Summary Basis of Decision for Plegridy

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 Plegridy is located below.

Recent Activity for Plegridy

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 Plegridy

Updated:

2019-01-04

The following table describes post-authorization activity for Plegridy, a product which contains the medicinal ingredient peginterferon beta-1a. 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 that are found in PAATs.

For additional information about the drug submission process, refer to the Management of Drug Submissions Guidance.

Drug Identification Numbers (DINs):

  • DIN 02444372 - 63 µg/0.5 mL peginterferon beta-1a, liquid, subcutaneous
  • DIN 02444380 - 94 µg/0.5 mL peginterferon beta-1a, liquid, subcutaneous
  • DIN 02444399 - 125 µg/0.5 mL peginterferon beta-1a, liquid, subcutaneous
  • DIN 02444402 - 63 µg/0.5 mL and 94 µg/0.5 mL peginterferon beta-1a, liquid, subcutaneous (Plegridy starter pack)

Post-Authorization Activity Table (PAAT)

Activity/submission type, control numberDate submittedDecision and dateSummary of activities
NC # 2182582018-07-16Issued NOL
2018-08-09		Submission filed as a Level II (90 day) Notifiable Change (Risk Management Change) to update the PM to reflect revisions in the company core data sheet. Changes were made to the PM Part III: Consumer Information. The submission was reviewed and considered acceptable, and an NOL was issued.
NC # 2150132018-03-29Issued NOL
2018-06-12		Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) to change the testing procedures and specifications used to release the the pre-filled pen. The submission was reviewed and considered acceptable, and an NOL was issued.
SNDS # 2041492017-03-30Issued NOC
2018-03-15		Submission filed as a Level I - Supplement to update the PM with new safety information from the completed 105MS302 and 105MS303 studies. The benefit/risk profile for Plegridy remains positive when used for its approved indication. The submission was reviewed and considered acceptable, and an NOC was issued.
NC # 2112352017-11-14Issued NOL
2018-02-06		Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) to introduce the use of an alternate syringe component for the pre-filled syringe and pre-filled pen. The submission was reviewed and considered acceptable, and an NOL was issued.
SNDS # 1984522016-09-16Issued NOC
2017-05-04		Submission filed as a Level I - Supplement for a new drug substance manufacturing site. The drug substance manufactured at the new site is comparable to the drug substance manufactured at the current site. The data were reviewed and considered acceptable, and an NOC was issued.
NC # 1953672016-05-25Issued No Objection Letter
2016-06-16		Submission filed as a Level II (90 day) Notifiable Change (Risk Management Change) to update the Product Monograph (PM) to include "pulmonary arterial hypertension" as an adverse drug reaction. As a result of the NC, additions were made to the Adverse Reactions section of the PM, and corresponding changes were made to the PM Part III: Consumer Information. The submission was reviewed and considered acceptable, and a No Objection Letter was issued.
NC # 1938352016-03-30Issued No Objection Letter
2016-06-28		Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) for changes to the manufacture of the drug substance. The submission was reviewed and considered acceptable, and a No Objection Letter was issued.
New safety review started by Health CanadaNot applicableStarted between
2015-10-01		Health Canada started a safety review for Avonex, Betaseron, Extavia, Plegridy, Rebif (Beta-interferons) between 2015-10-01 and 2015-10-31.
Drug product (DIN 02444399) market notificationNot applicableDate of first sale:
2015-09-29		The manufacturer notified Health Canada of the date of first sale pursuant to C.01.014.3 of the Food and Drug Regulations.
Drug product (DIN 02444402) market notificationNot applicableDate of first sale:
2015-09-25		The manufacturer notified Health Canada of the date of first sale pursuant to C.01.014.3 of the Food and Drug Regulations.
NC # 1874172015-09-02Cancellation Letter Received
2015-09-14		Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) to modify an in-process control. The submission was reclassified as out of the scope of the Post-Notice of Compliance (NOC) Changes: Quality Document (no change is applicable).
NDS # 1669742013-07-31Issued NOC
2015-08-10		Notice of Compliance issued for New Drug Submission.
Summary Basis of Decision (SBD) for Plegridy

Date SBD issued: 2015-10-14

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

Peginterferon beta-1a, 63 µg/0.5 mL, 94 µg/0.5 mL, and 125 µg/0.5 mL, liquid, subcutaneous

Drug Identification Number (DIN):

  • DIN 02444372 - 63 µg/0.5 mL, liquid
  • DIN 02444380 - 94 µg/0.5 mL, liquid
  • DIN 02444399 - 125 µg/0.5 mL, liquid
  • DIN 02444402 - 63 µg/0.5 mL and 94 µg/0.5 mL, liquid (Plegridy starter pack)

Biogen Canada Inc.

