`
`
`26 November 2013
`EMA/800904/2013 Corr. 1
`Committee for Medicinal Products for Human Use (CHMP)
`
`
`Assessment report
`
`
`Tecfidera
`
`Common Name: dimethyl fumarate
`
`
`
`Procedure No. EMEA/H/C/002601/0000/Rev 1
`
`
`Note
`Assessment report as adopted by the CHMP with all information of a commercially confidential
`nature deleted.
`
`
`
` 7
`
` Westferry Circus ● Canary Wharf ● London E14 4HB ● United Kingdom
`Telephone +44 (0)20 7418 8400 Facsimile +44 (0)20 7523 7455
`E-mail info@ema.europa.eu Website www.ema.europa.eu
`
`
`
`
`
`An agency of the European Union
`
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`Table of contents
`
`1. Background information on the procedure .............................................. 9
`1.1. Submission of the dossier ..................................................................................... 9
`1.2. Manufacturers ................................................................................................... 10
`1.3. Steps taken for the assessment of the product ...................................................... 10
`2. Scientific discussion .............................................................................. 12
`2.1. Introduction ...................................................................................................... 12
`2.2. Quality aspects .................................................................................................. 13
`2.2.1. Introduction ................................................................................................... 13
`2.2.2. Active substance ............................................................................................ 13
`2.2.3
` Finished Medicinal Product .............................................................................. 14
`2.2.3. Discussion on chemical, pharmaceutical and biological aspects ............................. 16
`2.2.4. Conclusions on the chemical, pharmaceutical and biological aspects ...................... 17
`2.2.5. Recommendation(s) for future quality development ............................................. 17
`2.3. Non-clinical aspects ............................................................................................ 17
`2.3.1. Introduction ................................................................................................... 17
`2.3.2. Pharmacology ................................................................................................. 17
`2.3.3. Pharmacokinetics ............................................................................................ 19
`2.3.4. Toxicology ...................................................................................................... 20
`2.3.5. Ecotoxicity/environmental risk assessment ......................................................... 25
`2.3.6. Discussion on non-clinical aspects ..................................................................... 25
`2.3.7. Conclusion on the non-clinical aspects ............................................................... 27
`2.4. Clinical aspects .................................................................................................. 27
`2.4.1. Introduction ................................................................................................... 27
`2.4.2. Pharmacokinetics ............................................................................................ 28
`2.4.3. Pharmacodynamics .......................................................................................... 30
`2.4.4. Discussion on clinical pharmacology .................................................................. 31
`2.4.5. Conclusions on clinical pharmacology ................................................................. 33
`2.5. Clinical efficacy .................................................................................................. 33
`2.5.1. Dose response study ....................................................................................... 33
`2.5.2. Main studies ................................................................................................... 35
`2.5.3. Discussion on clinical efficacy............................................................................ 78
`2.5.4. Conclusions on the clinical efficacy .................................................................... 82
`2.6. Clinical safety .................................................................................................... 82
`2.6.1. Patient exposure ............................................................................................. 82
`2.6.2. Adverse events ............................................................................................... 82
`2.6.3. Serious adverse event/deaths/other significant events ......................................... 86
`2.6.4. Laboratory findings.......................................................................................... 87
