Summary Basis of Decision for DaTscan

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 DaTscan is located below.

Recent Activity for DaTscan

SBDs written for eligible drugs approved after September 1, 2012 will be updated to include post-authorization information. This information will be compiled in a Post-Authorization Activity Table (PAAT). The PAAT will include brief summaries of activities such as submissions for new uses of the product, and whether Health Canada's decisions were negative or positive. PAATs will be updated regularly with post-authorization activity throughout the product's life cycle.

Post-Authorization Activity Table (PAAT) for DaTscan

Updated: 2024-02-09

The following table describes post-authorization activity for DaTscan, a product which contains the medicinal ingredient 123I-Ioflupane. 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.

Drug Identification Number (DIN):

  • DIN 02470624 - 74 MBq/mL, 123I-Ioflupane, solution, intravenous administration

Post-Authorization Activity Table (PAAT)

Activity/submission type, control number Date submitted Decision and date Summary of activities
NC # 273012 2023-03-03 Issued NOL 2023-06-08 Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) for a change in the controls for the materials used in the manufacture of the drug substance or the controls performed at critical steps in the process. The submission was reviewed and considered acceptable, and an NOL was issued.
NC # 266680 2022-08-02 Issued NOL 2022-08-24 Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) for a change in the controls for the materials used in the manufacture of the drug substance or the controls performed at critical steps in the process. The submission was reviewed and considered acceptable, and an NOL was issued.
NC # 265109 2022-06-10 Issued NOL 2022-07-21 Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) for a change in the drug substance and drug product release or shelf-life specifications, and a change in the post-approval stability protocol of the drug product. The submission was reviewed and considered acceptable, and an NOL was issued.
NC # 229876 2019-07-19 Issued NOL 2019-10-07 Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) for the introduction of new depyrogenation equipment. The submission was reviewed and considered acceptable, and an NOL was issued.
SNDS # 225713 2019-03-13 Issued NOC 2019-05-24 Submission filed as a Level I – Supplement revise the inner and outer labels to meet Health Canada’s Plain Language Labelling requirements. The submission was reviewed and considered acceptable, and an NOC was issued.
NC # 219553 2018-08-27 Issued NOL
2018-08-27		 Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) to add an alternate manufacturing site for the production of the drug product. The submission was reviewed and considered acceptable, and an NOL was issued.
Drug product (DIN 02470624) market notification Not applicable Date of first sale:
2018-04-03		 The manufacturer notified Health Canada of the date of first sale pursuant to C.01.014.3 of the Food and Drug Regulations.
DIN 02470624 issued Not applicable DIN issued
2017-12-11		 DIN issued pursuant to section C.01.014.2(1) of the Food and Drug Regulations.
NDS # 201481 2016-12-22 Issued NOC
2017-12-07		 Notice of Compliance issued for New Drug Submission
Health product advertising complaint closed Not applicable Date received:
2017-06-20		 A health product advertising complaint regarding the advertising of an unauthorized product including claims for serious disease for DaTscan was closed. Follow-up was completed and the company confirmed they stopped sale and advertising.
Summary Basis of Decision (SBD) for DaTscan

Date SBD issued: 2018-04-30

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

123I-Ioflupane 74 MBq/mL, solution, intravenous

Drug Identification Number (DIN):

  • Not Applicable

GE Healthcare Canada Inc.

New Drug Submission Control Number: 201481

 

On December 7, 2017, Health Canada issued a Notice of Compliance to GE Healthcare Canada Inc. for the diagnostic radiopharmaceutical DaTscan.

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 DaTscan is favourable for the visualization of functional striatal dopamine transporter using single photon emission computed tomography (SPECT) brain imaging. In adult patients with suspected Parkinsonian syndromes, DaTscan SPECT imaging may be used as an adjunct to other established evaluations to help differentiate essential tremor from tremor due to Parkinsonian syndromes related to idiopathic Parkinson's disease, multiple system atrophy and progressive supranuclear palsy.

