natgillin/translations-raw huggingface dataset:
• de forelagte farmakokinetiske data viser, at den systemiske eksponering for fluticason var lavere (67 %) efter inhalation af Iffeza end efter samtidig inhalation af fluticason og formoterol fra inhalationspræparater af monokomponenttypen. 
• In the pharmacokinetic data presented systemic exposure of fluticasone was lower (67%) following Iffeza inhalation than following the concurrent inhalation of fluticasone and formoterol from monoproduct pMDIs.
Fluticasonpropionat er et inhalationsglukokortikosteroid med høj lokal antiinflammatorisk virkning og lavere bivirkningsfrekvens end orale kortikosteroider. 
Fluticasone propionate is an inhaled glucocortosteroid with high local anti-inflammatory activity and a lower incidence of adverse effects than is seen with oral corticosteroids.
Udformningen af de kliniske undersøgelser gjorde det ikke muligt at fastslå ækvivalent inflammationskontrol, da en eventuel forskel mellem to præparater med inhalationskortikosteroid bør bestemmes ud fra forekomsten af eksacerbationer (navnlig svære eksacerbationer). 
The designs of the clinical studies were not appropriate to establish equivalent control of inflammation because in order to distinguish a potential difference between two ICS products, exacerbations (particularly severe exacerbations) are the indicated parameter.
Desuden konstaterede CHMP, at der ikke er krav om at godtgøre den farmakokinetiske eller terapeutiske ækvivalens med et referenceprodukt i denne ansøgning, der er indgivet i overensstemmelse med direktiv 2001/83/EF, artikel 10, litra b), for faste kombinationer - som kræver fuldstændige administrative data og fuldstændige data vedrørende kvalitet samt ikke-kliniske og kliniske data udelukkende for kombinationen. 
Furthermore, the CHMP noted that the need to demonstrate either pharmacokinetic equivalence or therapeutic equivalence to a reference product is not a requirement for this development, which was submitted according to Directive 2001/83/EC, Article 10b fixed combination application - requiring complete administrative and complete quality, non-clinical and clinical data on the combination only; the specific combination of these two well known active substances, fluticasone propionate and formorerol fumarate, is new, and therefore equivalence/therapeutic equivalence does not have to be proven.
Disse data, der er uddraget af de fem 8-12ugers hovedundersøgelser, viser den beskyttende virkning af Iffeza mod eksacerbationer sammenlignet med fluticasonpropionat-monoterapi. 
These data were generated from the five pivotal 8- to 12-week studies and demonstrate the protective benefit of Iffeza against exacerbations compared with fluticasone propionate monotherapy.
Disse endepunkter blev påviseligt drevet af inhalationskortikosteroid og/eller udviste dosisrespons for inhalationskortikosteroid, og de gav alle klart statistisk bevis for, at de inhalationskortikosteroidbetingede virkninger af Iffeza ikke var mindre end de tilsvarende virkninger af fluticasonpropionat + formoterolfumarat. 
These endpoints were demonstrably inhaled cortocosteroid-driven and/or inhaled corticosteroid dose-responsive and all provided rigorous statistical evidence that the inhaled corticosteroid effects of Iffeza were not less than those of fluticasone propionate + formoterol fumarate.
Kombinationen af et inhalationsglukokortikosteroid med en langtidsvirkende, selektiv adrenerg ß2agonist er anerkendt til regelmæssig behandling af voksne og børn med astma, hvor denne kombination er hensigtsmæssig. 
The products are orally inhaled products and the combined therapy of an inhaled glucocorticosteroid and a selective long-acting ß2 adrenergic agonist is well established for use in the regular treatment of adults and children with asthma where the use of such a combination is deemed appropriate.
Disse resultater må ses i sammenhæng med dem, der viser, at de kliniske virkninger af Iffeza er sammenlignelige med de kliniske virkninger af GSK fluticasonpropionat og Novartis formoterolfumarat indgivet samtidigt. 
These findings should be taken together with the results that show that the clinical effects of Iffeza are comparable with the clinical effects of GSK fluticasone propionate and Novartis formoterol fumarate given concomitantly.
