Summary Basis of Decision for Ruby-Fill ™
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:
Ruby-FillTM
Rubidium Chloride Rb 82, 100 mCi/unit, Liquid, Intravenous
Jubilant DraxImage Inc.
Submission control no: 138823
Date issued: 2012-01-23
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):
- Not Applicable
Therapeutic Classification:
Non-medicinal ingredients:
Submission type and control no:
Date of Submission:
Date of authorization:
2 Notice of decision
On September 20, 2011, Health Canada issued a Notice of Compliance to Jubilant DraxImage Inc. for the diagnostic radiopharmaceutical, Ruby-Fill™.
Ruby-Fill™ (Rubidium Rb 82 Generator) produces a parenteral solution of Rubidium Chloride Rb 82 Injection (82RbCl) for intravenous infusion.
Ruby-Fill™ is indicated as an accessory to positron emission tomography (PET) for imaging of the myocardium, to evaluate regional myocardial perfusion in adult patients, as an aid in the diagnosis or assessment of suspected or known coronary artery disease. Following intravenous administration, 82Rb rapidly clears from the blood and is extracted by myocardial tissue in a manner similar to potassium. The myocardial uptake of 82Rb reflects blood flow through the myocardium, and is useful for qualitative infarct imaging and for the detection of coronary artery stenosis and its severity.
Ruby-Fill™ must be used with an infusion system specifically labelled for use with the generator and capable of accurate measurement and delivery of adequate doses of 82RbCl. The 82RbCl is used under rest and hyperemic (pharmacological) stress conditions. The oversight for use of this product, and the cardiac PET image interpretation, should be carried out only by physicians and institutions with adequate training and experience in conducting and interpreting these procedures.
The market authorization was based on quality, non-clinical, and clinical information submitted. The sensitivity and specificity of Ruby-Fill™ was demonstrated in a retrospective study of 116 patients with known or suspected coronary artery disease (CAD). The prevalence of CAD in this patient population was 80%. The 82Rb-PET myocardial perfusion imaging was 94% sensitive and 88% specific for the detection of CAD. These results were comparable to the pooled literature review which included 7 studies with a total of 674 patients. The sensitivity and specificity differed by only 2.15% and 2.06%, respectively; these differences were statistically insignificant. In Canada, no adverse reactions specifically attributed to 82RbCl were reported from clinical trial use in over 7,200 patients.
Ruby-Fill™ [100 millicuries (mCi)/unit, Rubidium Chloride Rb 82] is presented as a liquid.
As with all radiopharmaceuticals, only the lowest dose of 82RbCl necessary to obtain adequate visualization should be used. The administered activity of 82RbCl should be individualized by considering body size and PET imaging systems. The typical adult single dose used for imaging on 3-dimensional scanners is 10 to 15 megabecquerels (MBq)/kilogram (kg), whereas double this activity may be required on 2-dimensional scanners. The maximum single dose of 3,700 MBq should only be administered to patients in the range of 250-370 kg. Most patients do not require the maximum dose of 82RbCl. Dosing guidelines are available in the Product Monograph.
There are no contraindications with the administration of 82RbCl; however 82RbCl should not be administered to pregnant women unless it is considered that the benefits to be gained by the patient outweigh the potential hazards to the foetus. 82RbCl 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 82RbCl are described in the Product Monograph.
Priority Review status was granted for the evaluation of Ruby-Fill™ as it appeared to provide substantial evidence of clinical efficacy for the diagnosis of a serious, life-threatening or severely debilitating disease such that the overall benefit/risk profile is improved over existing diagnostic agents marketed in Canada.
Based on the Health Canada review of data on quality, safety, and efficacy, Health Canada considers that the benefit/risk profile of Ruby-Fill™ is favourable as an accessory to PET for imaging of the myocardium, to evaluate regional myocardial perfusion in adult patients, as an aid in the diagnosis or assessment of suspected or known coronary artery disease.
3 Scientific and Regulatory Basis for Decision
On May 17, 2010, Jubilant DraxImage Inc. submitted to Health Canada a New Drug Submission for Ruby-Fill™. On December 1, 2010, a Notice of Deficiency (NOD) was issued because of numerous deficiencies in the clinical data, as well as in the chemistry and manufacturing. A response to the NOD was received on March 22, 2011. The issues pertaining to the data to support the use of Ruby-Fill™ were satisfactorily resolved. A Notice of Compliance was issued for Ruby-Fill™ on September 20, 2011.
3.1 Quality Basis for Decision
3.1.1 Drug Substance and Drug Product
General Information
Ruby-Fill™ (Rubidium Rb 82 Generator) contains accelerator-produced strontium-82 (82Sr) adsorbed on an α-hydrous tin oxide column in a shielded container and provides an elution of Rubidium Chloride Rb 82 Injection (82RbCl) which is a sterile, non-pyrogenic aqueous solution of 82RbCl in 0.9% sodium chloride with a pH of 4.0 to 8.0. The 82RbCl activity delivered in a given elution depends on the volume, the elution rate, and the 82Sr activity adsorbed on the generator column. Rubidium Chloride Rb 82 Injection contains no carrier or stabilizing agent.
Manufacturing Process and Process Controls
The active pharmaceutical ingredient, Rubidium Chloride Rb 82, is eluted directly from the Rb 82 generator, Ruby-Fill™, with a solution of sodium chloride 0.9% to give the final drug product Rubidium Chloride Rb 82 Injection.
Rubidium Chloride Rb 82 Injection is a generator-produced diagnostic radionuclide. Process controls are not applicable to radionuclides.
Characterization
This section is not applicablesince the radionuclide 82Rb is produced by decay of the parent radionuclide 82Sr.
Control of Drug Substance
The active pharmaceutical ingredient is not isolated but is eluted directly from the Rb 82 generator with a solution of sodium chloride 0.9% to give the final drug product Rubidium Chloride Rb 82 Injection. Therefore, this section is not applicable.
Stability
The active pharmaceutical ingredient is not isolated but is eluted directly from the Rb 82 generator with a solution of sodium chloride 0.9 % to give the final drug product Rubidium Chloride Rb 82 Injection. Therefore, this section is not applicable.
3.1.2 Drug Product
Description and Composition
Ruby-Fill™ (Rubidium Rb 82 Generator) is supplied in the form of 82Sr adsorbed on a hydrous stannic oxide column with an activity of 3.7 gigabecquerels of 82Sr at calibration time. The generator is encased in a lead shield container. Complete assay data for each generator are provided on the container label.
The specifications for the materials used in the manufacture of Ruby-Fill™ reflect current pharmacopoeia standards/methods, when applicable.
Ruby-Fill™ must be eluted with a sterile, additive and pyrogen-free, isotonic 0.9% sodium chloride for injection that complies with the United States Pharmacopeia (USP) monograph. The resulting column eluate, containing 0.9% sodium chloride, is administered directly to the patient. Only 0.9% Sodium Chloride Injection USP should be used to elute the generator. This eluent is not provided with the generator.
Pharmaceutical Development
Changes to the manufacturing process made throughout the pharmaceutical development are considered acceptable upon review.
Manufacturing Process and Process Controls
The manufacturing process for the production of Ruby-Fill™ (Rubidium Rb 82 Generator) was tested and analyzed. Pre-defined acceptance criteria were met in all generators for all process controls, critical parameters, and final product specifications.
The method of manufacturing is considered acceptable and the process is considered adequately controlled within justified limits.
Control of Drug Product
The quality of the Ruby-Fill™ generator system as a whole was tested by verifying the elution's radionuclide identification, radionuclidic purity, pH, chemical purity, assay, sterility, and levels of bacterial endotoxins. The test specifications and analytical methods are considered acceptable.
The validation process is considered complete. The validated method meets the criteria set forth in the validation protocol. The results from the batch analysis were within the proposed specification limits.
Stability
Ruby-Fill™ was shown to provide elutions that remain within specifications for up to 60 days post-calibration when eluted with sterile, pyrogen-free and additive-free 0.9% sodium chloride injection and when properly used as indicated in the Ruby-Fill™ Product Monograph.
The storage conditions for the Ruby-Fill™ generator are fully justified. The storage conditions are at room temperature (15oC to 25oC).
The integrity of the generator is ensured during the manufacturing process. The container closure system met all validation test acceptance criteria.
