FrancophonIA/ELRC3.0 huggingface dataset:
English: • The Committee considered the notification of the referral triggered by the United Kingdom under Article 29(4) of Directive 2001/83/EC where France and the Slovakia raised objections that were considered to be a potential serious risk to public health;
Danish: • udvalget behandlede den indbringelse, der var indledt af Det Forenede Kongerige i henhold til artikel 29, stk. 4, i direktiv 2001/83/EF, hvor Frankrig og Slovakiet rejste indvendinger, der blev betragtet som en potentiel alvorlig risiko for den offentlige sundhed
English: Limited within study comparisons are available.
Danish: Inden for de enkelte undersøgelser er der kun foretaget begrænsede sammenligninger.
English: The pre-defined criteria for bioequivalence were met for both Cmax and AUC.
Danish: De prædefinerede kriterier for bioækvivalens blev opfyldt for både Cmax og AUC.
English: During the CMDh referral procedure that followed, no consensus could be reached as the objecting EU Member States maintained their objections, which were considered to represent a potential serious risk to public health.
Danish: Ved den efterfølgende indbringelsesprocedure i CMDh var det ikke muligt at nå til enighed, da de indsigende medlemsstater fastholdt deres indsigelser, der blev anset for at udgøre en potentiel alvorlig risiko for den offentlige sundhed.
English: The CHMP endorsed the PKWP's advice.
Danish: CHMP tilsluttede sig rådgivningen fra PKWP.
English: The CMDh therefore referred the matter to the CHMP through an Article 29(4) referral procedure.
Danish: CMDh indbragte derfor sagen for CHMP ved en indbringelsesprocedure i henhold til artikel 29, stk. 4.
English: As requested by the CHMP, the applicant also performed a bibliographic search on the databases Medline and Embase.
Danish: Som anmodet af CHMP foretog ansøgeren desuden en bibliografisk søgning i databaserne Medline og Embase.
English: The results of the comparative bioavailability study under fasting conditions demonstrate bioequivalence between reference and test products for all pharmacokinetic parameters.
Danish: Resultaterne af den sammenlignende biotilgængelighedsundersøgelse under fastende betingelser viser bioækvivalens mellem reference- og testproduktet hvad angår alle farmakokinetiske parametre.
English: During the CHMP meeting the applicant presented their view in an oral explanation.
Danish: På CHMP's møde fremlagde ansøgeren mundtligt sine synspunkter.
English: Therefore, the CHMP is of the view that the benefit-risk is negative.
Danish: CHMP anser derfor benefit/risk-forholdet for at være negativt.
English: Therefore, the Committee recommends the refusal of the marketing authorisation of Diclofenac (Altergon) in the reference and concerned Member States.
Danish: Udvalget anbefaler derfor afslag på ansøgninger om markedsføringstilladelse for Diclofenac (Altergon) i referencemedlemsstaten og de berørte medlemsstater.
English: The mean Cmax reduction observed with food ranges from 21% to 69%.
Danish: Den gennemsnitlige iagttagne reduktion i Cmax ved fødeindtagelse er mellem 21 % og 69 %.
English: A summary of the bioequivalence study in the fasted state was presented as well as a review of the literature submitted.
Danish: Der blev forelagt en sammenfatning af bioækvivalensundersøgelsen i fastende tilstand og en gennemgang af den forelagte litteratur.
English: The marketing authorisation application (MAA) for Diclofenac (epolamine) 50 mg immediate release tablets was submitted according to Article 10(1) of Directive 2001/83/EC.
Danish: Ansøgningen om markedsføringstilladelse for Diclofenac (epolamin) 50 mg, tabletter med umiddelbar frigivelse, blev indgivet i henhold til artikel 10, stk. 1, i direktiv 2001/83/EF.
English: For the sodium and potassium salt, and the acid, a food effect is evident in most studies.
Danish: For natrium- og kaliumsaltet og syren ses i de fleste undersøgelser en effekt af fødeindtagelse.