Den klart lavere systemiske tilgængelighed af fluticasonpropionat i Iffeza end i GSK fluticasonpropionat-inhalatoren synes ikke at medføre ringere klinisk virkning. 
The apparent lower systemic availability of fluticasone propionate in Iffeza compared with GSK fluticasone propionate pMDI would not appear to result in a lesser clinical effect.
Udvalget fandt desuden, at de konstaterede kortikosteroide virkninger af Iffeza ikke er mindre end af GSK fluticasonpropionat-inhalatoren, og at formoterolfumarat ikke i nævneværdigt omfang ”maskerer” en eventuel nedsat kortikosteroid effekt. 
Committee was also of the opinion that the corticosteroid effects seen with Iffeza are no less than those seen with GSK fluticasone propionate pMDI and that formoterol fumarate does not appreciably “mask” any lesser corticosteroid effect.
Produktet er en inhalationsspray til astmabehandling bestående af en suspension, der findes i tre styrker og administreres gennem en inhalator (pMDI). 
It is intended for use in the management of asthma, formulated as a pressurised inhalation suspension in three strengths, and administered via a pressurised metered dose inhaler (pMDI).
På dette grundlag påberåbte ansøgeren sig, at det var logisk at ekstrapolere resultater vedrørende astmakontrol fra hovedundersøgelsernes til mere langvarig behandling. 
As such the applicant claimed that the asthma control results from the pivotal studies should logically be extrapolated to the longer-term.
Ansøgeren angav nogle eventuelle årsager til sådanne overensstemmelser: De kan være betinget af inhalationsprodukters særlige pulmonale farmakokinetik, idet blodkoncentrationen af inhalationsprodukter (modsat f.eks. tabletter) er et “post-event” (snarere end “pre-event”) surrogat for virkning, og idet sædvanlig farmakokinetisk analyse ikke nødvendigvis beskriver lægemidlets tilstedeværelse på det pulmonale virkningssted. 
The Applicant presented some reasons which could potentially explain such discordance: this could be a function of the deviation of orally inhaled product (OIP) pulmonary PK from standard PK principles, i.e. unlike conventional PK analysis (e.g. for tablets) blood concentrations of OIPs are a “post-event” (rather than “pre-event”) surrogate for efficacy and standard PK analysis does not necessarily define drug residence at the pulmonary site of action.
Forholdet mellem de årlige eksacerbationsrater var 0,98, dvs. meget tæt på 1, for Iffeza 500µg/20µg versus fluticasonpropionat 500µg + formoterolfumarat 24µg, hvilket således tyder på non-inferioritet, som dog ikke er statistisk sikker. 
An annual exacerbation rate ratio of 0.98, i.e. very close to unity for the comparison of Iffeza 500µg/20µg versus fluticasone propionate 500µg + formoterol fumarate 24µg was therefore suggestive of non-inferiority but was not statistically definitive.
På grundlag af den langsigtede prædiktive værdi af FEV1, de konstante FEV1-værdier efter 8-12ugers behandling og det iagttagne mønster af FEV1-dataene i de fem hovedundersøgelser konkluderede CHMP, at der ikke er grund til at forvente, at den langsigtede eksacerbationsrisiko med Iffeza er større end med fluticasonpropionat alene (“optrapningsindikationen”) eller med fluticasonpropionat kombineret med formoterolfumarat “substitutionsindikationen”). 
In conclusion, given the long-term predictive value of FEV1, given the static nature of FEV1 after 8 to 12 weeks of treatment, and given the pattern of the FEV1 data observed in the five pivotal studies, the CHMP considers there to be no reason to anticipate that the long-term exacerbation risk with Iffeza may exceed that with fluticasone propionate alone (the “Step-up” indication) or fluticasone propionate in combination with formoterol fumarate (the “Switch” indication).