3.1.3 Facilities and Equipment
The design, operations, and controls of the facilities and equipment that are involved in the production of Ruby-Fill™ are considered suitable for the activities and products manufactured.
The sites are rated Good Manufacturing Practices compliant for the manufacturing activities.
3.1.4 Adventitious Agents Safety Evaluation
Not applicable. The excipients used in this product are not from animal or human origin.
3.1.5 Conclusion
The Chemistry and Manufacturing information submitted for Ruby-Fill™ has demonstrated that the 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 processes.
3.2 Non-Clinical Basis for Decision
3.2.1 Non-clinical Pharmacology
The non-clinical data package was based on literature review. No new studies conducted by the sponsor were submitted for non-clinical review. In rationale for such a position, the sponsor noted that given a large body of available clinical studies is available in the public domain, it is unlikely that non-clinical studies will provide any useful information for the evaluation of the efficacy and safety of 82RbCl in the assessment of myocardial perfusion in patients with known or suspected CAD. This approach was considered to be adequate for purposes of the present submission.
3.2.2 Toxicology
No toxicology studies were submitted for review.
Rubidium is a Group IA alkali metal belonging to the same periodic series as lithium, sodium, potassium, and cesium. Rubidium is found in virtually all biological systems. Foods high in rubidium include coffee, black tea, fruits, vegetables (especially asparagus), poultry and fish. The typical daily dietary intake of rubidium is 1 to 5 mg. Rubidium is found in foods in daily doses that are much higher than in a maximum dose of 82RbCl. Furthermore, this product is neither for acute or chronic use. It is not likely to be administered more than a couple of times; once for imaging at rest, and once after a stress test.
3.2.3 Summary and Conclusion
The non-clinical program for Ruby-Fill™ is considered adequate. There are no pharmacological/toxicological issues which preclude approval of the requested product indication. Sufficient clinical data is available to provide useful information for the evaluation of the efficacy and safety on the use of Ruby-Fill™.
3.3 Clinical basis for decision
3.3.1 Clinical Pharmacology
The submission did not contain any product-specific clinical pharmacology study reports.
A human in vivo prospective radiation dosimetry study, The Biodistribution and Dosimetry of Rubidium Chloride Injection in Man, was included in this submission. The dosimetry data was based on the largest number of organs studied in a rubidium dosimetry study: a total of 275 organs in 30 subjects. The kidney was the critical organ, receiving a radiation dose of 4.7E-03 mSv/MBq. The effective dose coefficient was 7.3E-04 ± 9.2E-05 mSv/MBq. The mean administered activity of 990 MBq (11 MBq/kg) resulted in an effective dose of 0.72 ± 0.13 mSv. This finding was among the lowest values reported for rubidium chloride and this value was well below the effective dose resulting from other myocardial perfusion imaging procedures. The target organ, the heart, received the second highest radiation dose. There were no gender or age differences in the dosimetry of rubidium chloride. In and of its own accord, the human radiation dosimetry study methodology conducted and the data estimates reported are considered to be an adequate assessment and estimation for such considerations.
3.3.2 Clinical Efficacy
The primary efficacy study was a retrospective study performed in 116 patients (121 scans) with known or suspected CAD, using invasive coronary angiography as the truth standard. All of the clinical data was provided by the University of Ottawa Heart Institute (UOHI) utilizing a 82RbCl generator developed by UOHI, similar to Ruby-Fill™. None of the patients received doses of 82RbCl eluted from the Ruby-Fill™ generator. During product development, a technology transfer regarding the UOHI generator took place between UOHI and Jubilant Draximage Inc. to ensure that the final drug product consistently met the same specifications as the final product produced for the clinical studies that support this new drug submission. The quality attributes of the generators and the eluates were found to be comparable. Based on this comparative analysis, there was no reason to expect differences in the performance of the generator, and in the safety and efficacy profile of the injected drug.
The study population included: patients with single-, double- and triple-vessel disease; patients with a previous history of myocardial infarction, percutaneous coronary intervention, or coronary bypass grafting; patients with and without angina; patients with and without congestive heart failure. The overall prevalence of CAD in this patient population was 80.2%.
