Summary Basis of Decision for Radicava

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 Radicava is located below.

Recent Activity for Radicava

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.

Summary Basis of Decision (SBD) for Radicava

Date SBD issued: 2019-02-07

The following information relates to the new drug submission for Radicava.

Edaravone
30 mg/100 mL, solution, intravenous

Drug Identification Number (DIN):

  • 02475472

Mitsubishi Tanabe Pharma Corporation

New Drug Submission Control Number: 214391

On October 3, 2018, Health Canada issued a Notice of Compliance to Mitsubishi Tanabe Pharma Corporation for the drug product Radicava.

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 Radicava is favourable for the treatment of amyotrophic lateral sclerosis.

1 What was approved?

Radicava, a neuroprotective agent, was authorized for the treatment of amyotrophic lateral sclerosis.

Radicava is contraindicated in patients who are hypersensitive to this drug or to any ingredient in the formulation, including any non-medicinal ingredient, or component of the container.

The safety and effectiveness of Radicava in pediatric patients (<18 years of age) have not been established. Therefore, Radicava should not be used in this patient population.

Based on evidence from clinical studies and post-marketing experience, no overall differences in safety or effectiveness were observed in geriatric patients (>65 years of age) and younger patients.

Radicava 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.

Radicava (30 mg/100 mL edaravone) is presented as a solution for intravenous infusion. In addition to the medicinal ingredient edaravone, the solution also contains L-cysteine hydrochloride hydrate, sodium bisulfite, sodium chloride, phosphoric acid, sodium hydroxide, and water for injection.

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

2 Why was Radicava approved?

Health Canada considers that the benefit-risk profile of Radicava is favourable for the treatment of amyotrophic lateral sclerosis (ALS).

Amyotrophic lateral sclerosis is a progressive neurodegenerative disease that affects nerve cells in the brain and spinal cord. Rapid progression of symptoms directly results from degeneration in motor neurons causing the loss of motor function. Most patients will eventually need assistance with activities of daily living, with subsequent progression leading to respiratory compromise and eventual respiratory failure; which is the leading cause of death in ALS. The median survival times are reported as two to three years from diagnosis.

The etiology of ALS remains unknown. Researchers have proposed several hypotheses, including the involvement of excitatory amino acids, free radicals, and viral infection.

The sole drug indicated specifically for treatment of ALS is riluzole, which was approved in Canada in 2000. However, riluzole has only been shown to prolong the length of time until patients require a tracheostomy for ventilatory support, and has not demonstrated benefit in prolonging survival or improving muscle strength or neurological function. Other treatments for ALS are symptomatic, and are aimed at treating the complications of the decline in motor function. Medications and physical and occupational therapy can provide relief from symptoms, including muscle cramps and spasms, constipation, fatigue, excessive salivation, pain, depression, sleep problems and uncontrolled outbursts of laughing or crying.

Radicava is a free radical scavenger that was first approved in April 2001 in Japan for treatment of ischemic stroke. Edaravone (the medicinal ingredient in Radicava) inhibits lipid peroxide formation, decreases the concentration of hydroxyl radicals, and is believed to protect endothelial and neural cells at or adjacent to the site of ischemia. Based on the mechanism of action of edaravone, it was postulated that it might be effective against ALS, with its etiology potentially associated with oxidative stress due to free radicals.

Radicava has been shown to be efficacious in slowing the decline of function in daily activities in ALS patients who were living independently. The market authorization was based on one 6-month, randomized, placebo-controlled, double-blind pivotal study (Study MCI186-19). The primary efficacy endpoint was a comparison of the change between treatment arms in the ALS Functional Rating Scale-revised (ALSFRS-R) total scores from baseline to Week 24. The ALSFRS-R is a rating scale that consists of 12 questions which evaluate the fine motor, gross motor, bulbar, and respiratory function of patients with ALS. Each item on the scale is scored from 0 to 4, with higher scores representing greater functional ability. Based on ALSFRS-R, results obtained from the MCI186-19 study showed the decline in ALSFRS-R scores from baseline was significantly less in the Radicava-treated patients as compared to placebo.

In terms of safety, no major safety signal was identified during conduct of the clinical studies. The majority of patients in the Radicava program reported adverse events, but many of these represented worsening of their disease. In addition, the frequency of serious adverse events was low and generally comparable between Radicava and placebo groups. Spontaneous post-marketing reports following approval in Japan have identified cases of hypersensitivity reactions and anaphylaxis with use of Radicava. These risks are identified in the Radicava Product Monograph.

A Risk Management Plan (RMP) for Radicava was submitted by Mitsubishi Tanabe Pharma America 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.