CHMP bemærkede, at forskellen i biotilgængelighed mellem Iffeza og GSK fluticasonpropionat i undersøgelse FLT1501 (67 % relativ biotilgængelighed) ligger inden for den variation, der iagttages for samme patient (fra inhalation til inhalation) mellem forskellige batcher af samme produkt og mellem forskellige inhalatorer indeholdende samme aktive stof(fer). 
The CHMP noted that the differences of the magnitude observed between Iffeza and GSK fluticasone propionate in Study FLT1501 (67% relative bioavailability) are within the same range of variance as observed within patients (from inhalation to inhalation), between different batches of the same product and between different inhalers containing the same or more than one of the same active substances and are without adverse clinical consequences, and therefore are likely to be clinically irrelevant.
Desuden tyder uoverensstemmelsen mellem de farmakokinetiske og farmakodynamiske data for Iffeza på, at de farmakokinetiske data ikke afspejler den relative afsætning i lungerne nøjagtigt og ikke er et gyldigt surrogat for klinisk virkning. 
Furthermore, the discordance between the PK and PD data for Iffeza suggests that the PK data do not accurately reflect comparative pulmonary deposition and are not a valid surrogate for clinical effect.
CHMP fandt ikke, at der er behov for kliniske undersøgelser af 6-12 måneders varighed til yderligere belysning af graden af astmakontrol eller fastlæggelse af eksacerbationsraterne med Iffeza sammenlignet med fluticasonpropionat alene eller kombineret med formoterolfumarat. 
The CHMP was of the view that clinical data generated over 6 to 12 months to further elucidate the level of asthma control and to further assess exacerbation rates seen with Iffeza compared with fluticasone propionate administered concomitantly with formoterol fumarate or administered alone, are not required.
Hvad angår “substitutionsbehandling” accepterede CHMP den af ansøgeren fremlagte analyse og var af den opfattelse, at de kliniske virkninger af Iffeza på astmakontrol og eksacerbationsrisiko er sammenlignelige eller identiske med de kliniske virkninger af GSK fluticasonpropionat og Novartis formoterolfumarat givet samtidigt. 
With regard to the “Switch” therapy, the CHMP accepted the discussions presented by the Applicant and was of the view that the clinical effects of Iffeza in respect of asthma control and exacerbation risk are comparable with/similar to the clinical effects of GSK fluticasone propionate and Novartis formoterol fumarate given concomitantly.
Dataene fra ansøgeren viser, at der opnås bedre astmakontrol med Iffeza end med fluticasonpropionatinhalator alene, og at der opnås samme astmakontrol med Iffeza som med fluticasonpropionatinhalator + formoterolfumarat-inhalator. 
Data submitted by the Applicant demonstrated that asthma control with Iffeza is superior to that with fluticasone propionate pMDI alone and that asthma control with Iffeza is similar to that with fluticasone propionate pMDI + formoterol fumarate pMDI.
• Udvalget konkluderede derfor, at benefit/risk-forholdet for Iffeza til de ansøgte indikationer er gunstigt anbefalede CHMP udstedelse af markedsføringstilladelse, for hvilken produktresuméet, etiketteringen og indlægssedlen er uændrede svarende til endelige version, der er fastlagt ved behandlingen i koordinationsgruppen som anført i bilag III for Iffeza og relaterede navne (se bilag I). 
the CHMP has recommended the granting of the marketing authorisation for which the summary of product characteristics, labelling and package leaflet remain as per the final versions achieved during the Coordination group procedure as mentioned in Annex III for Iffeza and associated names (see Annex I).
Den relative steady state-biotilgængelighed af fluticasonpropionat efter administration af Iffeza var 67 % af biotilgængeligheden ved brug af GSK fluticasonpropionat-inhalator. 
The relative bioavailability of fluticasone propionate at steady state was 67% following Iffeza administration compared with GSK fluticasone propionate pMDI.
Disse farmakokinetiske og farmakodynamiske undersøgelser omfattede begge de samme styrker og doseringer af Iffeza, GSK fluticasonpropionatinhalator og Novartis formoterolfumarat-inhalator, og der blev anvendt samme afstandsstykke til alle produkter i de to undersøgelser. 