The controlled efficacy study included a large sample size (121 scans), ample detail of the image acquisition and interpretation procedures, a blinded read of the 82Rb-PET scan, and an acceptable "truth standard" in all patients. The results of the 116-patient retrospective study were compared to a 674-patient comprehensive literature review. Inter-reader variability was assessed using a 415-patient database. The chance-corrected agreement rate was excellent, with a kappa coefficient of 0.93.
The sensitivity and specificity of Ruby-Fill™ was demonstrated in the 116-patient retrospective study of patients with known or suspected CAD who underwent both 82Rb-PET perfusion imaging and coronary angiography. The prevalence of CAD in this study population was 80%. Sensitivity was 94.0% [a 95% confidence interval (CI95%) of 86% to 97%) and specificity was 88% (CI95% 67% to 97%) for the detection of CAD. The results of this study were compared to the pooled results of studies identified in the comprehensive literature review. The literature review included 7 studies with a total of 674 patients. Compared to the results from the pooled literature reviews, sensitivity differed by only 2.15% (CI95% -5.5% to 6.9%); specificity differed by 2.06% (CI95% -12.9% to 19.4%). These differences were statistically insignificant.
In the 116-patient retrospective study, the sensitivity and specificity results were also assessed excluding data for patients with repeat procedures, patients who exceeded a 90-day timeframe (for angiography) and those for whom a precise date of angiography could not be determined. In this instance, the number of scans was 84, the prevalence of CAD was noted as 81.0%, sensitivity was 93% (CI95% 83-97%) and specificity was 81% (CI95% 54-95%).
Overall, the retrospective study provided confirmation of the diagnostic performance and safety of the UOHI product and 82Rb-PET myocardial imaging for use in the diagnosis and assessment of CAD. Given the consistency of findings throughout the published studies, the reproducibility of results in many different institutions with different investigators, and the reproducible correlation with angiography (an accepted external truth standard), the retrospective study and the comprehensive literature review together provide sufficient evidence to support the effectiveness of Ruby-Fill™ to assess myocardial perfusion in the evaluation of CAD in patients with known or suspected CAD.
3.3.3 Clinical Safety
The safety of Rubidium Chloride Rb 82 Injection (82RbCl) is supported by the absence of documented adverse events in a 4,143-patient safety database (patients who received 82RbCl from 2002 to 2008), the absence of documented adverse events in the published literature, the product's pharmacological class, the knowledge of rubidium metabolism and its safety profile.
In terms of specific adverse events and information filed for this drug submission, no adverse events to 82RbCl were reported in over 7,200 patients at the UOHI (in clinical trial use at the UOHI since 1997). Consistent with the adverse event profile, no adverse events were reported in the 116-patient retrospective study. No adverse events were reported in any of the studies included in the comprehensive literature review.
However, during review for this product, an adverse event was reported further to use of the Jubilant Draximage product under an authorized Clinical Trial Application (CTA) in Canada. This adverse event involved an incident of suspect Strontium Sr-82/Sr-85 breakthrough and thus an unanticipated additional radiation dose exposure. This adverse event was determined under separate processes to be an isolated incident for one generator, and no regulatory action to the CTA was considered necessary.
3.3.4 Comparability Issue
Jubilant Draximage Inc. submitted the New Drug Submission (NDS) for the Rubidium Rb 82 Generator, Ruby-Fill™. However, the NDS did not contain any clinical efficacy and safety data produced from patient studies using the Jubilant Draximage generator. Instead, the submission contained clinical data from studies that utilized the UOHI-produced iteration of the product.
No specific in vivo bridging data was included to characterize performance between the radiopharmaceutical as eluted from the two generators [that is (i.e.), UOHI and Jubilant Draximage] and information was lacking on the manufacturing process for the Jubilant Draximage generator. A NOD was issued. The sponsor was advised that no new clinical data was required if Jubilant Draximage Inc. demonstrated pharmaceutical equivalence between the two generators.
Further to the NOD being issued and the post-NOD meeting held on January 24, 2011, an emphasis on the physiochemical comparability between products from the Chemistry and Manufacturing/Quality perspective was paramount for finalized decisions and recommendations. As a result, the sponsor supplied comparative studies to assess the physiochemical properties of the two products.