`2.6.5. Safety in special populations ............................................................................. 90
`2.6.6. Safety related to drug-drug interactions and other interactions ............................. 90
`2.6.7. Discontinuation due to adverse events ............................................................... 91
`2.6.8. Post marketing experience ............................................................................... 91
`2.6.9. Discussion on clinical safety .............................................................................. 91
`2.6.10. Conclusions on the clinical safety ..................................................................... 94
`2.7. Pharmacovigilance ............................................................................................. 94
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`2.8. Risk Management Plan ........................................................................................ 94
`2.9. User consultation ............................................................................................. 109
`2.10. New Active Substance Status ........................................................................... 109
`2.10.1. Quality aspects ........................................................................................... 109
`2.10.2. Non Clinical aspects ..................................................................................... 111
`2.10.3. Clinical Aspects ........................................................................................... 116
`2.10.4. Overall discussion and Conclusions ................................................................ 119
`3. Benefit-Risk Balance ........................................................................... 121
`
`4. Recommendations ............................................................................... 124
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`
`
`List of abbreviations
`
`
`9HPT
`
`AE
`
`AGIS
`
`AKr1b8
`
`ALT
`
`ANOVA
`
`ARR
`
`ASA
`
`AST
`
`ATP
`
`AUC
`
`B2M
`
`BCS
`
`BID
`
`BUN
`
`CEP
`
`CHMP
`
`CI
`
`Cl/F
`
`Cmax
`
`CNS
`
`CREA
`
`CV
`
`CYPs
`
`DMF
`
`Nine-Hole Peg Test
`
`Adverse Event
`
`Acute Gastrointestinal Symptom Scale
`
`Aldo-Keto Reductase Family 1 Member B8
`
`Alanine transaminase/Alanine Aminotransferase
`
`Analysis of Variance
`
`Annualised Relapse Rate
`
`Acetylsalicylic Acid
`
`Aspartate transaminase/Aspartate Aminotransferase
`
`Adenosine Triphosphate
`
`Area Under Curve
`
`Beta-2 Microglobulin
`
`Biopharmaceutics Classification System
`
`Twice Daily
`
`Blood Urea Nitrogen
`
`Certificate of Suitability of the European Pharmacopeia
`
`Committee For Medicinal Products for Human Use
`
`Confidence Interval
`
`Apparent Clearance
`
`Peak Plasma Concentration
`
`Central Nervous System
`
`Creatinine
`
`Cardiovascular
`
`Cytochromes
`
`Dimethyl Fumarate
`
`DMFAE
`
`Dimethylfumaric ester
`
`DMT
`
`DSC
`
`EAE
`
`ECG
`
`EDSS
`
`EE
`
`eGFR
`
`Disease Modifying Therapy
`
`Differential Scanning Calorimetry
`
`Experimental Autoimmune Encephalomyelitis
`
`Electrocardiogram
`
`Expanded Disability Status Scale
`
`Efficacy Evaluable
`
`Estimated Glomerular Filtration Rate
`
`
`
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`
`
`EQ-5D
`
`ERA
`
`ESRD
`
`FA
`
`FACT
`
`FT-IR
`
`GA
`
`GC
`
`Gclc
`
`GCP
`
`Gd
`
`GFSS
`
`GGT
`
`GI
`
`GLP
`
`GSH
`
`h
`
`HbsAg
`
`HDPE
`
`HIV
`
`HO-1
`
`HPLC
`
`HPMC
`
`HR
`
`i.m
`
`i.p
`
`European Quality of Life-5 Dimensions Health Survey
`
`Environmental Risk Assessment
`
`End Stage Renal Disease
`
`Fumaric Acid
`
`Fumaric acid compound therapy
`
`Fourier Transform Infra-Red Spectroscopy
`
`Glatiramer acetate
`
`Gas Chromatography
`
`Glutamate –cysteine ligase catalytic subunit
`
`Good Clinical Practices
`
`Gadolinium
`
`Global Flushing Severity Scale
`
`Gamma Glutamyl Transferase
`
`Gastrointestinal
`
`Good Laboratory Practices
`
`Gluthatione
`
`Hour(s)
`
`Hepatitis B Surface Antigen
`
`High Density Polyethylene
`
`human immunodeficiency virus
`
`Heme Oxygenase-1
`
`High Performance Liquid Chromatography
`
`Hydroxypropyl-methylcellulose
`
`Hazard Ratio
`
`Intramuscular
`
`Intraperitoneal
`
`i.v. or IV
`
`Intravenous
`
`ICH
`
`ILN
`
`INEC
`
`IR
`
`ITT
`
`IVRS
`
`Kim-1
`
`LC/MS
`
`International Conference on Harmonisation
`
`Lymph node
`
`Independent Neurology Evaluation Committee
`
`Infra-Red Spectroscopy
`
`Intention To Treat
`
`centralised interactive voice response system
`
`Kidney Injury Molecule 1
`
`Liquid Chromatography/Mass Spectrometry
`
`
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`
`LD50
`
`LDPE
`
`LFT
`
`LLN
`
`MAH
`
`MEF
`
`Median Lethal Dose
`
`Low Density Polyethylene
`
`Liver Function Test
`
`Lower Limit of Normal
`
`Marketing Authorisation Holder
`
`Monoethyl fumarate
`
`MEFAE
`
`Monoethylfumaric ester
`
`MI
`
`MLN
`
`MMF
`
`MRI
`
`MS
`
`MS
`
`MSFC
`
`MTD
`
`MTR
`
`NA
`
`NABT
`
`NADPH
`
`NAS
`
`NMR
`
`NOAEL
`
`NOEL
`
`NQ01
`
`NrF2
`
`OGISS
`
`Osgin 1
`
`PASAT3
`
`PBT
`
`PGD2
`
`PGE2
`
`PGF2α
`
`P-gp
`
`Ph.Eur.
