natgillin/translations-raw huggingface dataset:
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.
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.
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.
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.
• 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
• 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;
Ved en sammenlignende opløselighedstest ved pH 5,5 blev der desuden påvist umiddelbar frigivelse fra test- og referenceproduktet.
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.
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.
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.
Ansøgeren har forelagt data fra en undersøgelse af bioækvivalensen af diclofenacepolamin, tabletter, med Flector, granulat til oral opløsning, hos raske frivillige under fastende betingelser.
The applicant submitted data from one bioequivalence study of diclofenac epolamine tablets vs. Flector granules for oral solution in healthy volunteers under fasted conditions.
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.
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.
• 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.
• 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.
(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.
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.
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.
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.
Ved proceduren konsulteredes desuden arbejdsgruppen vedrørende farmakokinetik (PKWP).
The advice of PKWP was also sought during this procedure.
Forholdet mellem Cmax i postprandial/fastende tilstand var mellem 26 og 73 % for de forskellige formuleringer.
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.
Vurdering af benefit/risk-forholdet og diskussion
Benefit-risk assessment and discussion
Heterogeniteten kan også spille en rolle i de to studier.
The heterogeneity could also play a role in the two studies.
Den terapeutiske indikation for Lartruvo er som følger:
The therapeutic indication of Lartruvo is:
Kommissionen anmodede CHMP om at udtale sig om, hvorvidt markedsføringstilladelsen for dette produkt bør bevares, ændres, suspenderes eller tilbagekaldes.
The EC requested the CHMP to give its opinion on whether the marketing authorisation for this product should be maintained, varied, suspended or revoked.
I henhold til artikel 116 i direktiv 2001/83/EF anbefaler udvalget derfor tilbagekaldelse af markedsføringstilladelsen for Lartruvo.
Therefore, pursuant to Article 116 of Directive 2001/83/EC, the Committee recommends the revocation of the marketing authorisation for Lartruvo.
Resultaterne af ANNOUNCE-studiet bekræftede sikkerhedsprofilen fra det tidligere fase II-studie.
The results of the ANNOUNCE study confirmed the safety profile seen in the previous phase II study.
Det er plausibelt, at forskellig forekomst af en række histologier mellem de to studier kan have haft betydning for den observerede forskel i effekt.
It is plausible that a different rate of several histologies between the two studies could have had an impact in the dissimilar efficacy observed.
Selv behandlingen efter seponering er balanceret.
Even the post-discontinuation therapy is balanced.
Patient- og sygdomskarakteristika ved baseline syntes generelt at være i god balance.
Baseline patient and disease characteristics appeared overall well balanced.
Derudover sås der ingen klinisk gavn, hvad angår de centrale sekundære endepunkter.
Furthermore, there was no clinical benefit in key secondary efficacy endpoints.
Alle de anafylaktiske reaktioner opstod under den første olaratumabinfusion.
All anaphylactic reactions occurred during the first olaratumab infusion.
Ugunstige virkninger
Unfavourable effects
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.
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.
Sikkerhedsanalyse pr. alderskategori (< 65 vs. ≥ 65 år) viste højere toksicitet hos ældre patienter, om end dette sås i samme omfang i de to grupper.
Safety analysis by age category (<65 vs >=65 years) showed higher toxicity in older subjects, although this occurred equally in both arms.
Delgruppeanalyserne viser ingen delgruppe af interesse, hvor der kunne være en fordel.
The subgroup analyses do not reveal any subgroup of interest where there could be some benefit.
Der sås ingen forskel for nogen af de andre sekundære endepunkter, der blev analyseret i ITTpopulationen.
No difference was observed in any of the other secondary endpoints analysed in the ITT population.
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.
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.
Baselinekarakteristikaene synes at være ligeligt fordelt, både med hensyn til histologi og sygdom ved randomisering.
The baseline characteristics appear to be evenly balanced, both in histology and disease at randomization.
De forskellige eksponeringer for doxorubicin mellem den eksperimentelle gruppe og kontrolgruppen blev bemærket.
The different exposure to doxorubicin between investigational arm and the control group was noted.
Sidstnævnte studie viste en uventet overlevelsesfordel hos patienter med fremskredent/metastatisk bløddelssarkom, der var rekrutteret i USA.