New Drug Submission Control Number: 166974

On August 10, 2015, Health Canada issued a Notice of Compliance to Biogen Canada Inc. for the drug product, Plegridy.

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 Plegridy is favourable for the treatment of relapsing remitting multiple sclerosis (RRMS) for adult patients to reduce the frequency of clinical exacerbations and to slow the progression of disability.

1 What was approved?

Plegridy, an immunomodulator, was authorized for the treatment of relapsing remitting multiple sclerosis (RRMS) for adult patients to reduce the frequency of clinical exacerbations and to slow the progression of disability.

The safety and efficacy of Plegridy have not been established in patients with primary and secondary progressive multiple sclerosis.

The safety and efficacy of Plegridy in patients over the age of 65 have not been sufficiently studied due to the limited number of such patients included in clinical trials.

The safety and efficacy of Plegridy in patients below 18 years of age has not been studied.

Plegridy is contraindicated for patients with a history of hypersensitivity to natural or recombinant interferon beta or peginterferon, as well as patients with a history of hypersensitivity to any other component of the formulation or the container. Plegridy is also contraindicated in pregnant patients and in patients with current severe depression and/or suicidal ideation. Plegridy was approved for use under the conditions stated in the Plegridy Product Monograph taking into consideration the potential risks associated with the administration of this drug product.

Plegridy (63 µg/0.5 mL, 94 µg/ 0.5 mL, and 125 µg/0.5 mL; peginterferon beta-1a) is a liquid for subcutaneous injection provided in a pre-filled syringe or pre-filled pen. In addition to the medicinal ingredient, peginterferon beta-1a, the liquid contains L-arginine hydrochloride, glacial acetic acid, Polysorbate 20 in water for injection, and sodium acetate trihydrate.

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

2 Why was Plegridy approved?

Health Canada considers that the benefit/risk profile of Plegridy is favourable for the treatment of relapsing remitting multiple sclerosis (RRMS) for adult patients to reduce the frequency of clinical exacerbations and to slow the progression of disability.

Multiple sclerosis (MS) is a chronic, inflammatory, demyelinating disease of the central nervous system and is one of the most common causes of neurological disability in young adults. It is characterized by multi-focal recurrent attacks of neurological symptoms and signs with variable recovery. Deterioration is progressive in the majority of patients. The cause of MS is unknown, although an autoimmune process has been implicated.

The main goals in managing MS are the prevention of relapse and the prevention or delay of the accumulation of disability. The current standard of care for the treatment of MS is disease modifying agents, which also include immunomodulatory therapies such as interferon beta (IFNβ).

Three IFNβ products are currently approved for the treatment of RRMS: IFNβ-1b [Betaseron, subcutaneous (SC)], IFNβ-1a [Avonex, intramuscular (IM)], and IFNβ-1a (Rebif, SC).

Plegridy is a pegylated form of IFNβ-1a, an active biological substance used for the treatment of MS. Plegridy has a more optimized, less-frequent dosing regimen, with an efficacy and safety profile that is, at least, comparable to currently approved first-line injectable therapies.

Plegridy has been shown to be efficacious in adult patients with RRMS. The market authorization was based on two-year data obtained from a single pivotal trial. The primary endpoint of this study was to determine whether Plegridy (as compared with placebo) was effective in reducing the annualized relapse rate (ARR) at Year 1. Secondary endpoints included the reduction of the total number of new or newly enlarging T2 hyperintense lesions based on brain magnetic resonance imaging (MRI) scans and slowing of the progression of disability, as measured by the Kurtze Expanded Disability Status Scale (EDSS - a scale that measures the degree of disability in patients with MS with 0 being a normal neurological exam; 5 being ambulatory without aid for about 200 metres and disability that impairs full daily activities; and 10 being death due to MS).