`
`PIP
`
`Myocardial Infarction
`
`Mesenteric lymph node
`
`Monomethyl Fumarate
`
`Magnetic Resonance Imaging
`
`Multiple Sclerosis
`
`Mass Spectrometry (in Quality part)
`
`Multiple Sclerosis Functional Composite
`
`Maximum dose tolerated
`
`Magnetization Transfer Ratio
`
`Not Applicable
`
`normal appearing brain tissue
`
`Nicotinamide Adenine Dinucleotide Phosphate, Reduce form
`
`New Active Substance Status
`
`Nuclear Magnetic Resonance
`
`No Observed Adverse Effect Level
`
`No Observed Effect Level
`
`NAD(P)H dehydrogenase (quinone 1)
`
`Nuclear factor(erythroid-derived 2)-like 2
`
`Overall Gastrointestinal Symptom Scale
`
`Oxidative stress-induced growth inhibitor 1
`
`3- Second Paced Auditroy Serial Addition Test
`
`Persistent, Bioaccumulative, Toxic
`
`Prostaglandin D2
`
`Prostanglandin E2
`
`Prostanglandin 2 alpha
`
`P-glycoprotein
`
`European Pharmacopeia
`
`Paediatric Investigation Plan
`
`
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`PK
`
`PML
`
`PNM
`
`PP
`
`PPMS
`
`PRAC
`
`PTH
`
`QD
`
`QT
`
`QTc
`
`RA
`
`RH
`
`RMP
`
`RMS
`
`RRMS
`
`s.c
`
`SAE
`
`SAP
`
`SD
`
`SF-36
`
`SGOT
`
`SGPT
`
`SmPC
`
`SOC
`
`SPMS
`
`Srxn 1
`
`t1/2
`
`T25FW
`
`TCA
`
`TGA
`
`TID
`
`Tmax
`
`TNFα
`
`Trxnd1
`
`TSE
`
`Pharmacokinetics
`
`Progressive Multifocal Leukoencephalopathy
`
`Potentially Nephrotoxic Medication
`
`Per Protocol
`
`Primary Progressive Multiple Sclerosis
`
`Pharmacovigilance Risk Assessment Committee
`
`Parathyroid Hormone
`
`Once Daily
`
`Interval between the start of the Q wave and the end of the T wave in the heart’s
`electrical cycle
`
`Corrected QT interval
`
`Rhumatoid Arthritis
`
`Relative Humidity
`
`Risk Management Plan
`
`Relapsing Mutliple Sclerosis
`
`Relapsing Remitting Multiple Sclerosis
`
`Subcutaneous
`
`Serious Adverse Events
`
`Statistical Analysis Plan
`
`Standard Deviation
`
`Short Form 36 Heatlh Survey
`
`Serum glutamic oxaloacetic transaminase
`
`Serum Glutamic Pyruvate Transaminase
`
`Summary of Product Characteristics
`
`System Organ Class
`
`Secondary Progressive Multiple Sclerosis
`
`Thioredoxin reductase 1
`
`Half Life
`
`Time 25-Foot Walk
`
`Tricarboxylic Acid
`
`Thermogravimetric Analysis
`
`Three Times Daily
`
`Time to Peak Plasma Concentration
`
`Tumor Necrosis Factor-alpha
`
`Sulfiredoxin 1
`
`Transmissible Spongiform Encephalopathy
`
`
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`ULN
`
`UV/VIS
`
`VAS
`
`VFT
`
`vs
`
`WBC
`
`WT
`
`XRD
`
`Upper Limit of Normal
`
`Ultra-Violet/Visible Spectroscopy
`
`Visual Analogue Scale
`
`Visual Function Test
`
`Versus
`
`White Blood Cells
`
`Wild Type
`
`X-Ray Diffraction
`
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`1. Background information on the procedure
`
`1.1. Submission of the dossier
`
`The applicant Biogen Idec Ltd submitted on 28 February 2012 an application for Marketing
`Authorisation to the European Medicines Agency (EMA) for Tecfidera, through the centralised
`procedure under Article 3 (2)(b) of Regulation (EC) No 726/2004. The eligibility to the centralised
`procedure was agreed upon by the EMA/CHMP on 21 July 2011. The eligibility to the centralised
`procedure under Article 3(2)(b) of Regulation (EC) No 726/2004 was based on demonstration of
`significant therapeutic innovation.
`
`The applicant applied for the following indication:
`
`disease modifying therapy in adult patients with relapsing multiple sclerosis to reduce the
`frequency of relapses and to delay the progression of disability.
`
`The legal basis for this application refers to:
`
`Article 8(3) of Directive No 2001/83/EC
`
`The application submitted is composed of administrative information, complete quality data, non-
`clinical and clinical data based on applicants’ own tests and studies and/or bibliographic literature
`substituting/supporting certain test(s) or study(ies).
`
`Pursuant to Article 7 of Regulation (EC) No 1901/2006, the application included an EMA
`Decision(s) on the agreement of a paediatric investigation plan (PIP).
`
`At the time of submission of the application, the PIP P/76/2011 was not yet completed as some
`measures were deferred.
`
`Information relating to orphan market exclusivity
`
`Similarity
`
`Pursuant to Article 8 of Regulation (EC) No. 141/2000 and Article 3 of Commission Regulation
`(EC) No 847/2000, the applicant did not submit a critical report addressing the possible similarity
`with authorised orphan medicinal products because there is no authorised orphan medicinal
`product for a condition related to the proposed indication.
`
`
`Scientific Advice
`
`The applicant did not seek scientific advice at the CHMP.
`
`Licensing status
`
`A new application was filed in the following countries: USA, Switzerland.
`
`The product was not licensed in any country at the time of submission of the application.
`
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`1.2. Manufacturers
`
`Manufacturer responsible for batch release
`
`Biogen Idec Denmark Manufacturing ApS
`Biogen Idec Allé 1
`DK-3400 Hillerod
`Denmark
`
`1.3. Steps taken for the assessment of the product
`
`The Rapporteur and Co-Rapporteur appointed by the CHMP were:
`
`Rapporteur: Martina Weise
`
`
`
`Co-Rapporteur: Robert James Hemmings
`
`•
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`The application was received by the EMA on 28 February 2012.
`
`The procedure started on 21 March 2012.
`
`The Rapporteur's first Assessment Report was circulated to all CHMP members on 8 June
`2012. The Co-Rapporteur's first Assessment Report was circulated to all CHMP members on
`8 June 2012.
`
`During the meeting on 19 July 2012, the CHMP agreed on the consolidated List of Questions
`to be sent to the applicant. The final consolidated List of Questions was sent to the
`applicant on 20 July 2013.
`
`The applicant submitted the responses to the CHMP consolidated List of Questions on 11
`October 2012.
`
`The Rapporteurs circulated the Joint Assessment Report on the applicant’s responses to the
`List of Questions to all CHMP members on 23 November 2012.
`
`During the CHMP meeting on 13 December 2012, the CHMP agreed on a list of outstanding
`issues to be addressed in writing and/or in an oral explanation by the applicant.
`
`The applicant submitted the responses to the CHMP List of Outstanding Issues on 21
`January 2013.
`
`The Rapporteurs circulated the Joint Assessment Report on the applicant’s responses to the
`List of Questions to all CHMP members on 4 February 2013.
`
`During the PRAC meeting on 7 February 2013, the PRAC agreed on RMP Advice and
`Assessment Overview.
`
`During a meeting of a SAG on 13 February 2013, experts were convened to address
`questions raised by the CHMP.
`
`During the CHMP meeting on 21 February 2013, the CHMP agreed on a second list of
`outstanding issues to be addressed in writing by the applicant.
`
`The applicant submitted the responses to the second CHMP List of Outstanding Issues on
`27 February 2013.
`
`During the PRAC meeting on 7 March 2013, the PRAC agreed on RMP Advice and
`Assessment Overview.
`
`The Rapporteurs circulated the Joint Assessment Report on the applicant’s responses to the
`
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`second List of Outstanding Issues to all CHMP members on 11 March 2013.
`
`During the meeting on 21 March 2013, the CHMP, in the light of the overall data submitted
`and the scientific discussion within the Committee, issued a positive opinion for granting a
`Marketing Authorisation to Tecfidera.
`
`By a letter dated 18 September 2013, the European Commission (EC) requested the CHMP to
`assess if dimethyl fumarate is different from Fumaderm composed of dimethyl fumarate,
`calcium salt of ethyl fumarate, magnesium salt of ethyl hydrogen fumarate and zinc salt of
`ethyl hydrogen fumarate with a view to include an assessment of the new active substance
`(‘NAS’) status of dimethyl fumarate in Tecfidera, as per applicant request.
`
`The applicant’s request for NAS status was received by the EMA on 23 September 2013.
`
`The Rapporteur's Assessment Report on NAS status was circulated to all CHMP members on
`9 October 2013.
`
`The Co-Rapporteur's Assessment Report on NAS status was circulated to all CHMP members
`on 9 October 2013.
`
`The Rapporteurs circulated the Joint Assessment Report to all CHMP members on 18
`October 2013.
`
`During the CHMP meeting on 24 October 2013, the CHMP agreed on the consolidated List of
`Questions on NAS status to be sent to the applicant. The final consolidated List of Questions
`on NAS status was sent to the applicant on 24 October 2013.
`
`The applicant submitted the responses to the CHMP List of Questions on NAS status on 4
`November 2013.
`
`The Rapporteurs circulated the Joint Assessment Report on the applicant’s responses to the
`List of Questions to all CHMP members on 11 November 2013.
`
`During the meeting on 21 November 2013, the CHMP, in the light of the request from the
`EC, the overall data available and the scientific discussion within the Committee revised its
`initial opinion and considered that dimethyl fumarate is different from Fumaderm composed
`of dimethyl fumarate, calcium salt of ethyl fumarate, magnesium salt of ethyl hydrogen
`fumarate and zinc salt of ethyl hydrogen fumarate. Based on the review of the scientific
`evidence, and in line with clarification provided by the European Commission that:
`
`i) a new active substance under Directive 2001/83/EC is a chemical substance not previously
`authorised as a medicinal product in the European Union (Annex I to the Notice to applicants
`Volume 2A, Procedures for marketing authorisation, Chapter 1, Marketing authorisations,
`June 2013) and,
`
`ii) dimethyl fumarate is part of the medicinal product Fumaderm authorised in 1994 in Germany,
`but it has not been previously authorised as a medicinal product in the European Union,
`
`the active substance of Tecfidera, dimethyl fumarate, is a new active substance.
`
`•
`
`This assessment report was adopted by written procedure on 26 November 2013.
`
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`2. Scientific discussion
`
`2.1. Introduction
`
`Dimethyl fumarate1 (DMF) is the dimethyl ester of fumaric acid. Both DMF and its primary
`metabolite monomethyl fumarate (MMF) were found to activate the “Nuclear factor (erythroid-
`derived 2) like 2” (Nrf2) transcriptional pathway which is the principle cellular defence system for
`responding to a variety of potentially toxic stimuli, including inflammatory and oxidative stress. By
`activating the Nrf2 pathway, DMF is claimed to reduce inflammatory responses in both peripheral
`and central cells, and promotes cytoprotection of central nervous system cells against toxic
`stressors, demonstrating beneficial effects on pathways known to exacerbate multiple sclerosis
`pathology.
`
`The following indication was initially applied for: disease modifying therapy in adult patients with
`relapsing multiple sclerosis to reduce the frequency of relapses and to delay the progression of
`disability. The proposed posology was a starting dose of 120 mg twice a day. After 7 days, the
`dose is increased to the recommended dose of 240 mg twice a day.
`
`The final recommended indication was: treatment of adult patients with relapsing remitting
`multiple sclerosis.
`
`Multiple sclerosis (MS) is a chronic, progressive, autoimmune, debilitating neurodegenerative
`disorder with multifocal demyelination affecting the brain, optic nerves, and spinal cord and this
`process leads to neurological impairment and severe disability. It is one of the most common
`neurological diseases in young adults and the leading cause of non-traumatic disability in young
`and middle-aged adults. Typically, it begins in the second or third decade of life. In 2008, the
`global incidence was estimated at 2.5 individuals per 100 000 and the global prevalence was
`estimated at 30 individuals per 100 000, with women being at a two times higher likelihood to
`develop MS than men. Regionally, the estimated median prevalence of MS is greatest in Europe
`(80 per 100 000), followed by the Eastern Mediterranean (14.9 per 100 000), the Americas (8.3
`per 100 000), the Western Pacific (5 per 100 000), Southeast Asia (2.8 per 100 000), and Africa
`(0.3 per 100 000).
