Summary Basis of Decision for Netspot

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:

Drug

Summary Basis of Decision (SBD) documents provide information related to the original authorization of a product. The SBD for Netspot is located below.

Recent Activity for Netspot

The SBDs written for eligible drugs (as outlined in Frequently Asked Questions: Summary Basis of Decision [SBD] Project: Phase II) 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. The PAATs will be updated regularly with post-authorization activity throughout the product life cycle.

 

The following table describes post-authorization activity for Netspot, a product which contains the medicinal ingredient oxodotreotide. For more information on the type of information found in PAATs, please refer to the Frequently Asked Questions: Summary Basis of Decision (SBD) Project: Phase II and to the List of abbreviations found in Post-Authorization Activity Tables (PAATs).

 

For additional information about the drug submission process, refer to the Guidance Document: The Management of Drug Submissions and Applications.

 

Updated: 2024-07-25

 

Drug Identification Number (DIN):

DIN 02490005 - 40 mcg/vial, oxodotreotide, intravenous administration

 

Post-Authorization Activity Table (PAAT)

 

Activity/Submission Type, Control Number

Date Submitted

Decision and Date

Summary of Activities

NC # 283374

2024-01-31

Issued NOL 2024-05-02

Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) for changes related to the transition to a multi-dose kit. The submission was reviewed and considered acceptable, and an NOL was issued.

NDS # 282568

2024-01-05

Issued NOC 2024-02-28

Submission filed to transfer ownership of the drug product from Advanced Accelerator Applications USA, Inc. to Novartis Pharmaceuticals Canada Inc. An NOC was issued.

SNDS # 278864

2023-09-06

Issued NOC 2024-02-22

Submission filed as a Level I – Supplement to update the outer label to be used for training kits. The submission was reviewed and considered acceptable, and an NOC was issued.

SNDS # 276879

2023-06-30

Cancellation Letter Received 2023-07-25

Submission filed as a Level I – Supplement for labelling changes related to the transition to a multi-dose kit and editorial corrections. The changes were not in scope of an SNDS but were considered to be in scope of an NC. The sponsor cancelled the submission administratively.

SNDS # 249080

2021-02-01

Issued NOC 2021-06-30

Submission filed as a Level II – Supplement (Safety) to update the PM, and migrate it to the 2020 format. The submission was reviewed and considered acceptable. As a result of the SNDS, modifications were made to the Dosage and Administration; Warnings and Precautions; and Dosage Forms, Strengths, Composition and Packaging sections of the PM, and corresponding changes were made to Part III: Patient Medication Information and to the package insert. An NOC was issued.

NC # 234162

2019-12-05

Issued NOL 2020-03-26

Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) for changes in the drug product manufacturing process. The submission was reviewed and considered acceptable, and an NOL was issued.

Drug product (DIN 02490003) market notification

Not applicable

Date of first sale: 2020-03-18

The manufacturer notified Health Canada of the date of first sale pursuant to C.01.014.3 of the Food and Drug Regulations.

SNDS # 234422

2019-12-13

Issued NOC 2020-02-21

Submission filed as a Level I – Supplement for labelling updates related to the authorization and use of the 68Ge/68Ga generator. The submission was reviewed and considered acceptable. As a result of the SNDS, modifications were made to the Dosage and Administration section of the PM. An NOC was issued.

NC # 231138

2019-08-28

Issued NOL 2019-12-23

Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) for a change in the primary container closure system. The submission was reviewed and considered acceptable, and an NOL was issued.

SNDS # 230871

2019-08-21

Cancellation Letter Received 2019-08-29

Submission filed as a Level I – Supplement for changes related to the use of a 68Ge/68Ga generator and revision of the proper name of the drug substance. The proposed changes cross-referenced NDS # 221824, which had not yet been authorized by Health Canada. In addition, the proposed changes to the proper name of the drug substance were not in scope of a Level I SNDS but were considered to be a Level III change. The submission was cancelled administratively by the sponsor at Health Canada’s request.

NDS # 218346

2018-07-20

Issued NOC 2019-07-03

NOC issued for New Drug Submission.
Summary Basis of Decision (SBD) for Netspot

Date SBD issued: 2020-03-02

The following information relates to the New Drug Submission for Netspot.

