Business Subjects). All accounting work experience must be reported in months and years. TSBPA FORM X0004. (Rev. 6/2020). Page 1 of 1.
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District Code District Discription Yrs Levied Start Date X0004 White
X0004. White Pines Street Lighting ongoing. X0012. Refuse Collection ongoing. X0066. Pardee Lake Weed Control. 5 yrs. 2021. X0086. Grand Beach Weed Control.
The IRBT X004 from ABB is the only track motion platform on the market to guarantee high speed precision accuracy
IRBT X Datasheet US Letter
27 févr. 2020 EMEA/H/C/004648/X/0004. Note. Assessment report as adopted by the CHMP with all information of a commercially confidential nature deleted.
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28 févr. 2019 EMEA/H/C/004390/X/0004/G. Note. Assessment report as adopted by the CHMP with all information of a commercially confidential nature deleted.
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30 juin 2021 X0004-0096. 01 January 2020. 31 December 2020. EUR. 0.4414. 30 June 2021. Yes. 0.0000. N/A. Xtrackers SICAV. Xtrackers MSCI Europe UCITS ETF.
Reporting Funds Xtrackers
29 oct. 2015 Avant-propos ........................................................................................................................... 4.
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Outstanding speed and accuracy. As first on the market ABB's track motions and its respective robot is a seven-axis dynamic model. ABB's unique Quick-.
PR EN R IRBT X trackmotion
13 mai 2018 The Maps and Surveys Office requires a minimum of at least 24 hours advance notice to make arrangements for pick up of the brass disc survey ...
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20 sept. 2012 ACC. American College of Cardiology. ACS acute coronary syndrome. ADR adverse drug reaction. AE adverse event. AF atrial fibrillation.
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210405
28 February 2019
EMA/188111/2019
Committee for Medicinal Products for Human Use (CHMP)
CHMP assessment report on extension of marketing
authorisation and an extension of indication variation
Dupixent
International non-proprietary name: dupilumab
Procedure No. EMEA/H/C/004390/X/0004/G
Note Assessment report as adopted by the CHMP with all information of a commercially confidential nature deleted.
30 Churchill Place
ł Canary Wharf ł London E14 5EU ł United Kingdom
An agency of the European Union
Telephone +44 (0)20 3660 6000 Facsimile +44 (0)20 3660 5520 Send a question via our website www.ema.europa.eu/contact
Table of contents
1. Background information on the procedure .............................................. 6
1.1. Submission of the dossier ..................................................................................... 6
1.2. Steps taken for the assessment of the product ........................................................ 7
2. Scientific discussion ................................................................................ 8
2.1. Problem statement ............................................................................................... 8
2.1.1. Epidemiology .................................................................................................... 8
2.1.2. Biologic features, Aetiology and pathogenesis ....................................................... 9
2.1.3. Clinical presentation .......................................................................................... 9
2.1.4. Management ................................................................................................... 10
2.2. Quality aspects .................................................................................................. 12
2.2.1. Introduction.................................................................................................... 12
2.2.2. Active Substance ............................................................................................. 12
2.2.3. Finished Medicinal Product ................................................................................ 16
2.2.4. Discussion on chemical,
pharmaceutical and biological aspects.............................. 20
2.2.5. Conclusions on the chemical, pharmaceutical and biological aspects ...................... 21
2.2.6. Recommendation(s) for future quality development ............................................. 21
2.3. Non-clinical aspects ............................................................................................ 22
2.3.1. Introduction.................................................................................................... 22
2.3.2. The applicant submitted some non clinical data supporting the asthma indication as outlined
below. No new pharmacokinetic and toxicology data were submitted in this application as they were submitted with the original atopic dermatitis application . . Pharmacology................ 22
2.3.3. Pharmacokinetics ............................................................................................ 23
2.3.4. Toxicology ...................................................................................................... 24
2.3.5. Ecotoxicity/environmental risk assessment ......................................................... 26
2.3.6. Discussion on non
-clinical aspects ..................................................................... 26
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 .......................................................................................... 34
2.4.4. Discussion on clinical pharmacology ................................................................... 36
2.4.5. Conclusions on clinical pharmacology ................................................................. 38
2.5. Clinical efficacy .................................................................................................. 39
2.5.1. Dose response study........................................................................................ 40
2.5.2. Main studies ................................................................................................... 49
2.5.3. Supportive studies ......................................................................................... 101
2.5.4. Discussion on clinical efficacy .......................................................................... 104
2.5.5. Conclusions on clinical efficacy ........................................................................ 110
2.6. Clinical safety .................................................................................................. 111
EMA/188111/2019 Page 2/161
2.6.1. Discussion on clinical safety ............................................................................ 142
2.6.2. Conclusions on clinical safety .......................................................................... 146
2.7. Risk Management Plan ...................................................................................... 146
2.8. Pharmacovigilance ........................................................................................... 150
2.9. Product information .......................................................................................... 150
2.9.1. User consultation .......................................................................................... 150
2.9.2. Additional monitoring ..................................................................................... 151
3. Benefit-Risk Balance ........................................................................... 151
3.1. Therapeutic Context ......................................................................................... 151
3.1.1. Disease or condition ...................................................................................... 151
3.1.1. Available therapies and unmet medical need ..................................................... 151
3.1.2. Main clinical studies ....................................................................................... 152
3.2. Favourable effects ............................................................................................ 152
3.3. Uncertainties and limitations about favourable effects ........................................... 153
3.4. Unfavourable effects ......................................................................................... 154
3.5. Effects Table .................................................................................................... 156
3.6. Benefit-risk assessment and discussion ............................................................... 158
3.6.1. Importance of favourable and unfavourable effects ............................................ 158
28 February 2019
EMA/188111/2019
Committee for Medicinal Products for Human Use (CHMP)
CHMP assessment report on extension of marketing
authorisation and an extension of indication variation
Dupixent
International non-proprietary name: dupilumab
Procedure No. EMEA/H/C/004390/X/0004/G
Note Assessment report as adopted by the CHMP with all information of a commercially confidential nature deleted.