`
`The classification of MS into 4 distinct clinical categories was suggested by Lublin and Reingold
`shortly after the availability of the first disease-modifying treatments as a means to aid physicians
`in providing care. The following categories were included: relapsing-remitting (RR) MS, with clearly
`defined disease relapses (clinical attacks) with full recovery or with sequelae and residual deficit
`upon recovery, and with periods between relapses characterized by a lack of disease progression;
`secondary–progressive (SP) MS, with continuous neurological decline with or without superimposed
`relapses, that follows an initial period of RR disease; Primary–progressive (PP) MS, characterized
`by a slow worsening from onset, without superimposed relapses; and progressive–relapsing (PR)
`MS, indicating slow worsening from the onset, but with superimposed relapse events as well.
`
`Relapsing forms of MS are the most frequent clinical presentation of the disease. Eighty-two (82)
`to 85 % of all patients present with relapsing-remitting (RR) MS, which is characterised by
`unpredictable acute episodes of neurological dysfunction named relapses, followed by variable
`recovery and periods of clinical stability. Within ten years more than 50% of patients who
`presented with a RR form eventually develop sustained deterioration with or without superimposed
`relapses; this form is called the secondary progressive variety of MS (SPMS).
`
`
`1 Also called BG00012 through the report
`
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`The term relapsing MS (RMS) applies to those patients either with a RRMS form or a SPMS form
`that are suffering relapses. Patients with RMS, in spite of suffering from different MS forms,
`constitute a common target for current treatments.
`
`Currently, most of the available disease modifying therapies for MS are administered
`subcutaneously, intramuscularly or intravenously. These therapies aim to prevent relapses and
`ultimately to diminish the accumulation of disability. Due to their safety profiles (e.g. risk of
`opportunistic infections and secondary malignancies), most of the recently authorised products
`were considered as second line options.
`
`2.2. Quality aspects
`
`2.2.1. Introduction
`
`The finished product is presented as gastro-resistant hard capsule containing 120 mg and 240 mg
`of dimethyl fumarate as active substance. The composition is described in section 6.1. of the
`SmPC.
`
`The product is available in PVC/PE/PVDC-PVC/Alu blisters as described in section 6.5 of the SmPC.
`
`2.2.2. Active substance
`
`Dimethyl fumarate is a white to off-white powder, non-hygroscopic, BCS class 1 (highly soluble and
`highly permeable). The chemical name is Dimethyl (E)-butenedioate and has the following
`structural formula:
`
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`The molecular structure of the dimethyl fumarate has been confirmed by 1H-NMR-, 13C-NMR-,
`UV/VIS- spectroscopy, MS, FT-IR-spectrometry and X-ray powder diffraction. Typical spectra have
`been provided along with a detailed interpretation of signals. Only one crystal form has been
`observed by powder XRD and DSC investigations. Results of DSC/TGA thermograms confirm the
`affinity to sublimation.
`
`Dimethyl fumarate has a non-chiral molecular structure. Polymorphism has not been observed for
`dimethyl fumarate.
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`Manufacture
`
`The active substance is manufactured by two manufacturers. It is synthesized in two main steps
`using commercially available, well defined starting materials.
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`Dimethyl fumarate is synthesized by acid-catalysed esterification reaction (Fischer esterification).
`The manufacturing process of both manufacturers is the same except production scale batch sizes.
`
`Adequate in-process controls are applied during the synthesis. The specifications and control
`methods for intermediate products, starting materials and reagents have been presented.
`
`Specification
`
`The active substance specification includes tests for appearance, identity (FT-IR, HPLC), assay
`(HPLC), impurities (HPLC), sulphate (Ph.Eur.), residual solvents (GC), heavy metals (Ph.Eur.),
`residue on ignition (Ph.Eur.) and particle size (laser diffraction).
`
`Each specification parameter was sufficiently justified. Acceptance criteria for non-compendial tests
`have been set in accordance with batch results and CHMP/ICH guidelines.
`
`Batch analysis data are provided for 36 production scale batches produced with the proposed
`synthetic route, from both manufacturing sites, and the batch analysis data show that the active
`ingredient can be manufactured reproducibly. The results are within the specifications and
`consistent from batch to batch.
`
`Sufficient information is provided on potential impurities and residual solvents. Levels of impurities
`found in the batches of the active substance are low and well below specification limits.
`
`Analytical procedures have been adequately described and appropriately validated.