Several factors played a role in Health Canada's decision to accept the suitability of the Ruby-Fill™ generator:
- The Ruby-Fill™ generator from Jubilant Draximage Inc was developed based on a successful generator design employed in the clinical studies by UOHI.
- The sponsor provided information to support the development and performance of the Ruby-Fill™ generator, including a side-by-side comparison of the generators produced by UOHI and the Ruby-Fill™ generator with regard to their product specifications. Despite a few modification differences and a few minor differences in product specifications, the eluates from both versions meet the same USP specifications.
- The active pharmaceutical ingredient is a radionuclide resulting from the nuclear decay of a parent radionuclide accomplished naturally under the laws of physics. Issues of comparability that arise between products that are synthetically derived or produced in biological systems do no exist.
- Formulation of the final product for administration arises from the elution buffer which for both generators is 0.9% sodium chloride, and the product is administered intravenously.
From Health Canada's perspective, there is no reason to believe that the eluate from the Ruby-Fill™ generator would behave any differently in a patient compared to the eluate from the UOHI generator that was used to generate the clinical data provided in support of the NDS.
3.4 Benefit/Risk Assessment and Recommendation
3.4.1 Benefit/Risk Assessment
Priority Review status was granted for the evaluation of Ruby-Fill™ as no other drug, approved and available on the Canadian market for the assessment of myocardial perfusion as an aid in diagnosis of CAD, appeared to have the same accuracy or safety profile as that represented in this drug submission.
The diagnostic accuracy of Rubidium Chloride Rb 82 Injection as well as its prognostic value in the assessment of myocardial perfusion in patients with known or suspected CAD has been clearly demonstrated in prospective, retrospective, and outcome studies. No significant safety issues have been identified. No adverse events have been reported in over 7,200 patients treated at the UOHI. The absorbed radiation dose from 82Rb PET is lower than the dose from other radiopharmaceuticals commonly used for myocardial perfusion imaging.
No dose-response and dose-toxicity relationships were established. The most common total dose used was 1,000 MBq (13 MBq/kg), which is at the lower end of the present European Association of Nuclear Medicine/European Society of Cardiology guidelines. No differential effects were identified in different sub-populations. While being both more sensitive and more specific, 82Rb PET results in the lowest radiation dose of any myocardial perfusion imaging agent. It is a minimally invasive test with no known adverse events, apart from the one incident reported in the Canadian CTA. 82Rb PET may be used to complement or provide an alternative to existing coronary perfusion tests in patients with known or suspected CAD.
The clinical data submitted confirmed the diagnostic performance and safety of the UOHI generator and 82Rb PET myocardial imaging for use in the diagnosis and assessment of CAD. The submission did not contain sufficient clinical data produced or sourced from a patient studies using the Ruby-Fill™ generator; however, the sponsor provided information that supported the fact that the eluate from the UOHI generator is comparable to the Ruby-Fill™ generator. Therefore both generators would perform in the same manner. Taking this into account, Ruby-Fill™ has a favourable benefit-risk profile for use in the evaluation of patients with CAD.
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 Ruby-Fill™ is favourable as an accessory to positron emission tomography (PET) for imaging of the myocardium, to evaluate regional myocardial perfusion in adult patients, as an aid in the diagnosis or assessment of suspected or known coronary artery disease. The NDS 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: Ruby-FillTM
| Submission Milestone | Date |
|---|---|
| Pre-submission meeting: | 2008-07-15 |
| Request for priority status | |
| Filed: | 2010-01-21 |
| Approval issued by Biologics and Genetics Therapies Directorate: | 2010-02-19 |
| Submission filed: | 2010-05-17 |
| Screening | |
| Screening Acceptance Letter issued: | 2010-06-15 |
| Review | |
| Notice of Deficiency (NOD) issued by Director General efficacy and quality issues): | 2010-12-01 |
| Response filed: | 2011-02-28 |
| Screening 1 | |
| Screening Acceptance Letter issued: | 2011-03-25 |
| Review 1 | |
| Quality Evaluation complete: | 2011-09-19 |
| Clinical Evaluation complete: | 2011-09-19 |
| Biostatistics Evaluation complete: | 2011-09-19 |
| Labelling Review complete: | 2011-09-15 |
| Notice of Compliance (NOC) issued by Director General: | 2011-09-20 |