Summary Basis of Decision for Locametz

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.


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Summary Basis of Decision (SBD)

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

Recent Activity for Locametz

The 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. The PAATs will be updated regularly with post-authorization activity throughout the product life cycle. At this time, no PAAT is available for Locametz. When the PAAT for Locametz becomes available, it will be incorporated into this SBD.

Summary Basis of Decision (SBD) for Locametz

Date SBD issued: 2023-06-21

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

Kit for the preparation of gallium (68Ga) gozetotide solution for injection

Drug Identification Number (DIN): DIN 02537117 - 25 mcg gozetotide/vial, powder for solution, intravenous administration

Advanced Accelerator Applications USA, Inc.

New Drug Submission Control Number: 263638

Submission Type: New Drug Submission (New Active Substance)

Therapeutic Area (Anatomical Therapeutic Chemical [ATC] Classification, second level): V09 Diagnostic radiopharmaceuticals

Date Filed: 2022-04-22

Authorization Date: 2023-04-05

On April 5, 2023, Health Canada issued a Notice of Compliance to Advanced Accelerator Applications USA, Inc. for Locametz, a kit for the preparation of gallium (68Ga) gozetotide solution for injection. Gallium‑68, a positron (β+)-emitting radionuclide, is not supplied with Locametz.

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 Locametz, after radiolabelling with gallium‑68, is favourable as a radioactive diagnostic agent indicated for positron emission tomography (PET) of prostate-specific membrane antigen (PSMA)-positive lesions in men with prostate cancer:

  • with suspected metastasis who are candidates for initial definitive therapy.

  • with suspected recurrence based on elevated serum prostate-specific antigen (PSA) level.

  • for identification of patients with progressive metastatic castration-resistant prostate cancer (mCRPC), for whom PSMA-targeted therapy is indicated.

1 What was approved?

Locametz, after radiolabeling with gallium‑68, is a radioactive diagnostic agent indicated for positron emission tomography (PET) of prostate-specific membrane antigen (PSMA)-positive lesions in men with prostate cancer:

  • with suspected metastasis who are candidates for initial definitive therapy.

  • with suspected recurrence based on elevated serum prostate-specific antigen (PSA) level.

  • for identification of patients with progressive metastatic castration-resistant prostate cancer (mCRPC), for whom PSMA-targeted therapy is indicated.

No data are available to Health Canada regarding the use in patients younger than 18 years of age; therefore, Health Canada has not authorized an indication for pediatric use.

Based on the data submitted to Health Canada, gallium (68Ga) gozetotide has been extensively studied in men 65 years or older. No clinically relevant differences in safety and efficacy were observed between these patients and younger patients.

Locametz is a radiopharmaceutical multi-dose kit for the preparation of gallium (68Ga) gozetotide solution for injection. The kit contains one vial of white lyophilized powder. In addition to gozetotide, the vial contains gentisic acid, sodium acetate trihydrate, and sodium chloride. The radionuclide gallium‑68 is not part of the kit; it is obtained from an approved germanium‑68 (68Ge)/gallium‑68 (68Ga) generator. After radiolabelling with gallium‑68, each vial contains a sterile, clear, colourless solution without undissolved matter of gallium (68Ga) gozetotide at an activity of up to 1,369 megabecquerel (MBq) (37 millicurie [mCi]) in up to 10 mL at calibration date and time.

The use of Locametz is 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 Locametz 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 Locametz approved?

Health Canada considers that the benefit-risk profile of Locametz, after radiolabelling with gallium‑68, is favourable as a radioactive diagnostic agent indicated for positron emission tomography (PET) of prostate-specific membrane antigen (PSMA)-positive lesions in men with prostate cancer:

  • with suspected metastasis who are candidates for initial definitive therapy.

  • with suspected recurrence based on elevated serum prostate-specific antigen (PSA) level.

  • for identification of patients with progressive metastatic castration-resistant prostate cancer (mCRPC), for whom PSMA-targeted therapy is indicated.

In Canadian males, prostate cancer is the most commonly diagnosed cancer, accounting for approximately 20% of new cases. It is also the third leading cause of cancer death in this population. Several imaging modalities have been applied to prostate cancer; however, none have optimal performance. Improved prostate cancer imaging is needed due to a relatively high recurrence rate of up to 30% after definitive therapy (surgery or radiation) and because efforts to localize lesions through imaging fail in many patients with biochemical recurrence. Many imaging techniques have been used to diagnose prostate cancer, including transrectal ultrasound, computed tomography (CT), bone scans, and multiparametric magnetic resonance imaging (MRI). Despite recent advances in imaging, the diagnosis of prostate cancer remains challenging.

