FrancophonIA/ELRC3.0 huggingface dataset:
English: If you experience dizziness or you feel unusually tired, take special care when driving or using machines.
Danish: Det skal du tage hensyn til, hvis du skal færdes i trafikken eller arbejde med maskiner.
English: Influenza like illness Chills
Danish: Influenzalignende symptomer Kulderystelser
English: Erythema Alopecia
Danish: Alopeci
English: Torsade de pointes
Danish: Nedsat nyrefunktion
English: Impaired healing
Danish: pværdi behandling
English: n Oropharyngeal and pharyngolaryngeal pain.
Danish: Hudreaktion og hudsygdomme w
English: Rhabdomyolysis* Myopathy
Danish: Rabdomyolyse Myopati
English: Pulmonary embolism* Pleural effusion*
Danish: Mucosainflammation Træthed Ødem
English: • Cough.
Danish: • Hoste.
English: The CHMP considers that:
Danish: CHMP finder:
English: The applicant presented his rationale in writing and at an oral explanation.
Danish: Ansøgeren forelagde sit rationale skriftligt og ved en mundtlig høring.
English: This is in agreement with the conclusions of the Scientific Advisory Group (SAG) consulted.
Danish: Dette svarer til konklusionerne fra den videnskabelige rådgivende gruppe, som er blevet rådspurgt.
English: Scientific conclusions and grounds for refusal of the variation presented by the European Medicines Agency
Danish: Videnskabelige konklusioner og begrundelse for afslaget på ændringsansøgningen fremlagt af Det Europæiske Lægemiddelagentur
English: In addition, some assessments may have been influenced by knowledge of progression status.
Danish: Desuden kan visse vurderinger være blevet påvirket af kendskabet til progressionsstatus.
English: However, there are no established methods of analysis that can remedy this after cross-over has occurred.
Danish: Der findes imidlertid ingen anerkendte analysemetoder, som kan afhjælpe dette efter at overkrydsning har fundet sted.
English: Overall, the toxicity of bevacizumab in this regimen and combination did not, in itself, raise major concerns.
Danish: Overordnet gav toksiciteten af bevacizumab i dette behandlingsregime og i denne kombination ikke i sig selv anledning til større betænkeligheder.
English: Disease progression was assessed using adapted Macdonald criteria (Chinot et al., 2013).
Danish: Sygdomsprogression blev vurderet efter modificerede Macdonaldkriterier (Chinot et al., 2013).
English: Similar limitations apply to the determination of performance status.
Danish: Tilsvarende begrænsninger gælder for fastlæggelse af præstationsstatus
English: However, in this analysis, progressive disease (which suffers of the limitations described above) was included as a deterioration event.
Danish: I analysen blev progressiv sygdom (som er behæftet med ovennævnte begrænsninger) imidlertid medregnet som en forværringshændelse.
English: These analyses should be interpreted with caution since relevant data were not collected systematically after disease progression and the consequent impact of (potentially informative) censoring on the results is unclear.
Danish: Disse analyser bør tolkes med forsigtighed, da der efter sygdomsprogression ikke systematisk indsamledes relevante data, og den deraf følgende virkning af censurering (potentielt af informationer) af resultaterne er uklar.
English: This analysis resulted in an estimated benefit of smaller magnitude, based on an analysis that, necessarily but problematically, introduces some informative censoring.
Danish: Denne analyse resulterede i en skønnet fordel, som var mindre, baseret på en analyse, som nødvendigvis, men problematisk, indfører nogen censurering af oplysninger.
English: These apparent responses are not always necessarily indicative of a true antiglioma effect.
Danish: Denne tilsyneladende respons er ikke altid nødvendigvis et tegn på en egentlig virkning mod gliom.
English: According to this analysis, 84% of the PFS events could be considered unequivocal.
Danish: Ifølge denne analyse kunne 84 % af hændelserne vedrørende progressionsfri overlevelse anses for klare.
English: Bevacizumab was administered at a dose of 10 mg/kg every two weeks in the concurrent phase and the maintenance phase, and at a dose of 15 mg/kg every three weeks in the monotherapy phase.
Danish: Bevacizumab blev administreret i en dosis på 10 mg/kg hver anden uge i den sideløbende fase og vedligeholdelsesfasen og i en dosis på 15 mg/kg hver tredje uge i monoterapifasen.
English: Summary of the applicant's response to the grounds for re-examination:
Danish: Sammenfatning af ansøgerens begrundelse for fornyet overvejelse:
English: Changes in corticosteroid use, normally considered indicative for disease progression are confounded by the overlapping physiological effects of corticosteroids and bevacizumab.
Danish: Ændringer i kortikosteroidforbrug, der normalt anses for tegn på sygdomsprogression, konfunderes af overlapningen mellem de fysiologiske virkninger af kortikosteroider og bevacizumab.
English: • In the absence of established efficacy, a positive benefit-risk balance has not been established.
Danish: • at der i mangel af dokumenteret virkning ikke er påvist et positivt benefit/risk-forhold.
