Summary Basis of Decision for Cantrace ™
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:
CantraceTM
18F-Fluorodeoxyglucose, ≤1.4 GBq/mL, Solution, Intravenous
IPET Pharmaceuticals, Inc.
Submission control no: 091404
Date issued: 2008-01-28
Foreword
Health Canada's Summary Basis of Decision (SBD) documents outline the scientific and regulatory considerations that factor into Health Canada regulatory decisions related to drugs and medical devices. SBDs are written in technical language for stakeholders interested in product-specific Health Canada decisions, and are a direct reflection of observations detailed within the evaluation reports. As such, SBDs are intended to complement and not duplicate information provided within the Product Monograph.
Readers are encouraged to consult the 'Reader's Guide to the Summary Basis of Decision - Drugs' to assist with interpretation of terms and acronyms referred to herein. In addition, a brief overview of the drug submission review process is provided in the Fact Sheet entitled 'How Drugs are Reviewed in Canada'. This Fact Sheet describes the factors considered by Health Canada during the review and authorization process of a drug submission. Readers should also consult the 'Summary Basis of Decision Initiative - Frequently Asked Questions' document.
The SBD reflects the information available to Health Canada regulators at the time a decision has been rendered. Subsequent submissions reviewed for additional uses will not be captured under Phase I of the SBD implementation strategy. For up-to-date information on a particular product, readers should refer to the most recent Product Monograph for a product. Health Canada provides information related to post-market warnings or advisories as a result of adverse events (AE).
For further information on a particular product, readers may also access websites of other regulatory jurisdictions. The information received in support of a Canadian drug submission may not be identical to that received by other jurisdictions.
Other Policies and Guidance
Readers should consult the Health Canada website for other drug policies and guidance documents. In particular, readers may wish to refer to the 'Management of Drug Submissions Guidance'.
1 Product and submission information
Brand name:
Manufacturer/sponsor:
Medicinal ingredient:
International non-proprietary Name:
Strength:
Dosage form:
Route of administration:
Drug identification number(DIN):
Therapeutic Classification:
Non-medicinal ingredients:
Submission type and control no:
Date of Submission:
Date of authorization:
2 Notice of decision
On July 27, 2006, Health Canada issued a Notice of Compliance to IPET Pharmaceuticals Inc. for the diagnostic radiopharmaceutical CanTrace.
CanTrace contains the medicinal ingredient 18F-Fluorodeoxyglucose (18F-FDG) which is a positron-emitting radiopharmaceutical used in conjunction with positron emission tomography (PET).
CanTrace is indicated for diagnostic use in: breast cancer (evaluation of recurrence/residual disease, distant metastases [staging/restaging], and disease/therapeutic monitoring); colorectal cancer (evaluation of recurrence/restaging, distant metastases and disease/therapeutic monitoring); and lung cancer (evaluation of single pulmonary nodules [diagnosis], staging, distant metastases, recurrence/restaging, and disease/therapeutic monitoring). 18F-FDG is transported from blood to tissue in a manner similar to glucose. It is initially modified by intracellular enzymes, however, it cannot be further broken down due to its altered structure. As a result, it becomes trapped in tissue in proportion to the rate of glycolysis or glucose utilisation of that tissue. As cancer cells require large amounts of glucose for energy production and growth, 18F-FDG tends to accumulate in cancerous regions. Imaging of the subject using a PET scanner takes advantage of the positron-emitting decay of 18F to identify those tissues that have abnormal glucose metabolism and accumulation of the radioisotope.
Priority review status was granted for CanTrace as it offers a significant improvement over existing diagnostic approaches used in Canada for the diagnosis and treatment of cancer.
The market authorization was based on quality and clinical information submitted. Submitted clinical information consisted of safety and efficacy data. Safety data was analyzed from patients in a safety trial, a bridging trial, and a treatment trial. Efficacy data was analyzed from patients in a bridging trial and a retrospective trial (with patients in the latter study enrolled either in the treatment trial or as other protocol eligible patients). CanTrace has been shown to be useful in characterizing the presence of the diseases for whose imaging it is indicated, however, caution must be exercised as the extent of disease may be overestimated or underestimated. An understanding of lesion size (such as micrometastases) with respect to 18F-FDG relative accumulation and to PET imaging instrumentation system resolution should be considered as it has been shown that 18F-FDG imaging may have a lower sensitivity in evaluating lesion sizes less than 1 cm.