The latter showed an unexpected survival gain in patients with advanced/metastatic STS recruited in the United States.
I januar 2019 fremsendte indehaveren af markedsføringstilladelsen de foreløbige højniveauresultater fra JGDJ-studiet til Det Europæiske Lægemiddelagentur.
In January 2019, the marketing authorisation holder communicated to the European Medicines Agency high level preliminary results of the JGDJ study.
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.
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.
Gavnlige virkninger
Favourable effects
Infusionsrelaterede reaktioner, hjertearytmier og hjertedysfunktion anses for at være hændelser af særlig interesse for olaratumab.
Infusion related reactions, cardiac arrhythmia and cardiac dysfunction are considered events of special interest for olaratumab.
Hverken den eksplorative analyse af PDGFR-α-ekspression eller immunogenicitet synes at kunne forklare den manglende gavnlige effekt.
Neither the exploratory analysis of PDGFR-α expression nor the immunogenicity appear to explain the absence of benefit.
Forekomsten er imidlertid højere i den eksperimentelle gruppe.
However, this remains higher in the investigational arm.
• Som følge heraf vurderede udvalget, at Lartruvo mangler terapeutisk effekt, og at benefit/riskforholdet for Lartruvo er ugunstigt.
• The Committee, as a consequence, concluded that Lartruvo lacks therapeutic efficacy and that the benefit-risk of Lartruvo is not favourable.
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.
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.
Populationsstørrelsen, studiegennemførelsen, endepunkterne, de statistiske metoder eller randomiseringen ser ikke ud til at kunne forklare diskrepansen mellem ANNOUNCE-studiet og fase IIstudiet JGDG.
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.
Det var designet til at bekræfte den fordel, hvad angår samlet overlevelse, der tidligere er vist i det mindre fase 1b/2-studie JGDG.
It was designed to confirm the OS benefit previously shown in the smaller phase 1b/2 study JGDG.
Der synes ikke at være en enkeltstående årsag, der kan forklare resultatdiskrepansen mellem fase IIstudiet JGDG og fase III-studiet ANNOUNCE.
It seems no single reason can explain the discrepancy in results between phase II JGDG and phase III ANNOUNCE studies.
Desuden var forekomsten af (konsoliderede) smerter i bevægeapparatet sammenlignede i de 2 behandlingsgrupper.
In addition, the rate of (consolidated) musculoskeletal pain was similar between the 2 treatment arms.
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).
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).
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.
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.
Disse data synes at pege på forskellig tolerabilitet over for doxorubicin alt efter gruppe; tolerabiliteten ser ikke ud til at være den samme som i det tidligere fase II-studie, hvor eksponeringen for doxorubicin var højere hos patienter i den eksperimentelle gruppe end i kontrolgruppen (7 vs. 4).
These data seem to suggest a different tolerability to doxorubicin depending on the group, which appears to be different from that observed in the previous phase II trial, where the exposure to doxorubicin was higher for patients in the investigational group as compared to the control group (7 vs 4).
Imidlertid var den mediane varighed af doxorubicinbehandlingen i den eksperimentelle gruppe og kontrolgruppen på hhv. 18 og 23 uger.
However, the median duration of doxorubicin treatment was 18 weeks and 23 weeks for the investigational and control groups, respectively.
Forekomsten af hæmatologiske toksiciteter (neutropeni, trombocytopeni, anæmi og febril neutropeni) og gastrointestinale toksiciteter (kvalme, opkastning og diarré) var balanceret mellem behandlingsgrupperne.
The rate of haematological toxicities (neutropenia, thrombocytopenia, anaemia and febrile neutropenia) and gastrointestinal toxicities (nausea, vomiting and diarrhoea) was balanced between the treatment arms.
Bløddelssarkom er en sygdom med mange varierende tumorhistologier, der har forskellige prognoser og kræver specifik behandling.
STS is a disease which encompasses a wide range of different tumour histologies, some of them with different prognosis and specific treatments.
Alle følsomhedsanalyserne i ANNOUNCE-studiet peger i samme retning, både i ITT-populationen og LMS-gruppen (ingen gavnlig effekt af olaratumab).
All the sensitivity analyses carried out in the ANNOUNCE study, both in the ITT population an in the LMS group, point in the same direction (no favourable effect of olaratumab).