 

1 What was approved?

 

DaTscan, a diagnostic pharmaceutical, was authorized for the visualization of functional striatal dopamine transporter using single photon emission computed tomography (SPECT) brain imaging. In adult patients with suspected Parkinsonian syndromes, DaTscan SPECT imaging may be used as an adjunct to other established evaluations to help differentiate essential tremor from tremor due to Parkinsonian syndromes related to idiopathic Parkinson's disease, multiple system atrophy and progressive supranuclear palsy.

DaTscan is unable to discriminate between Parkinson's disease, multiple system atrophy and progressive supranuclear palsy.

DaTscan is contraindicated in patients who are hypersensitive to this drug or to any ingredient in the formulation or component of the container.

DaTscan 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.

DaTscan [74 MBq/mL, 123I-Ioflupane, Ioflupane(123I), 123I-FP-CIT] is presented as a solution for injection. In addition to the medicinal ingredient, the solution for injection contains acetic acid, sodium acetate, ethanol, and water for injections.

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 DaTscan Product Monograph, approved by Health Canada and available through the Drug Product Database.

 

2 Why was DaTscan approved?

 

Health Canada considers that the benefit-risk profile of DaTscan is favourable for the visualization of functional striatal dopamine transporter using single photon emission computed tomography (SPECT) brain imaging. In adult patients with suspected Parkinsonian syndromes, DaTscan SPECT imaging may be used as an adjunct to other established evaluations to help differentiate essential tremor from tremor due to Parkinsonian syndromes related to idiopathic Parkinson's disease, multiple system atrophy and progressive supranuclear palsy.

DaTscan (123I-Ioflupane) solution for injection is an intravenously administered diagnostic radiopharmaceutical intended for use with a gamma ray camera in order to acquire SPECT images of the brain to detect the presence or loss of functional nigrostriatal dopaminergic neurons. Such neuronal loss is known to occur in some movement disorders including Parkinson's disease and other Parkinsonian syndromes, but not in others, such as essential tremor (ET).

Clinical diagnosis of movement disorders can be difficult, particularly in the early stages. Diagnosis of Parkinson's disease is largely based on clinical assessment using established diagnostic criteria guidelines, as there is no biomarker or specific imaging test for Parkinson's disease. However, clinical trials have shown that the diagnostic accuracy of Parkinson's disease is suboptimal due to the overlap of symptoms with other movement disorders. As the disease course, therapy, and prognosis differ considerably among patients with movement disorders; there is a need for additional diagnostic tests to discriminate between degenerative and non-degenerative diseases.

 

Research has shown that the dopamine transporter (DaT) is present exclusively on dopamine synthesizing neurons and that DaT can therefore be considered a specific marker of these neurons in the central nervous system. In addition to dopamine, the DaT protein can bind to cocaine and cocaine analogs. Investigation of radio-labelled cocaine analogs as DaT-targeted diagnostic imaging agents led to the development of DaTscan for the detection of striatal dopaminergic deficit. The detection or exclusion of a striatal dopaminergic deficit may help narrow the differential diagnosis and when combined with other clinical information, may allow a more accurate diagnosis.

The efficacy and safety of DaTscan for the specified indication is based on the results of two Phase III multicentre clinical trials, DP008-003 and PDT03004 (also known as PDT304). The aim of both trials was to determine the diagnostic efficacy of DaTscan SPECT imaging and its ability to differentiate between Parkinsonian syndromes compared to non-Parkinsonian syndromes. The premise of both trials was based on the assumption that striatal dopaminergic deficit (SDD) is present in patients diagnosed with any of the Parkinsonian syndromes (e.g., Parkinson's disease, multiple system atrophy, and progressive supranuclear palsy) and absent in subjects diagnosed with essential tremor and in healthy volunteers. Results from both clinical trials confirmed that DaTscan did demonstrate the diagnostic efficacy to distinguish between patients with Parkinsonian syndromes (SDD present) and non-Parkinsonian syndrome patients (SDD absent).

The safety data submitted for DaTscan demonstrates that it is generally safe and well tolerated. In addition, the safety profile is consistent with that of other diagnostic radiopharmaceuticals. The incidence of adverse events was low and most events were mild in nature. The most commonly reported adverse events were hypersensitivity and injection site reactions.