Oxodotreotide

Drug Identification Number (DIN):

  • DIN 02490005 - 40 mcg/vial, intravenous administration

Advanced Accelerator Applications USA, Inc.

New Drug Submission Control Number: 218346

 

On July 3, 2019, Health Canada issued a Notice of Compliance to Advanced Accelerator Applications USA, Inc. for the diagnostic radiopharmaceutical Netspot.

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 Netspot [kit for the preparation of gallium (68Ga) oxodotreotide injection], after radiolabeling with gallium (68Ga), is favourable for use with positron emission tomography (PET), as an adjunct to other diagnostic tests for localization of somatostatin receptor-positive neuroendocrine tumors (NETs).

 

1 What was approved?

 

Netspot, a diagnostic radiopharmaceutical, was authorized for use with positron emission tomography (PET), as an adjunct to other diagnostic tests for localization of somatostatin receptor-positive neuroendocrine tumors (NETs).

Radiopharmaceuticals should be used only by those health professionals who are appropriately qualified in the use of radioactive prescribed substances in or on humans.

Based on the data submitted and reviewed by Health Canada, the safety and efficacy of Netspot in pediatric patients has not yet been established, therefore, Health Canada has not authorized a specific indication for pediatric use.

Netspot was approved for use under the conditions stated in its Product Monograph taking into consideration the potential risks associated with the administration of this drug product.

Clinical studies of Netspot did not include sufficient numbers of subjects aged 65 and over, to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients.

Netspot (40 mcg oxodotreotide) is supplied as a single dose kit which contains two vials for preparation of gallium (68Ga) oxodotreotide injection. Vial 1 (reaction vial with lyophilized powder) contains 40 mcg oxodotreotide, 5 mcg of 1,10-phenanthroline, 6 mcg gentisic acid, and 20 mg D-mannitol for injection as a white lyophilized powder in a 10 mL glass vial with light-blue flip-off cap. Vial 2 (buffer vial) contains a clear, and colorless reaction buffer solution (60 mg formic acid, 56.5 mg sodium hydroxide in approximately 1 mL volume) in a 10 mL olefin polymer vial with a yellow flip-off cap.

Gallium (68Ga) is obtained from a Germanium 68/Gallium 68 (68Ge/68Ga) generator that is authorized by Health Canada.

After reconstitution with gallium (68Ga) and pH adjustment with Reaction Buffer, Vial 1 contains a sterile solution of gallium (68Ga) -oxodotreotide at a strength of 79.3 to 201.8 MBq/mL (2.1 to 5.45 mCi/mL).

For more information, refer to the Clinical, Non-clinical, and Quality (Chemistry and Manufacturing) Basis for Decision sections.

Additional information may be found in the Netspot Product Monograph, approved by Health Canada and available through the Drug Product Database.

 

2 Why was Netspot approved?

 

Health Canada considers that the benefit-risk profile of Netspot is favourable for use with positron emission tomography (PET), as an adjunct to other diagnostic tests for localization of somatostatin receptor-positive neuroendocrine tumors (NETs).

Neuroendocrine tumors consist of a spectrum of malignancies that arise from neuroendocrine cells throughout the body. Neuroendocrine tumors are considered rare; prevalence is estimated to be 350 per million. All neuroendocrine tumors are characterized by their ability to produce peptides that are secreted into the bloodstream that cause characteristic hormonal syndromes and present with a variety of signs and symptoms that may impact quality and quantity of life. Five-year survival rates vary depending upon the primary site of origin and the degree of differentiation.

Well-differentiated carcinoid tumors over-express somatostatin subtype 2 receptors (SSTR2) which is a common feature of all neuroendocrine tumors. Gallium (68Ga) oxodotreotide has a high affinity for SSTRs, particularly subtype 2, and therefore is used with PET to visualize regions of pathologic or physiologic somatostatin receptor (SSTR) overexpression in malignant or non-malignant tissues. Gallium (68Ga) oxodotreotide was developed for the diagnosis and management of somatostatin receptor bearing gastro-enteropancreatic neuroendocrine tumors (GEP NET), by aiding in their localization, characterization, staging, and restaging.