English: However, in the absence of established efficacy, the toxicity of this regiment cannot be considered acceptable.
Danish: I mangel af dokumenteret virkning kan toksiciteten af dette behandlingsregime imidlertid ikke anses for acceptabel.
English: Regarding the MRI evaluation of disease progression, the CHMP maintained the view that the impact of the use of adapted criteria in Study BO21990 remains unclear.
Danish: Vedrørende MRI-vurderingen af sygdomsprogression fastholdt CHMP, at betydningen af anvendelsen af modificerede kriterier i undersøgelse BO21990 fortsat er uklar.
English: Although standard response assessment criteria have been further developed (RANO criteria) aiming to minimise this issue and inform treatment decisions, validation of these criteria as clinical benefit endpoints is still ongoing (Wen et al., 2010).
Danish: Skønt standardkriterierne for responsvurdering er blevet videreudviklet (RANO-kriterierne) for at minimere dette problem og danne grundlag for afgørelser om behandling, pågår der fortsat en validering af disse kriterier som endepunkter for klinisk fordel (Wen et al.,2010).
English: Several strategies were applied prospectively in Avaglio in order to minimize the possibility of incorrectly interpreting the MRI scan including implementation of an algorithm for the determination of pseudo-progression.
Danish: Der er prospektivt anvendt flere forskellige strategier i Avaglio til at minimere muligheden for ukorrekt fortolkning af MR-skanningerne, herunder en algoritme til bestemmelse af pseudoprogression.
English: Regarding clinical outcomes, the applicant proposed that only maintenance of QoL to the time of disease progression may be expected, and this can be accepted.
Danish: Vedrørende de kliniske resultater fremførte ansøgeren, at livskvaliteten kun kan forventes opretholdt til tidspunktet for sygdomsprogression, hvilket kan godtages.
English: Finally, the applicant provided a post-hoc analysis in line with the RANO criteria (Wen et al., 2010), which are the current standard used in clinical trials.
Danish: Endelig forelagde ansøgeren en post hoc-analyse i henhold til RANO-kriterierne (Wen et al., 2010), som er den nuværende standard i kliniske undersøgelser.
English: The number of PD events may have been overestimated in the placebo arm and underestimated in the bevacizumab arm.
Danish: Antallet af hændelser knyttet til sygdomsprogression kan være blevet overvurderet i placeboarmen og undervurderet i bevacizumab-armen.
English: In particular, the applicant did not clearly justify how the criteria chosen to exclude specific patients or events in the various sensitivity analyses were able to address the biases/uncertainties around the assessment of progression.
Danish: Navnlig har ansøgeren ikke klart redegjort for, hvordan de valgte kriterier for udelukkelse af bestemte patienter eller hændelser i de forskellige følsomhedsanalyser tog højde for skævheder/usikkerheder omkring vurderingen af progression.
English: While the Applicant acknowledged that limited data was captured beyond the time of progression, they contended that this does not diminish the value of the data captured on study.
Danish: Ansøgeren vedgik, at der kun var indsamlet begrænsede data efter progressionstidspunktet, men hævdede, at dette ikke nedsætter værdien af de data, der er indsamlet i undersøgelsen.
English: The median PFS was estimated to be 10.6 months in the bevacizumab arm and 6.2 months in the placebo arm.
Danish: Den mediane progressionsfrie overlevelse beregnedes til 10,6 måneder i bevacizumab-armen og 6,2 måneder i placeboarmen.
English: The CHMP assessed all the detailed grounds for re-examination and argumentations presented by the applicant.
Danish: CHMP gennemgik alle punkter i ansøgerens detaljerede begrundelse for fornyet overvejelse og argumentation.
English: Recommendations following re-examination
Danish: Anbefalinger vedrørende fornyet overvejelse
English: Due to these reasons, the clinical relevance of the observed difference in the primary analysis of PFS is unknown.
Danish: Af disse grunde er den kliniske relevans af den observerede forskel i den primære analyse af progressionsfri overlevelse ukendt.
English: Radiotherapy and TMZ were administered in line with standard regimens used in the setting of newly diagnosed glioblastoma (Stupp et al., 2005).
Danish: Strålebehandling og temozolomid blev administreret i henhold til standardregimer, der anvendes ved nydiagnosticeret glioblastom (Stupp et al., 2005).
English: Furthermore, it was unclear to what extent HRQoL data collection could have been influenced by knowledge of the response status.
Danish: Desuden var det uklart, i hvilket omfang indsamlingen af data om helbredsrelateret livskvalitet kan være blevet påvirket af kendskabet til responsstatus.
English: While the applicant acknowledged that there is an on-going evolution of the criteria used to assess disease progression in brain tumours, they contended that the criteria used in Avaglio study represent the most advanced and accepted technology in line with expert recommendations.
Danish: Ansøgeren vedgik, at der pågår en løbende udvikling af de kriterier, der anvendes til vurdering af sygdomsprogression ved hjernetumorer, men hævdede, at de anvendte kriterier i Avaglio-undersøgelsen repræsenterer den mest avancerede og anerkendte teknologi i henhold til ekspertanbefalinger.