By the end of Year 1, the efficacy results of the pivotal trial reached statistical significance for the primary endpoint of reducing ARR, as well as the secondary endpoints which included the MRI endpoint and disability progression. Despite this data, the clinical meaningfulness of the Year 1 results was unclear due to the large proportion of patients with no relapses (for ARR) and the low proportion of patients with disability progression (for EDSS) at the end of Year 1. Subsequent assessment of two-year data with additional statistical analyses, as requested by Health Canada, revealed that the statistically significant efficacy results for the primary and secondary endpoints were further supported by results obtained from the two-year data.

Overall, the safety profile of Plegridy is comparable to Avonex with the exception of the rate of injection site reactions [66% for Plegridy versus (vs.) 3% for Avonex]; however, considering the different routes of administration (SC for Plegridy vs. IM for Avonex), such a difference is not unexpected. The safety profile over 2 years did not indicate any new safety finding of significant concern. There was no increase in mortality, the risk of serious adverse events, or the risk infection. The overall immunogenicity of Plegridy over 2 years was low and comparable to Year 1.

A number of potential safety issues exist with the use of IFNβ, including, but not limited to: hepatic injury, serious hypersensitivity reactions, injection-site necrosis, decreased peripheral blood counts, seizure, worsening cardiac disease, immunogenicity, hyperthyroidism, and metabolism and nutritional disorders. Furthermore, the identified safety concerns also include depression and suicidal ideation which have been reported to occur with increased frequency in patients receiving IFNβ. If a patient develops depression or other severe psychiatric symptom, cessation of Plegridy should be considered.

Caution should be used and close monitoring considered when administering Plegridy to patients with severe hepatic impairment. Patients should be monitored for signs of hepatic injury and caution exercised when interferons are used concomitantly with other drugs associated with hepatic injury.

There are no adequate and well controlled studies for the use of Plegridy in pregnant or nursing women. Plegridy should only be prescribed during pregnancy if the potential benefit justifies the potential risk to the fetus. Administration of Plegridy to mature female rhesus monkeys resulted in menstrual irregularities accompanied by decreases in serum progesterone and 17-beta estradiol, consistent with the known abortifacient effects of non-pegylated IFNβ-1a. Female patients should be advised of the abortifacient potential of Plegridy and be instructed to take adequate contraceptive measures.

These safety issues have been addressed through appropriate labelling in the Plegridy Product Monograph and included in the risk management plan.

The analysis of the two-year data provided assurance regarding the maintenance of efficacy beyond the placebo-phase (Year 1) of the pivotal study. Other benefits included a reduction in the number of injections, in addition to an easier route of administration for Plegridy as compared to Avonex, which is marketed by the same manufacturer (SC every 2 weeks vs. IM once a week). The safety profile of Plegridy was comparable to Avonex. Taking into consideration the clinical efficacy over two years of treatment and the acceptable safety profile, the benefit/risk ratio of Plegridy is considered favourable.

A Risk Management Plan (RMP) for Plegridy was submitted by Biogen 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. As a post-approval commitment, the sponsor has been requested to provide an updated RMP to reflect the Canadian Labelling and the required post-market activities to be carried out after authorization.

Health Canada reviewed the Look-alike Sound-alike Report submitted by the sponsor and accepted the proprietary name for the drug product.

Overall, the therapeutic benefits seen in the pivotal study are comparable to the comparators and the benefits of Plegridy therapy are considered to outweigh the potential risks. Plegridy 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 Plegridy 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 Plegridy?