These PK and PD studies both included the same strengths/doses of Iffeza, GSK fluticasone propionate pMDI and Novartis formoterol fumarate pMDI, and all products in both studies were administered via the same spacing device, so allowing a valid comparison of PK and PD data.
Den indsigende medlemsstat anførte, at der ikke er påvist ækvivalent biotilgængelighed eller inflammationskontrol i de farmakokinetiske og kliniske undersøgelser, eftersom: 
Based on the results of the pharmacokinetic and clinical studies the objecting Member State stated that proof of equivalent bioavailability or control of inflammation is not established because:
En analyse af den årlige eksacerbationsrate i denne undersøgelse gjorde det imidlertid muligt at differentiere virkningerne af højdosis-ICS-LABA - (inhaleret kortikosteroid + langtidsvirkende β2-agonist) (Iffeza 500µg/20µg og fluticasonpropionat 500µg + formoterolfumarat 24µg) - fra lavdosis-ICS-LABA (fluticasonpropionat 100µg/10µg) og fra fluticasonpropionat 500µg som monoterapi. 
However, an analysis of annualised exacerbation rates in this study was able to differentiate the effects of high dose ICS-LABA (inhaled corticosteroid - long-acting β2 agonist) treatments (Iffeza 500µg/20µg and fluticasone propionate 500µg + formoterol fumarate 24µg) from low dose ICS-LABA treatment (fluticasone propionate 100µg/10µg) and fluticasone propionate 500µg monotherapy.
• til patienter, der allerede er velkontrollerede på et inhalationskortikosteroid kombineret med en langtidsvirkende β2-agonist (“substitutionsindikationen”) 
• For patients already adequately controlled on both an inhaled corticosteroid and a long-acting β2
Langtidsvirkende β agonister virker modulerende på flere endepunkter, der afspejler disse forskellige facetter af astmakontrol. 
Several endpoints which reflect these different facets of asthma control are modulated by long-acting β-agonists.
Ca. 20 personer i hver arm af dette parallelgruppeforsøg fik enten Iffeza, 500/20 (fluticasonpropionat 500µg og formoterolfumarat 20µg) eller GSK fluticasonpropionat-inhalator, 500µg, + Novartis formoterolfumarat-inhalator, 24µg. 
Approximately 20 subjects in each arm of this parallel group study were administered Iffeza 500/20 (fluticasone propionate 500µg and formoterol fumarate 20µg) or GSK fluticasone propionate 500µg pMDI + Novartis formoterol fumarate 24µg pMDI.
• til patienter, der ikke er velkontrollerede på inhalationskortikosteroider og en PN-ordineret korttidsvirkende inhaleret β2-agonist (“optrapningsindikationen”) 
• For patients not adequately controlled with inhaled corticosteroids and ‘as required' inhaled shortacting β2 agonist.
Ansøgerens undersøgelser viser, at med henblik på “optrapning” var odds for “enhver” eksacerbation 33 % højere på fluticasonpropionat end på Iffeza (p=0,019), og den årlige eksacerbationsrate 49 % højere på fluticasonpropionat end på Iffeza (p=0,004). 
Turning to the available data in the Applicant's studies, for the “Step-up” comparison the odds of “any” exacerbation were 33% higher in fluticasone propionate- than Iffeza-treated patients (p=0.019) whilst the annual exacerbation rate was 49% higher in fluticasone propionate- than Iffeza-treated patients (p=0.004).
De kliniske resultater indikerer non-inferioritet af den kliniske virkning af fluticasonpropionat i Iffeza i forhold til GSK fluticasonpropionat. 
The clinical findings suggest that fluticasone propionate in Iffeza is non-inferior in respect of clinical effects to GSK fluticasone propionate.
Ansøgerens egne data viser, at sammenhængen mellem FEV1 og risikoen for efterfølgende eksacerbationer er den samme, uanset om der er tale om kort- eller langsigtede undersøgelser. 
The Applicant's own short- and long-term studies have demonstrated the same association between FEV1 and future exacerbation risk.
Denne undersøgelses FEV1-data før dosering var igen bestemt af en påviseligt inhalationskortikosteroid-medieret virkning og gav ikke holdepunkt for, at Iffeza skulle resultere i ringere inhalationskortikosteroid-virkning end fluticasonpropionat + formoterolfumarat. 
The pre-dose FEV1 data in this study which were again a demonstrably inhaled corticosteroid-mediated effect provided no evidence of a lesser inhaled corticosteroid effect with Iffeza than seen with fluticasone propionate + formoterol fumarate.
I rammerne af henvisningen i henhold til artikel 29, stk. 4, blev ansøgeren anmodet om at besvare følgende: “De foreliggende farmakokinetiske data viser lavere systemisk eksponering for fluticasonpropionat-komponenten i det faste kombinationsprodukt. 
In the frame of the referral under article 29(4), the Applicant was requested to respond to the following: “In the light of the available pharmacokinetic data showing a lower systemic exposure of the fluticasone propionate component of this fixed-dose combination product, there is concern that patients receiving this fixed-dose combination, whether for the 'substitution' indication or for the 'step-up' indication, may not experience the same level of efficacy in respect of long-term asthma control.
For “optrapningsindikationen” accepterede CHMP ligeledes ansøgerens analyse og fandt, at Iffeza udviser superioritet med hensyn til astmakontrol i forhold til GSK fluticasonpropionat administreret alene. 
With regard to the “Step-up” indication, again the CHMP accepted the discussions presented by the Applicant and was of the view that the clinical effects of Iffeza in respect of asthma control are superior to the clinical effects of GSK fluticasone propionate administered alone.
Det var instruktivt, at den farmakodynamiske undersøgelse desuden omfattede en lavere dosis af Iffeza (100µg/10µg). 
The inclusion of a second, lower dose of Iffeza (100µg/10µg) in the PD study was also instructive.
Selv hvis de farmakokinetiske data for Iffeza nøjagtigt afspejler lægemidlets relative afsætning i lungerne i forhold til GSK fluticasonpropionat-inhalator, viser litteraturdata, at denne forskel ikke er klinisk relevant. 
Literature data indicate that even if the PK data accurately reflect comparative pulmonary drug deposition for Iffeza versus GSK fluticasone propionate pMDI, such differences are not of clinical relevance.
Ansøgeren gennemgik FEV1-data og disses prædiktive værdi for yderligere at imødekomme de rejste betænkeligheder vedrørende varigheden af de kliniske undersøgelser og supplere data om eksacerbationer og andre kliniske forhold. 
To further address the concerns raised regarding the duration of the Applicant's clinical studies and to supplement the exacerbations data and other clinical data, the Applicant reviewed the FEV1 data and their predictive value.
Iffeza i den lave dosis (100µg/10µg) havde samme virkning på FEV1 før dosering som den høje dosis af GSK fluticasonpropionat, 500µg (alene eller kombineret med formoterolfumarat, 24µg). 
Effects with the low dose of Iffeza (100µg/10µg) upon pre-dose FEV1 were similar to those with the high dose of GSK fluticasone propionate 500µg (alone or in combination with formoterol fumarate 24µg).
Denne sammenligning viste, at trods den mindre relative biotilgængelighed af fluticasonpropionat var virkningen på FEV1 før dosering (som påviseligt blev medieret af fluticasonpropionat alene i undersøgelse FLT3503) i absolutte tal større med Iffeza, 500µg/20µg, end med GSK fluticasonpropionat, 500µg (enten alene eller kombineret med Novartis formoterolfumarat, 24µg). 
This comparison showed that despite a lower relative fluticasone propionate bioavailability, the effect upon pre-dose FEV1 (which was demonstrably mediated by fluticasone propionate alone in Study FLT3503) was numerically greater with Iffeza 500µg/20µg than with GSK fluticasone propionate 500µg (either alone or in conjunction with Novartis formoterol fumarate 24µg).