English: The potential serious risk to public health (PSRPH) concern was maintained, and the procedure was referred by the RMS to the CMDh.
Danish: Betænkeligheden ved den potentielle alvorlige risiko for den offentlige sundhed blev fastholdt, og referencemedlemsstaten indbragte proceduren for CMDh.
English: This was a single-dose openlabel randomised 2x2 crossover study of acceptable design.
Danish: Undersøgelsen var en åben, randomiseret 2x2 overkrydsningsundersøgelse med enkeltdosering med acceptabelt design.
English: However the objecting EU Member States argued that the effect of food on Cmax may be formulationdependent in the case of diclofenac, and that from the available evidence the potential difference in bioavailability (Cmax decrease of up to 70%) may reach such a high level so as to compromise the safe and effective use of the drug.
Danish: De indsigende EU-medlemsstater hævdede imidlertid, at virkningen af fødeindtagelse på Cmax kan være formuleringsafhængig for diclofenacs vedkommende, og at den foreliggende evidens viser, at den potentielle forskel i biotilgængelighed (mindskelse af Cmax med op til 70 %) kan være så stor, at den berører lægemidlets sikkerhed og effektivitet.
English: Considering this, it was argued that it was necessary to request a fed study in order to rule out any risk of bio-in-equivalence under fed conditions.
Danish: I betragtning heraf blev det hævdet, at der måtte anmodes om en postprandial undersøgelse for at udelukke al risiko for manglende bioækvivalens ved postprandiale betingelser.
English: Section 4.2 of the proposed SmPC for Diclofenac (epolamine) 50 mg immediate release tablets is in line with the reference product, and recommends that: '… tablets should be swallowed whole with a glass of water, preferably during or after meals.
Danish: Punkt 4.2 i det foreslåede produktresumé for Diclofenac (epolamin) 50 mg, tabletter med umiddelbar frigivelse, er i overensstemmelse med referenceproduktet og anbefaler, at: "... tabletterne skal synkes hele med et glas vand, fortrinsvis sammen med eller efter et måltid.
English: Diclofenac is a nonsteroidal anti-inflammatory drug (NSAID) that inhibits prostaglandin synthesis via inhibition of both COX-1 and COX-2 isoenzymes of the arachidonic acid pathway.
Danish: Diclofenac er et non-steroidt antiinflammatorisk lægemiddel (NSAID), der hæmmer prostaglandinsyntesen gennem hæmning af både COX-1- og COX-2-isoenzymer i arachidonsyremetabolismen.
English: • The Committee reviewed the data submitted by the applicant in support of this particular medicinal product Diclofenac (Altergon) 50mg tablets;
Danish: • udvalget gennemgik de data, der er forelagt af ansøgeren til støtte for produktet Diclofenac (Altergon) 50 mg, tabletter
English: Given the strong evidence of a food effect on the Cmax and Tmax, this effect is concluded to be both drug substance and formulation dependent.
Danish: På baggrund af den stærke evidens for en effekt af fødeindtagelse på Cmax og Tmax konkluderes det, at denne effekt er både lægemiddelstof- og formuleringsafhængig.
English: In summary this review of literature by the applicant about the magnitude of the food-effect on the rate of absorption with diclofenac immediate release formulations, allowed to conclude that it reached on average, 50% decrease on Cmax and various delays on tmax, without any loss in the amount of systemic exposure.
Danish: Sammenfattende kunne det af ansøgerens litteraturgennemgang vedrørende omfanget af fødeindtagelses virkning på absorptionsgraden for diclofenac-formuleringer med umiddelbar frigivelse konkluderes, at Cmax i gennemsnit blev 50 % nedsat og tmax i vekslende grad forsinket uden tab i omfanget af den systemiske eksponering.
English: The CHMP agreed with the applicant that the food effect on Cmax of diclofenac is both drug substance and formulation dependent, based on the review of the literature, which includes potassium and sodium salts, and the acid.