`
`Stability
`
`Total number of 11 batches of the active substance from both manufacturing sites were put on
`stability testing as per ICH conditions: under long term (25°C/60%RH) and intermediate
`(30°C/65%RH) conditions for up to 60 months, and accelerated (40°C/75%RH) for up to 6
`months.
`
`The following parameters were tested: description, assay and impurities. Particle size does not
`change during storage, as confirmed by a suitable study; therefore, it is not necessary for it to be
`tested routinely in stability studies.
`
`Photostability testing and forced degradation studies were conducted during the development. The
`results provide good information on degradation patterns of the active substance.
`
`The stability results presented are well within specification. Re-test period of 60 months without
`special storage condition is considered justified.
`
`2.2.3 Finished Medicinal Product
`
`Pharmaceutical Development
`
`
`The formulation development has been adequately described. The aim was to develop a delayed-
`release formulation that prevents release of the active ingredient in the gastric environment while
`allowing for rapid release of the active ingredient in the intestine region. Design of the finished
`product formulation was based on the desired gastro-resistant properties and on the physico-
`chemical properties of the active substance, which is highly soluble, independent of pH, and has
`high permeability. No physicochemical characteristics of the active substance were identified as
`critical.
`
`The finished product is developed as 2 mm enteric-coated microtablets in size 0 hard gelatin
`capsules, in strengths 120 mg and 240 mg, respectively. The 120 mg strength capsules have white
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`body with green cap, for the 240 mg strength capsules with green body and green cap are used.
`The capsules are imprinted with company identifiers. The microtablets are composed of immediate
`release tablet core (dimethyl fumarate, crosscarmellose sodium as disintegrant, microcrystalline
`cellulose as diluent and binder, magnesium stearate as lubricant and talc (for 120 mg strength
`only) and colloidal anhydrous silica as glidants), and two layers of coating. All excipients used are
`compendial.
`
`The 120 mg strength product was first developed and was used in the earlier phases of clinical
`development. The 240 mg strength capsule was developed subsequently based on the formulation
`for the 120 mg finished product. The composition of the microtablet cores slightly differs between
`the strengths. A bioequivalence study between the 120 mg and the 240 mg capsules shows
`bioequivalence between the two strengths in fasted state. The difference in excipients amounts has
`no impact on release and dissolution behaviour of the product. Both product strengths showed no
`significant release in 0.1 N HCl after 120 minutes (acid stage). In the buffer stage, percent
`dissolution was determined at the 10, 20, 30, 45, and 60 minute time points and a rapid release
`was observed for both product strengths.
`
`Adventitious agents
`
`
`Gelatine obtained from bovine/limed bone is used in the product. Valid TSE CEPs from the suppliers
`of gelatine used in the capsule manufacture are provided.
`
`Magnesium stearate is of vegetable origin.
`
`Manufacture of the product
`
`
`During the manufacturing process, the excipients and active substance are blended together and
`compressed into microtablets. The microtablets are then coated and finally encapsulated into hard
`gelatin capsules. The capsules are packaged in PVC/PE/PVDC-PVC/Alu blisters. The material of the
`packaging complies with the Ph.Eur. requirements.
`
`Critical quality attributes of the dosage form include friability, assay, content uniformity and
`disintegration in acid solution. All process steps related to these attributes are monitored by
`appropriate in-process controls. However, none of the manufacturing steps is considered critical.
`There are no intermediates in the manufacturing process of the product.
`
`The manufacturing process was successfully validated on all product manufacturing steps, for three
`commercial scale batches per strength. All acceptance criteria have been met during validation,
`providing a high degree of assurance that the process will consistently produce material meeting its
`pre-determined specifications and quality attributes.
`
`Product specification
`
`
`The finished product release specifications include appropriate tests for this kind of dosage form.
`The product is tested for description of the capsule, description of the capsule content,
`identification (HPLC, UV), assay and impurities (HPLC), residual solvent isopropylalcohol (GC),
`uniformity of dosage units (Ph.Eur.), dissolution (Ph.Eur. – acid and buffer stage) and water
`content (Karl Fischer). The active substance is a known inhibitor of mould and bacteria growth.
`This was confirmed by a number of tests during the product development. Therefore, it is
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`acceptable to test microbial purity in the specification of the product only at first 10 commercial
`batches and then introduce skip testing, if microbial growth is not observed.
`
`The acceptance criteria for all specification parameters are justified by batch results and comply
`with CHMP/ICH guidelines. Two impurities/degradation products are specified in the finished
`product. One of them is an