and plantar fasciitis were only seen to be active on PET/CT images but not on MR images. CONCLUSION: [(18)F]fluoride PET/CT has a substantial therapeutic impact on management in patients with unclear foot pain.