Danish: CHMP var enig med ansøgeren i, at virkningen af fødeindtagelse på Cmax for diclofenac både afhænger af lægemiddelstoffet og formuleringen, baseret på en litteraturgennemgang, der omfatter både kaliumog natriumsalt og syren.
English: Diclofenac 50 mg Tablets contain diclofenac epolamine, a salt of diclofenac, formed by the combination of diclofenamic acid with the tertiary amine N-(2-hydroxyethyl)-pyrrolidine.
Danish: Diclofenac 50 mg, tabletter, indeholder diclofenacepolamin, der er et salt af diclofenac dannet ved kombination af diclofenacsyre med den tertiære amin N-(2-hydroxyethyl)-pyrrolidin.
English: Grounds for the CHMP opinion Whereas
Danish: Begrundelse for CHMP's udtalelse
English: No food-effect study was identified with Diclofenac epolamine.
Danish: Der blev ikke fundet undersøgelser af effekten af fødeindtagelse på diclofenacepolamin.
English: Chen et al (2015)2 reported a 69% reduction in Cmax for a buffered potassium solution vs a 28% reduction for a potassium tablet, in the fed state vs. fasted state.
Danish: Chen et al (2015)2 beskrev en reduktion i postprandial i forhold til fastende tilstand på 69 % i Cmax for en bufret kaliumopløsning, og en reduktion på 28 % for en kaliumtablet.
English: However no data was submitted to show the food effect between test and reference product to support this application, given that the SmPC recommendation in section 4.2 is that Diclofenac epolamine tablets should be swallowed whole with a glass of water, preferably during or after meals.
Danish: Der blev imidlertid ikke til underbygning af ansøgningen forelagt data, der viser effekten af fødeindtagelse for henholdsvis test- og referenceproduktet, skønt det i produktresuméets punkt 4.2 anbefales, at Diclofenacepolamin, tabletter, synkes hele med et glas vand, fortrinsvis under eller efter et måltid.
English: • The Committee was of the view that in this case bioequivalence of Diclofenac 50 mg tablets vs. the reference product Flector granules for oral solution should be demonstrated in fed conditions as well, in view of the available literature demonstrating that the Cmax of different formulations of diclofenac is affected differently in fed conditions;
Danish: • udvalget var den opfattelse, at der i dette tilfælde også skulle påvises bioækvivalens af Diclofenac, tabletter, 50 mg med referenceproduktet, Flector, granulat til oral opløsning, i postprandial tilstand, hvilket har baggrund i den foreliggende litteratur, der viser, at Cmax for forskellige formuleringer af diclofenac påvirkes forskelligt i postprandial tilstand
English: Furthermore, comparative dissolution testing at pH 5.5 demonstrated immediate release from test and reference product, which was used to support the comparative rate and extent of absorption in vivo in the fed state.
Danish: Ved en sammenlignende opløselighedstest ved pH 5,5 blev der desuden påvist umiddelbar frigivelse fra test- og referenceproduktet.
English: Therefore the CHMP is of the opinion that the bioequivalence of Diclofenac epolamine tablets and the reference product diclofenac epolamine granules for solution has not been demonstrated for this Article 10(1) marketing authorisation application, since bioequivalence cannot be concluded in the absence of a bioequivalence study in the fed state.
Danish: CHMP er derfor af den opfattelse, at der ikke er påvist bioækvivalens af Diclofenacepolamin, tabletter, med referenceproduktet diclofenacepolamin, granulat til opløsning, med henblik på denne markedsføringstilladelsesansøgning i henhold til artikel 10, stk. 1, da der ikke kan drages en konklusion om bioækvivalens uden en bioækvivalensundersøgelse i postprandial tilstand.
English: Differential pharmacokinetics of diclofenac sodium for oral solution vs immediate-release tablets from a randomised trial: effect of fed and fasting conditions.
Danish: Chen C, Bujanover S, Kareht S, Rapoport AM. Differential pharmacokinetics of diclofenac sodium for oral solution vs immediate-release tablets from a randomised trial: effect of fed and fasting conditions.