Interactions with commonly used medications are of a concern when undergoing investigations with DaTscan due to the possibility of interference with DaTscan's uptake in the striatum which can result in incorrect interpretation of images. Withholding such medications may pose a potential risk to the patient. As such, the benefit-risk of using DaTscan must be carefully assessed in these circumstances.

Two warnings have been included in a Serious Warnings and Precautions box in the Product Monograph for DaTscan as follows: radiopharmaceuticals should only be used by health care professionals qualified in the use of radioactive prescribed substances in or on humans, and hypersensitivity reactions have been reported following DaTscan administration. Therefore, prior to the administration of DaTscan appropriate resuscitation equipment should be available.

A Risk Management Plan (RMP) for DaTscan was submitted by GE Healthcare Canada Inc. 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 DaTscan was accepted.

Based on the data reviewed, the benefit-risk assessment for DaTscan used for the visualization of functional striatal dopamine transporter using SPECT brain imaging is considered favourable. DaTscan has an acceptable safety profile based on non-clinical data and clinical studies. Appropriate warnings and precautions are in place in the DaTscan Product Monograph to address the identified safety concerns.

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

 

A pre-submission meeting was held between Health Canada and the sponsor on November 18, 2010. On February 23, 2016, the sponsor filed a request to have the DaTscan submission reviewed under the Priority Review Policy. The submitted request was assessed by Health Canada; however at the time of the request it was determined that the data submitted by the sponsor was considered inadequate to support a clinical conclusion. As a result, the request for a review under the Priority Review Policy was denied by Health Canada on March 18, 2016. The submission was subsequently filed and reviewed as a regular new drug submission.

 

Submission Milestones: DaTscan

Submission Milestone Date
Pre-submission meeting: 2010-11-18
Request for priority status  
Filed: 2016-02-23
Rejection issued by the Director, Centre for Evaluation of Radiopharmaceuticals and Biotherapeutics (CERB): 2016-03-18
Submission filed: 2016-12-22
Screening  
Screening Acceptance Letter issued: 2017-02-10
Review  
On-Site Evaluation:  
Quality Evaluation complete: 2017-12-04
Clinical Evaluation complete: 2017-12-06
Review of Risk Management Plan complete: 2017-10-23
Labelling Review complete, including Look-alike Sound-alike brand name assessment: 2017-11-30
Notice of Compliance issued by Director General, Biologics and Genetic Therapies Directorate: 2017-12-07

 

The Canadian regulatory decision on the quality (chemistry and manufacturing), non-clinical and clinical review of DaTscan 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 DaTscan?

 

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 DaTscan 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

DaTscan, (123I-Ioflupane) is a radiolabelled tropane compound with high affinity for the dopamine transporter (DaT). The DaT is present exclusively on dopamine synthesizing neurons and DaT can therefore be considered a specific marker of these neurons in the central nervous system. Because DaT distribution in the central nervous system coincides with dopaminergic innervation, tropane analogues with high DaT binding affinity have been developed for use in neuroimaging as in vivo markers of functional dopaminergic systems. Biological studies in vitro and in vivo have demonstrated that when radiolabelled with the gamma-emitting isotope iodine-123, 123I-Ioflupane has the appropriate characteristics to enable single photon emission computed tomography (SPECT) visualization of regions of the brain with a high expression of the DaT.

Administration of radiolabelled Ioflupane is intended to detect or exclude a substantial (>60%) loss of nigrostriatal dopaminergic neurons in patients with the signs and symptoms of movement disorders. The mechanism of action involved is that the active component in DaTscan (radiolabelled Ioflupane) distributes to the brain and preferentially binds to the DaT located predominantly on the nigrostriatal dopaminergic neurons. In healthy humans, this results in visualization of the striata as two "comma"- or "half-moon"-shaped areas of brightness on SPECT imaging. However, loss of the nigrostriatal dopaminergic neurons (e.g., Parkinson's disease) results in loss of the DaT associated with those neurons. This results in the absence of signal where it normally would be expected.