Locametz is a radiopharmaceutical kit for the preparation of gallium (68Ga) gozetotide solution for injection; a positron (β+)-emitting radiopharmaceutical that is administered intravenously and allows for the detection of PSMA-positive lesions in men with prostate cancer using PET imaging. Prostate-specific membrane antigen is highly expressed in adenocarcinoma of the prostate, which is the most frequent prostate cancer histological type. Different levels of PSMA expression can also be present in other forms of prostate cancer. Due to its low expression in normal tissues and overexpression in prostate cancer, particularly in advanced-stage prostate cancer, PSMA is an attractive target because of its specificity for prostate tissue. There have been substantial clinical studies of PSMA-labelled radiotracers over the last decade. Locametz is the second radiopharmaceutical kit authorized in Canada for the diagnosis of PSMA via PET imaging.

The primary evidence supporting the efficacy of Locametz was obtained from two pivotal controlled Phase III studies (ProPSMA and PSMA-BCR) published in peer-reviewed journals and the pivotal controlled Phase III VISION study conducted by the sponsor.

Studies ProPSMA and PSMA-BCR were provided to support the diagnostic performance of Locametz for the detection and localization of PSMA-positive prostate cancer. In the ProPSMA study, a total of 295 subjects with follow-up received a single mean dose of 164.2 megabecquerel (MBq) (4.4 millicurie [mCi]) of gallium (68Ga) gozetotide via slow intravenous injection. The primary efficacy endpoints were sensitivity and specificity of PSMA PET for the detection of nodal or distant metastatic disease compared to conventional imaging (whole-body bone scan and abdomen and pelvis CT imaging). Each image of the primary efficacy population was read by two blinded independent central readers. The sensitivity and specificity of gallium (68Ga) gozetotide PET were 85% and 98%, respectively, compared to 38% and 91%, respectively, for conventional imaging. In the PSMA-BCR study, 223 patients with composite validation and 93 patients with histopathologic validation were included in the efficacy cohorts. The patient-level positive predictive value was 84%.

The results of the VISION study were provided to support the use of Locametz in the identification of patients with progressive mCRPC, for whom PSMA-targeted therapy is indicated. A total of 1,003 adult male patients with mCRPC received gallium (68Ga) gozetotide by intravenous administration and underwent PET imaging. Gallium (68Ga) gozetotide PET imaging was interpreted in conjunction with contrast-enhanced CT and/or MRI for all patients. Of the patients evaluated by the central reader, 86.6% were found to be PSMA positive and 12.6% were found to be PSMA negative. Improved overall survival was reported in the PSMA-targeted therapy arm.

The safety of Locametz was evaluated in the VISION study and involved the entire data set of patients injected with a single dose of gallium (68Ga) gozetotide. No serious adverse reactions were identified, and the most common adverse reaction of any grade was fatigue (1.2%).

Overall, Locametz was found to have a favourable benefit-risk profile based on the evidence reviewed.

Appropriate warnings and precautions are in place in the Locametz Product Monograph to address the identified safety concerns. A Serious Warnings and Precautions box has also been included indicating that 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) for Locametz was submitted by Advanced Accelerator Applications USA, Inc. to Health Canada. 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. Upon review, the RMP was considered to be acceptable.

The submitted inner and outer labels, package insert, and Patient Medication Information section of the Locametz Product Monograph met the necessary regulatory labelling, plain language, and design element requirements.

The sponsor submitted a brand name assessment that included testing for look‑alike sound‑alike attributes. Upon review, the proposed name Locametz was accepted.

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 Locametz?

The New Drug Submission (NDS) for Locametz 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 review of Locametz was based, in part, on data from the scientific literature and market experience.

The NDS for Locametz was reviewed under Project Orbis, an initiative of the United States Food and Drug Administration (FDA) Oncology Center of Excellence. The project is an international partnership designed to give cancer patients faster access to promising cancer treatments. The NDS for Locametz was classified as a Project Orbis Type C submission, where the FDA had already issued a positive decision and subsequently shared its completed review documents with Health Canada. For this NDS, reviews completed by the FDA and responses to questions provided by the European Medicines Agency were used as added references. The Canadian regulatory decision on the Locametz NDS was made independently and 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 and Applications Guidance.