The standard of care options available in Canada for the diagnosis, staging/restaging, and assessment of treatment response for neuroendocrine tumors includes computed tomography (CT), magnetic resonance imaging (MRI), ultrasound, and scintigraphy. Somatostatin receptor scintigraphy (SRS) is highly useful for imaging neuroendocrine tumors since many express somatostatin receptors. The use of 111In-DTPA-Octreotide in both planar and single photon emission computed tomography (SPECT) imaging is the current standard of care for SRS. However, positron-emission tomography provides better image resolution than SPECT, and 68Ga labelled analogues for positron-emission tomography imaging have clinical advantages over 111In-DTPA-Octreotide including lower radiation exposure to the patient. Current Canadian and international consensus guidelines recommends the use of 68Ga labelled analogues for positron-emission tomography over 111In-octreotide scintigraphy, due to higher sensitivity demonstrated in published studies.

Netspot has been shown to be efficacious as an adjunct to other diagnostic tests for localization of somatostatin receptor-positive neuroendocrine tumors. Clinical pharmacokinetic and pharmacodynamics studies have demonstrated that following intravenous administration, 68Ga-oxodotreotide is immediately and completely bioavailable, as it is rapidly cleared from the blood and distributes in all SSTR-expressing organs such as pituitary, thyroid, spleen, adrenals, kidney, pancreas, prostate liver, and salivary glands. As 68Ga-oxodotreotide has a high affinity for SSTR2, malignant cells which overexpress SSTR2 will have high uptake of the radiotracer. Gallium (68Ga) oxodotreotide is largely excreted intact via the renal system.

The New Drug Submission (NDS) for Netspot was filed at Health Canada as a Submission Relying on Third-Party Data (SRTD) for which evidence of safety and efficacy is based on published literature in the absence of clinical data. Accordingly, the market authorization of Netspot was based on a systematic review of the scientific literature on the use of 68Ga oxodotreotide as a radiodiagnostic agent in the management of patients with neuroendocrine tumors. However, 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's pre-planned meta-analysis could not be conducted. Therefore, individual studies were selected for assessment of the efficacy and safety of 68Ga oxodotreotide in the imaging of neuroendocrine tumors. The efficacy of 68Ga oxodotreotide was therefore evaluated based primarily on the following three studies:

  • Deppen 2016 - Safety and Efficacy of gallium 68Ga dotatate [oxodotreotide] positron emission tomography (PET)/computed tomography (CT) for diagnosis, staging, and treatment management of neuroendocrine tumors.
  • Haug 2012 - The role of gallium 68Ga dotatate [oxodotreotide] and positron emission tomography (PET)/computed tomography (CT) in suspected neuroendocrine tumors.
  • Haug 2014 - Neuroendocrine tumor recurrence: diagnosis with 68Ga dotatate [oxodotreotide] and positron emission tomography/computed tomography.

The safety of gallium 68Ga oxodotreotide was evaluated in a survey of the scientific literature. Based on the evaluation of the literature, no serious adverse reactions were identified in these studies. Based on published studies that reported safety findings, adverse reactions following 68Ga-oxodotreotide administration were infrequent, usually mild to moderate and transient. The risk profile of 68Ga-oxodotreotide is mainly characterised by nausea/vomiting, injection site conditions and hypersensitivity reactions.

Cumulative post-marketing data for Netspot indicates that nausea, injection site reactions, and vomiting were the most commonly reported serious and non-serious adverse reactions. Other reported adverse reactions include abdominal pain, erythema, pruritus, rash, urticaria, burning sensation, dizziness, flushing, and hypersensitivity.

In terms of radiation dose to the patient resulting from one imaging procedure, the administration of the commonly used activity of 68Ga oxodotreotide leads to approximately 4 8 fold lower radiation dose to the patient than after administration of usual activity of 111In-pentetreotide for planar or tomographic scintigraphy.

The efficacy and safety of 68Ga-oxodotreotide during pregnancy or lactation or in patients with renal or hepatic impairment has not been studied. The ionization radiation from 68Ga-oxodotreotide is potentially harmful to a fetus or to a nursing infant; therefore, standard warnings and precautions for use of radiopharmaceuticals in pregnancy or breast feeding are included in the product labelling. Based on data that demonstrates the lack of metabolism, rapid tumor uptake and fast radioactive decay, hepatic or renal impairment is not expected to have any relevant impact on the performance or safety of the product.

