Summary Basis of Decision for NETVision
Review decision
The Summary Basis of Decision explains why the product was approved for sale in Canada. The document includes regulatory, safety, effectiveness and quality (in terms of chemistry and manufacturing) considerations.
Product type:
Summary Basis of Decision (SBD) documents provide information related to the original authorization of a product. The SBD for NETVision is located below.
Recent Activity for NETVision
SBDs written for eligible drugs approved after September 1, 2012 will be updated to include post-authorization information. This information will be compiled in a Post-Authorization Activity Table (PAAT). The PAAT will include brief summaries of activities such as submissions for new uses of the product, and whether Health Canada's decisions were negative or positive. PAATs will be updated regularly with post-authorization activity throughout the product's life cycle.
Summary Basis of Decision (SBD) for NETVision
Date SBD issued: 2022-05-26
The following information relates to the new drug submission for NETVision.
Gallium (68Ga) Oxodotreotide
Drug Identification Number (DIN):
- DIN 02525542 - ≤122 MBq/mL gallium (68Ga) oxodotreotide, solution, intravenous administration
Canadian Molecular Imaging Probe Consortium (CanProbe)
New Drug Submission Control Number: 248874
On February 24, 2022, Health Canada issued a Notice of Compliance to the Canadian Molecular Imaging Probe Consortium (CanProbe) for the diagnostic radiopharmaceutical NETVision.
The market authorization was based on quality (chemistry and manufacturing), non-clinical (pharmacology and toxicology), and clinical (pharmacology, safety, and efficacy) information submitted. Based on Health Canada’s review, the benefit-risk profile of NETVision is favourable for use with positron emission tomography (PET), as an adjunct to other diagnostic tests, for the detection and localization of somatostatin receptor-positive neuroendocrine tumours (NETs).
1 What was approved?
NETVision, a diagnostic radiopharmaceutical, was authorized for use with positron emission tomography (PET), as an adjunct to other diagnostic tests, for the detection and localization of somatostatin receptor-positive neuroendocrine tumours (NETs).
NETVision is not authorized for use in pediatric patients (<18 years of age), as its safety and efficacy have not been established in this population.
Clinical studies of gallium (68Ga) oxodotreotide in the literature do not provide sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. To date, published reports of clinical experience have not identified differences in the responses between the elderly and younger patients.
NETVision (≤122 MBq/mL gallium [68Ga] oxodotreotide) is presented as a solution. In addition to the medicinal ingredient, the solution contains ethanol and phosphate-buffered saline.
The use of NETVision is contraindicated in patients who are taking disulfiram. NETVision is also contraindicated in patients who are hypersensitive to this drug or to any ingredient in the formulation, including any non-medicinal ingredient, or component of the container.
The drug product was approved for use under the conditions stated in its Product Monograph taking into consideration the potential risks associated with its administration. The NETVision Product Monograph is available through the Drug Product Database.
For more information about the rationale for Health Canada's decision, refer to the Clinical, Non-clinical, and Quality (Chemistry and Manufacturing) Basis for Decision sections.
2 Why was NETVision approved?
Health Canada considers that the benefit-risk profile of NETVision is favourable for use with positron emission tomography (PET), as an adjunct to other diagnostic tests, for the detection and localization of somatostatin receptor-positive neuroendocrine tumours (NETs).
Neuroendocrine tumours are the second most common neoplasm of the diffuse endocrine system and represent a diverse and uncommon group of malignancies. In Canada, the incidence of NETs is approximately 2 to 6 per 100,000 people. Neuroendocrine tumours arise from neuroamine and polypeptide hormone-secreting neuroendocrine cells and typically present with non-specific symptoms or remain asymptomatic until later stages of disease. Diagnosis is difficult, and given that it is often not confirmed until patients have progressed to late stages of disease, limited therapeutic options are available. Imaging methodologies capable of detecting smaller lesions at earlier stages of disease are needed.
Neuroendocrine tumours are a heterogeneous disease characterized by the overexpression of somatostatin receptors (SSTRs). NETVision (gallium [68Ga] oxodotreotide) is a radiopharmaceutical used in the detection and localization of SSTR-positive tumours like NETs. It consists of an octreotate (TATE) moiety that binds to SSTRs, which is conjugated using a DOTA chelator to 68Ga, a positron (β+) emitting radionuclide with an emission yield that allows PET imaging.