CanTrace (≤1.4 GBq/mL, 18F-FDG) is provided as a solution for intravenous injection. The minimum dose is 370 MBq for those whose weight is 50 kg and below. The maximum dose is 555 MBq for those whose weight is 100 kg or greater. Patients whose weight is greater than 50 kg and less than 100 kg should be given an intermediate dose calculated using the weight adjustment formula outlined in the Product Monograph. The fasting serum glucose level is required to rule out uncontrolled diabetes. Blood glucose should be stabilised in non-diabetic patients by fasting prior to CanTrace administration. Diabetic patients may need stabilisation of blood glucose on the day preceding and on the day of the CanTrace PET scan. The patient dose should be measured by a suitable radioactivity calibration system prior to intravenous administration. Dosing guidelines are available in the Product Monograph.
CanTrace is contraindicated for patients who are hypersensitive to this drug or to any ingredient in the formulation or component of the container. CanTrace should be administered under the conditions stated in the Product Monograph taking into consideration the potential risks associated with the administration of this drug product. Detailed conditions for the use of CanTrace are described in the Product Monograph.
Based on the Health Canada review of data provided in support of quality, safety, and effectiveness, Health Canada considers that the benefit/risk profile of CanTrace is favourable for the indications stated above.
3 Scientific and Regulatory Basis for Decision
3.1 Quality Basis for Decision
3.1.1 Drug Substance (Medicinal Ingredient)
General Information
18F-Fluorodeoxyglucose (18F-FDG), the medicinal ingredient of CanTrace, is a positron-emitting radiopharmaceutical used for diagnostic purposes in conjunction with positron emission tomography (PET).
18F-FDG is transported from blood to tissue in a manner similar to glucose, where it is phosphorylated by hexokinase to 18F-FDG-6-phosphate. As 18F-FDG-6-phosphate is not a substrate for subsequent glycolytic pathways, and has very low membrane permeability, it becomes trapped in tissue in proportion to the rate of glycolysis or glucose utilization of that tissue. Imaging of the subject using a PET scanner takes advantage of the positron decay of F-18 to identify those tissues that have an abnormal glucose metabolism and accumulation of the radioisotope.
Manufacturing Process and Process Controls
Radionuclide
PETNET Pharmaceuticals, Inc. provided a short summary of the information regarding production and supply of [18F]-fluoride to the CanTrace manufacturer (IPET Pharmaceuticals Inc.). The document was reviewed and found to be acceptable to support the chemistry and manufacturing of the [18F]-fluoride used by IPET Pharmaceuticals Inc. in its manufacture of 18F-FDG.
Drug substance, precursor and catalyst
Specification for mannose triflate starting reagent and other materials and reagents have been provided. All tests and acceptance criteria have been found to be acceptable.
Description of Synthesis/Fabrication
An overview and general description of the production process has been provided. The chemical process of manufacturing 18F-FDG is done in an automated radiochemical synthesis instrument. The Chemistry Process Control Unit (CPCU) used during manufacturing has been described.
Characterization
This section does not generally apply to radionuclides because the manufacturing process usually leads rapidly to the generation of the drug product or does not allow clear separation of drug substance from drug product. Please refer to Section 3.1.2 Drug Product, Characterization.
Control of Drug Substance
This section does not generally apply to radionuclides because the manufacturing process usually leads rapidly to the generation of the drug product or does not allow clear separation of drug substance from drug product. Please refer to Section 3.1.2 Drug Product, Control of Drug Product.
Stability
This section does not generally apply to radionuclides because the manufacturing process usually leads rapidly to the generation of the drug product or does not allow clear separation of drug substance from drug product.
3.1.2 Drug Product
Description and Composition
CanTrace is provided as a ready-to-use, isotonic, sterile, pyrogen-free, clear and colourless solution. The solution is supplied in a multi-dose, septum-capped, 30 mL glass vial and does not contain any preservative. Each vial of product contains up to 18.5 Gbq of no-carrier-added 18F-FDG (at calibration) in approximately 13 mL of normal saline at a radioactive concentration of 1.4 Gbq/mL.
All excipients found in the drug product are acceptable for use in drugs according to the Food and Drug Regulations. The compatibility of 18F-FDG with the excipients is demonstrated by the stability data presented on the proposed commercial formulation.