An identified drug interaction is the interference of 68Ga oxodotreotide imaging performance by concomitant treatment with long acting analogues of somatostatin within 30 days. Non-radioactive somatostatin analogs competitively bind to the same somatostatin receptors as 68Ga-oxodotreotide. To prevent interference in visualization, image patients with 68Ga-oxodotreotide positron emission tomography just prior to dosing with long-acting analogs of somatostatin. Short-acting analogs of somatostatin can be used up to 24 hours before imaging with 68Ga oxodotreotide.

Some evidence exists that corticosteroids can induce down-regulation of somatostatin receptor subtype -2 (SST2) receptors. Repeated administration of high-doses of glucocorticosteroids prior to 68Ga-oxodotreotide administration may cause insufficient SST2 receptor expression for adequate visualization of somatostatin receptor-positive neuroendocrine tumors.

A Risk Management Plan (RMP) for Netspot was submitted by Advanced Accelerator Applications to Health Canada. Upon review, the RMP was considered to be acceptable. The 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.

A Look alike Sound alike brand name assessment was performed and the proposed name Netspot was accepted.

Overall, the evaluation of the safety data for 68Ga-oxodotreotide found no significant safety concerns. The safety profile of Netspot is consistent with that of diagnostic radiopharmaceuticals, which are single administration products that contains a sub-pharmacologic mass dose and therefore are generally well tolerated. In addition, the efficacy of Netspot is supported by the totality of evidence from data presented from published clinical trials of 68Ga oxodotreotide. When compared to the current standard of care somatostatin receptor imaging modality (111In-DTPA-octreotide used with single photon scintigraphy), 68Ga oxodotreotide used with positron emission tomography showed greater diagnostic performance in the localization of somatostatin receptor positive neuroendocrine tumors, and particularly in identifying smaller lesions.

This New Drug Submission complies with the requirements of sections C.08.002 and C.08.005.1 and therefore Health Canada has granted 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 Netspot?

 

Submission Milestones: Netspot

Submission Milestone Date
Submission filed: 2018-07-20
Screening  
Screening Acceptance Letter issued: 2018-09-06
Review  
On-Site Evaluation:  
Quality Evaluation complete: 2019-07-02
Clinical/Medical Evaluation complete: 2019-07-02
Biostatistics Evaluation complete: 2019-07-01
Review of Risk Management Plan complete: 2019-03-15
Labelling Review complete, including Look-alike Sound-alike brand name assessment: 2019-06-28
Notice of Compliance issued by Director General, Biologics and Genetic Therapies Directorate: 2019-07-03

 

The Canadian regulatory decision on the review of Netspot was based on a critical assessment of the data package submitted to Health Canada.

For additional information about the drug submission process, refer to the Management of Drug Submissions Guidance.

 

4 What follow-up measures will the company take?

 

Requirements for post-market commitments are outlined in the Food and Drugs Act and Regulations.

 

5 What post-authorization activity has taken place for Netspot?

 

Summary Basis of Decision documents (SBDs) for eligible drugs authorized after September 1, 2012 will include post-authorization information in a table format. The Post-Authorization Activity Table (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. The PAAT will continue to be updated during the product's life cycle.

The PAAT for Netspot is found above.

For the latest advisories, warnings and recalls for marketed products, see MedEffect Canada.

 

6 What other information is available about drugs?

 

Up to date information on drug products can be found at the following links:

 

7 What was the scientific rationale for Health Canada's decision?
7.1 Clinical Basis for Decision

 

Clinical Pharmacology

The Netspot New Drug Submission was submitted in accordance with the Health Canada Guidance, Drug Submissions Relying on Third-Party Data (Literature and Market Experience). In the absence of clinical data generated using the Sponsor's drug product Netspot, the sponsor relied on publicly available information on 68Ga oxodotreotide to support the safety and efficacy of Netspot as a diagnostic radiopharmaceutical for the localization of somatostatin receptor positive neuroendocrine tumours (NETs).

Well differentiated carcinoid tumors overexpress somatostatin subtype 2 receptors (SSTR2) which is a common feature of all NETs. Gallium (68Ga) oxodotreotide binds to somatostatin receptors, with highest affinity for subtype 2 receptors (SSTR2), and therefore is used with positron-emission tomography to visualize regions of pathologic or physiologic somatostatin receptors (SSTR) in malignant or non malignant tissues. Gallium (68Ga) is a ß+ emitting radionuclide with an emission yield that allows for positron emission tomography imaging.