• Udvalget behandlede sagen vedrørende Lartruvo i henhold til artikel 20 i forordning (EF) nr. 726/2004.
• The Committee considered the procedure under Article 20 of Regulation (EC) No 726/2004 for Lartruvo.
Kvalme, neutropeni og træthed var de hyppigst indberettede behandlingsrelaterede uønskede hændelser.
Nausea, neutropenia and fatigue were the most frequently reported TEAEs.
Det mediane antal gennemførte serier var højere i kontrolgruppen (6 vs. 7), og den mediane kumulative dosis pr. legemsoverflade (mg/m2) var også højere i kontrolgruppen (409 vs. 483).
The median of the number of cycles received were higher in the control arm (6 vs 7) and the median of cumulative dose per body surface area (mg/m2) was also higher for the control group (409 vs 483).
Der foreligger heller ingen data vedrørende toksicitet hos patienter i den eksperimentelle gruppe ved vedligeholdelsesbehandling med olaratumab.
There are also no data regarding the toxicity observed in subjects in the investigational arm when treated with olaratumab maintenance.
• Udvalget gennemgik resultaterne af ANNOUNCE (JGDJ)-studiet, der blev gennemført for at opfylde det specifikke krav om bekræftelse af det påberåbte gunstige benefit/risk-forhold i forbindelse med den betingede markedsføringstilladelse for Lartruvo, jf. artikel 14a, i forordning (EF) nr. 726/2004.
• The Committee reviewed the results of the ANNOUNCE (JGDJ) study, which was conducted to fulfil the specific obligation with a view to confirming a favourable benefit-risk balance for the conditional marketing authorisation for Lartruvo, pursuant to Article 14-a of Regulation (EC) No
Der blev rapporteret om umiddelbare ikkeanafylaktiske reaktioner (grad 1/2) hos 9,3 % af patienterne.
Immediate non-anaphylactic reactions were reported in 9.3% patients and were grade 1/2 in severity.
Studiets primære endepunkt var den samlede overlevelse i ITT-populationen og i LMS-populationen.
The primary endpoint for this study was OS in the ITT population and in the LMS population.
Den 9. november 2016 fik Lartruvo en betinget markedsføringstilladelse med gyldighed i hele EU, jf. artikel 14, stk. 7, i forordning (EF) nr. 726/2004.
Lartruvo was granted a conditional marketing authorisation under Article 14(7) of Regulation (EC) No. 726/2004, valid throughout the European Union, on 9 November 2016.
Doxorubicin blev administreret i maksimalt 8 serier hver 3. uge parallelt med olaratumab/placebo, der blev fortsat efter 8 serier indtil sygdomsprogression, uacceptabel toksicitet, død eller andre seponeringskriterier.
Doxorubicin was administered for a maximum of 8 cycles every 3 weeks, along with olaratumab/placebo which was continued after 8 cycles until PD, unacceptable toxicity, death, or other withdrawal criteria.
Kaplan-Meier-kurverne for samlet overlevelse er overlappende.
The Kaplan-Meier curves for OS are overlapping.
I alt 170 (66,1 %) vs. 158 (63,5 %) patienter døde i henholdsvis den eksperimentelle gruppe og kontrolgruppen, fortrinsvis som følge af deres sygdom (63,4 % vs. 61 %).
A total of 170 (66.1%) vs 158 (63.5%) of patients died in the investigational vs control arm, respectively, mostly attributed to study disease (63.4% vs 61%).
Patientfordelingen i ANNOUNCE-studiet peger ikke på større forskelle mellem grupperne, hvad angår grundene til seponering.
The patient disposition of the ANNOUNCE trial does not indicate major differences between arms in reasons for treatment discontinuation.
Forekomsten af dødsfald, der skyldtes uønskede hændelser, var omtrent den samme i de to grupper (7 [2,7 %] vs. 6 [2,4 %]).
Deaths due to adverse events were overall similar in both arms (7[2.7%] vs 6 [2.4%]).
Da ANNOUNCE-studiet blev gennemført for at opfylde det specifikke krav om at bekræfte virkningen og sikkerheden ved olaratumab i den godkendte indikation, bør den betingede markedsføringstilladelse for Lartruvo derfor tilbagekaldes.