Pharmaceutical Development
Pharmaceutical development data, including development of the container closure system, are considered acceptable. Data provided in this section include composition of CanTrace, rationale for choice of formulation, manufacturing process including packaging, information on batches used in in vitro studies for characterization and discussion on the effect of formulation change on the safety and/or efficacy of CanTrace. Studies which justified the type and proposed concentration of excipients to be used in the drug product were also reviewed and are considered to be acceptable.
Changes to the manufacturing process and formulation made throughout the development are considered acceptable.
Manufacturing Process and Process Controls
18F-FDG is manufactured via a multi-step synthesis. As discussed above, the very first step in the manufacture of 18F-FDG is the production of 18F-fluoride. The other steps include synthesis, purification, sterilization by membrane filtration, and quality control of 18F-FDG. Each step of the manufacturing process is considered to be controlled within acceptable limits:
- The sponsor has provided information on the quality and controls for all materials used in the manufacture of the drug substance.
- The drug substance specifications are found to be satisfactory. Impurity limits satisfy ICH guidelines.
- The processing steps have been evaluated and the appropriate ranges for process parameters have been established.
- Processing reproducibility has been demonstrated by submitted batch records.
The manufacturing process is considered to be adequately controlled within justified limits.
Characterization
The structure of 18F-FDG has been adequately explained and the representative structure elucidation data have been provided. Physical and chemical properties have been described and are found to be satisfactory.
Control of Drug Product
Quality control information submitted included formulation, manufacturing, batch analyses, stability and validation studies for residual solvents, sterility, and bacterial endotoxin data.
CanTrace is tested to verify that the appearance, radiochemical purity, radionuclidic identity and purity, pH, and osmolality are within acceptance criteria. Due to the short half-life of 18F (109 minutes) and short shelf-life of CanTrace (8 hours post-calibration), tests for residual solvents (acetonitrile, ether, and ethanol), Kryptofix 222, sterility, and bacterial endotoxins are performed retrospectively.
During the initial review, a significant concern was raised with respect to a high level of acetonitrile (residual solvent) present in the final product. This issue has been addressed by the sponsor, and a new specification of <4.1 mg/batch has been confirmed. This level is within the limits recommended by ICH and USP, and therefore considered acceptable.
Validation reports submitted for all analytical procedures used for in-process and release testing of the drug product are satisfactory, and justify the specifications of the drug product. Use of analytical procedures is in compliance with ICH guidelines.
Stability
Based upon the real-time stability data submitted, the proposed 8-hour expiry time at 18-25°C for CanTrace is considered acceptable. The solution should be stored upright at room temperature in a lead-shielded container and should be used within 8 hours from the time of calibration.
The compatibility of the drug product with the container closure system was demonstrated through compendial testing and stability studies. The container closure system met all validation test acceptance criteria.
3.1.3 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. All of the proposed manufacturing sites comply with the requirements of Division 2 of the Food and Drug Regulations.
3.1.4 Adventitious Agents Safety Evaluation
N/A
3.1.5 Conclusion
The Chemistry and Manufacturing information submitted for CanTrace has demonstrated that the radionuclide 18F-fluoride, drug substance, and drug product can be consistently manufactured to meet the approved specifications. Proper development and validation studies were conducted, and adequate controls are in place for the commercial production. The concern over the high level of acetonitrile (residual solvent) in the finished product has been addressed along with a new specification of <4.1 mg/batch, which is within the limits recommended by ICH and USP, and therefore considered acceptable.
3.2 Non-Clinical Basis for Decision
No pharmacodynamic (PD) or pharmacokinetic (PK) data were provided from original studies by the sponsor. All data were extracted from published literature. Therefore, the pharmacological properties of the product are described below in a general fashion.