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

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

Overall, the therapeutic benefits of Radicava therapy seen in the pivotal study are positive and outweigh the potential risks. Radicava has an acceptable safety profile based on the non-clinical data and clinical studies. The identified safety issues can be managed through labelling and adequate monitoring. Appropriate warnings and precautions are in place in the Radicava 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 Radicava?

The drug submission for Radicava was reviewed under the Priority Review Policy. Sufficient evidence was provided demonstrating Radicava showed a significant increase in efficacy with an improved benefit-risk profile compared to existing therapies for amyotrophic lateral sclerosis, a condition that is not adequately managed by a drug marketed in Canada.

Submission Milestones: Radicava

Submission MilestoneDate
Pre-submission meeting:2017-09-07
Request for priority status
Filed:2017-08-16
Approval issued by Director, Bureau of Medical Sciences:2018-02-09
Submission filed:2018-03-09
Screening
Screening Acceptance Letter issued:2018-04-06
Review
Clinical Evaluation complete:2018-09-14
Review of Risk Management Plan complete:2018-09-18
Quality Evaluation complete:2018-09-27
Labelling Review complete, including Look-alike Sound-alike brand name assessment:2018-09-28
Medical Evaluation complete:2018-10-01
Notice of Compliance issued by Director General, Therapeutic Products Directorate:2018-10-03

The Canadian regulatory decision on the non-clinical and clinical review of Radicava was based on a critical assessment of the data package submitted to Health Canada. The foreign reviews completed by the United States Food and Drug Administration (FDA) and the Japanese regulatory agency were used as an added reference.

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 Radicava?

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.

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

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

6 What other information is available about drugs?

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

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

Clinical Pharmacology

The mechanism by which edaravone (medicinal ingredient in Radicava) exerts its therapeutic effect in patients with amyotrophic lateral sclerosis (ALS) is unknown.

Five pharmacokinetic studies were conducted in healthy volunteers, three in Japanese subjects and two in Caucasian subjects. As similarly observed in the animal studies, edaravone is metabolized to sulfate and glucuronide conjugates. The protein binding rate of edaravone to human serum protein is approximately 91% to 92%. The protein binding rate of the sulfate and glucuronide were 99% and 36% to 39%, respectively. Edaravone is rapidly eliminated primarily by renal excretion. The terminal half-life of edaravone was approximately 4.5 to 6 hours.

No dosage adjustments are required based on intrinsic or extrinsic factors; yet, it is possible that edaravone exposure may be increased in patients with hepatic impairment. No dose adjustment is required for patients with mild or moderate hepatic impairment; however, no specific dosing recommendation can be provided for patients with severe hepatic impairment.

With respect to safety, there were no concerning signals in Phase I and II clinical studies. The potential for edaravone-drug interactions is considered low, and edaravone does not appear to have abuse potential or induce physical dependence.

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

Clinical Efficacy

The efficacy of Radicava for the treatment of amyotrophic lateral sclerosis (ALS) was based on a single Phase III study (MCI186-19) conducted in Japanese patients with ALS. An additional subgroup analysis from a prior negative Phase III study (MCI186-16) was also considered as supportive data for efficacy.

Study MCI186-19

Study MCI186-19 was a 6-month, Phase III, randomized, placebo-controlled double-blind study conducted in Japanese patients with ALS who were living independently. The study enrolled 69 patients in the Radicava arm and 68 in the placebo arm. Baseline characteristics were similar between these groups, with over 90% of patients in each group being treated with riluzole.

The design of the study included 2 treatment periods: a 6 cycle 'double-blind period' (Radicava versus placebo) followed by an 'active treatment period' of 6 cycles, where all patients received Radicava. The double-blind period was the main basis for efficacy assessment. Persistence of efficacy was assessed descriptively in the active treatment period, where no statistical analyses were conducted.

Radicava was administered as an intravenous infusion of 60 mg given over a 60 minute period according to the following schedule:

  • An initial treatment cycle with daily dosing for 14 days followed by a 14-day drug-free period (Cycle 1)
  • Subsequent treatment cycles with daily dosing for 10 days out of 14-day periods, followed by 14-day drug-free periods (Cycles 2 to 6)

In the 'double-blind period', the change (or decline) in ALS Functional Rating Scale-Revised (ALSFRS-R) score was the primary efficacy endpoint and was evaluated as the difference from baseline in Cycle 1 to end of Cycle 6 (or discontinuation). Results based on the primary efficacy endpoint (ALSFRS-R score) demonstrated that the decline in ALSFRS-R scores from baseline was significantly less in the Radicava-treated patients (mean change -5.01 ± 0.64) compared to placebo (-7.50 ± 0.66). The between group difference of 2.49 ± 0.76 (p = 0.0013) was considered as clinically meaningful, as each 1-point score change reflects a functional change. These results were further supported by pre-planned sensitivity analyses. In regards to the effect of Radicava on mortality, this could not be assessed given no deaths occurred in either group.