Submission Milestones: Locametz

Submission Milestone

Date

Pre-submission meeting

2021-10-15

New Drug Submission filed

2022-04-22

Screening

Screening Acceptance Letter issued

2022-06-10

Review

Review of Risk Management Plan completed

2023-03-05

Clinical/medical evaluation completed

2023-04-03

Non-clinical evaluation completed

2023-04-03

Labelling review completed

2023-04-03

Quality evaluation completed

2023-04-04

Biostatistics evaluation completed

2023-04-05

Notice of Compliance issued by Director General, Biologic and Radiopharmaceutical Drugs Directorate

2023-04-05
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 Locametz?

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 life cycle.

At this time, no PAAT is available for Locametz. When available, the PAAT will be incorporated into this SBD.

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

Locametz is a radiopharmaceutical kit for the preparation of gallium (68Ga) gozetotide solution for injection. Gallium (68Ga) gozetotide binds to cells that express prostate-specific membrane antigen (PSMA), including malignant prostate cancer cells, which overexpress PSMA. Gallium‑68 is a positron (β+)-emitting radionuclide with an emission yield that allows for positron emission tomography (PET) imaging.

The pharmacokinetics of Locametz was assessed through the analysis of biodistribution, dosimetry, and pharmacokinetic data from published literature. The recommended radioactivity dose to be administered for PET imaging in adult patients is 3 to 7 millicurie (mCi), administered via slow intravenous injection. The individual dose contains a mass dose of 25 mcg gallium (68Ga) gozetotide. Gallium (68Ga) gozetotide is mainly eliminated via the renal route. Approximately 14% of the gallium (68Ga) gozetotide dose administered is excreted in the urine 2 hours post injection. Published literature demonstrated a bi-exponential behaviour in blood activity with 6.5‑minute and 4.4‑hour half-life components. The highest absorbed radiation dose was found in the kidneys, salivary glands, bladder wall, lacrimal glands, spleen, and liver.

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

Clinical Efficacy

The efficacy and safety of Locametz for the diagnosis of adult men with PSMA-positive prostate cancer in patients with suspected metastasis who are candidates for initial definitive therapy (also referred to as proPSMA) or patients with suspected recurrence based on elevated serum prostate-specific antigen (PSA) (also referred to as PSMA-BCR) were evaluated in the two pivotal Phase III studies published in peer-reviewed journals. Study protocols were provided as supplementary content. The third indication, for identification of patients with progressive metastatic castration-resistant prostate cancer (mCRPC), for whom PSMA-targeted therapy is indicated, was supported by the Phase III VISION study conducted by the sponsor.

ProPSMA study

ProPSMA was a prospective, open-label, randomized, controlled Phase III study performed at 10 centres in Australia. It was designed to compare the diagnostic accuracy of PSMA-PET/computed tomography (CT) to that of conventional imaging for detecting nodal or distant metastatic disease in high-risk patients preparing for radical prostatectomy or radiotherapy. The primary efficacy endpoints were sensitivity and specificity of PSMA-PET compared to conventional imaging (CT and bone scanning). A total of 295 subjects with follow-up received a single mean dose of 164.2 megabecquerel (MBq) (interquartile range: 141.0 MBq to 182.0 MBq) of gallium (68Ga) gozetotide via intravenous injection. Subjects underwent PET imaging 45 to 75 minutes after injection of gallium (68Ga) gozetotide. Image acquisition was performed from the upper thighs to the base of the skull. Each image of the primary efficacy population was read by two blinded independent central readers. The sensitivity and specificity of gallium (68Ga) gozetotide PET were 85% (95% confidence interval [CI]: 74% to 96%) and 98% (95% CI: 95% to 100%), respectively, compared 38% (95% CI: 24% to 52%) and 91% (95% CI: 85% to 97%), respectively, for conventional imaging. Overall, PET imaging with gallium (68Ga) gozetotide outperformed conventional imaging for the detection of nodal or distant metastatic disease.

PSMA-BCR study

PSMA-BCR was a prospective, open-label, single-arm Phase III study in patients with prostate cancer. The primary endpoint was positive predictive value (PPV) on a per-patient and per-region basis confirmed by histopathology/biopsy. A total of 316 subjects were included in the efficacy cohorts (223 patients with composite validation and 93 patients with histopathologic validation). The patient level PPV was 84% (95% CI: 75% to 90%). The per-region PPV and sensitivity were similar to the per-patient analysis at 84% (95% CI: 76% to 91%). These results exceeded the PPV goal of 70%.