A New Drug Submission (NDS) for Plegridy was filed with Health Canada on July 31, 2013. Upon review, it was found that the data submitted were insufficient to make a thorough assessment of the efficacy and safety of the product. In particular, the lack of a direct comparator in the pivotal study and difficulties of external validation against other multiple sclerosis trials, prevented conclusions from being drawn regarding comparable efficacy and safety with currently approved first-line injectable therapies including Avonex. As for the stand-alone therapeutic product, due to the very low proportion of patients with events of interest for both the treatment and placebo groups at Year 1 and the lack of statistical robustness of the Kurtze Expanded Disability Status Scale (EDSS) data at Year 1, the data were considered insufficient to allow an adequate assessment of the clinical applicability of Plegridy in reducing the frequency of clinical exacerbations and delaying the accumulation of disability.

As a result, a Notice of Deficiency (NOD) was issued for Plegridy on July 17, 2014. As part of the NOD, Health Canada requested that in order to address the above deficiencies, the sponsor needed to submit the full two-year study report. In response to the NOD, the sponsor submitted the requested information and all of the concerns that led to the NOD were satisfactorily addressed. Based on the data provided, Plegridy was shown to have a positive benefit/risk profile and a Notice of Compliance was issued to Biogen Canada Inc. on August 10, 2015.

Submission Milestones: Plegridy

Submission MilestoneDate
Pre-submission meeting:2013-06-12
Submission filed:2013-07-31
Screening 1
Screening Acceptance Letter issued:2013-09-20
Review 1
Notice of Deficiency (NOD) issued by Director General (safety and efficacy issues):2014-07-17
Response filed:2014-09-08
Screening 2
Screening Acceptance Letter issued:2014-10-14
Review 2
On-Site Evaluation2014-01-13 - 2014-01-17
Quality Evaluation complete:2015-05-21
Clinical Evaluation complete:2015-08-10
Labelling Review complete:2015-08-06
Notice of Compliance issued by Director General:2015-08-10

The Canadian regulatory decision on the non-clinical and clinical review of Plegridy was based on a critical assessment of the Canadian data package. The United States Food and Drug Administration (FDA) and European Medicines Agency (EMA) Quality questions and responses were provided in the submission and were considered during the review.

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?

As part of the marketing authorization for Plegridy, Health Canada requested and the sponsor agreed to several commitments to be addressed post-market. In addition to requirements outlined in the Food and Drugs Act and Regulations, commitments include (but are not limited to):

  • To submit to Health Canada Development Safety Update Reports (DSURs) (including hepatic injury, depression and suicide, hypersensitivity reactions, blood disorders, cardiovascular events, etc.) that occurred in all clinical trials with Plegridy.
  • To provide Health Canada with all reports/correspondence that impact (add, modify or delete) post-approval commitments, from major Regulatory Authorities [for example, the United States Food and Drug Administration (FDA), the European Medicines Agency (EMA), etc.].
  • To provide Health Canada with an updated Canadian Risk Management Plan (RMP) to reflect the Canadian labelling and to capture the post-approval commitments to Health Canada and other regulatory agencies.
  • To provide Health Canada with Periodic Safety Update Reports (PSURs)/Periodic Benefit Risk Evaluation Reports (PBRER) for Plegridy on a yearly basis. Include in each PSUR/ PBRER an analysis of all Adverse Drug Events as per the Pharmacovigilance Plan and safety updates from all ongoing clinical trials with Plegridy.
  • To provide Health Canada with regular safety updates from the Pregnancy Registry (postmarketing observational study) committed to the FDA. This should be indicated in the updated RMP requested above.

5 What post-authorization activity has taken place for Plegridy?

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 decision was negative or positive. The PAAT will continue to be updated during the product's lifecycle.

The PAAT for Plegridy 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

Multiple Sclerosis (MS) is a long-term illness that affects the central nervous system including the brain and spinal cord. In MS, the body's immune system damages the protective covering (myelin) that surrounds the nerves in the brain and spinal cord. This disrupts the messages between the brain and other parts of the body causing the symptoms of MS.

A definitive mechanism of action of Plegridy in MS is not known; however, Plegridy seems to work by stopping the body's immune system from damaging myelin. Plegridy binds to the type I interferon receptor on the surface of cells and elicits a cascade of intracellular events leading to the regulation of interferon-responsive gene expression including the up-regulation of anti-inflammatory cytokines [for example (e.g.) interleukin (IL)-4, IL-10, IL-27), down-regulation of pro-inflammatory cytokines (e.g. IL-2, IL-12, interferon gamma (IFN-γ,) tumour necrosis factor alpha (TNF-α), and inhibiting the migration of activated T cells across the blood brain barrier.

The clinical pharmacology included reports on the human pharmacodynamic and pharmacokinetic studies. The clinical pharmacological data support the use of Plegridy for the specified indication.

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

Clinical Efficacy

The clinical efficacy of Plegridy was supported by a single Phase III, two-year, pivotal study. The study included a one-year placebo-controlled treatment period, followed by a second year of treatment during which all patients received Plegridy. The primary endpoint of the study was to determine whether at Year 1, Plegridy as compared with placebo, was effective in reducing the annualized relapse rate (ARR). Secondary endpoints included the reduction of the total number of new or newly enlarging T2 hyperintense lesions based on brain magnetic resonance imaging (MRI) scans, as well a slowing of the progression of disability, as measured using the Kurtze Expanded Disability Status Scale (EDSS - a scale that measures the degree of disability in patients with MS with 0 being a normal neurological exam; 5 being ambulatory without aid for about 200 metres and disability that impairs full daily activities; and 10 being death due to MS).

The mean age of the study population was 37 (18-61) years, the mean disease duration was 3.6 (0-40) years and the mean EDSS at baseline was 2.46 (0.0-5.5). The majority of the patients were female (71%). There were 171 (11%) patients aged 50 years and over in the study.

The pivotal study explored a single dose of Plegridy (125 µg) administered subcutaneously with two dosing frequencies (dosing every 2 or 4 weeks) as compared to placebo. Based on the results of the study, the dose regimen of 125 µg [subcutaneous (SC)] every 2 weeks (Q2W) was proposed by the sponsor.

The study enrolled patients with active disease who had experienced at least two relapses within the prior three years including at least one in the year prior to randomization. Patients had an EDSS score ranging from 0 to 5. Prior treatment with interferons could not exceed 4 weeks and patients must have discontinued interferon treatment 6 months prior to baseline. Neurological evaluations were performed at baseline, every 12 weeks, and at the time of a suspected relapse. Brain MRI evaluations were performed at baseline, and at Weeks 24 and 48. At the time of filing, the sponsor submitted completed Year 1 results and interim analyses for Year 2.

Of the 1,332/1,512 (88%) patients who completed Year 1, all patients received at least one dose of study treatment during Year 2. The 456 patients in the placebo group who completed Year 1 were re-randomized to the Plegridy treatment groups with 228 patients randomized into the Plegridy every 4 weeks (Q4W) group and 228 patients randomized into the Plegridy Q2W group. Patients who were in Plegridy treatment groups in Year 1 continued in the same treatment group in Year 2.

By the end of Year 1, the adjusted ARR was 0.397 [95% Confidence Interval (CI): 0.328, 0.481) in the placebo group, compared with 0.256 (95% CI: 0.206, 0.318) in the Plegridy every 2 weeks (Q2W) group. The rate ratio obtained from the negative binomial regression model was 0.644 (p = 0.0007) for Plegridy Q2W versus (vs.) placebo. This indicated that the ARR at Year 1 was significantly reduced by 35.6% following treatment with Plegridy Q2W, compared with placebo; however, given that 82% of the Plegridy-treated patients had no exacerbations, compared to 72% of placebo patients, the numerical difference of 10% in the proportion of patients who had no exacerbations in this patient population was considered small as well as clinically modest.

The main concerns with the initial submission included the lack of a direct comparator in the pivotal study and difficulties of external validation against other MS trials. As a result, no conclusions could be made on the comparable efficacy and safety profile of Plegridy with currently approved first-line injectable therapies including Avonex. As for the stand-alone therapeutic product, due to the very low proportion of patients with events of interest for both the Plegridy and placebo groups at Year 1, as well as the lack of statistical robustness of the EDSS data at year 1, the data were considered insufficient to allow an adequate assessment of the clinical applicability of Plegridy in reducing the frequency of clinical exacerbations and delaying the accumulation of disability. In order to address these deficiencies as well as others identified with other areas of the review, Health Canada suggested that the full two-year study report be submitted and a Notice of Deficiency (NOD) was issued.

In addition, concerns regarding the handling of missing data for the secondary endpoint of new or newly enlarging T2 lesions needed to be further evaluated. Overall, the handling of withdrawals and missing data needed to be closely examined with the two-year data given that the proportion of patients who either withdrew or had missing data was expected to be higher at Year 2. Finally, given that no active control was included in the Phase III study, an external validation of the study results was required in order to ensure that Plegridy provides the clinical benefits expected from approved interferon beta (IFNβ) therapies. Such an external validation is best performed using two-year data.

In the sponsor's NOD response, efficacy analyses over 2 years were provided using the intent-to-treat (ITT) population based on three treatment groups according to the original randomized treatment: Plegridy Q4W, Plegridy Q2W, and placebo. This approach allowed a valid comparison to demonstrate the continued effects of Plegridy on the efficacy endpoints. Of the 1,332 patients who entered Year 2, 1,198 (90%) completed Year 2 study treatment.

The ARR over 2 years based on the ITT population [Number of patients (n) = 512)] for patients in the Plegridy Q2W group was 0.221, and the estimated proportion of patients with disability progression confirmed at 12 weeks was 11.2%.

Results from the second year of the study provided evidence that the efficacy of Plegridy was maintained over 2 years, especially for the Plegridy Q2W dose group. Compared with Year 1, patients who received Plegridy in both years showed sustained or improved ARRs and number of T2 lesions during Year 2. Even though the comparison was made using the group of patients originally randomized to placebo for the first year and dosed with Plegridy in the second year (since placebo was not used during the second year), Plegridy Q2W continued to demonstrate a positive effect on relapse rates, disability progression, and MRI endpoints compared to patients who received placebo in Year 1 and Plegridy in Year 2.

Overall Analysis of Efficacy

The assessment of the two-year data with additional statistical analyses as requested by Health Canada revealed that the statistically significant efficacy results for the key endpoints of ARR, number of new or newly enlarging T2 hyperintense lesions, and the proportion of patients relapsed and progression of disability as measured by EDSS obtained at Year 1 and submitted in the original New Drug Submission (NDS) were supported by the results over 2 years presented in the response to the NOD. In addition, further issues raised by Health Canada were addressed and additional analyses were provided. External validation of the study results against other MS trials was considered less critical given that results from the placebo-controlled phase of the study (Year 1) were statistically significant for the primary and key secondary endpoints. More importantly, the Year 1 results were supported by results over 2 years based on ITT analyses that preserve the original randomization.

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

Clinical Safety

The clinical safety of Plegridy was evaluated in the pivotal clinical study described in the Clinical Efficacy section.

The most common adverse drug reactions for Plegridy 125 µg Q2W were injection site erythema, influenza-like illness, pyrexia, headache, myalgia, chills, injection site pain, asthenia, injection site pruritus, and arthralgia. Multiple sclerosis relapse was the most frequent serious adverse event (SAE) with 7% of patients in the Plegridy Q2W group experiencing at least one SAE vs. 11% in the placebo group. The most commonly reported adverse event (AE) leading to discontinuation in patients treated with Plegridy 125 µg Q2W was influenza-like illness (<1%).

The incidence of serious adverse events (SAEs) observed in Year 2 for placebo patients who started Plegridy treatment in Year 2 was 19% and 16% in the Q4W and Q2W groups, respectively. For patients who continued treatment with Plegridy from Year 1, the incidence of SAE was 15% and 9% in the Q4W and Q2W groups, respectively. The overall percentage of patients discontinuing study treatment and withdrawing from study due to an AE was low and balanced between the Plegridy dose frequency groups in Year 1 (5% each), with similar findings for Year 2 and cumulatively over 2 years.

Influenza-like illness was experienced by 47% of patients receiving Plegridy 125 µg Q2W and 13% of patients receiving placebo. The incidence of flu-like symptoms [for example (e.g.) influenza-like illness, chills, hyperpyrexia, musculoskeletal pain, myalgia, pain, pyrexia] was highest during the initiation of treatment and generally decreased over the first 6 months. Of the patients who reported flu-like symptoms 90% reported them as mild or moderate in severity. None were considered serious in nature. Less than 1% of patients who received Plegridy during the placebo-controlled phase of the study discontinued treatment due to flu-like symptoms.

Injection site reactions (e.g. injection site erythema, pain, pruritus, or oedema) were reported by 66% of patients who received Plegridy 125 µg Q2W compared to 11% of patients receiving placebo. Injection site erythema was the most commonly reported injection site reaction. Of the patients who experienced injection site reactions 95% reported them as mild or moderate in severity. One patient out of 1,468 patients who received Plegridy in clinical studies experienced an injection site necrosis which resolved with standard medical treatment.

The incidence of hepatic transaminase increases was greater in patients receiving Plegridy compared to placebo. The majority of enzyme elevations were <3 times the upper limit of normal (ULN). Elevations of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) (>5 times ULN), were reported in 1% and <1% of placebo-treated patients and 2% and <1% of patients treated with Plegridy, respectively. Elevations of serum hepatic transaminases combined with elevated bilirubin were observed in two patients who had pre-existing liver test abnormalities prior to receiving Plegridy in the clinical trials. Both cases resolved following discontinuation of Plegridy.

Decreases in white blood cell counts of <3.0 × 109/L were observed in 7% of patients receiving Plegridy and in 1% receiving placebo. Mean white blood cell counts remained within normal limits in patients treated with Plegridy. Decreases in white blood cell counts were not associated with an increased risk of infections or serious infections. The incidence of potentially clinically significant decreases in lymphocyte counts (<0.5 × 109/L) (<1%), neutrophil (≤1.0 × 109/L) (<1%) counts, platelet counts (≤100 × 109/L) (≤1%) was similar in Plegridy-treated patients compared to placebo-treated patients. Two serious cases were reported in patients treated with Plegridy: one patient (<1%) experienced severe thrombocytopenia (platelet count <10 × 109/L), another patient (<1%) experienced severe neutropenia (neutrophil count <0.5 × 109/L). In both patients, cell counts recovered after discontinuation of Plegridy. Compared to placebo, there were no significant differences observed in red blood cell counts in Plegridy treated patients.

Based on the known safety profile of the IFNβ therapy class, several areas of interest were analyzed in more depth to better assess any potential effects of Plegridy. These areas of interest included flu-like symptoms, injection site reactions, infections, cardiovascular disorders, hepatic disorders, autoimmune disorders, malignancy, seizures, depression and suicidal ideations, and hypersensitivity events. No treatment or dose-related trends were observed in the incidence of infections, serious infections or opportunistic infections. Plegridy treatment did not appear to increase the risk of cardiovascular, hypersensitivity, seizure events, depression and suicidal ideations, or autoimmune disorders. The incidence and type of malignancies observed in Plegridy-treated patients is consistent with that expected in the general MS population.

Reductions in hematology parameters and increases in liver enzymes are known side effects of IFNβ therapies. Data from this study demonstrated that Plegridy has a profile consistent with that of other IFNβ therapies. In this study, there was a dose-dependent effect on the proportion of patients with shifts to low in white blood cells (WBC), absolute neutrophil count (ANC), and platelets, and a dose-dependent effect on the proportion of patients with shifts to high in alanine transaminase (ALT)/aspartate transaminase (AST) levels in Year 1, Year 2, and over 2 years cumulatively; however, the majority of these shift changes were not clinically significant and did not result in discontinuation of the study treatment. There were no clinically meaningful changes from baseline in other laboratory assessments, including electrocardiogram (ECG), between the placebo and the Plegridy dose frequency groups.

The overall immunogenicity to Plegridy over two years was low and comparable to Year 1.

Overall, safety data from the 1,512 subjects who received at least 1 dose of study treatment (placebo or Plegridy treatment) over a 2-year study period demonstrated that Plegridy administered Q2W and Q4W was generally well-tolerated, with no significant differences in the safety profile between Plegridy dose frequency groups.

The safety profile over two years did not indicate any new safety finding of significant concern. There was no increase in the mortality rate, no increase in the risk of SAEs, and no increase in the risk of infection.

Overall, the safety profile of Plegridy is comparable to Avonex, with the exception of the rate of injection site reactions (66% vs. 3%); however, considering the different routes of administration (subcutaneous vs. intramuscular for Plegridy and Avonex, respectively), such a difference is not unexpected.

Appropriate warnings and precautions are in place in the approved Plegridy Product Monograph to address the identified safety concerns.

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

7.2 Non-Clinical Basis for Decision

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

The Sponsor's rationale and responses to deficiency comments regarding non-clinical studies for the NOD of the submission have been reviewed and judged acceptable. Some uncertainties regarding the long-term safety (e.g. repeat-dose toxicity) remain unresolved due to immunogenicity and the lack of relevant animal species models. The main concerns noted from the animal studies are: menstrual irregularities, anovulation, abortifacient effects and decreased serum progesterone levels.

Appropriate warnings and precautionary measures are in place in the Plegridy Product Monograph to address the identified safety concerns.

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

7.3 Quality Basis for Decision

Plegridy is a pegylated form of recombinant interferon beta-1a (IFNβ-1a) which is intended for the treatment of patients with relapsing multiple sclerosis. Currently available first‑line IFNβ therapies require frequent dosing (3-4 times/week) when injected subcutaneously. Plegridy or peginterferon β-1a consists of an IFNβ-1a molecule modified with a polyethylene glycol molecule. The addition of this latter molecule reduces the clearance rate of the interferon from the body without altering its biological activity.

Characterization of the Drug Substance

Extensive characterization of peginterferon β-1a was performed that confirmed its physicochemical properties and its biological activity.

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

The drug substance, peginterferon β-1a, is manufactured using a serum-free cell culture process consisting in the Working Cell Bank thaw, inoculum preparation, expansion into seed bioreactors and production within a 2,000 L bioreactor. Subsequent operations include clarification of the cell culture fluid and purification of interferon β‑1a. Purified interferon β‑1a is then pegylated, further purified and the resulting drug substance formulated into a pH 4.8 buffer. The manufacturing process was validated at commercial‑scale.

The drug product, Plegridy, is a sterile liquid formulation available in three strengths 63 µg, 94 µg, and 125 µg. Each strength is filled in a nominal volume of 0.5 mL in pre-filled syringes or pre-filled pens.

Plegridy is manufactured by first diluting peginterferon β-1a drug substance with formulation buffer. After dilution, sterile filtration and fill/finish operations are performed. All pre-filled syringes operations were validated at commercial-scale.

The manufacturing process for the pen consists of the assembly of the pen's components around the pre-filled syringe presentation. This process was validated using both the high and low capacity assembly equipment.

The method of manufacturing and the controls used during the manufacturing process for both the drug substance and drug product are valid and considered to be adequately controlled within justified limits.

Control of the Drug Substance and Drug Product

Drug substance and drug product release specifications include tests for identity, purity, potency and safety. Established test specifications and validated analytical test methods are considered acceptable.

Specifications intended for the Canadian market were harmonized with those agreed upon with the United States Food and Drug Administration (FDA) and European Medicines Agency (EMA). The sponsor also provided a commitment to re-evaluate the drug substance specifications following the manufacture of 30 lots or within 3 years whichever is sooner. The same commitment was provided for the drug product where specifications will be re‑evaluated once the drug product lots are manufactured from the 30 drug substance lots or within 3 years whichever is sooner.

Through Health Canada's lot release testing and evaluation program, consecutively manufactured final product lots were tested, evaluated, and found to meet the specifications of the drug product and demonstrate consistency in manufacturing.

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 36‑ month shelf-life at 2‑8°C for the drug product Plegridy is considered acceptable.

The proposed packaging and components are considered acceptable.

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.

An On-Site Evaluation (OSE) of the facility involved in the manufacture of the drug substance has been successfully conducted by the Biologics and Genetic Therapies Directorate, Health Canada.

An OSE of the facility involved in the manufacture of the drug product was not warranted since the facility was recently evaluated and obtained a satisfactory rating.

Adventitious Agents Safety Evaluation

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

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