Consequently, as the ANNOUNCE study was imposed as a specific obligation to confirm the efficacy and safety of olaratumab in the authorised indication, the conditional marketing authorisation for Lartruvo should be revoked.
Selvom ANNOUNCE-studiet ikke gav anledning til nye sikkerhedsmæssige betænkeligheder, betyder eventuelle sikkerhedsmæssige betænkeligheder ved olaratumab, at benefit/risk-forholdet for Lartruvo er negativt, for så vidt angår den manglende terapeutiske effekt, der er observeret i studiet.
Even though no new safety concerns arose from the ANNOUNCE study, any safety concerns associated with olaratumab render the benefit-risk balance of Lartruvo negative in view of the lack of therapeutic efficacy observed in the study.
Som bekræftelsesstudie var ANNOUNCE specifikt designet til at påvise forskelle i samlet overlevelse.
ANNOUNCE as the confirmatory trial was specifically designed to show differences in OS.
Analyserne i ANNOUNCE-studiet viste, at PDGFR-α-status ikke havde nogen prædiktiv rolle for responset på olaratumab, hvad angår samlet overlevelse eller progressionsfri overlevelse, og at PDGFR-α-status udgjorde en ringe prognostisk faktor, hvilket er konsistent med litteraturens data.
The analyses of ANNOUNCE study showed that PDGFR-α status did not have any predictive role of the response to olaratumab in terms of OS or PFS, and that PDGFR-α was a poor prognostic factor, consistently with literature data.
Selvom studiets primære endepunkt (progressionsfri overlevelse) ikke viste en tydelig forsinkelse i tumorprogression i den eksperimentelle gruppe, understøttede den længere overlevelse ved olaratumab-kombinationsbehandling udstedelsen af en betinget markedsføringstilladelse.
Even though the primary endpoint of that study (PFS) did not reveal a clear delay in the tumour progression for the experimental arm, the longer survival associated with the olaratumab combination treatment supported the granting of a conditional marketing authorisation.
Forekomsten af potentielle umiddelbare overfølsomhedsreaktioner (dvs. som opstår på infusionsdagen) var højere i den eksperimentelle gruppe for hændelser af alle grader (11,7 % vs. 7,2 %) og hændelser af grad ≥ 3 (2,3 % vs. 0,8 %), men der sås ingen hændelser med dødelig udgang.
The rate of potential immediate (i.e. occurring on the day of infusion) hypersensitivity reactions was higher in the investigational arm for all grade events (11.7% vs. 7.2%) and Grade ≥3 events (2.3% vs 0.8%) but no fatal events were reported.
I alt 509 patienter var randomiseret til behandling med enten Lartruvo + doxorubicin (efterfulgt af Lartruvo alene indtil progression) eller placebo + doxorubicin (efterfulgt af placebo alene indtil progression).
In total, 509 patients were randomised to treatment either with Lartruvo + doxorubicin (followed by Lartruvo monotherapy until progression) or with placebo + doxorubicin (followed by placebo monotherapy until progression).
• Udvalget bemærkede, at der ikke sås nogen gavnlig virkning ved tilføjelse af Lartruvo til doxorubicin ved behandling af patienter med fremskredent bløddelssarkom, sammenholdt med doxorubicin alene.
• The Committee noted that no benefit was observed from adding Lartruvo to doxorubicin in the treatment of patients with advanced soft tissue sarcoma, when compared to doxorubicin alone.
Derefter blev der stillet specifikt krav om gennemførelse af ANNOUNCE (JGDJ)-studiet for at bekræfte virkningen og sikkerheden ved olaratumab i den population, som Lartruvo aktuelt er indiceret til.
The ANNOUNCE (JGDJ) study was then requested as a specific obligation to confirm the efficacy and safety of olaratumab in same population for whom Lartruvo is currently indicated.
Bilag Videnskabelige konklusioner
Annex Scientific conclusions
"Lartruvo i kombination med doxorubicin er indiceret til behandling af voksne patienter med avanceret bløddelssarkom, som ikke er egnede til kurativ behandling med kirurgi eller strålebehandling, og som ikke tidligere er blevet behandlet med doxorubicin."
‘in combination with doxorubicin, for the treatment of adult patients with advanced soft tissue sarcoma who are not amenable to curative treatment with surgery or radiotherapy and who have not been previously treated with doxorubicin'.