Clinical pharmacokinetic and pharmacodynamics studies have demonstrated that following intravenous administration, 68Ga oxodotreotide is immediately and completely bioavailable, as it is rapidly cleared from the blood and distributes in all somatostatin receptor (SSTR) expressing organs such as pituitary, thyroid, spleen, adrenals, kidney, pancreas, prostate liver, and salivary glands. As 68Ga-oxodotreotide has a high affinity for SSTR2, malignant cells which overexpress SSTR2 will have high uptake of the radiotracer. Gallium (68Ga) oxodotreotide is largely excreted intact via the renal system.

For further details, please refer to the Netspot Product Monograph, approved by Health Canada and available through the Drug Product Database.

Clinical Efficacy

The Netspot New Drug Submission (NDS) was submitted in accordance with the Health Canada Guidance, Drug Submissions Relying on Third-Party Data (Literature and Market Experience). In the absence of any clinical data generated using the sponsor's drug product, Netspot, the sponsor submitted publicly available information on 68Ga oxodotreotide to support the efficacy and safety of Netspot as a diagnostic radiopharmaceutical for the localization of somatostatin receptor positive neuroendocrine tumours. Relevant studies were selected based on criteria set out in a predefined systematic review protocol. 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's pre-planned meta-analysis could not be conducted. Therefore, individual studies were selected for assessment of the efficacy and safety of 68Ga-oxodotreotide in the imaging of neuroendocrine tumors.

Deppen 2016 - Safety and Efficacy of gallium 68Ga dotatate [oxodotreotide] positron emission tomography (PET)/computed tomography (CT) for diagnosis, staging, and treatment management of neuroendocrine tumors.

As key supporting evidence for the Netspot New Drug Submission (NDS), the sponsor provided data from the Vanderbilt University Medical Center (VUMC) study (Deppen 2016) which was a prospective study to evaluate the efficacy and safety of 68Ga oxodotreotide positron emission tomography/computed tomography (PET/CT) compared with 111In pentetreotide imaging for diagnosis, staging, and restaging of pulmonary and gastroenteropancreatic neuroendocrine tumors. The sponsor included in the Netspot NDS a declaration that Netspot is similar to the VUMC drug product, and provided information for Quality Review. Results from other comparative and non comparative trials provided additional support for the efficacy and safety of 68Ga oxodotreotide imaging in patients with NETs.

In Deppen 2016, a total of 97 adult patients (41 male, 56 female) with known or suspected neuroendocrine tumors were consecutively enrolled and received a single intravenous injection of 196 MBq (5.3 mCi) 68Ga-oxodotreotide. Positron emission tomography/computed tomography images were collected beginning at 65 minutes (range 55 to 93 minutes) after injection. The gallium (68Ga) oxodotreotide images were then read by two independent readers blinded to clinical information. The reads were then compared to CT and/or magnetic resonance (MR) images and to indium (111In) pentetreotide images obtained with Single Photon Emission Computed Tomography (SPECT) within the previous 3 years.

Among 78 patients in whom CT and/or MR images and indium (111In) pentetreotide images were available, 68Ga oxodotreotide PET was in agreement with the reference standard in 74 patients. Out of 50 patients with NETs as per the reference standard, 68Ga oxodotreotide was positive in 48 patients including 13 patients in whom indium (111In) pentetreotide was negative. Gallium (68Ga) -oxodotreotide was negative in 26 out of 28 patients in whom the reference standard was negative.

Haug 2012 - The role of gallium (68Ga) -dotatate [oxodotreotide] and positron emission tomography (PET)/computed tomography (CT) in suspected neuroendocrine tumors

The aim of this study was to evaluate 68Ga oxodotreotide PET in patients with clinically suspected NET, using present symptoms, elevated levels of chromogranin A (CgA), or the presence of a suspected mass in conventional imaging. A total of 104 patients (52 male, 52 female; mean age 58 [age range 1 to 83 years]) were enrolled in the study.