3.2.1 Pharmacodynamics
Highly active glucose utilization in tumour cells, as a consequence of their enhanced rate of aerobic glycolysis and mitotic index, has been known for more than half a century. Like glucose, FDG is transported into the cell by specific membrane transport system receptors (GLUTs, especially GLUT-1 and GLUT-3 for tumour cells) where it is phosphorylated by hexokinase (especially hexokinase type 2 in tumour cells) to 2-fluoro-2-deoxyglucose-6-phosphate (FDG-6-phosphate). Both GLUT transporters and hexokinase are known to be present in elevated levels (and/or in highly active forms) in tumour cells. Glucose-6-phosphate is then converted to fructose-6-phosphate by phosphohexoseisomerase (glucose-6-phosphatase) during which the aldose function is changed to a ketone via a cis-enediol intermediate, a process that is not possible for FDG since no oxygen group is present at the C-2 position. Due to the low membrane permeability and the low concentration of FDG-6-phosphate (hindering the reverse reaction) this metabolite tends to accumulate in the cells. Thus, through increased uptake and a structure that resists catalytic breakdown, the radioisotopic analogue of FDG, 18F-FDG, is distributed to many tumour types preferentially to surrounding normal tissue and this accumulation can be imaged externally with the PET scan. Nonetheless, there are many reports of further metabolism past the 18F-FDG-6-phosphate stage to various extents depending on the time after administration and tissue type including the detection of FDG-1-phosphate, 2-fluoro-2-deoxy-mannose-1-phosphate, and several other phosphorylated derivatives. Since these secondary metabolites are also predominantly retained by the cell at least over the time frame of an 18F-FDG scan, their significance is likely limited to the quantitative measurement of glucose metabolic rate constants that are utilized in some cerebral studies. The secondary metabolites are unlikely to have any effect on the typical clinical delineation of areas of relative enhanced uptake used in oncological applications. These cellular biochemical features help explain the clinical 18F-FDG observations of differential normal cell uptake based on a range of transporter/enzyme levels/activities and energy substrate requirements as well as the influence of excessive serum glucose levels competing for 18F-FDG cellular uptake.
3.2.2 Pharmacokinetics
One published study examined the tissue distribution of 18F-FDG in animals. In mice, 18F-FDG distributed uniformly to the kidneys, heart, brain, lungs, and liver. It cleared rapidly from all tissues except the heart, where it remained constant for at least 2 hours and, to a lesser extent, in the brain where it decreased slowly from 1 to 2 hours. The rapid clearance of 18F-FDG from the liver, lungs, and kidneys, and its retention by the heart and brain, is a result of metabolic trapping within these organs and is reflective of glucose utilization. Urinary excretion of intact 18F-FDG was 15-25% of the injected dose at 90 minutes post-dosing.
Another study examined groups of mice (CD-1) and rats (Sprague-Dawley) injected intravenously (IV) with tracer amounts of 18F-FDG and sacrificed at 1, 5, 30, 60, and 120 minutes for tissue biodistribution analysis. It also studied two mongrel dogs with imaging at 40 - 80 minutes post-IV injection of tracer doses for tissue biodistribution analysis. Arterial blood sampling occurred at 0-10, 15, 20, 30, 40, 45, 60, and 90 minutes. Tissue biodistribution (%ID/gram) for blood, brain, liver, spleen, lung, heart, kidney, bone, muscle, and bladder over the time periods indicated for mice and rats was reported. Tissue biodistribution (%ID/gram/1%body weight) for blood, brain (left and right hemisphere, cerebellum), liver, spleen, lung, heart (left and right atria and ventricle), kidney, bone, muscle, and bladder wall for the dogs was reported. Tissue PK parameters in the heart and brain were estimated.
The studies of animals show uniform extraction of 18F-FDG by internal organs but 18F-FDG clears rapidly except from brain and heart. The level of the tracer remains stable for about 2 hours in the case of the heart, and for about 1-2 hours in the case of the brain. 18F-FDG is cleared by urinary excretion in mostly unchanged form.
3.2.3 Toxicology
No toxicology studies were conducted by the sponsor in support of this submission. The toxicology assessment below is based on information from the literature. No data on genotoxicity or carcinogenicity were provided.
Fluorodeoxyglucose (FDG)
One study examined non-radioactive FDG administered to a variety of normal and tumour-bearing mice and rats in daily intraperitoneal (IP) doses up to 400mg/kg for 5 days. Twenty-four hours after IP administration no morphological changes in the liver were observed. From this study an LD50 of 600 mg/kg was reported in both mice and rats.
Two additional studies looked at the toxicology of FDG in mice and dogs. Mice were injected IP with FDG at 14.3 mg/kg weekly for three weeks (3000 times the human dose). Weight gain in treated animals was similar to controls, and the terminal gross and microscopic histopathological analysis of the brain, heart, spleen, kidneys, and lungs showed no abnormalities. Dogs were injected IV with 0.72 mg/kg weekly for three weeks and showed no clinical signs or symptoms of adverse effects. No significant abnormalities were detected in the blood, urine, or cerebrospinal fluid. No significant gross or microscopic abnormalities were noted in the internal organs.