30 Churchill Place
ł Canary Wharf ł London E14 5EU ł United Kingdom
An agency of the European Union
Telephone +44 (0)20 3660 6000 Facsimile +44 (0)20 3660 5520 Send a question via our website www.ema.europa.eu/contact
Table of contents
1. Background information on the procedure .............................................. 6
1.1. Submission of the dossier ..................................................................................... 6
1.2. Steps taken for the assessment of the product ........................................................ 7
2. Scientific discussion ................................................................................ 8
2.1. Problem statement ............................................................................................... 8
2.1.1. Epidemiology .................................................................................................... 8
2.1.2. Biologic features, Aetiology and pathogenesis ....................................................... 9
2.1.3. Clinical presentation .......................................................................................... 9
2.1.4. Management ................................................................................................... 10
2.2. Quality aspects .................................................................................................. 12
2.2.1. Introduction.................................................................................................... 12
2.2.2. Active Substance ............................................................................................. 12
2.2.3. Finished Medicinal Product ................................................................................ 16
2.2.4. Discussion on chemical,
pharmaceutical and biological aspects.............................. 20
2.2.5. Conclusions on the chemical, pharmaceutical and biological aspects ...................... 21
2.2.6. Recommendation(s) for future quality development ............................................. 21
2.3. Non-clinical aspects ............................................................................................ 22
2.3.1. Introduction.................................................................................................... 22
2.3.2. The applicant submitted some non clinical data supporting the asthma indication as outlined
below. No new pharmacokinetic and toxicology data were submitted in this application as they were submitted with the original atopic dermatitis application . . Pharmacology................ 22
2.3.3. Pharmacokinetics ............................................................................................ 23
2.3.4. Toxicology ...................................................................................................... 24
2.3.5. Ecotoxicity/environmental risk assessment ......................................................... 26
2.3.6. Discussion on non
-clinical aspects ..................................................................... 26
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 .......................................................................................... 34
2.4.4. Discussion on clinical pharmacology ................................................................... 36
2.4.5. Conclusions on clinical pharmacology ................................................................. 38
2.5. Clinical efficacy .................................................................................................. 39
2.5.1. Dose response study........................................................................................ 40
2.5.2. Main studies ................................................................................................... 49
2.5.3. Supportive studies ......................................................................................... 101
2.5.4. Discussion on clinical efficacy .......................................................................... 104
2.5.5. Conclusions on clinical efficacy ........................................................................ 110
2.6. Clinical safety .................................................................................................. 111
EMA/188111/2019 Page 2/161
2.6.1. Discussion on clinical safety ............................................................................ 142
2.6.2. Conclusions on clinical safety .......................................................................... 146
2.7. Risk Management Plan ...................................................................................... 146
2.8. Pharmacovigilance ........................................................................................... 150
2.9. Product information .......................................................................................... 150
2.9.1. User consultation .......................................................................................... 150
2.9.2. Additional monitoring ..................................................................................... 151
3. Benefit-Risk Balance ........................................................................... 151
3.1. Therapeutic Context ......................................................................................... 151
3.1.1. Disease or condition ...................................................................................... 151
3.1.1. Available therapies and unmet medical need ..................................................... 151
3.1.2. Main clinical studies ....................................................................................... 152
3.2. Favourable effects ............................................................................................ 152
3.3. Uncertainties and limitations about favourable effects ........................................... 153
3.4. Unfavourable effects ......................................................................................... 154
3.5. Effects Table .................................................................................................... 156
3.6. Benefit-risk assessment and discussion ............................................................... 158
3.6.1. Importance of favourable and unfavourable effects ............................................ 158