Pharmacology

The pharmacodynamic data showed that DaTscan has high affinity and some selectivity for the DaT, which supports the use of DaTscan as a qualitative marker of dopaminergic neuronal density. Estimates from Phase II studies indicate that DaTscan occupies less than 1% of DaT proteins in the brain, with no expected pharmacological effect at this level of occupancy. Although FP-CIT (Ioflupane) is a cocaine analogue, no pharmacological effects were observed in humans following the intravenous administration of the proposed dose of ≤0.325 µg. The DaT occupancy required by cocaine to induce any psychotropic effects in humans is approximately 45% of the total DaT in the striatum. There have been no human studies to investigate drug interactions with use of DaTscan. Drug interactions are considered a possibility based on the mechanism of action of reversible binding to the DaT protein.

Pharmacokinetics

The biodistribution of 123I-Ioflupane (also known as 123I-FP-CIT) has been studied in 12 healthy adults. Sequential images of the whole body, performed up to 48 hours following the administration of 123I-Ioflupane, showed that 123I-Ioflupane is cleared rapidly from the blood; only 5% of the administered activity remains in whole blood at 5 minutes post-injection. Uptake in the brain is rapid, reaching about 7% of the injected radioactivity at 10 minutes post- injection and decreasing to 3% after 5 hours; striatal activity is relatively constant between 3- and 6-hours post-injection. Approximately 30% of the whole brain radioactivity is attributed to striatal uptake. The majority of 123I Ioflupane is excreted through the urinary tract. At 48 hours post-injection, approximately 60% of the injected radioactivity is excreted in the urine, with fecal excretion calculated at approximately 14%.

Radiation Dosimetry

Based on the biodistribution data, the radiation exposure (effective dose) was estimated to be 0.025 mSv/MBq; identical to the data from the International Commission on Radiological Protection (ICRP) Publication 128 (2015) which was based on the most recent updated tissue weighting factors and the software (OLINDA EXM. 2.0). Therefore, the table of organ absorbed doses from ICRP 128 was adopted for the DaTscan Product Monograph.

For further details on the clinical pharmacology, pharmacokinetics, and radiation dosimetry, please refer to the DaTscan Product Monograph, approved by Health Canada and available through the Drug Product Database.

Clinical Efficacy

The clinical efficacy of DaTscan was based on the results of two Phase III, prospective, clinical trials (PDT03004 and DP008-003) to determine the sensitivity and specificity of DaTscan SPECT imaging to differentiate between Parkinsonian syndrome patients and non-Parkinsonian syndrome patients. The primary aim of these studies were to determine the sensitivity and specificity of visual interpretations of DaTscan SPECT images in detecting the loss of functional nigrostriatal dopaminergic neurons, also known as striatal dopaminergic deficit (SDD). Visual assessments of DaTscan images were compared to the clinical diagnosis which was the surrogate to pathology as the standard of truth (SOT). The studies were based on the assumption that SDD is present in patients diagnosed with any of the Parkinsonian syndromes (Parkinson's disease, multiple system atrophy, progressive supranuclear palsy), and absent in patients diagnosed with essential tremor and in healthy volunteers.

Clinical Trial PTD304

Clinical trial PTD304 was an open-label, multicentre, Phase III trial which evaluated the diagnostic performance of DaTscan SPECT images in differentiating between patients with early symptoms and signs of movement disorders, specifically Parkinsonism (SDD present), other causes of tremor (mainly essential tremor, SDD absent), and healthy volunteers (SDD absent). The study included patients with early features of Parkinsonism without clear diagnosis. Patients with known cause of tremors, multiple system atrophy or progressive supranuclear palsy were excluded from the trial.

 

DaTscan imaging was performed at baseline, 18 months and 36 months. At each time point, SPECT imaging was conducted 3 to 6 hours following a single intravenous injection of 111 to 185 MBq (3 to 5 mCi) of 123I Ioflupane. Visual interpretations of the images were conducted independently by three blinded readers.

A total of 202 patients enrolled in the clinical trial, including 3 healthy volunteers, with all trial centres located exclusively in Europe and with 98% of enrolled patients being Caucasian. A total of 179 patients received DaTscan at baseline, and 99 patients completed the trial. During the 36-month study duration, a total of 80 patients (45%) withdrew from the study; the majority due to patient request and patients being lost to follow-up. The demographics were similar between loss-to-follow-up patients and the efficacy sets. The final intent-to-diagnose population (i.e., had DaTscan SPECT imaging at months 0, 18, and 36 and were evaluated against the SOT) for efficacy analysis was 102 patients, including 3 healthy volunteers.

The primary endpoint was diagnostic efficacy of DaTscan SPECT images taken at Month 0 compared with the SOT. The SOT was established by two experts at 36 months based on the clinical information and videotape assessment of patients' neurological examination, and without knowledge of the findings of the DaTscan images.

Based on the SOT established by the experts, the sensitivity for the detection of SDD ranged from 77.5% to 78.6% (mean across all three readers, 78.0%); the specificity was 96.8% for all three readers (mean, 96.8%). Good inter-observer concordance was observed. Pairwise inter-reader agreement (Cohen's kappa) among the blinded readers ranged from 0.98 to 1.00. In most patients, the blinded SPECT interpretation (normal versus abnormal) remained the same over the whole course of the trial.

The study demonstrated an acceptable sensitivity of 78% and high specificity of 97% in the differentiating between patients with Parkinsonian syndromes (SDD present) and non-Parkinsonian syndrome patients (without SDD). The scan appears to be most useful in excluding Parkinsonian syndromes in patients with signs and symptoms of early onset movement disorder.

Clinical Trial DP008-003

Clinical trial DP008-003 was a multicentre, Phase III trial which evaluated the diagnostic performance of DaTscan images in patients diagnosed with movement disorders and in healthy volunteers. Patients aged 40 to 80 with a clinically established diagnosis of Parkinson's disease, multiple system atrophy, progressive supranuclear palsy or essential tremor and healthy volunteers aged 50 to 80 were enrolled into the study.

The primary efficacy endpoint was the diagnostic efficacy of the DaTscan SPECT image assessment by institutional reader. Secondary endpoints were the diagnostic efficacy of the DaTscan SPECT image visual assessment by blinded consensus read and semi-quantitative Region of Interest (ROI) analysis of SPECT images.

During the trial, each patient received a single intravenous injection of 111 to 185 MBq (3 to 5 mCi) DaTscan followed 3 to 6 hours later by SPECT imaging. In addition, a Blinded Image Evaluation (BIE) was performed on images that had been processed to a uniform color scale and format, blinded, and randomized. In both image evaluations, images were classified as normal or abnormal based on the appearance of the striata. The BIE was performed by a panel consisting of five of the study's 13 investigators; each of these five readers independently viewed and classified all blinded images. "Consensus" (majority) blinded image interpretations were derived from the individual blinded readers' interpretations for each patient. As an additional analysis in the original trial protocol, a semi-quantitative assessment was performed by the core-imaging laboratory based on region-of-interest (ROI) analysis.

Each image interpretation was compared to the SOT (categorization of patient status at trial entry as SDD present or absent), to classify the assessments as true negative, true positive, false negative, and false positive. The per-reader sensitivity of the blinded visual assessment for the intent to diagnose (ITD) population in identifying a SDD ranged from 92.4% to 96.8%, and specificity ranged from 80.6% to 96.8%. Inter reader agreement (Cohen's kappa) ranged from 0.81 to 0.95. The results of the semi-quantitative ROI analysis were consistent with the visual image assessments and with the known pathology of these disorders.

Overall, the data from the two Phase III studies in patients with movement disorders demonstrated the diagnostic efficacy of DaTscan to distinguish between patients with Parkinsonian syndromes and non-Parkinsonian syndrome conditions. The higher sensitivity of DaTscan observed in Trial DP008-003 could be attributed to having enrolled patients with clinically-established diagnoses; hence more advanced disease which is associated with a greater extent of SDD. The results of clinical trial PDT304 demonstrated the clinical usefulness of DaTscan to rule out Parkinsonian syndromes in clinically uncertain cases (e.g., patients with early features of Parkinsonism without clear diagnosis).