English: The applicant submitted data from one bioequivalence study of diclofenac epolamine tablets vs. Flector granules for oral solution in healthy volunteers under fasted conditions.
Danish: Ansøgeren har forelagt data fra en undersøgelse af bioækvivalensen af diclofenacepolamin, tabletter, med Flector, granulat til oral opløsning, hos raske frivillige under fastende betingelser.
English: Although it was argued by the applicant that a failure of bioequivalence under fasting state is predictive of a failure of bioequivalence under fed state based on the submitted literature, the CHMP was of the view that the reverse argument could not be upheld i.e that bioequivalence under fasting state is predictive of bioequivalence under fed state, without any evidence to support it.
Danish: Ansøgeren gjorde ud fra den forelagte litteratur gældende, at manglende bioækvivalens i fastende tilstand er prædiktiv for manglende bioækvivalens i postprandial tilstand, men CHMP fandt, at man ikke uden underbyggende evidens tilsvarende kunne slutte, at bioækvivalens i fastende tilstand er prædiktiv for bioækvivalens i postprandial tilstand.
English: • The Committee therefore concluded that there was a lack of appropriate data to support the positive benefit-risk of this medicinal product Diclofenac 50mg tablets.
Danish: • udvalget konkluderede derfor, at der savnedes tilstrækkelige data til dokumentation af et positivt benefit/risk-forhold for lægemidlet Diclofenac 50 mg, tabletter finder udvalget følgelig, at benefit/risk-forholdet for Diclofenac ikke er positivt.
English: According to Desjardins et al (2015)1, there was 60% decrease in Cmax for a diclofenac acid capsule, compared to a 43% decrease in Cmax for a potassium tablet, in the fed state vs fasted.
Danish: (2015)1 medførte indtagelse i postprandial i forhold til fastende tilstand en reduktion af Cmax på 60 % for en kapsel med diclofenacsyre, og 43 % for en kaliumtablet.
English: Therefore as Diclofenac epolamine tablets and the reference product diclofenac epolamine granules for solution are different oral pharmaceutical formulations, and because literature data show that the food effect on Cmax of diclofenac is not only dependent on the drug substance but also on the formulation, in this case, bioequivalence can only be concluded if bioequivalence is shown under fed as well as fasted conditions.
Danish: I dette tilfælde kan der derfor kun konkluderes at foreligge bioækvivalens, hvis dette påvises ved både postprandiale og fastende betingelser, fordi Diclofenacepolamin, tabletter, og referenceproduktet diclofenacepolamin, granulat til opløsning, er forskellige orale farmaceutiske formuleringer, og fordi litteraturdata viser, at effekten af fødeindtagelse på Cmax for diclofenac ikke kun afhænger af lægemiddelstoffet, men også af formuleringen.
English: The advice of PKWP was also sought during this procedure.
Danish: Ved proceduren konsulteredes desuden arbejdsgruppen vedrørende farmakokinetik (PKWP).
English: In summary, the view of the PKWP was that under fed conditions the Cmax is highly variable; Cmax ratio fed/fasted ranged from 26-73% for the different formulations, and formulations that are bioequivalent in the fasted state may not be bioequivalent in the fed state, especially if the dosage form is different.
Danish: Forholdet mellem Cmax i postprandial/fastende tilstand var mellem 26 og 73 % for de forskellige formuleringer.
English: Benefit-risk assessment and discussion
Danish: Vurdering af benefit/risk-forholdet og diskussion
English: The heterogeneity could also play a role in the two studies.
Danish: Heterogeniteten kan også spille en rolle i de to studier.
English: The therapeutic indication of Lartruvo is:
Danish: Den terapeutiske indikation for Lartruvo er som følger:
English: The EC requested the CHMP to give its opinion on whether the marketing authorisation for this product should be maintained, varied, suspended or revoked.
Danish: Kommissionen anmodede CHMP om at udtale sig om, hvorvidt markedsføringstilladelsen for dette produkt bør bevares, ændres, suspenderes eller tilbagekaldes.