Patients received a single 200 MBq dose of 68Ga oxodotreotide and PET/CT scans were taken 60 minutes later. Diagnostic performance of 68Ga oxodotreotide PET in localizing tumor sites was retrospectively assessed using a reference standard: histopathology (Number of patients [n] = 49) or clinical follow-up of up to 5-month duration (n = 55). Images were interpreted by consensus between two on site readers who were not blinded to clinical information. NET sites were localized by reference standard in 36 patients (all by histopathology). Out of these, 68Ga oxodotreotide was positive, correctly identifying a NET site, in 29 out of 36 patients and was falsely negative in seven. In 68 patients with no NET identified by a reference standard, the images were negative in 61 and falsely positive in seven patients.

Haug 2014 - Neuroendocrine tumor recurrence: diagnosis with 68Ga dotatate [oxodotreotide] and positron emission tomography/computed tomography

The aim of this study was to evaluate the diagnostic performance of 68Ga oxodotreotide for detection of recurrent NETs. A total of 63 adult patients (34 males, 29 females; mean age 58 [age range 20 to 84 years]), were referred between 2007 and 2011 to the Department of Nuclear Medicine, Hospital of the University of Munich, Germany. Inclusion criteria comprised a history of curative resection of the primary NET without suspicion.

Patients were treated with a single 200 MBq intravenous injection and PET/CT scans were taken 60 minutes later. Gallium (68Ga) -oxodotreotide images were interpreted independently by two central readers blinded to clinical information.

These results were then compared with standard of truth (histopathology) or clinical follow up. Sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were calculated. Reader 1 correctly localized NETs in 23 out of 29 reference standard-positive patients and reader 2 correctly localized NETs in 22 such patients. In 34 patients with no NET identified by a reference standard, reader 1 was correct in 29 patients and reader 2 in 32.

Efficacy conclusion

Based on the efficacy data presented in the Netspot NDS submission, and on information presented in current clinical practice guidelines (Canadian and international), the totality of evidence support the use of gallium (68Ga) -oxodotreotide as an adjunct diagnostic agent for the identification of somatostatin receptor positive neuroendocrine tumors. However, due to inherent limitations with data obtained from the literature, no statistical inferences can be made from the published results; therefore, only descriptive data has been captured in the Netspot Product Monograph.

Indication

The New Drug Submission for Netspot was filed by the sponsor with the following indication:

  • Netspot, after radiolabelling with Ga 68, is a radioactive diagnostic agent indicated for:
    • use with positron emission tomography (PET) for localization of somatostatin receptor-positive neuroendocrine tumors (NETs) in adult and pediatric patients.

Health Canada revised the proposed indication for clarity purposes along with a recommended dosage. Accordingly, Health Canada approved the following indication:

  • Netspot [kit for the preparation of gallium (68Ga) -oxodotreotide injection], after radiolabeling with gallium 68 (68Ga), is indicated for use with positron emission tomography (PET), as an adjunct to other diagnostic tests for localization of somatostatin receptor-positive neuroendocrine tumors (NETs).
  • The recommended amount of radioactivity to be administered for PET imaging is 2 MBq/kg of body weight (0.054 mCi/kg) up to a total of 200 MBq (5.4 mCi).

For more information, refer to the Netspot Product Monograph, approved by Health Canada and available through the Drug Product Database.

Clinical Safety

A literature search for published relevant safety information was conducted, in order to collect and provide data to support the safety of Netspot. Based on the literature data provided in the NDS, it is estimated that more than 1,460 patients were exposed to gallium (68Ga) DOTATE in independent clinical trials. Safety data for the sponsor's product, Netspot, is only available from post market safety reports. The most recent safety update report for Netspot indicates that over 28,000 patients have been exposed to the product since the time of its approval in the United States of America.

In the VUMC study, safety and toxicity were assessed by comparing vital signs and laboratory values before and after the administration of 68Ga-oxodotreotide. No serious or severe adverse events were observed, and no participants had a trial related event requiring additional medical care. Clinically relevant findings assessed by the investigators as possibly related to 68Ga-oxodotreotide were mild tachycardia, hyperglycemia, and aspartate aminotransferase increase.

Based on published studies that reported safety findings, adverse reactions following 68Ga-oxodotreotide administration were infrequent, usually mild to moderate and transient. The risk profile of 68Ga-oxodotreotide is mainly characterised by nausea/vomiting, injection site conditions and hypersensitivity reactions.

Cumulative post marketing data for Netspot indicates that nausea, injection site reactions, and vomiting were the most commonly reported serious and non-serious adverse reactions. Other reported adverse reactions include abdominal pain, erythema, pruritus, rash, urticaria, burning sensation, dizziness, flushing, and hypersensitivity.

In terms of radiation dose to the patient resulting from one imaging procedure, the administration of the commonly used activity of 68Ga-oxodotreotide leads to approximately 4-8 fold lower radiation dose to the patient than after administration of usual activity of 111In-pentetreotide for planar or tomographic scintigraphy.

The efficacy and safety of 68Ga-oxodotreotide during pregnancy or lactation or in patients with renal or hepatic impairment has not been studied. The ionization radiation from 68Ga-oxodotreotide is potentially harmful to a fetus or to a nursing infant; therefore, standard warnings and precautions for use of radiopharmaceuticals in pregnancy or breast-feeding are included in the product labelling. Based on data that demonstrates the lack of metabolism, rapid tumor uptake and fast radioactive decay, hepatic or renal impairment is not expected to have any relevant impact on the performance or safety of the product.

An identified drug-interaction is the interference of 68Ga-oxodotreotide imaging performance by concomitant treatment with long acting analogues of somatostatin within 30 days.

Based on the overall safety assessment, some inadequacies in safety labelling in the Netspot Product Monograph were noted. Additional warnings and precautions or strengthening of existing information was needed in the Netspot label. In particular, as hypersensitivity reactions have been reported, anaphylaxis is a potential risk. Although Netspot is a single administration product, there is a possibility that patients may receive future single administrations over the course of their disease. Prior exposure to Netspot or to therapeutic somatostatin analogues is a risk factor for hypersensitivity. The Netspot kit must be reconstituted using gallium 68 (68Ga) from an authorized 68Ge/68Ga generator that is not supplied with the Netspot. The complex procedures for the reconstitution differ among the generators that will potentially be authorized in Canada. Therefore, it is necessary to include detailed preparation instructions in the Netspot Product Monograph in order to minimize the risk of reconstitution errors that may affect the safety and efficacy of the final product.

Overall, the evaluation of the safety data for 68Ga-oxodotreotide found no significant safety concerns. The safety profile of 68Ga-oxodotreotide is consistent with that of diagnostic radiopharmaceuticals, which are single administration products that contains a sub-pharmacologic mass dose and therefore are generally well tolerated.

For more information, refer to the Netspot Product Monograph, approved by Health Canada and available through the Drug Product Database.

 

 

 

7.2 Non-Clinical Basis for Decision

 

A comprehensive preclinical package, including in vitro binding, biodistribution in animal models, metabolism, safety pharmacology, toxicology, and genotoxicity studies, is already available for the therapeutic agent 177Lu-oxodotreotide (Lutathera), which has the same DOTA-peptide moiety as 68Ga oxodotreotide. A Notice of Compliance was issued by Health Canada for Lutathera in January 2019. Therefore, considering the similarity between these two products, their equal physico chemical and receptor binding properties, the package of pre clinical studies prepared for 177Lu-oxodotreotide registration is also considered to be applicable for the registration of the kit for the preparation of 68Ga oxodotreotide.

The existing pre-clinical package supporting the registration of 177Lu-oxodotreotide, and the single dose toxicity and local tolerance study performed with the 68Ga-oxodotreotide formulation, show that the DOTA-peptide has a favourable toxicology/safety pharmacology profile. The DOTA-peptide safety margins relative to the injection of 68Ga-oxodotreotide were estimated using the NOEL or NOAEL, based on the available toxicology and safety pharmacology studies. Considering that the maximum amount of DOTA-peptide in a single dose of 68Ga-oxodotreotide is about 7-fold lower than in a single dose of 177Lu-oxodotreotide (40 µg vs. 270 µg, respectively), the estimated safety margin of the DOTA-peptide dose with respect to a 68Ga-oxodotreotide injection dose, is even higher.

The in vitro metabolism data, indicate no significant hepatic metabolization of the compound. Moreover, the absence of significant inhibitory or induction effects on human CYP450 enzymes and P-gp specific interactions, indicate no potential for the DOTA-peptide to cause clinically relevant drug-drug interactions.

Carcinogenicity and reproductive toxicology studies are typically not warranted for radiopharmaceutical drugs. Radiopharmaceuticals are inherently potentially genotoxic/carcinogenic, due to their radioactive nature. For diagnostic radiopharmaceuticals, this risk is relatively low, considering the short-term use (single dose or few doses in a lifetime), the low radioactivity dose and the short half-life of the radioisotope, as in the case of 68Ga-68 (68 minutes).