The 'active treatment period' assessed the persistence of efficacy over 48 weeks (Radicava-Radicava group) and examined efficacy data for patients who received placebo for 24 weeks before being administered Radicava (placebo-Radicava group). Only descriptive summaries were compiled for the results of the 'active treatment period' because no statistical analyses were conducted. Both groups showed a progressive decline in functional parameters. However, in the placebo-Radicava group, the slope of time-dependent change in the 'active treatment period' was less than what was observed in patients receiving placebo during the double-blind period and was similar to that observed in the Radicava-Radicava group. The between-group difference was 2.8 in favor of Radicava for the first 6 cycles (from baseline in Cycle 1 to baseline in Cycle 7) while it was 2.9 for the entire 12 cycle period (from baseline in Cycle 1 to end of Cycle 12). These findings suggest that a similar trend may be observed when Radicava treatment is started at a relatively early stage of onset of ALS with mild severity and when Radicava treatment is started 6 months later. For this reason, it was considered justified not to restrict Radicava treatment solely to early stage ALS patients.

Supportive study

Study MCI186-16

Study MCI186-16 was designed to demonstrate efficacy of Radicava in a subset of patients with ALS in the early phase of disease progression. The primary efficacy endpoint was the same as that specified in Study MCI186-19. While results based on the ALSFRS-R score demonstrated a slight benefit towards Radicava-treated patients (mean change -5.70 points) compared to placebo (mean change -6.35 points), the between-group difference of 0.65 points was not statistically significant. Therefore a negative efficacy result was shown for this study.

A post hoc analysis of the negative study was undertaken by the sponsor to evaluate two subpopulations. Based on the first subpopulation analyses, a beneficial trend with Radicava was observed in patients who retained functionality in most activities of daily living along with normal respiratory function. This subpopulation was labeled as the 'Efficacy Expected Subpopulation' (EESP). The mean change in ALSFRS-R score observed in the EESP group was -4.85 points in Radicava-treated patients and -7.06 points in the placebo group. The between-group difference observed was 2.20 points and considered statistically significant (p = 0.0360) in favour of the Radicava treatment group. A subgroup of patients in the EESP group was also evaluated. This EESP subgroup had a 'Definite or Probable' ALS diagnosis and was no more than 2 years from ALS symptom onset. This subpopulation was labeled as 'Definite or Probable/EESP/2years'. The mean change observed in the 'Definite or Probable/EESP/2years' group was -4.58 points in Radicava-treated patients and -7.59 points in the placebo group. The between-group difference was 3.01 points which was also considered statistically significant (p = 0.0270) in favour of the Radicava treatment group.

In sum, both subpopulation analyses (EESP and 'Definite or Probable/EESP/2years') demonstrated a statistically significant difference in favour of the Radicava treatment group. As such, this data was considered as supportive evidence for efficacy as seen in the MCI186-19 study.

Indication

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

  • Radicava (edaravone) is indicated for the treatment of amyotrophic lateral sclerosis.

  • Pediatrics (<18 years of age): Safety and effectiveness of Radicava in pediatric patients have not been established.

  • Geriatrics (>65 years of age): Evidence from clinical studies and experience suggests that use in the geriatric population is not associated with differences in safety or effectiveness.

Health Canada approved the following indication:

  • Radicava (edaravone) is indicated for the treatment of amyotrophic lateral sclerosis.

  • Pediatrics (<18 years of age): No data are available to Health Canada; therefore, Health Canada has not authorized an indication for pediatric use.

  • Geriatrics (>65 years of age): Evidence from clinical studies and experience suggests that use in the geriatric population is not associated with differences in safety or effectiveness.

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

Clinical Safety

The safety profile of Radicava compared to placebo was assessed in three clinical studies:

  • Two double-blind, randomized, placebo-controlled studies conducted in patients with grade 1 to 2 ALS (Japanese severity classification) with a total of 343 patients enrolled. These two studies (MCI186-19 and MCI186-16) were previously described in the Clinical Efficacy section.
  • One double-blind, randomized, placebo-controlled study conducted in patients with grade 3 ALS with a total of 25 patients enrolled. This study (MCI186-18) was designed as an exploratory study to investigate efficacy and safety in a limited number of more advanced ALS patients (severity grade 3). No primary efficacy endpoint was defined for this study, nor was it powered to detect a statistical difference between placebo and Radicava. For the purpose of this New Drug Submission, results of this study remained focused in support of the safety data.