Acetonitrile and Kryptofix 222
Potential impurities that have been observed in small amounts in 18F-FDG are acetonitrile and Kryptofix 222 and therefore, the potential impact of their presence on product safety was also assessed.
Toxicological data for acetonitrile was compiled from animal studies and from human environmental exposure. The principal concern with acetonitrile exposure is its potential conversion to cyanide in vivo. In rats, about 2-4% of the IP injected dose of 600 mg/kg was found to be in form of cyanide after 11 days.
Three male human subjects were tested for the effects of inhalation of acetonitrile. None of them experienced any adverse effects and they had no measurable amounts of cyanide in blood with exposure to a concentration of 40 ppm acetonitrile in the inhaled air over four hours. However, one of them experienced a slight tightness of the chest that evening and a cooling sensation in the lungs the following morning. The sensation persisted for approximately 24 hours. He also had a slight increase in urinary thiocyanate. He was not tested for inhalation of 80 and 160 ppm of acetonitrile contrary to the two other subjects, therefore acetonitrile cannot be discounted as the potential cause of this reaction. In one of the patients, acetonitrile levels of 160 ppm produced the side effects consisting of slight, transient flushing of the face and bronchial tightness.
The systemic dose calculated based on absorption through the lungs was 241.2 mg and 484.2 mg for acetonitrile concentrations of 80 ppm and 160 ppm, respectively, in the inhaled air. This suggests a systemic level of acetonitrile by inhalation in a 60 kg individual of approximately 4 mg/kg and 8 mg/kg for acetonitrile concentrations of 80 ppm and 160 ppm, respectively. Based on the above study, it is not possible to estimate the first observable biological response in humans.
A summary of the acute toxicity parameters reported in the literature for acetonitril in rats, mice, and rabbits in comparison to the specification limit for CanTrace, provided a safety ratio in the range of 157 to 5821, depending on the system evaluated. A safety ratio of approximately 60 from the standardized no-observed-effect-level (NOEL) dose calculations (based on the cumulative animal data in standard regulatory toxicological evaluations) was determined. Based on animal data, the NOEL was determined to be 50.7 mg/kg.
During the initial review of the CanTrace submission, an excessive content of acetonitrile in the final product was found. This issue has been addressed and the content of acetonitrile was lowered to an acceptable level.
The acute toxicity of Kryptofix 222 was evaluated in rats and mice. The LD50 of an IV dose in mice was 35 mg/kg and 110 mg/kg by IP administration. The LD50 of an IV dose in rats was 32 mg/kg and 153 mg/kg by IP administration.
Toxicity of Kryptofix 222 was also studied in rats which were injected with doses up to 500 μmoles/kg (approx. 188 mg/kg, route not specified). Levels of alanine transaminase (ALT), aspartate aminotransferase (AST), alkaline phosphatase, cholesterol, protein, and creatinine were determined within six hours to seven days post-injection, and histopathological examinations were performed. The highest doses produced transient elevations in liver enzymes, but no other histopathological changes were evident. AST and ALT levels increased by 11 and 3 times, respectively, over control values at six hours, however they returned to control levels within three days and remained unchanged up to seven days. No changes in the levels of alkaline phosphatase, creatinine, protein, or cholesterol were observed. Histopathological examinations were normal. During clinical trials of CanTrace, one patient had an elevation in the liver function test (AST increase from 44 to 83), and although the elevation was not extreme, there was no follow up of this change and it is unknown how transient it was. Ongoing quality control of the Kryptofix 222 content in CanTrace batches assures the safety of the product.
The amount of Kryptofix 222 that may be present in CanTrace has a limit of 50 μg/mL (approx. 655 μg/batch). For potential patients, this value is more than two orders of magnitude below the IV lethal dose in rodents.
3.2.4 Conclusion
18F-FDG was studied in a standard set of non-clinical PK/PD and toxicological studies, which demonstrated no evidence of risk for the health of humans at the recommended diagnostic dose.
3.3 Clinical basis for decision
3.3.1 Human Pharmacology
No human PK or PD studies were conducted by the sponsor in support of this submission. (Please refer to section 3.2.1 and 3.2.2 for non-clinical PK/PD information.) The pharmacology of 18F-fluorodeoxyglucose is well established in the literature. A summary of the literature data was provided in the submission.