English: Therefore, pursuant to Article 116 of Directive 2001/83/EC, the Committee recommends the revocation of the marketing authorisation for Lartruvo.
Danish: I henhold til artikel 116 i direktiv 2001/83/EF anbefaler udvalget derfor tilbagekaldelse af markedsføringstilladelsen for Lartruvo.
English: The results of the ANNOUNCE study confirmed the safety profile seen in the previous phase II study.
Danish: Resultaterne af ANNOUNCE-studiet bekræftede sikkerhedsprofilen fra det tidligere fase II-studie.
English: It is plausible that a different rate of several histologies between the two studies could have had an impact in the dissimilar efficacy observed.
Danish: Det er plausibelt, at forskellig forekomst af en række histologier mellem de to studier kan have haft betydning for den observerede forskel i effekt.
English: Even the post-discontinuation therapy is balanced.
Danish: Selv behandlingen efter seponering er balanceret.
English: Baseline patient and disease characteristics appeared overall well balanced.
Danish: Patient- og sygdomskarakteristika ved baseline syntes generelt at være i god balance.
English: Furthermore, there was no clinical benefit in key secondary efficacy endpoints.
Danish: Derudover sås der ingen klinisk gavn, hvad angår de centrale sekundære endepunkter.
English: All anaphylactic reactions occurred during the first olaratumab infusion.
Danish: Alle de anafylaktiske reaktioner opstod under den første olaratumabinfusion.
English: Unfavourable effects
Danish: Ugunstige virkninger
English: On 25 January 2019 the European Commission (EC) triggered a procedure under Article 20 of Regulation (EC) No 726/2004, and requested the CHMP to assess the above concerns and their impact on the benefit-risk balance of Lartruvo.
Danish: Den 25. januar 2019 indledte Europa-Kommissionen en procedure i henhold til artikel 20 i forordning (EF) nr. 726/2004 og bad CHMP om at vurdere ovenstående problemstillinger og disses betydning for benefit/risk-forholdet for Lartruvo.
English: Safety analysis by age category (<65 vs >=65 years) showed higher toxicity in older subjects, although this occurred equally in both arms.
Danish: Sikkerhedsanalyse pr. alderskategori (< 65 vs. ≥ 65 år) viste højere toksicitet hos ældre patienter, om end dette sås i samme omfang i de to grupper.
English: The subgroup analyses do not reveal any subgroup of interest where there could be some benefit.
Danish: Delgruppeanalyserne viser ingen delgruppe af interesse, hvor der kunne være en fordel.
English: No difference was observed in any of the other secondary endpoints analysed in the ITT population.
Danish: Der sås ingen forskel for nogen af de andre sekundære endepunkter, der blev analyseret i ITTpopulationen.
English: The strength of the evidence from the phase III ANNOUNCE study is necessarily higher due to higher patient numbers and the blinded design with no cross-over.
Danish: Styrken af evidensen i fase III-studiet ANNOUNCE er i sagens natur højere som følge af et større antal patienter og det blindede design uden overkrydsning.
English: The baseline characteristics appear to be evenly balanced, both in histology and disease at randomization.
Danish: Baselinekarakteristikaene synes at være ligeligt fordelt, både med hensyn til histologi og sygdom ved randomisering.
English: The different exposure to doxorubicin between investigational arm and the control group was noted.
Danish: De forskellige eksponeringer for doxorubicin mellem den eksperimentelle gruppe og kontrolgruppen blev bemærket.
English: The latter showed an unexpected survival gain in patients with advanced/metastatic STS recruited in the United States.
Danish: Sidstnævnte studie viste en uventet overlevelsesfordel hos patienter med fremskredent/metastatisk bløddelssarkom, der var rekrutteret i USA.
English: In January 2019, the marketing authorisation holder communicated to the European Medicines Agency high level preliminary results of the JGDJ study.
Danish: I januar 2019 fremsendte indehaveren af markedsføringstilladelsen de foreløbige højniveauresultater fra JGDJ-studiet til Det Europæiske Lægemiddelagentur.