Based on the clinical studies conducted, no major safety signals were identified. The majority of patients in these studies reported adverse events, but many of these represented worsening of their disease. In addition, the frequency of serious adverse events was also low and generally comparable between Radicava and placebo groups.

The most common adverse reactions which occurred in ≥10% of Radicava-treated patients were contusion (Radicava = 15%; Placebo = 9%), gait disturbance (Radicava = 13%; Placebo = 9%), and headache (Radicava = 10%; Placebo = 6%).

Post-marketing experience following approval in Japan identified cases of hypersensitivity reactions (redness, wheals, and erythema multiforme) and anaphylaxis (urticaria, decreased blood pressure, and dyspnea) with use of Radicava. These risks are identified in the Radicava Product Monograph. Post-marketing experience following treatment of ischemic stroke patients identified liver and kidney adverse events as potential additional safety concerns. However, no safety signal was identified during the ALS clinical program. Therefore, the safety profile of Radicava is considered acceptable, and the overall benefit-risk balance of Radicava for treatment of ALS is considered positive.

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

7.2 Non-Clinical Basis for Decision

A review of the United States Food and Drug Administration's (FDA) non-clinical evaluation report was conducted and accepted to supplement Health Canada's review of the non-clinical data. In brief, pharmacokinetic studies in mice, rats, dogs, and monkeys indicated transport across the blood brain barrier, extensive accumulation in the aorta (likely due to protein binding), and extensive partitioning into the kidney. The primary route of elimination is through renal excretion.

Toxicity studies of edaravone showed transient central nervous system signs (e.g., sedation and hypoactivity) and decreases in weight gain at moderate doses following intravenous bolus or short (i.e., ≤4 h) infusion in rats and dogs. Continuous infusion was associated with hematologic signs of regenerative anemia and peripheral nerve degeneration. The degeneration was typically restricted to axons and may be partially reversible. A mechanistic explanation for this degeneration was not completely established, but a role for vitamin B6 deficiency was suggested. It is noteworthy to mention that this nerve degeneration was dose and duration dependent and was only observed during continuous intravenous infusion (24 hours) at higher doses and not observed at lower doses. No reports of nerve degeneration have been reported in humans since edaravone's approval for acute ischemic stroke in 2001.

Post-marketing, renal toxicity has been observed in patients treated with edaravone for acute ischemic stroke in Japan. Renal toxicity was not seen in animal toxicology studies; however, mechanistic studies in rats suggested that edaravone may increase renal exposure to cephalosporin antibiotics under experimental dehydration conditions. It appeared that higher doses of edaravone, as compared to clinical doses, may promote renal impairment when concomitant cephem antibiotic medications are used in a water deprived condition in an animal stroke model. Since the sponsor considers the dehydration and subsequent renal disorders caused by the cephem-edaravone interaction to be specific to acute ischemic stroke patients, they did not recommend the interaction be included in the Radicava Product Monograph. After internal discussion at Health Canada, it was agreed that edaravone was unlikely to cause renal dysfunction in ALS patients, therefore no revisions to the Product Monograph were requested.

For this submission, no carcinogenicity studies were conducted by the sponsor. As such, the carcinogenic potential of edaravone could not be adequately assessed. However, currently there is a post-market commitment to complete a 26-week carcinogenicity study in transgenic mice by October 2020 and a 2-year carcinogenicity study in rats by February 2022. Given the lack of evidence thus far of carcinogenic effects in the stroke population, the lack of evidence in the non-clinical studies already conducted, and the fact that the anticipated lifespan of ALS patients is typically 2 to 4 years after diagnosis, the post-marketing commitment to conduct carcinogenicity studies in these two species is considered sufficient for approval at this time.

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

7.3 Quality Basis for Decision

The Chemistry and Manufacturing information submitted for Radicava has demonstrated that the 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 processes. Changes to the manufacturing process and formulation made throughout the pharmaceutical development are considered acceptable upon review. Based on the stability data submitted, the proposed shelf life of 36 months is acceptable when the drug product is stored at room temperature (15ºC to 30ºC) and protected from light.

Proposed limits of drug-related impurities are considered adequately qualified (i.e., within International Council for Harmonisation [ICH] limits and/or qualified from toxicological studies).

All sites involved in production are compliant with Good Manufacturing Practices.

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

Report a problem or mistake on this page
Please select all that apply:
Date modified: