2014-04-11

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Summary Basis of Decision (SBD)

Summary Basis of Decision (SBD) documents provide information related to the original authorization of a product. The SBD for Tecfidera is located below.

Recent Activity for Tecfidera

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 decision was negative or positive. PAATs will be updated regularly with post-authorization activity throughout the product's life cycle.

Post-Authorization Activity Table (PAAT) for Tecfidera

Updated: 2014/04/01

The following table describes post-authorization activity for Tecfidera, a product which contains the medicinal ingredient dimethyl fumarate. 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.

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

Drug Identification Number (DIN):

DIN 02404508 - 120 mg dimethyl fumarate, capsule, oral

DIN 02420201 - 240 mg dimethyl fumarate, capsule, oral

Post-Authorization Activity Table (PAAT)Activity/Submission Type, Control NumberDate SubmittedDecision and DateSummary of ActivitiesSNDS 1653522013/06/11Issued NOC 2014/01/27This SNDS was submitted in order to add a new 240 mg strength of Tecfidera to the already approved 120 mg strength.On review, Health Canada determined that all information and data provided in the submission, including results of comparative in vivo and in vitro studies between the already approved 120 mg strength and the proposed 240 mg strength, were in accordance with the Health Canada Guidance Document: Post-Notice of Compliance Changes: Quality Document and considered acceptable to support the new 240 mg strength.

The information and data submitted in support of the 240 mg strength do not modify the benefit-risk profile of Tecfidera.Drug product (DIN 02404508) market notificationNot applicableDate of first sale: 2013/04/12The manufacturer notified Health Canada of the date of first sale pursuant to C.01.014.3 of the  Food and Drug Regulations.NDS # 1547762012/04/16Issued NOC 2013/04/03Notice of Compliance issued for New Drug Submission.(the most recent activities are listed first)Summary Basis of Decision (SBD) for Tecfidera

Date SBD Issued: 2013/05/27

The following information relates to the original authorization of the new drug submission for Tecfidera.

Dimethyl fumarate
120 mg capsule, oral
Drug Identification Number (DIN): 02404508
Biogen Idec Canada Inc.
New Drug Submission Control Number: 154776

On April 3, 2013, Health Canada issued a Notice of Compliance to Biogen Idec Canada Inc. for the drug product, Tecfidera.

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 Tecfidera is favourable as monotherapy for the treatment of relapsing remitting multiple sclerosis (MS) to reduce the frequency of clinical exacerbations and to delay the progression of disability.

What was approved?

Why was Tecfidera approved?

What steps led to the approval of Tecfidera?

What follow-up measures will the company take?

What post-authorization activity has taken place for Tecfidera?

What other information is available about drugs?

What was the scientific rationale for Health Canada's decision?

1. What was approved?

Tecfidera, a nervous system drug, was authorized as monotherapy for the treatment of relapsing remitting multiple sclerosis (MS) to reduce the frequency of clinical exacerbations and to delay the progression of disability.

The efficacy of Tecfidera in patients with primary progressive MS has not been established.

Tecfidera should only be prescribed by clinicians who are experienced in the diagnosis and management of MS.

Clinical studies of Tecfidera did not include sufficient numbers of patients aged 65 and over to determine whether the safety and efficacy of Tecfidera may differ in elderly patients compared to younger patients. The safety and efficacy of Tecfidera in patients younger than 18 years of age have not been evaluated.

Tecfidera is contraindicated for patients who are hypersensitive to this drug or to any ingredient in the formulation or component of the container. Tecfidera was approved for use under the conditions stated in the Tecfidera Product Monograph taking into consideration the potential risks associated with the administration of this drug product.

Tecfidera (dimethyl fumarate) is presented as a delayed-release capsule (120 mg). In addition to the medicinal ingredient, dimethyl fumarate, the capsule also contains the following non-medicinal ingredients: microcrystalline cellulose; croscarmellose sodium; talc; colloidal silicon dioxide; magnesium stearate; triethyl citrate; methacrylic acid copolymer (type A); methacrylic acid copolymer dispersion; simethicone; sodium lauryl sulfate; and polysorbate 80. The capsule shell contains gelatin, titanium dioxide, FD&C Blue 1, yellow iron oxide, and black iron oxide.

It was recommended that this new drug submission for Tecfidera (dimethyl fumarate) enteric-coated micro-tablets in a hard gelatin capsule, by Biogen Idec Canada Inc., Control Number 154776, not be granted clearance with respect to safety and efficacy for a 240 mg capsule because a comparison of the 120 mg capsule to the 240 mg capsule under fed conditions was not provided.

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

2. Why was Tecfidera approved?

Health Canada considers that the benefit/risk profile of Tecfidera is favourable as monotherapy for the treatment of relapsing remitting multiple sclerosis (RRMS) to reduce the frequency of clinical exacerbations and to delay the progression of disability.

Multiple sclerosis (MS) is a serious and severely debilitating chronic autoimmune and neurodegenerative disease of the central nervous system (CNS) that affects approximately 55,000 to 75,000 Canadians. It is associated with irreversible progression of disability that includes physical and cognitive impairments, fatigue, pain, depression, and bladder dysfunction. Most patients exhibit an initial relapsing-remitting course (RRMS), which is characterized by acute attacks of neurological disability and relapses caused by acute inflammatory lesions in the CNS with full recovery or residual effects. The acute inflammatory lesions in the CNS characterize the autoimmune aspects of the disease, while the accumulated residual effects of the lesions contribute to the neurodegenerative aspects of the disease.

Tecfidera has been shown to be efficacious in the treatment of RRMS. Two Phase III clinical studies provided evidence of reductions in the risk of relapses, as measured by the annualized relapse rate, and the proportion of patients relapsed at 2 years in patients treated with Tecfidera compared to patients that received placebo. One of the studies provided evidence of a reduction in the risk of 12-week confirmed progression of disability with Tecfidera compared to placebo. Both studies provided evidence of reductions in various types of brain lesions evaluated by Magnetic Resonance Imaging (MRI) including, T2 hyperintense lesions (areas of edema, inflammation, demyelination, axonal loss), gadolinium (Gd) enhancing lesions (active lesions), and T1 hypointense lesions (older lesions where there may be tissue damage/loss) with Tecfidera treatment compared to placebo. The available data indicate that Tecfidera reduced effects on outcomes that mainly reflect the inflammatory component of the disease which, over time, contribute to neurodegeneration and accumulation of disability.

The safety data indicated that the adverse event (AE) profile of Tecfidera is characterized mainly by high frequencies of gastrointestinal AEs [for example (e.g.), nausea, vomiting, diarrhea, abdominal pain, upper abdominal pain, dyspepsia, gastroenteritis] and flushing AEs (including flushing, hot flush, warmth, redness, itching, burning sensation). These AEs occurred most frequently during the first month of treatment and usually decreased over time, but for a small percentage of patients these events also occurred after longer treatment durations. Serious gastrointestinal and flushing AEs or gastrointestinal and flushing AEs leading to treatment discontinuation were infrequent.

Other important safety observations included: reductions in white blood cell (WBC) counts (decreased 10%-15% from baseline) and lymphocyte counts (decreased 30% from baseline) for the duration of treatment with no increased incidence of infections or serious infections; asymptomatic increases in hepatic transaminases during the first 6 months of treatment; and a slight increase in the incidence of proteinuria, but no associated increased incidence of other renal AEs. Although the clinical studies did not show major safety concerns with Tecfidera, the potential risks associated with the observed hematological and clinical chemistry abnormalities indicate that precautionary information and recommendations in the labelling to monitor for these abnormalities are warranted.

A Risk Management Plan (RMP) for Tecfidera was submitted by Biogen Idec 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.

At this time, the risk/benefit profile of Tecfidera as monotherapy for the treatment of RRMS is considered favourable when used according to the conditions described in the Tecfidera Product Monograph. Appropriate warnings and precautions are described in the Tecfidera 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 (NOC) 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 Tecfidera?

Submission Milestones: TecfideraSubmission MilestoneDatePre-submission meeting:2012/02/02Submission filed:2012/04/16ScreeningScreening Acceptance Letter issued:2012/04/16ReviewBiopharmaceutics Evaluation complete:2013/01/10Quality Evaluation complete:2013/03/19Clinical Evaluation complete:2013/04/01Labelling Review complete:2013/03/15Notice of Compliance issued by Director General, Therapeutic Products Directorate:2013/04/03For 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 Tecfidera?

Summary Basis of Decision documents (SBDs) for eligible drugs authorized after September 1, 2012 will include post-authorisation 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 Tecfidera 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:

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

See the Notice of Compliance (NOC) Database for a listing of the authorization dates for all drugs that have been issued an NOC since 1994.

See the Drug Product Database (DPD) for the most recent Tecfidera Product Monograph. The DPD contains product-specific information on drugs that have been approved for use in Canada and have been market notified (that is, the company has told Health Canada the product is being marketed).

See the Notice of Compliance with Conditions (NOC/c)-related documents for the latest fact sheets and notices for products which were issued an NOC under the Notice of Compliance with Conditions (NOC/c) Guidance, if applicable. Clicking on a product name links to (as applicable) the Fact Sheet, Qualifying Notice, and Dear Health Care Professional Letter.

See the Patent Register for patents associated with medicinal ingredients, if applicable.

See the Register of Innovative Drugs for a list of drugs that are eligible for data protection under C.08.004.1 of the  Food and Drug Regulations, if applicable.

7. What was the scientific rationale for Health Canada's decision?

Clinical Basis for Decision

Clinical Pharmacology

The mechanism by which Tecfidera (dimethyl fumarate) exerts therapeutic effects in multiple sclerosis (MS) is not known. Dimethyl fumarate and its active metabolite monomethyl fumarate (MMF) have been shown to activate the Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) pathway which is involved in the cellular response to a variety of potentially toxic stimuli, including inflammatory and oxidative stress. Additionally, Tecfidera has demonstrated anti-inflammatory effects which are thought to reduce aberrant immune cell activation, which occurs in auto-immune diseases such as MS.

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

For further details on the clinical pharmacology of Tecfidera, please refer to the Tecfidera Product Monograph, approved by Health Canada and available through the Drug Product Database.

Clinical Efficacy

The safety and efficacy of Tecfidera (dimethyl fumarate) for the treatment of patients with relapsing remitting multiple sclerosis (RRMS) were evaluated in two pivotal, Phase III, randomized, placebo-controlled, clinical studies in which patients were treated for up to 24 months. The two studies (Study 1 and Study 2) were similar to each other and to clinical studies that evaluated other recently approved therapies for RRMS, with respect to inclusion/exclusion criteria and the safety and efficacy endpoints evaluated. Both studies compared two doses of Tecfidera, 240 mg twice a day (BID) and 240 mg three times a day (TID) to placebo. Study 2 also included a reference comparator arm in which patients received open label glatiramer acetate (GA). Because GA was administered as a daily subcutaneous injection and Tecfidera was administered orally, patients receiving GA in Study 2 were not blinded to their treatment, but study personnel were blinded to all study treatments.

Patients were randomized 1:1:1 to placebo, Tecfidera 240 mg BID, and Tecfidera 240 mg TID in Study 1; and 1:1:1:1 to placebo, Tecfidera 240 mg BID, Tecfidera 240 mg TID, and GA in Study 2. Study 1 included approximately 400 patients per treatment arm (Tecfidera BID: n = 410; Tecfidera TID: n = 416; placebo: 408) and Study 2 included approximately 350 patients per treatment arm (Tecfidera BID: n = 359; Tecfidera TID: n = 345; placebo: n = 363; GA: n = 350). In total, approximately 760-770 patients were treated with each dose of Tecfidera. Patients randomized to Tecfidera received a reduced dose (120 mg BID or TID) for the first week, and the full dose (240 mg BID or 240 mg TID) from Week 2 onward.

In both studies, patient demographics were representative of RRMS patients, with the majority being female and the median age being 37-39 years. The majority of patients were Caucasian. Patients met the 2005 revised McDonald criteria for RRMS diagnosis, had documentation of at least 1 relapse in the previous year, and had an Expanded Disability Status Scale (EDSS) score of 0 to 5.5 (5.5 corresponds to being ambulatory without aid or rest for approximately 100 metres; the disability precludes full daily activities). Baseline disease characteristics indicated that the median EDSS was 2.0-2.5 and the median disease duration since diagnosis was 3-4 years. Patients who were treatment naïve and patients who had been treated previously with other therapies (mainly interferon-beta therapies) were included, with the majority being treatment naïve. Most types of co-morbid medical conditions were potential reasons for exclusion from these studies, including the presence of abnormal hepatic transaminase levels, low white blood cell counts, and urinalysis (proteinuria, hematuria, glycosuria) at screening. The most common types of medical conditions reported in medical histories were consistent with conditions expected in an MS population (neurological, genitourinary, musculoskeletal conditions). With the exception of smoking and alcohol consumption, potential risk factors for cardiovascular disease were reported in relatively low percentages of patients.

All of the efficacy endpoints were standard, validated endpoints for assessing the efficacy of MS therapies in clinical trials, including clinical endpoints that assessed effects of treatment on relapses [annualized relapse rate (ARR), proportion of patients relapsed at 2 years], confirmed progression of disability, and magnetic resonance imaging (MRI) endpoints that assessed changes in inflammatory lesion numbers and volume, which are biomarkers for central nervous system (CNS) tissue damage and loss. Flushing is a very common and visible adverse event (AE) with Tecfidera, which potentially could have unblinded treatment assignments. Although procedures were in place in the studies to minimize the potential for study personnel to become unblinded to treatment assignments in patients who experienced flushing AEs, there was no way to avoid patients potentially being unblinded to their treatment if they experienced flushing AEs. Analyses of clinical efficacy endpoint results in patients with and without flushing AEs did not reveal any meaningful impact of these AEs on efficacy outcomes. Overall, there were no meaningful differences between the treatment effects observed with 240 mg BID and 240 mg TID for any of the endpoints in either study, suggesting that there was no additional benefit from the 240 mg TID dose. Therefore, only results for the 240 mg BID dose are described.

In Study 1, the primary endpoint was the proportion of patients relapsed at 2 years. The proportion of patients relapsed was 27% with Tecfidera compared to 46% with placebo, and the corresponding hazard ratio was 0.51 [95% confidence interval (CI) 0.40, 0.66], representing a reduction in the risk of relapse of 49% (p 10% of patients treated with Tecfidera included urinary tract and upper respiratory tract infections, but these AEs were reported at only slightly higher frequencies with Tecfidera compared to placebo. The high frequencies of flushing and gastrointestinal AEs were consistent in the Phase III studies and in the Phase II study in RRMS patients, and were also common in the clinical pharmacology studies in healthy volunteers after single doses. The majority of these AEs were mild to moderate in severity and occurred most frequently during the first month of treatment. Serious flushing or gastrointestinal AEs were reported for

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