For “substitutionsindikationen” var den andel af patienterne, der fik eksacerbationer i hovedundersøgelsen vedrørende “substitution” (undersøgelse FLT3503), den samme på Iffeza og fluticasonpropionat + formoterolfumarat (henholdsvis 36,4 % og 35,3 %). 
With regard to the “Switch” indication, the proportion of patients experiencing exacerbations in the pivotal “Switch” study (Study FLT3503) was similar in Iffeza and fluticasone propionate + formoterol fumarate treated patients (36.4% and 35.3%, respectively) although this analysis lacked discriminative capacity as the proportion of fluticasone propionate monotherapy-treated patients experiencing exacerbations was similar (37.4%).
Den indsigende medlemsstat anførte, at hverken farmakokinetiske eller kliniske undersøgelser påviser, at det nye faste kombinationspræparat giver samme inflammationskontrol gennem fluticason, som når fluticason gives som monoterapi eller kombineret med andre langtidsvirkende β2-agonister. 
The objecting Member State stated that proof of similar control of inflammation by fluticasone in this new fixed-dose combination product compared with fluticasone as monotherapy or in combination with other long-acting β2 agonists has not been established either in pharmacokinetic studies or in clinical studies.
Ved sammenholdelse af disse farmakokinetiske data med de farmakodynamiske data fra undersøgelse FLT3503 ses, at uanset at biotilgængeligheden af fluticasonpropionat i det nye faste kombinationsprodukt var relativt mindre, var virkningen på FEV1 inden dosering (påviseligt medieret af fluticasonpropionat alene i undersøgelse FLT3503) numerisk større med Iffeza, 500µg/20µg, end med GSK fluticasonpropionat, 500µg (hvad enten dette blev administreret alene eller sammen med Novartis formoterolfumarat, 24µg). 
In addition, the comparison of these PK data with PD data, Study FLT3503, shows that despite the lower relative bioavailability of fluticasone propionate in this new fixed-dose combination product the effect upon predose FEV1 (which was demonstrably mediated by fluticasone propionate alone in Study FLT3503) was numerically greater with Iffeza 500µg/20µg than with GSK fluticasone propionate 500µg (either administered alone or administered together with Novartis formoterol fumarate 24µg).
I den tredje undersøgelse havde formoterol nogen resterende virkning på FEV1-værdierne før dosering, dog ikke tilstrækkelig til at forklare forskellen mellem Iffeza og fluticasonpropionatinhalator hvad angår behandlingseffekten på FEV1-værdierne før dosering. 
Assessment of the pre-dose FEV1 data in the three specified studies demonstrated that in two of the three studies formoterol fumarate has no effect upon pre-dose FEV1 whilst in the third study there was some residual formoterol effect upon pre-dose FEV1 but it was insufficient to explain the magnitude of the predose FEV1 treatment effect difference between Iffeza and fluticasone propionate pMDI.
Odds for forekomst af enhver eksacerbation var således 33 % højere og den årlige eksacerbationsrate 49 % højere for patienter på GSK fluticasonpropionat end på Iffeza (p= henholdsvis 0,019 og 0,004). 
The data presented in respect of exacerbations demonstrate an increased protective benefit of Iffeza compared with GSK fluticasone propionate administered alone - the odds of any exacerbation occurring were 33% higher and the annual exacerbation rate was 49% higher in patients receiving GSK fluticasone propionate than in patients receiving Iffeza, p=0.019 and p=0.004, respectively.
For “substitutionsindikationen” var virkningerne på FEV1 både før og efter dosering i absolutte tal gunstigere med Iffeza end med fluticasonpropionat + formoterolfumarat (både for Per Protocol- og Intention-to-Treat-populationen). 
Turning to the data in the Applicant's clinical studies: For the “Step-up” indication both pre-dose and post-dose FEV1 effects at 8 to 12 weeks were significantly greater with Iffeza than with fluticasone propionate; for the “Switch” indication both pre-dose and post-dose FEV1 effects numerically favoured Iffeza over fluticasone propionate + formoterol fumarate (in both Per Protocol and Intention-to-Treat population comparisons).