For more information, refer to the Netspot Product Monograph, approved by Health Canada and available through the Drug Product Database.

 

 

7.3 Quality Basis for Decision

 

The drug substance in Netspot is called oxodotreotide. This ingredient binds to tumors (called somatostatin receptor positive neuroendocrine tumors [NETs]) and helps to locate them with use of positron emission tomography (PET). However, before oxodotreotide can be used with PET it must be mixed with another solution and radioactive gallium (68Ga) chloride to make gallium (68Ga) -oxodotreotide. This process is called radiolabeling. The dose given is then based on your weight, which usually for an adult is approximately 100 MBq to 200 MBq (MBq = megabecquerel, the unit used to express radioactivity).

Characterization of the Drug Substance

Netspot is a kit used to prepare the radiopharmaceutical (radioactive) product gallium (68Ga) oxodotreotide. The Netspot kit is comprised of two sterile vials, which consists of:

  • Vial-1 (reaction vial with lyophilized powder): 40µg of oxodotreotide and selected excipients to be reconstituted with 68GaCl3 aqueous solution eluted from a 68Ge/68Ga generator;
  • Vial-2 (buffer vial): contains clear and colorless reaction buffer to be added to the reconstituted Vial-1.

The drug substance present in Netspot (kit Vial-1) is oxodotreotide. This drug substance binds to tumors (called somatostatin receptor positive neuroendocrine tumors [NETs]) and helps to locate them with use of positron emission tomography (PET). However, before oxodotreotide can be used with PET, it must be mixed with another solution (kit Vial-2) and radiolabelled with radioactive gallium (68Ga) chloride to make gallium (68Ga) oxodotreotide. After reconstitution and radiolabelling, Netspot contains a sterile solution of 68Ga oxodotreotide at a strength of 79.3 to 201.8 MBq/mL (2.1 to 5.45 mCi/mL).

Detailed characterization studies were performed to provide assurance that the identity and structure of oxodotreotide consistently exhibit the desired characteristic structure.

Results from process validation studies indicate that the processing steps adequately control the levels of product- and process-related impurities. The impurities that were reported and characterized were found to be within established limits.

Manufacturing Process and Process Controls of the Drug Substance and Drug Product

The manufacturing process of the drug product consists of a series of stages that include bulk solution, filtration, sterile filtration, aseptic filling, lyophilization, sealing/capping, and visual inspection. The materials used in the manufacture process for the kit Vial-1 are considered suitable for their intended use.

All critical steps during the manufacturing process are controlled by relevant in-process controls that are well established.

The materials used in the manufacture of the Netspot are considered suitable and meet standards appropriate for their intended use.

All non-medicinal ingredients (excipients) found in the drug product are acceptable for use in drugs according to the Food and Drug Regulations.

Control of the Drug Substance and Drug Product

The drug substance and drug product are tested against suitable reference standards to verify that they meet approved specifications and analytical procedures are validated and in compliance with general standards of the European Pharmacopoeia and that of radiopharmaceutical preparations.

Stability of the Drug Substance and Drug Product

The stability and compatibility of the final product 68Ga oxodotreotide has been extensively evaluated. Based on the stability data submitted, the proposed shelf life and storage conditions for the drug product were adequately supported and are considered satisfactory. Based on the collective results, a 12-month shelf life is proposed for kit Vial 1 lyophilized formulation and Vial 2 (Reaction Buffer vial) in the final commercial product, when stored its original packaging at a temperature below 25°C (do not freeze). Once reconstituted and radiolabelled, the finished drug product should be administered within 4 hours after reconstitution at room temperature.

The compatibility of the drug product with the container closure system was demonstrated through stability studies. The container closure system met all validation test acceptance criteria.

The proposed packaging and components are considered acceptable.

Facilities and Equipment

The design, operations, and controls of the facilities and equipment involved in the production are considered suitable for the activities and products manufactured.

On-site evaluation of the facilities involved in the manufacture and testing of Netspot was not conducted as it is not required for radiopharmaceutical products.

Adventitious Agents Safety Evaluation

No materials of animal or human origin are used during the manufacture of the drug substance and the drug product.

 

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