Supportive Studies

The DaTscan new drug submission also included results of a pivotal Phase III trial, PDT301, in support of the proposed dementia-associated claim. Upon review of the proposed claim, it became apparent that this indication could not be considered acceptable because the diagnostic value of DaTscan could not be justified for patients based on the risk and benefit assessment of the data and results. The clinical data were deemed inconclusive because the clinical trial PDT301 was not considered robust. Furthermore, the data were not considered to constitute sufficient evidence of diagnostic usefulness for patients. Although it was reported that the trial achieved statistical significance, trial design issues and limitations, coupled with the questionable clinical significance of having adequately defined a proposed population most in need and of maximal clinical benefit, required that additional data be supplied to support such a proposed indication and use. As a result of the deficiencies identified with the proposed dementia-associated claim, the sponsor was informed of the option to voluntarily withdraw the proposed indication. The sponsor subsequently withdrew the proposed indication on September 13, 2017 and the other review elements proceeded (i.e., the Parkinsonian syndromes-associated claim).

Indication

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

Sponsor proposed indication:
DaTscan (123I Ioflupane Injection) is indicated for detecting loss of functional dopaminergic neuron terminals in the striatum:

  • In adult patients with clinically uncertain Parkinsonian Syndromes (PS), for example those with early symptoms, in order to help differentiate Essential Tremor (ET) from PS related to idiopathic Parkinson's Disease (PD), Multiple System Atrophy (MSA) and Progressive Supranuclear Palsy (PSP). DaTscan is unable to discriminate between PD, MSA and PSP.
  • In adult patients, to help differentiate probable dementia with Lewy bodies (DLB) from Alzheimer's disease (AD). DaTscan is unable to discriminate between DLB and PD dementia.*

*Note, the second indication was withdrawn during review. See discussion under Clinical Efficacy, Supportive Studies.

To ensure safe and effective use of the product, Health Canada approved the following indication:

DaTscan (123I-Ioflupane Injection) is a radiopharmaceutical indicated for striatal dopamine transporter visualization using single photon emission computed tomography (SPECT) brain imaging. In adult patients with suspected Parkinsonian syndromes, DaTscan SPECT imaging may be used as an adjunct to other established evaluations to help differentiate essential tremor from tremor due to Parkinsonian syndromes related to idiopathic Parkinson's disease, multiple system atrophy and progressive supranuclear palsy.

DaTscan is unable to discriminate between Parkinson's disease, multiple system atrophy and progressive supranuclear palsy.

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

Clinical Safety

The safety profile of DaTscan was based primarily on the two Phase III clinical trials previously described in the Clinical Efficacy section. Additional safety data from six other supportive studies were included as part of the safety assessment. In total, the safety profile was based on a total of 942 patients who were administered a single dose or up to three doses (Study PDT304) of DaTscan.

Overall, 588 adverse events were reported, and of these, 73 (12%) were considered by the investigator to be at least possibly related to the administration of DaTscan. A total of 231 (25%) patients experienced at least one adverse event, and 39 (4%) of these patients experienced an adverse event that was considered by the investigator to be at least possibly related to the administration of DaTscan. Of the 39 patients who experienced an adverse event possibly related to DaTscan, the most common of these events were headache, nausea, vertigo, dry mouth, hunger, and dizziness (each ≤1%).

A total of 10 (1%) patients experienced an adverse event that led to discontinuation from the trial, and no patient experienced a possible DaTscan-related adverse event that led to discontinuation from the study. A total of 36 (4%) patients experienced at least one serious adverse event, but no patient experienced a serious adverse event that was considered by the investigator to be related to the administration of DaTscan. A total of five (<1%) patients experienced an adverse event which led to death, but no patient experienced a possible DaTscan-related adverse event that led to death.

There were no notable age-related or gender-related differences in adverse event frequencies. The ionization radiation from 123I-Ioflupane is potentially harmful to a fetus or to a nursing infant; therefore the standard warnings and precautions for use of radiopharmaceuticals in pregnancy or breast-feeding are included in the DaTscan Product Monograph.

Interactions with medications commonly used by patients in the target population are of concern for DaTscan due to the possibility of interference with its binding to DaT, which may result in incorrect interpretation of images. Withholding such medications could also pose a risk to the patient, therefore the benefit and risk of administering DaTscan must be weighed in these situations.

Cumulative post-marketing data indicates that hypersensitivity and injection site reactions were the most commonly reported serious and non-serious adverse reactions. Other reported adverse reactions such as erythema, pruritus, dyspnea, edema, generalized pruritus, skin lesion, and skin discolouration are consistent with hypersensitivity. Appropriate warnings and precautions are included in the DaTscan Product Monograph.

Overall, the evaluation of the safety data for DaTscan found no significant safety concern. Reported adverse reactions following DaTscan administration were infrequent and usually mild to moderate with subsequent complete recovery in most cases. The risk profile of DaTscan is mainly characterised by hypersensitivity reactions and injection site conditions. The safety profile of DaTscan is consistent with that of diagnostic radiopharmaceuticals, which are generally well-tolerated.

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

 

 

 

 

7.2 Non-Clinical Basis for Decision

 

In vitro and in vivo studies demonstrated the affinity and selectivity of 123I Ioflupane for dopamine transporter (DaT). In studies using recombinant transporters, 123I Ioflupane demonstrated higher selectivity for human DaT compared to serotonin transporter (SERT) and noradrenergic transporter (NET). The in vivo imaging data from mouse, rat, monkey, and baboon showed selective retention of 123I Ioflupane in the striatum. For these imaging studies, significant correlation was demonstrated between the in vivo signal of 123I Ioflupane to both ex vivo quantitative dissection data and neuropathology induced by a number of different treatment regimes.

Acute toxicity studies of Ioflupane in rats, rabbits, dogs and cynomolgus monkeys showed no signs of toxicity or resulted in death at doses of approximately 27,000; 3,200; 30,000 and 5,500 times respectively, the maximum human equivalent dose of Ioflupane. In 14-day repeat-dose studies, no evidence of toxicity was observed in rats, rabbits, or dogs following daily doses of Ioflupane that were between 100 and 32,000 times the maximum human single dose. Due to similarity in the pharmacology of FP CIT (Ioflupane) to that of other DaT ligands like cocaine, hyperactivity and stereotypic behavior was observed at high doses. In vitro and in vivo cardiovascular safety studies demonstrated that Ioflupane is unlikely to induce any cardiovascular adverse effect at the clinical dose.

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

 

 

7.3 Quality Basis for Decision

 

DaTscan is a diagnostic radiopharmaceutical containing 123I Ioflupane which has a high affinity for DaT. The DaT is present exclusively on dopamine synthesizing neurons and DaT can therefore be considered a specific marker of these neurons in the central nervous system. Because DaT distribution in the central nervous system coincides with dopaminergic innervation, tropane analogues (like that of I Ioflupane) which have high DaT binding affinity have been developed for use in neuroimaging as in vivo markers of functional dopaminergic systems. Biological studies in vitro and in vivo have demonstrated that when radiolabelled with the gamma-emitting isotope iodine-123, Ioflupane has the appropriate characteristics to enable SPECT visualization of regions of the brain with a high expression of the DaT.

Characterization of the Drug Substance

The two precursors of the drug substance, 123I-Ioflupane, are sodium 123I-iodide and N-ω-fluoropropyl-2β-carbomethoxy-3β-(4-trimethylstannylphenyl) nortropane (SnFP-CT). The scale of the manufacturing process for the drug substance 123I-Ioflupane is dictated by finished product order requirements. Due to a varying overall yield, batch size is defined as the amount of 123I-iodide starting material used in the manufacture of a batch of 123I-Ioflupane drug substance. This is currently validated for a range of 4.8 GBq to 27.8 GBq 123I-iodide.

The formation of 123I-Ioflupane is a two-step synthesis. The first step is the synthesis of 123I-Ioflupane based on the two precursors specified above. The second step is that of purification of123I-Ioflupane. Impurities and degradation products arising from manufacturing were reported and characterized. These products were found to be within established limits and are considered to be acceptable.

Results from process validation studies indicate that the processing steps are adequately controlled.

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

The synthesis of 123I-Ioflupane drug substance is a two-stage process starting from the precursors sodium 123I-iodide and N-ω-fluoropropyl-2β-carbomethoxy-3β-(4 trimethylstannylphenyl) nortropane (SnFP-CT).

  • The first stage involves the synthesis of 123I-Ioflupane which is prepared from sodium 123I-iodide via an oxidative iododestannylation of the trimethyltin compound SnFP-CT. The specific activity of the drug substance is controlled by the addition of non-radioactive sodium iodide to the solution of sodium 123I-iodide in sodium hydroxide. The reaction mixture is purified by high performance liquid chromatography (HPLC) (reverse phase) where the impurities are washed off and the drug substance is eluted with water.
  • The second stage involves purification of 123I-Ioflupane which is achieved by preparative HPLC (reverse phase) using a 0.2 M sodium acetate:ethanol (33:67) mixture as mobile phase and C18 reverse phase column. The 123I-Ioflupane elution is monitored using a radioactivity detector in conjunction with a ultraviolet detector and the appropriate fractions are collected. The collected HPLC fractions, containing the purified 123I-Ioflupane are diluted with sodium acetate/ethanol solution and then used in the manufacture of drug product DaTscan. The drug substance is immediately process into a batch of drug product.

The synthesis of the finished product DaTscan is also a two-stage process involving formulation and dispensing. The batch size is 0.96-18 GBq.

  • The first stage is that of formulation which includes a dilution followed by sterile filtered into the formulated bulk vial. Then a second dilution is performed to reach the final activity concentration of 74 MBq/mL at reference with a sterile solution of sodium acetate buffer (pH = 4.7). Before each dilution, the radioactivity concentration is measured to determine the volume of sodium acetate buffer required. A final check is performed to verify that the drug product solution has the desired radioactive concentration at reference. The bulk formulated stock solution is then transferred to the dispensing facility.
  • The second stage involves dispensing 2.5 or 5 mL of the bulk solution through a filter into sterile vials which are then sealed with rubber closures and sterile aluminium overseals. The sterilising filter is integrity tested after use by bubble-point testing. After dispensing, the vials are individually checked by visual inspection for particulate contamination.

The method of manufacturing and the controls used during the manufacturing process for both the drug substance and drug product are valid and are considered to be adequately controlled within justified limits. The materials used in the manufacture of the drug substance and drug product are considered suitable and meet the standards appropriate for their intended use.

In-process controls and lot release tests for the drug substance and drug product were established and validated.

Impurities and degradation products arising from manufacturing and/or storage were reported and characterized. These products were found to be within established limits and are considered to be acceptable.

All non-medicinal ingredients (excipients) found in the drug product are acceptable for use in drugs according to the Food and Drug Regulations. The compatibility of the 123I Ioflupane with the excipients is supported by the stability data provided.

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.

Batch analyses for three consecutive drug product qualification lots were provided as well as for the batches manufactured for clinical studies. All batches met all specifications, demonstrating that the process is robust and can consistently produce DaTscan drug product that meets established specifications.

The validation reports submitted for analytical procedures used for in-process and release testing of the drug product are considered satisfactory, and justify the specifications of the drug product. The analytical procedures are validated and in compliance with International Council for Harmonisation guidelines.

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 7 hours (from reference time for the 2.5 mL vial) and the 20 hours (from the reference time for the 5.0 mL vial) when stored at room temperature (20° to 25°C) in a lead shielded container is considered acceptable.

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.

Facilities and Equipment

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

On-Site Evaluations of the facilities involved in the manufacture and testing of DaTscan were not conducted as they are 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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