Current standard of care options for Canadians with NETs include ultrasound (US), computed tomography (CT), magnetic resonance imaging (MRI), and scintigraphy, including the current gold standard gamma (γ)-emitting SSTR-targeting agent 111Indium-diethylenetriaminepentaacetic acid-D-phenylalanine-octreotide (¹¹¹In-DTPA-OC) using somatostatin receptor scintigraphy (SRS) with or without single photon emission computed tomography (SPECT). Due to their heterogeneous nature, no single modality is entirely effective at detecting and localizing NETs. Unlike anatomical imaging (e.g., US, CT and MRI), functional PET SSTR imaging has broader applicability, irrespective of NET subtype.
The market authorization for NETVision was based on evidence obtained through a systematic review of the scientific literature supporting the safety and efficacy of its use as a diagnostic radiotracer to detect and localize SSTR-positive NETs. In recent years, clinical use of 68Ga-oxodotreotide PET/CT imaging has increased and its use is currently supported by Canadian and international practice guidelines. Numerous studies have demonstrated the robust and highly sensitive and specific performance of 68Ga-oxodotreotide PET/CT for the detection, localization, staging, and follow-up/surveillance of recurrence of different types of NETs alone and/or in relation to other imaging modalities such as CT/MRI and ¹¹¹In-DTPA-OC. The literature indicates that 68Ga-oxodotreotide shows a higher affinity for SSTR2, higher tumour-to-background ratios, and superior detection of small lesions (<1 cm, especially lymph node and liver metastases) and NETs with low SSTR2 density.
Fifteen pivotal studies were identified by the sponsor through a systematic literature review to support the use of 68Ga-oxodotreotide PET/CT for the detection and localization of SSTR-positive NETs. These studies represented 806 patients with well differentiated (Grade I or Grade II) NETs who underwent 68Ga-oxodotreotide PET/CT imaging between the years 2010 and 2019. The different NET subtypes included were gastroenteropancreatic (GEP)-NET, pheochromocytoma and paraganglioma (PPGL), mixed/unknown NET and medullary thyroid carcinoma (MTC). The 68Ga-oxodotreotide PET/CT protocol, including the dosing regimen and timing of imaging post injection, was similar across studies. Intravenous administration of 68Ga-oxodotreotide was at a dose of 100 to 200 MBq and the mean start of imaging was reported as 40 to 65 min post-injection. Primary efficacy endpoints were 68Ga-oxodotreotide PET/CT sensitivity and specificity for the detection and localization of SSTR-positive NETs. Overall, the median sensitivity was 91.5% to 100% across four NET subtypes (GEP-NET, PPGL, mixed/unknown and MTC) while the median specificity was 89% to 100% across three NET subtypes (GEP-NET, PPGL and mixed/unknown). The results demonstrated that 68Ga-oxodotreotide is a highly sensitive and specific diagnostic radiotracer which often identified more lesions and, in many cases, additional lesions that had been missed by other imaging techniques.
According to available data from the literature, 68Ga-oxodotreotide is well tolerated by patients and no serious or severe adverse reactions have been reported. The microdose (≤50 µg) drug level is not expected to elicit any pharmacological effects, and the total effective dose of 2.6 to 5.2 mSv is approximately 50% lower than ¹¹¹In-DTPA-OC and within the range of other commonly used positron-emitting radiopharmaceuticals (e.g., 18F-Fludeoxyglucose). Another benefit of 68Ga-oxodotreotide is the single time point image acquisition of PET/CT which is 45 to 90 minutes post injection versus ¹¹¹In-DTPA-OC SPECT/CT which requires patients to be scanned at 4 and 24 hours post injection.
The following warning has been included in a Serious Warnings and Precautions box in the Product Monograph for NETVision: Radiopharmaceuticals should be used only by those health professionals who are appropriately qualified in the use of radioactive prescribed substances in or on humans.
A Risk Management Plan (RMP) is designed to describe known and potential safety issues, to present the monitoring scheme and when needed, to describe measures that will be put in place to minimize risks associated with the product. An RMP for NETVision was not submitted by the Canadian Molecular Imaging Probe Consortium (CanProbe) to Health Canada. Health Canada agreed with the sponsor's position that an RMP was not necessary for several reasons. First, NETs are considered an orphan disease and the target population in Canada is relatively small. Second, consistent with most diagnostic positron emitting radiopharmaceuticals, this product presents inherently low risks to the target population. Based on the literature, 68Ga-oxodotreotide has a well-characterized safety profile and all potential safety concerns are sufficiently controlled via drug product specifications or information in the Product Monograph. Finally, CanProbe operates under the Centre for Probe Development and Commercialization’s (CPDC) existing Pharmacovigilance System. The CPDC has previously been found to be in compliance by Health Canada with respect to effectively monitoring for new safety signals for diagnostic PERs. The safety profile of NETVision will be monitored in accordance with this system and the applicable provisions of the Food and Drug Regulations.
The submitted inner and outer labels, and Patient Medication Information section of the NETVision Product Monograph meet the necessary regulatory labelling, plain language and design element requirements.
The sponsor submitted a NETVision assessment that included testing for look-alike sound-alike attributes. Upon review, the proposed name NETVision was accepted.
NETVision has a positive benefit-risk profile based on the non-clinical and clinical data analyzed from the literature studies. The identified safety issues can be managed through labelling and adequate monitoring. Appropriate warnings and precautions are in place in the NETVision Product Monograph to address the identified safety concerns.
This New Drug Submission complies with the requirements of sections C.08.002 and C.08.005.1 and therefore Health Canada has issued the Notice of Compliance pursuant to section C.08.004 of the Food and Drug Regulations. For more information, refer to the Clinical, Non-clinical, and Quality (Chemistry and Manufacturing) Basis for Decision sections.
3 What steps led to the approval of NETVision?
The New Drug Submission for NETVision was filed as a Submission Relying on Third-Party Data (SRTD), according to the Guidance Document: Drug Submissions Relying on Third-Party Data (Literature and Market Experience).
For additional information about the drug submission process, refer to the Management of Drug Submissions and Applications Guidance.
Submission Milestones: NETVision
| Submission Milestone | Date |
|---|---|
| New Drug Submission filed | 2021-03-12 |
| Screening | |
| Screening Acceptance Letter issued | 2021-05-03 |
| Review | |
| Quality evaluation completed | 2022-01-21 |
| Non-clinical evaluation completed | 2022-02-24 |
| Clinical/medical evaluation completed | 2022-02-24 |
| Biostatistics evaluation completed | 2022-02-24 |
| Labelling review completed | 2022-02-24 |
| Notice of Compliance issued by Director General, Biologic and Radiopharmaceutical Drugs Directorate | 2022-02-24 |
4 What follow-up measures will the company take?
Requirements for post-market commitments are outlined in the Food and Drugs Act and Regulations.
6 What other information is available about drugs?
Up-to-date information on drug products can be found at the following links:
- See MedEffect Canada for the latest advisories, warnings and recalls for marketed products.
- See the Notice of Compliance (NOC) Database for a listing of the authorization dates for all drugs that have been issued an NOC since 1994.
- See the Drug Product Database (DPD) for the most recent Product Monograph. The DPD contains product-specific information on drugs that have been approved for use in Canada.
- See the Notice of Compliance with Conditions (NOC/c)-related documents for the latest fact sheets and notices for products which were issued an NOC under the Notice of Compliance with Conditions (NOC/c) Guidance Document, if applicable. Clicking on a product name links to (as applicable) the Fact Sheet, Qualifying Notice, and Dear Health Care Professional Letter.
- See the Patent Register for patents associated with medicinal ingredients, if applicable.
- See the Register of Innovative Drugs for a list of drugs that are eligible for data protection under C.08.004.1 of the Food and Drug Regulations, if applicable.
7 What was the scientific rationale for Health Canada's decision?
7.1 Clinical basis for decision
The New Drug Submission for NETVision was filed as a Submission Relying on Third-Party Data (SRTD), according to the Guidance Document: Drug Submissions Relying on Third-Party Data (Literature and Market Experience). As such, the sponsor relied on publicly available data to support the safety and efficacy of NETVision for the proposed indication for use with positron emission tomography (PET), as an adjunct to other diagnostic tests, for the detection and localization of somatostatin receptor-positive neuroendocrine tumours (NETs).
Following a systematic review of the literature, the sponsor identified 20 studies, 15 of which were subsequently characterized as pivotal and five as non-pivotal. Due to inherent limitations with data obtained from the literature, as well as the heterogeneity among the selected publications in terms of study populations and study design, the sponsor could not perform a meta-analysis.
Clinical Pharmacology
NETVision (gallium [68Ga] oxodotreotide) binds with nanomolar affinity to somatostatin receptors, with highest affinity for somatostatin receptor 2 (SSTR2), which are characteristically overexpressed by NET cells. Gallium-68 is a β+ emitting radionuclide with an emission yield that allows positron emission tomography (PET) imaging.
Clinical pharmacokinetic studies have demonstrated that following intravenous administration of 68Ga-oxodotreotide, it is immediately and completely bioavailable and rapidly cleared from the blood. The highest 68Ga-oxodotreotide uptake in healthy organs was seen in those which naturally express SSTR2. Uptake in the kidneys and bladder was attributed to excretion through the renal system, while liver uptake was thought to reflect hepatic metabolism of the peptide. Significantly higher uptake was reported for tumour versus normal tissues, with 68Ga-oxodotreotide displaying the longest residency time in diseased SSTR2-positive organs. No pharmacodynamic studies have been performed in humans with 68Ga-oxodotreotide, however, given that it is administered at microdose levels no pharmacological effects are expected.
The clinical pharmacology data support the use of NETVision for the recommended indication. For further details, please refer to the NETVision Product Monograph, approved by Health Canada and available through the Drug Product Database.
Clinical Efficacy
The evaluation of the efficacy of NETVision is based on a systematic review of the scientific literature on the use of 68Ga-oxodotreotide as a radiodiagnostic agent in patients with NETs. The literature review searched for comparable studies providing clinical efficacy data on the use of 68Ga-oxodotreotide PET/computed tomography (CT), either alone or in comparison with conventional imaging techniques (CT and/or magnetic resonance imaging [MRI]) or with 111Indium-diethylenetriaminepentaacetic acid-D-phenylalanine-octreotide (¹¹¹In-DTPA-OC), the previous gold standard and other commercially-approved SSTR imaging agent in Canada.
A pivotal study was defined as one that enrolled patients with histological/clinical confirmation of NET or suspected NET, allowed extraction of per-patient sensitivity and/or specificity data for 68Ga-oxodotreotide, and was not excluded during the screening against the exclusion criteria. Fifteen pivotal studies were identified by the sponsor to support the use of 68Ga-oxodotreotide for the detection and localization of SSTR-positive NETs. These studies represented 806 patients with well differentiated (Grade I or Grade II) or suspected NETs who underwent 68Ga-oxodotreotide PET/CT imaging between the years 2010 and 2019. The different NET subtypes included were gastroenteropancreatic (GEP)-NET, pheochromocytoma and paraganglioma (PPGL), mixed/unknown NET, and medullary thyroid carcinoma (MTC). All studies were non-randomized and study inclusion and exclusion criteria were deemed reasonable given the heterogeneous nature of the patient population. The key similarity between studies was the confirmation of well differentiated Grade I or Grade II NETs based on clinical parameters and/or comparative imaging and/or SSTR expression via histopathology. Additionally, the 68Ga-oxodotreotide PET/CT protocol, including the dosing regimen and timing of imaging post-administration, was similar across studies. Intravenous administration of 68Ga-oxodotreotide was at a dose of 100 to 200 MBq in the majority of studies and the mean start of imaging was reported as 40 to 65 min post-injection. Images were interpreted by two or three readers who were often but not always blinded.
Primary efficacy endpoints were 68Ga-oxodotreotide PET/CT sensitivity and specificity for the detection and localization of SSTR-positive NETs. Overall, the median sensitivity was 91.5% to 100% across four NET subtype groupings (GEP-NETs, PPGL, mixed/unknown NETs, and MTC) while the median specificity was 89% to 100% across three NET subtype groupings (GEP-NET, PPGL and mixed/unknown NETs). Study results are described below according to NET subtype.
Gastroenteropancreatic (GEP) Neuroendocrine Tumours
Three studies retrospectively evaluated 68Ga-oxodotreotide performance in 166 patients (approximately 44% females, 56% males) with GEP-NETs. The mean patient age was 56 years (range: 18 to 84 years of age). In these studies, the median sensitivity was 92% (range: 68 to 100%; three studies) and the median specificity was 89% (range: 89 to 100%; two studies).
Pheochromocytoma and Paraganglioma (PPGL)
Four prospective studies and one retrospective study evaluated 68Ga-oxodotreotide performance in 108 patients (51% females, 49% males) with PPGL. The mean patient age was 46 years (range: 16 to 84 years of age). In these five studies, the median sensitivity was 100% (range: 93 to 100%) and the specificity in the retrospective study was 100%.
Mixed/Unknown Neuroendocrine Tumours
Five retrospective studies and two prospective studies evaluated 68Ga-oxodotreotide performance in 517 patients (approximately 50% females, 50% males) with mixed/unknown NETs. The mean patient age was 56 years (range: 1 to 87 years of age). In these studies, the median sensitivity was 94% (range: 81 to 96%; seven studies) and median specificity was 92% (range: 50 to 100%; six studies).
Medullary Thyroid Carcinoma (MTC)
One study prospectively examined 68Ga-oxodotreotide performance in 15 patients (53% females, 47% males). The mean patient age was 44 years (range: 20 to 68 years of age) with histologically confirmed medullary thyroid carcinoma (MTC) but negative conventional imaging after thyroidectomy. Using histology, conventional imaging and clinical/imaging follow up as the reference standard, sensitivity was 100% (15/15 patients) while specificity was not calculated.
False Positives and False Negatives
In these studies, the most commonly reported causes of false positive results were inflammation (including SSTR2-expressing macrophages) and misinterpretation of faint 68Ga-oxodotreotide uptake. False positive uptake has also been reported due to benign tumoral lesions (e.g., hemangioma, meningioma, fibrous dysplasia and breast fibroadenoma) and other non-neoplastic uptake (e.g., arthritis, reactive lymph nodes and accessory spleen). Uptake in the pancreas should also be interpreted cautiously due to high physiological uptake in the pancreatic head. The most commonly reported causes of false negative results were small lesion size (<5 mm) and poorly differentiated/high grade NETs which have low or no SSTR2 expression.
Overall Analysis of Efficacy
Together, these pivotal studies demonstrated that 68Ga-oxodotreotide is a highly sensitive and specific diagnostic radiotracer which often identified more lesions and, in many cases, additional lesions that had been missed by other imaging techniques. Due to inherent limitations with these studies (e.g., small cohort sizes and mixed patient populations), no statistical inferences can be made and therefore only descriptive data have been included the NETVision Product Monograph.
Indication
The New Drug Submission for NETVision was filed by the sponsor with the following indication:
NETVision (gallium [68Ga] oxodotreotide injection) is indicated for the detection and localization, with positron emission tomography (PET), of somatostatin receptor-positive neuroendocrine tumours (NETs).
To support safe and effective use of the product, Health Canada approved the following indication:
NETVision (gallium [68Ga] oxodotreotide injection) is indicated for use with positron emission tomography (PET), as an adjunct to other diagnostic tests, for the detection and localization of somatostatin receptor-positive neuroendocrine tumours (NETs).
For more information, refer to the NETVision Product Monograph, approved by Health Canada and available through the Drug Product Database.
Clinical Safety
The evaluation of the safety of NETVision is based on a systematic review of the scientific literature on the use of gallium (68Ga) oxodotreotide as a radiodiagnostic agent in patients with NETs. Safety data were compiled from studies identified through the systematic literature review which included 20 clinical studies and two meta-analyses. The meta-analyses included an evaluation of safety and the results are captured in the Product Monograph. The Sponsor also highlighted safety information from an investigator-led trial conducted with CanProbe-manufactured 68Ga-oxodotreotide. Altogether, the data represent a total of 2,967 patients administered 68Ga-oxodotreotide between the years 2010 and 2019 (1,493 patients in the literature and 1,474 patients administered CanProbe-manufactured product).
According to the literature data, 68Ga-oxodotreotide was well tolerated by patients and no serious or severe adverse reactions were reported. The risk profile was mainly characterized by nausea/vomiting, injection site conditions and hypersensitivity reactions as well as non-serious, uncommon and transient reactions such as tachychardia and abdominal pain. The microdose (≤50 µg) is not expected to elicit any pharmacological effects, and the total effective dose of 2.6 to 5.2 mSv is approximately 50% lower than ¹¹¹Indium (¹¹¹In)-Octreotide and within the range of other commonly used positron-emitting radiopharmaceuticals (PERs; e.g., 18F-Fludeoxyglucose).
The adverse reactions below, all non-serious but possibly related to 68Ga-oxodotreotide injection, have been reported in the literature:
- Unilateral whole-body edema ipsilateral to the injected upper extremity (spontaneously resolved) (n = 1)
- abdominal pain in patients with a history of gastritis (n = 2)
- Itching at injection site (minor, spontaneously resolved) (n = 1)
- Tachycardia, asymptomatic (spontaneously resolved) (n = 1)
The following suspected non-serious adverse reactions were also reported to CanProbe by investigators in clinical trials using CanProbe-manufactured 68Ga-oxodotreotide and were assessed by the investigators as possibly or probably related to 68Ga-oxodotreotide (reported frequencies based on total verified doses of product supplied by CanProbe at time of this assessment):
- Vomiting (uncommon)
- Nausea (uncommon), grade 1 (n = 2) and nausea, grade 1 (n = 1)
- Allergic reaction (temporary generalized itching that resolved spontaneously; uncommon)
- Metallic taste in mouth (uncommon)
- Injection site reactions (e.g., pain, itching, redness, burning, stinging, tingling; common)
In addition, hypersensitivity reactions may occur such as rash and pruritus, and less frequent reactions include angioedema or cases with features of anaphylaxis.
There have only been isolated reports of non-serious adverse events considered possibly-related to 68Ga-oxodotreotide in the last >15 years of investigational and commercial use. The CanProbe-conducted literature review identified a total of 1,493 unique patients who were administered gallium 68Ga-oxodotreotide. However, the actual number of patients worldwide who have been administered 68Ga-oxodotreotide to date is much higher, as this number ignores other studies and increased commercial use (of kit-based presentations) of this product since mid-2016.
The efficacy and safety of 68Ga-oxodotreotide during pregnancy or lactation or in patients with renal or hepatic impairment has not been studied. Since ionization radiation from 68Ga-oxodotreotide is potentially harmful to a fetus or a nursing infant, standard warnings and precautions are included in the Product Monograph.
The concomitant use of 68Ga-oxodotreotide with somatostatin analogues (SSAs) poses a theoretical drug-drug interaction as both bind SSTRs. Additionally, concomitant use of corticosteroids with SSAs poses a theoretical drug-drug interaction since some evidence indicates that corticosteroids can induce down-regulation of SSTR2 receptors. In the absence of a clinical consensus, the various guidelines or literature references have been summarized in the Product Monograph with a recommendation for the treating physician to consider the goals of the PET imaging and the patient’s situation before deciding to suspend these therapies.
NETVision contains ≤10% ethanol, which would yield a maximum blood alcohol concentration of ~8.9 mg/dL assuming the maximum administered volume of 4.5 mL and human blood volume of 4 L. Patients taking disulfiram (Antabuse) should not receive gallium 68Ga-oxodotreotide due to potentially serious side effects at a blood alcohol concentration as low as 5 mg/dL.
These findings, taken together with the extensive use of this imaging agent in current clinical practice guidelines (Canadian and international), support the safe and effective use of 68Ga-oxodotreotide PET/CT for the detection and localization of somatostatin receptor-positive NETs.
Appropriate warnings and precautions are in place in the approved NETVision Product Monograph to address the identified safety concerns. The following warning has been included in a Serious Warnings and Precautions box in the Product Monograph for NETVision: Radiopharmaceuticals should be used only by those health professionals who are appropriately qualified in the use of radioactive prescribed substances in or on humans.
For more information, refer to the NETVision Product Monograph, approved by Health Canada and available through the Drug Product Database.
7.2 Non-Clinical Basis for Decision
The New Drug Submission (NDS) for NETVision was filed as a Submission Relying on Third-Party Data (SRTD), according to the Guidance Document: Drug Submissions Relying on Third-Party Data (Literature and Market Experience). As such, no non-clinical studies were conducted by the sponsor to support this NDS. A survey of the literature was conducted to identify relevant non-clinical studies using the 68Ga-oxodotreotide drug substance or unlabelled oxodotreotide moiety.
A comparative analysis of in vitro somatostatin receptor (SSTR) binding affinities for various somatostatin analogues (SSAs) was conducted using data from published studies in the scientific literature. All studies were performed in SSTR-expressing tumour cells. 68Ga-oxodotreotide showed the highest in vitro SSTR2 binding affinity of the investigated SSAs: >10x higher than DOTATOC and DOTANOC and 100x higher than the gold standard, 111Indium-diethylenetriaminepentaacetic acid-D-phenylalanine-octreotide (111In-DTPA-OC). Oxodotreotide was also the most specific to SSTR2, which is the receptor subtype commonly over-expressed by NETs. Furthermore, it was found that changes to the radioligand and minor changes to the chelator or SSA component had a significant effect on SSTR affinity and biodistribution. Notably, the use of gallium appears to significantly increase SSTR2 affinity versus yttrium-labelled or unlabelled oxodotreotide.
Literature-based evidence was provided to demonstrate that SSTR2-positive tumour cells are able to internalize the TATE moiety in vivo as well as 68Ga-oxodotreotide in vitro. Taken together, these studies provide evidence of tumour-specific uptake of 68Ga-oxodotreotide.
No secondary pharmacodynamic studies were submitted, however, no significant secondary pharmacodynamic effects are expected given the very low amount (<50 ug) of oxodotreotide peptide that is administered for diagnostic purposes.
Biodistribution studies performed in healthy rats reported the highest standard uptake values for the kidney, pancreas and adrenal glands. These organs are known to express SSTRs under normal physiological conditions. The most rapid uptake was reported in the kidneys, which is consistent with excretion of the drug primarily through the renal system.
Four studies provided evidence of high tumour to normal uptake and tumour retention of 68Ga-oxodotreotide in tumour cells in vivo. This data support the diagnostic performance of 68Ga-oxodotreotide for the detection of SSTR-expressing tumour cells.
One study reported evidence regarding the stability of oxodotreotide in human serum and found the mean extent of 68Ga-oxodotreotide plasma protein binding (PPB) to be 30.6%. This extent of PPB is consistent with the hydrophilic nature of the drug, short plasma half-life, and rapid clearance from blood.
In the absence of non-clinical toxicity studies for 68Ga-oxodotreotide, in the scientific literature, a single-dose acute toxicity study was referenced which was carried out using unlabelled oxodotreotide peptide in healthy Wistar rats (total number [n] = 5) and BALB/c mice (n = 5). Animals were administered a single dose of unlabeled oxodotreotide peptide (via intravenous penile injection in saline) at 1,000x the target 200 µg human peptide dose for the related therapeutic agent 177Lu-oxodotreotide. No behavioral abnormalities were seen 24 h post injection and post-mortem examinations showed no macroscopic pathology or microscopic histological (liver, kidney, stomach, spleen, lungs and intestine) abnormalities, yielding a no-observed-effects level (NOEL) of ~752 µg/kg in rats. The NOEL in rats for oxodotreotide is equivalent to a 200 µg/kg human dose (assuming a 50 kg individual) or 10 mg peptide. Since the maximum human target peptide dose for 68Ga-oxodotreotide is 50 µg, this yields a safety margin of ≥200x.
The sponsor did not include genotoxicity/mutagenicity, carcinogenicity, or reproductive and developmental toxicity studies with this submission. These studies are generally not required for radiopharmaceutical drugs. Nevertheless, the ability of radiation to act as a carcinogen and/or mutagen has been noted in the label. As 68Ga-oxodotreotide is a diagnostic positron-emitting radiopharmaceutical intended for single or infrequent administration at a microdose (≤50 µg) level, there is a relatively low risk of genotoxic effects. Still, mention of possible genotoxic effects due to chromosome damage from Auger electrons within cells that take up the drug is noted in the label.
In view of the intended use of NETVision, there are no pharmacological/toxicological issues identified within the reviewed literature which preclude authorization of the product.
For more information, refer to the NETVision Product Monograph, approved by Health Canada and available through the Drug Product Database.
7.3 Quality Basis for Decision
NETVision (gallium [68Ga] oxodotreotide injection) is a diagnostic positron-emitting radiopharmaceutical (PER) for intravenous injection. It is intended for use in the detection and localization of somatostatin receptor 2 (SSTR2)-expressing neuroendocrine tumours (NETs). The drug substance, 68Ga-oxodotreotide, consists of 68Ga conjugated to an SSTR2-targeting somatostatin analog octreotate via the universal chelator DOTA.
The drug product is supplied as a sterile solution containing a target dose of 100 to 200 MBq at the time of injection.
Characterization of the Drug Substance
This section is not applicable. The manufacturing of the drug substance and drug product is a continuous process. Due to the radioactive decay of 68Ga and rapid synthesis time, isolation of the drug substance is not possible. Therefore, all drug substance related testing is performed on the drug product.
Manufacturing Process of the Drug Substance and Drug Product and Process Controls
The starting material, 68Ga in the form of 68GaCl3, is eluted from a commercially obtained and qualified 68Ge/68Ga-generator.
To manufacture the drug substance, the oxodotreotide precursor is mixed with reaction buffer and 68GaCl3, followed by radiolabelling (via heating and shaking) to chelate 68Ga to oxodotreotide. The solution is then transferred onto a purification cartridge, trapping the crude drug substance while the reaction solution passes through the cartridge to waste.
The critical in-process controls are the radiolabeling reaction conditions, including reaction temperature and time.
The manufacturing process continues with the elution of the drug substance with ethanol into a bulk vial containing phosphate buffered saline, yielding the formulated drug product. The drug product is then transferred via a reusable transfer line through a tandem filter chain into a final bulk product vial in a Grade A hot cell. The activity is then measured, reflecting the end of synthesis (EOS) for the final sterilized drug product.
Filter integrity is assessed by bubble point testing. Quality control, sterility and retain samples are then dispensed, and if applicable, followed by the drug product doses dispensed into the 10 mL or 30 mL final container closures. The bulk vial itself can also be used as a patient dose vial.
The critical in-process controls include a sterile filter integrity test, radioactivity concentration at EOS (≤122 MBq/mL), and pressure differential, air velocity and environmental monitoring of the Grade A area.
The continuous manufacturing process for the drug substance and drug product and process controls have been validated. The results from the process validation batches demonstrated that the process can consistently produce high quality drug product suitable for commercial supply.
None of the non-medicinal ingredients (excipients, described earlier) found in the drug product are prohibited by the Food and Drug Regulations. The compatibility of the 68Ga-oxodotreotide with the excipients is supported by the stability data provided.
Control of the Drug Substance and Drug Product
The drug substance is not isolated and tested. Each lot of NETVision drug product is tested for appearance, pH, identity, purity, impurities, total peptide content, ethanol content, bacterial endotoxin, and sterility. The drug product specifications are well justified and considered acceptable. The analytical procedures were validated according to the International Council for Harmonisation (ICH) guidelines. The methods for bacterial endotoxin and sterility were verified as per United States Pharmacopeia (USP) standards.
Stability of the Drug Substance and Drug Product
The proposed shelf life for the drug product is 5 hours post end of synthesis (EOS) when stored at 15 °C to 30 °C with the container closure in an upright position. The drug product shelf life and storage condition are adequately supported by the stability data and considered acceptable. The stability results also demonstrated the compatibility of the drug product with the container closure system.
The primary container closure system meets compendial specifications.
The proposed packaging materials are considered acceptable.
Facilities and Equipment
The design, operations, and controls of the facility and equipment that are involved in the production are considered suitable for the activities and products manufactured.
The site involved in the production is compliant with good manufacturing practices.
Adventitious Agents Safety Evaluation
Gallium (68Ga) oxodotreotide injection is a sterile endotoxin-free aqueous solution intended for intravenous injection. It does not contain antimicrobial preservatives and has no known inherent antimicrobial properties. The microbiological content is controlled throughout the manufacturing process to minimize bioburden.
Overall, the microbiological controls used for the facility, materials and reagents, solution preparation, and during the manufacturing process are acceptable.
The bioburden testing method was validated, and the results demonstrated that 68Ga-oxodotreotide injection does not adversely affect the reliability of the bioburden test and there is no detectable antimicrobial activity inherent in the drug product. Bioburden levels were assessed using the validated method on four decayed batches of pre-sterile filtered drug product. The results demonstrated that the process is well-controlled with respect to bioburden and potential microbial contamination. Therefore, routine monitoring of bioburden is not considered necessary for commercial manufacture.
The sponsor provided a general bovine spongiform encephalopathy/transmissible spongiform encephalopathy (BSE/TSE) attestation, which states that all raw materials and product contact components used in the NETVision manufacturing process either involve no animal ingredients or meet the BSE/TSE standard.
The excipients used in the drug product formulation are not of animal or human origin.
Related Drug Products
| Product name | DIN | Company name | Active ingredient(s) & strength |
|---|---|---|---|
| NETVISION | 02525542 | UNIVERSITY HEALTH NETWORK | GALLIUM 68 Ga OXODOTREOTIDE 122 MBq / ML |