3.3.2 Clinical Efficacy
This was a non-standard new drug submission (NDS) in that the evidence presented to support the proposed indications was largely literature based and was bridged to the sponsor's product by a single retrospective trial. There is a large body of literature for 18F-FDG as this compound has been used in research and in the clinical setting since the 1980's. This approach was agreed upon in consultation with stakeholders during development of the Health Canada draft policy, Regulatory Framework for Positron-Emitting Radiopharmaceuticals, June 10, 2004.
The sponsor did not submit any pivotal studies in support of this submission. Clinical safety and efficacy for CanTrace were evaluated from a single Bridging Study that assessed sensitivity, specificity, and accuracy of the product, and safety was also looked at in a single Phase I Safety Study. A review of patients previously enrolled in an open label study was also conducted, referred to below as the Retrospective Study.
The purpose of the Bridging Study was to investigate 18F-FDG for its ability to detect non-small cell lung cancer, head and neck cancer, colorectal cancer, breast cancer, lymphoma, sarcoma, and melanoma. The primary objective of the study was to determine the sensitivity, specificity, and accuracy of the 18F-FDG PET scan for proven malignancies and a suspected site of disease measuring at least 1 cm. The secondary objective of the study was to review the collected data after completion of the study and assess the usefulness of the PET scan for initial diagnosis, staging, restaging, localization, and recurrence of the cancer, and to analyze the effects of the 18F-FDG PET scan on the management of the patient. The Bridging Study also monitored the safety of 18F-FDG.
Seventy-five patients who were 18 years old or older were selected for the Bridging Study. 18F-FDG was administered as a single IV dose varying from 370 to 555 MBq and the exact injected dose was calculated base on the weight of the patient and the time of the procedure. The imaging study was done within 40 minutes from injection time and the whole procedure took place over one day for each individual patient.
Three literature references were also chosen for analysis; one of the three is a systematic review of the literature/meta-analysis (deemed to be a quality systematic review) covering the literature from 1990-1999, while the other two publications are studies that were published from 2001 to 2002. The combined data was necessary to increase the number of recurrent breast cancer patients and thereby increase the power of the analysis.
The efficacy of 18F-FDG is discussed by indication:
Recurrent Breast Cancer, including residual and recurrent primary and distant metastases (restaging)
The data from the Bridging and Retrospective studies was statistically not significantly different from the literature data in terms of sensitivity, specificity, and accuracy of 18F-FDG PET in the assessment of recurrent breast cancer. There is a limitation of 18F-FDG in the assessment of nodal status as it tends to underestimate the number of involved nodes due to spatial resolution limitations in detecting small volume disease. This limitation has been addressed in the Product Monograph.
The literature studies provided concluded that 18F-FDG is a useful diagnostic tool in detecting not only recurrence, but axilliary lymph node involvement and distant metastases. From these studies, the combined data for the diagnostic parameters appear to be high, with reasonable confidence intervals. By extrapolation, the IPET product should be able to perform similarly to the other 18F-FDG products reported in the literature in the evaluation of distant metastases and disease monitoring in breast cancer. Although the studies indicate that 18F-FDG is a useful tool in detecting axillary node involvement, the usefulness of 18F-FDG for assessment of nodal status is less compelling due to the spatial resolution limitations in detecting small volume disease.
Recurrent colorectal cancer, including residual and recurrent primary and distant metastases (restaging)
Standard treatment for colorectal cancer involves resection and lymph node dissection but for 30-40% of patients, disease will recur, usually within two years. Importantly, in 20% of the cases using current methodology, recurrence is localized and therefore amenable to curative resection. Detection of recurrence using serial CEA (carcino-embryonic antigen) assays, CT (computed tomography), and MRI (magnetic resonance imaging) lack the required degree of accuracy although they are still routinely performed. Recurrent disease may also be accompanied by distant disseminated metastases, a finding that is critical to the decision regarding resection vs. palliative or adjuvant treatment. Liver is the primary site of metastatic spread with lung and bone observed less frequently. Approximately 10% of all patients with colorectal cancer will develop hepatic metastasis. Surgical resection in the form of a partial hepatectomy can offer long-term survival and even cure in up to 25% of patients with localized liver metastases. 18F-FDG has been shown useful for the evaluation of this specific type of metastasis.
For extrahepatic metastasis, 18F-FDG has also been shown to be more sensitive and specific than CT and MRI. In addition, it results in more reliable restaging due to the detection of occult metastatic sites (6-32% of patients) and these whole body scans can be conducted concurrent to evaluations for hepatic involvement. Four literature references were chosen based on extensive criteria; two of the four are systematic reviews of the literature/meta-analyses covering the literature from 1990-2002, while the other two publications are studies that were published in 2003, therefore there is no overlap with the other publications.
Data from the original Bridging Study and the Retrospective Study has shown that the performance of CanTrace in the evaluation of recurrent colorectal cancer is not statistically different from that of 18F-FDG reported in the literature; however, overall the data indicate a lower confidence in the specificity and Negative Predictive Value of 18F-FDG. The proposed indications are supported by general literature evidence, however the literature also cautions that the extent of disease can be underestimated due to lower specificity (false negatives in small lesions, usually <1 cm).
Single Pulmonary Nodule (SPN) Evaluation in Lung Cancer (malignant versus benign pulmonary nodules)
The differential diagnosis of benign from malignant nodules is a critical clinical issue given the high probability of lengthy survival after resection and the general estimate of 20-40% of SPNs being malignant. Benign lesions can be classified as non-malignant tumours, and infectious, inflammatory, vascular, or developmental masses. Typical practice for SPN evaluation includes analysis of X-ray or CT images for degree of calcification, internal and marginal features, and growth characteristics, but more often by transthoracic needle aspiration and thorascopy or thoracotomy. This current use of sub-optimal, non-invasive imaging to avoid unnecessary surgical procedures highlights the critical need for improved reliability of diagnostic imaging methods to correctly diagnose and thereby avoid unnecessary interventions. It is estimated that 50% of all SPNs will be resected in spite of benign pathology. The cumulative results of over 30 independent studies of suitable quality and up-to-date status involving thousands of patients worldwide have demonstrated the accuracy of 18F-FDG in diagnosis of SPN malignancy. The bulk of the evidence presented is taken from the meta-analysis of literature from 1990-1999, involving 1246 patients. Two other more recent studies provide data from 171 patients. The broad spectrum from the meta-analysis provides considerable confidence in the calculated sensitivity value of 94% and the specificity value of 77%. Specificity reduction observed was due to selected populations with a high prevalence of 18F-FDG avid fungal pulmonary infections. Also, it may be less accurate in the less proliferative carcinoid and bronchoalveolar tumours and in very small (<1 cm) tumours. The imaging results can also be influenced by a wide range of infection and inflammatory lesions that can reduce specificity.
The performance of CanTrace in the evaluation of SPNs in lung cancer is not statistically different from that of 18F-FDG reported in the literature; however, the overall data indicates a lower confidence in the specificity of 18F-FDG. As concluded in the literature, and demonstrated by the IPET data, although FDG-PET is a useful non-invasive tool for the characterization of indeterminate pulmonary nodules, there are limitations which lower its specificity. Smaller lesions (<1 cm) can be missed and carcinoid or bronchoalveolar tumours may not be identified.
Distant Metastases, Recurrence/Restaging and Disease/Therapeutic Monitoring
It is estimated that up to 35-45% of patients will have detectable distant metastases at presentation. Approximately 20% will have a relapse after radical treatment for apparently localized disease, likely due to underestimation of the extent of original disease. A significant benefit of 18F-FDG is the detection of new or unexpected sites of metastases, however accurate delineation of these findings is complicated by the lack of confirmatory testing. The evaluation of equivocal lesions on CT for malignancy by 18F-FDG can mitigate surgical confirmation. Several authors have noted the value of 18F-FDG for radiotherapy planning and therapy monitoring as specific aspects of disease/ therapeutic monitoring in lung cancer. Clinical literature supports the evaluation of distant metastases, recurrence/restaging, and disease/therapeutic monitoring by 18F-FDG, showing sensitivity values of 94%, specificity of 91%, and accuracy of 93%.
3.3.3 Clinical Safety
In the Safety Study, ten adult patients with malignant or potentially malignant lesions underwent whole body PET imaging scan using 18F-FDG. The patients were examined for clinical and/or laboratory evidence of adverse events during the procedure. Limited efficacy data were to be collected and analyzed. The number of the patients was arbitrary and there was no control group arranged. The study was also not randomized. 18F-FDG was administered IV as a single dose, determined by the body weight of the patient and the time of injection. The dose varied from 370 to 555 MBq per injection. The test was done within one day. Prior to injection of 18F-FDG, each patient had a blood sample collected as well as their pulse, blood pressure (BP), respiratory rate, and temperature taken. The patient's pulse, BP, and temperature were taken again pre- and post-imaging. The vital signs were collected every 15 minutes and an additional blood sample was taken 2 hours post-injection.
The results from the combined Safety and Bridging Studies indicated that the PET scanning procedure resulted in 28 cases of elevated BP levels above the normal upper limit of 140/90 mmHg. Of these, 13 had either mild or moderate hypertension. Pulse values lower than 60 bpm (bradycardia) or higher than 100 bpm (tachycardia) were recorded in 31 patients from the two studies. Patients from the Retrospective Study who had vital sign measurements available (a total of 124) were analyzed and deviations from normal BP levels or pulse rates were noted in 70 patients (57 had elevated BP levels and 25 had elevated pulse rates above normal). There were no allergic reactions or other adverse reactions during the PET scanning procedures. One patient had a pneumothorax while he was undergoing the lung biopsy.
The elevated BP levels seen in patients from the Safety, Bridging, and Retrospective studies were most likely attributed to either pre-existing hypertension (either diagnosed or undiagnosed) or anxiety related to undergoing medical procedures. The overall rate of hypertension in this group was 29%, well within the accepted range for the prevalence of hypertension in the normal population. The remaining single elevations could be associated with anxiety related to the procedure. None of these elevations were considered by the investigators to be significant or attributable to CanTrace, and would not impact existing cardiovascular disease in this population of patients.
With respect to pulse rate, the reports of tachycardia were considered either not medically significant and/or related to anxiety felt by the subjects while undergoing the medical procedures associated with the PET scan. Due to their transient nature, they would have no effect on existing cardiovascular disease.
The main safety issue regarding the high acetonitrile content of the product was addressed in the Quality (Chemistry and Manufacturing) section of this report and the specification limits are considered acceptable.
3.4 Benefit/Risk Assessment and Recommendation
3.4.1 Benefit/Risk Assessment
The clinical safety and efficacy of CanTrace were evaluated from a single Bridging Study and a Retrospective Study that assessed sensitivity, specificity, and accuracy of the product, as well as from a single Phase I Safety Study. Results were compared to information available in published literature.
Priority Review status was granted for CanTrace as it offers a significant improvement over existing diagnostic approaches used in Canada for the diagnosis and treatment of cancer.
18F-FDG PET imaging results were found to be comparable to the values found in the literature, and sensitivity, specificity, and accuracy of the procedure were higher than for other commonly used diagnostic methods such as CT and MRI. No safety concerns of note were observed in the clinical trials, and the main safety issue regarding the level of acetonitrile present in the product that arose during manufacturing has been addressed. The new limit of <4.1 mg acetonitrile per batch is considered safe and acceptable, and therefore the risk/benefit ratio for CanTrace is considered favourable.
3.4.2 Recommendation
Based on the Health Canada review of data on quality, safety and efficacy, Health Canada considers that the benefit/risk profile of CanTrace is favourable for diagnostic use in breast cancer (evaluation of recurrence/residual disease, distant metastases [staging/restaging], and disease/therapeutic monitoring); colorectal cancer (evaluation of recurrence/restaging, distant metastases and disease/therapeutic monitoring); and lung cancer (evaluation of single pulmonary nodules [diagnosis], staging, distant metastases, recurrence/restaging, and disease/therapeutic monitoring). The 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.
4 Submission Milestones
Submission Milestones: CantraceTM
| Submission Milestone | Date |
|---|---|
| Request for priority status 1 | |
| Filed | 2003-11-17 |
| Rejection issued | 2003-12-17 |
| Request for priority status 2 | |
| Filed | 2004-01-13 |
| Rejection issued | 2004-01-17 |
| Submission filed | 2004-05-03 |
| Screening 1 | |
| Screening Acceptance Letter issued | 2004-06-08 |
| Review 1 | |
| Quality Evaluation complete | 2005-10-07 |
| Clinical Evaluation complete | 2005-10-21 |
| NON issued by Director General | 2005-10-26 |
| Response filed | 2006-04-18 |
| Screening 2 | |
| Screening Acceptance Letter issued | 2006-04-28 |
| Review 2 | |
| Quality Evaluation complete | 2006-07-27 |
| Clinical Evaluation complete | 2006-07-27 |
| Labelling Review complete | 2006-07-25 |
| NOC issued by Director General | 2006-07-27 |