VISION study

VISION was a randomized, multicentre, open-label, Phase III study which established the efficacy of PSMA-targeted therapy (lutetium [177Lu] vipivotide tetraxetan) plus best standard of care (number of patients [n] = 551) compared to best standard of care alone (n = 280). Only patients with PSMA-positive lesions were eligible for randomization and to receive PSMA-targeted therapy. A total of 1,003 adult male patients with mCRPC received gallium (68Ga) gozetotide by intravenous administration and underwent PET imaging. Gallium (68Ga) gozetotide PET imaging was interpreted in conjunction with contrast-enhanced CT and/or magnetic resonance imaging of the chest, abdomen, and pelvis for all patients. Gallium (68Ga) gozetotide PET and anatomical imaging was interpreted by one central reader who was blinded to clinical information and other PET and bone imaging. Of the patients evaluated by the central reader, 869 (86.6%) were found to be eligible (PSMA positive) and 126 (12.6%) were found to be ineligible (PSMA negative) for PSMA-targeted therapy. Improved overall survival was reported in the PSMA-targeted therapy arm.

Indication

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

Locametz (kit for the preparation of gallium [68Ga] gozetotide solution for injection), after radiolabeling with gallium‑68, is indicated for:

  • the identification of prostate-specific membrane antigen (PSMA)-positive lesions by positron emission tomography (PET) in adult patients with prostate cancer.

To reflect the primary evidence provided by the sponsor, Health Canada approved the following indication:

Locametz (kit for the preparation of gallium [68Ga] gozetotide solution for injection), after radiolabeling with gallium‑68, is a radioactive diagnostic agent indicated for positron emission tomography (PET) of prostate-specific membrane antigen (PSMA)-positive lesions in men with prostate cancer:

  • with suspected metastasis who are candidates for initial definitive therapy.

  • with suspected recurrence based on elevated serum prostate-specific antigen (PSA) level.

  • for identification of patients with progressive metastatic castration-resistant prostate cancer (mCRPC), for whom PSMA-targeted therapy is indicated.

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

Clinical Safety

The safety of Locametz was evaluated in the VISION study (see Clinical Efficacy section) and involved the entire data set of patients injected with a single dose of gallium (68Ga) gozetotide. Mild-to-moderate adverse drug reactions occurred in patients receiving gallium (68Ga) gozetotide, with the exception of a Grade 3 fatigue event (0.1%). No serious adverse drug reactions were identified and the most common adverse drug reaction of any grade (incidence ≥1%) was fatigue (1.2%). All other events were reported in less than 1.0% of patients and included nausea, constipation, vomiting, diarrhea, dry mouth, injection site reactions, and chills.

Appropriate warnings and precautions are in place in the approved Locametz Product Monograph to address the identified safety concerns. A Serious Warnings and Precautions box has also been included, indicating that 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 Locametz Product Monograph, approved by Health Canada and available through the Drug Product Database.

7.2 Non-Clinical Basis for Decision

The data on primary pharmacodynamics, secondary pharmacodynamics, safety pharmacology, pharmacokinetics, radiation dosimetry, and toxicology were mainly provided based on studies from the literature and sponsor-conducted non-clinical studies. Pharmaceutical equivalence was established between the gallium (68Ga) gozetotide used in the studies from the literature and that which was used in Locametz.

In vitro pharmacology data demonstrated that the microdose administration of gallium (68Ga) gozetotide resulted in nanomolar affinity for prostate-specific membrane antigen (PSMA) in both the cell-based and enzyme-based assays. In vivo pharmacology data showed the uptake and internalization of gallium (68Ga) gozetotide in PSMA-positive tumour xenografts, with little to no uptake into PSMA-negative xenografts. In vivo imaging using positron emission tomography/computed tomography showed a rapid systemic clearance from the blood and most normal tissues in mice, while uptake and retention in PSMA-positive tumour xenografts was evident.

Four safety pharmacology studies conducted by the sponsor aimed to evaluate the effect of gozetotide on in vitro human ether-à-go-go-related gene (hERG) tail current and in vivo central nervous system, respiratory system, and cardiovascular safety. Overall, gozetotide didn’t show an effect on hERG tail current at any of the tested concentrations. No effect was shown on behavioral, neurologic, autonomic, or respiratory parameters in rats and no effect was shown on heart rate, arterial blood pressure, and electrocardiographic readings in minipigs.

Five pharmacokinetics studies were conducted by the sponsor. The results demonstrated that gozetotide was moderately bound to plasma proteins when tested at concentrations of both 1 and 5 mcg/mL in all species evaluated. Blood-to-plasma partitioning showed that gozetotide is not majorly distributed into erythrocytes. Gozetotide demonstrated good stability when incubated with either plasma, liver S9, or kidney S9 from rats, minipigs, and humans. In addition, the renal system was demonstrated to be the primary route of elimination, with comparably low liver and intestinal distribution.

Two toxicology studies were conducted by the sponsor. A Good Laboratory Practice extended single-dose toxicity study was performed in male and female rats. Gozetotide was well tolerated when administered to rats by single intravenous bolus injection at doses of 0.67 and 1.33 mg/kg. The highest dose administered is approximately 530‑fold higher than the maximum human dose (25 mcg) based on body surface area scaling. It was also considered the no-observed-adverse-effect level.

The results of the non-clinical studies as well as the potential risks to humans have been included in the Locametz Product Monograph. In view of the intended use of Locametz, there are no pharmacological/toxicological issues within this submission which preclude authorization of the product.

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

7.3 Quality Basis for Decision

Characterization of the Drug Substance

The drug substance, gozetotide (supplied as trifluoroacetate salt), is a small molecule human prostate-specific membrane antigen (PSMA)-targeting ligand. It is the active ingredient in Locametz used for radiolabelling with gallium‑68 chloride.

Detailed characterization studies were performed to provide assurance that gozetotide consistently exhibits the desired characteristic identity and structure.

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

Drug Substance

The manufacturing process of the drug substance consists of a series of steps which include the synthesis of a PSMA building block, peptide synthesis involving coupling to a radiometal chelator, isolation of crude peptide, purification, filtration, lyophilization, and filling of the bulk substance into sterile single-use polyethylene terephthalate glycol bottles with high-density polyethylene screw caps.

In-process control and release data for the validation batches were reviewed against the proposed acceptance criteria. All acceptance criteria were met.

Drug Product

The Locametz kit manufacturing process consists of a series of steps, which include solution compounding, sterilizing filtration, aseptic filling, lyophilization, stoppering and sealing of vials, visual inspection, labelling, and packaging.

Validation studies have been performed to demonstrate the suitability of the manufacturing conditions to support consistent and reproducible quality of the drug product. The method of manufacturing and the controls used during the manufacturing process for the drug product are validated and considered to be adequately controlled within justified limits.

Control of the Drug Substance and Drug Product

Drug Substance

Gozetotide is used as a chemical precursor for radiopharmaceutical preparations. Accordingly, the proposed release specifications met the requirements of the European Pharmacopeia (Ph. Eur. monograph 2902 for chemical precursors for radiopharmaceutical preparations).

The analytical methods proposed for the analysis of gozetotide are scientifically based, commonly used, and suitable for general peptide analysis. The analytical methods were well described, and the validation elements met the acceptance criteria predefined in validation protocols, demonstrating the suitability of the analytical methods for accessing the quality of gozetotide.

Drug Product

Locametz is tested against suitable reference standards to verify that it meets approved specifications, and analytical procedures are validated and in compliance with International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) guidelines.

Batch analysis data showed that the process validation batches met the drug product release specification, demonstrating that the manufacturing process is consistent and robust.

Stability of the Drug Substance and Drug Product

Based on the stability data submitted, the proposed shelf life and storage conditions for the drug substance and drug product were adequately supported and are considered to be satisfactory. The proposed 12-month shelf life at 25 ºC for Locametz is considered acceptable.

The container closure system in the drug product met all validation test acceptance criteria.

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.

Adventitious Agents Safety Evaluation

The Locametz manufacturing process incorporates adequate control measures to prevent contamination and maintain microbial control. Pre-harvest culture fluid from each lot is tested to ensure freedom from adventitious microorganisms (bioburden, mycoplasma, and viruses) and appropriate limits are set. Purification process steps designed to remove and inactivate viruses are adequately validated.

No materials of animal or human origin are used during the manufacture of Locametz.

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