English: The study gave rise to concerns about lack of efficacy, because it did not meet the primary objective to prolong survival in the overall population or in the leiomyosarcoma sub-population.
Danish: Studiet gav anledning til bekymring på grund af manglende effekt, idet det ikke opfyldte det primære formål, der var at forlænge overlevelsen hos den samlede population eller i leiomyosarkomdelpopulationen.
English: Favourable effects
Danish: Gavnlige virkninger
English: Infusion related reactions, cardiac arrhythmia and cardiac dysfunction are considered events of special interest for olaratumab.
Danish: Infusionsrelaterede reaktioner, hjertearytmier og hjertedysfunktion anses for at være hændelser af særlig interesse for olaratumab.
English: Neither the exploratory analysis of PDGFR-α expression nor the immunogenicity appear to explain the absence of benefit.
Danish: Hverken den eksplorative analyse af PDGFR-α-ekspression eller immunogenicitet synes at kunne forklare den manglende gavnlige effekt.
English: However, this remains higher in the investigational arm.
Danish: Forekomsten er imidlertid højere i den eksperimentelle gruppe.
English: • The Committee, as a consequence, concluded that Lartruvo lacks therapeutic efficacy and that the benefit-risk of Lartruvo is not favourable.
Danish: • Som følge heraf vurderede udvalget, at Lartruvo mangler terapeutisk effekt, og at benefit/riskforholdet for Lartruvo er ugunstigt.
English: Overall, the results of the ANNOUNCE study are mature and robust to draw the conclusion that the study showed lack of therapeutic efficacy associated with olaratumab treatment in the authorised indication.
Danish: Samlet set er resultaterne af ANNOUNCE-studiet modne og robuste, så det kan konkluderes, at studiet påviser manglende terapeutisk effekt ved olaratumab-behandling i den godkendte indikation.
English: The sample size, conduct of the study, endpoints, statistical methods or randomisation do not seem to explain the discrepancy between ANNOUNCE and the phase II JGDG.
Danish: Populationsstørrelsen, studiegennemførelsen, endepunkterne, de statistiske metoder eller randomiseringen ser ikke ud til at kunne forklare diskrepansen mellem ANNOUNCE-studiet og fase IIstudiet JGDG.
English: It was designed to confirm the OS benefit previously shown in the smaller phase 1b/2 study JGDG.
Danish: Det var designet til at bekræfte den fordel, hvad angår samlet overlevelse, der tidligere er vist i det mindre fase 1b/2-studie JGDG.
English: It seems no single reason can explain the discrepancy in results between phase II JGDG and phase III ANNOUNCE studies.
Danish: Der synes ikke at være en enkeltstående årsag, der kan forklare resultatdiskrepansen mellem fase IIstudiet JGDG og fase III-studiet ANNOUNCE.
English: In addition, the rate of (consolidated) musculoskeletal pain was similar between the 2 treatment arms.
Danish: Desuden var forekomsten af (konsoliderede) smerter i bevægeapparatet sammenlignede i de 2 behandlingsgrupper.
English: According to the protocol, doxorubicin 75 mg/m2 was to be administered (after olaratumab or placebo) on day 1 of cycles 1 to 8 (of 3 weeks each).
Danish: I henhold til protokollen skulle doxorubicin 75 mg/m2 administreres (efter olaratumab eller placebo) på dag 1 i serie 1-8 (a hver 3 uger).
English: When excluding the event of oedema not associated with an AE suggestive of cardiac dysfunction or a significant decrease in left ventricular function, the true incidence of cardiac dysfunction was 9.3% in the investigational arm and 6.8% in the control arm.
Danish: Når der ses bort fra ødemer, der ikke var forbundet med en bivirkning relateret til hjertedysfunktion eller signifikant nedsat funktion i venstre ventrikel, var den faktiske forekomst af hjertedysfunktion 9,3 % i den eksperimentelle gruppe og 6,8 % i kontrolgruppen.