English: The most frequent toxicity associated with the bevacizumab treatment group were gastrointestinal (nausea, constipation, vomiting), alopecia, fatigue, thrombocytopenia, headache and hypertension.
Danish: De hyppigste toksiske virkninger i bevacizumab-gruppen var gastrointestinale virkninger (kvalme, konstipation, opkastning), alopeci, træthed, trombocytopeni, hovedpine og hypertension.
English: At the time of disease progression, the data indicated a trend for deterioration in functional status and HRQoL compared to the assessments prior to progression, which underscores the clinical importance for the patients of delaying the time until disease progression.
Danish: På tidspunktet for sygdomsprogression viste dataene tendens til forringelse af funktionel status og helbredsrelateret livskvalitet i forhold til før progression, hvilket vidner om den kliniske betydning for patienterne af forlængelse af tiden til sygdomsprogression.
English: The demonstration of efficacy was based on a randomized, double-blind, placebo controlled, multicenter phase III trial (study BO21990, “AVAglio”) of bevacizumab, temozolomide and radiotherapy (concomitant phase) followed by bevacizumab and temozolomide (maintenance phase) followed by bevacizumab (monotherapy phase) versus placebo, temozolomide (TMZ) and radiotherapy followed by placebo and temozolomide followed by placebo in patients with newly diagnosed glioblastoma (GBM).
Danish: Påvisningen af virkning var baseret på en randomiseret, dobbeltblindet, placebokontrolleret fase III-multicenterundersøgelse (BO21990, “AVAglio”) af bevacizumab, temozolomid og strålebehandling (samtidig fase) efterfulgt af bevacizumab og temozolomid (vedligeholdelsesfase) efterfulgt af bevacizumab (monoterapifase), sammenlignet med placebo, temozolomid og strålebehandling efterfulgt af placebo og temozolomid efterfulgt af placebo, hos patienter med nydiagnosticeret glioblastom.
English: The results of the post hoc analysis according to the RANO criteria were not considered sufficiently robust to resolve the uncertainties around the PFS results.
Danish: Resultaterne af post hoc-analysen i henhold til RANO-kriterierne blev ikke anset for tilstrækkelig robuste til at afklare usikkerhederne omkring resultaterne for progressionsfri overlevelse.
English: All the additional analyses cannot exclude the possibility of important bias and the estimated effect is not regarded as sufficiently reliable to conclude that a clinically relevant therapeutic efficacy has been established.
Danish: Ingen af de supplerende analyser kan udelukke muligheden for betydelig skævhed, og den skønnede virkning anses ikke for tilstrækkelig sikker til at konkludere, at der er fastslået en klinisk relevant terapeutisk virkning.
English: Overall the conclusion on the efficacy of bevacizumab in this setting was that the clinical relevance of the observed effect on PFS cannot be determined and that a relevant effect has not been established on the basis of any other clinical relevant endpoint.
Danish: Overordnet konkluderes det om virkningen af bevacizumab i dette scenarie, at det ikke er muligt at fastslå den kliniske relevans af den iagttagne virkning på progressionsfri overlevelse, og at der ikke er konstateret relevant virkning på grundlag af noget andet klinisk relevant endepunkt.
English: Nominally, statistically significant results were retained for some parameters when PD was not counted as a deterioration event.
Danish: Nominelt opnåedes signifikante resultater for visse parametre, når sygdomsprogression ikke blev anset som en forværringshændelse.
English: The SAG also commented on the long survival observed for numerous patients with early progression and concluded that this finding was counterintuitive and possibly a further indication of the lack of clinical meaningfulness of the PFS adjudication criteria used in the study.
Danish: Den videnskabelige rådgivende gruppe kommenterede også den lange overlevelse af mange patienter med tidlig progression og konkluderede, at dette fund var kontraintuitivt og muligvis et yderligere tegn på den manglende kliniske betydning af vurderingen af progressionsfri overlevelse i undersøgelsen.
English: Arterial thromboembolic events, mainly ischaemic strokes, were observed at a slightly higher incidence rate in this trial (5.0%) than in previous bevacizumab trials (up to 3.8% in combination with different chemotherapies), and higher than in the placebo group (1.6%).
Danish: I denne undersøgelse blev der iagttaget lidt højere forekomst af arterielle tromboemboliske hændelser, hovedsagelig iskæmisk apopleksi (5,0 %), end i tidligere undersøgelser med bevacizumab (op til 3,8 % i kombination med forskellige kemoterapeutika), og højere end i placebogruppen (1,6 %).
English: An effect was claimed based on analysis of the secondary endpoint time to definitive deterioration in HRQoL.
Danish: Der blev påberåbt virkning baseret på analyse af det sekundære endepunkt tiden til definitiv forværring i helbredsrelateret livskvalitet.
English: However, the CHMP concluded that the positive effects claimed by the applicant are mainly driven by the inclusion of PD as an event in these analyses, and therefore, they cannot provide independent support or insight into the clinical benefits of delaying progression.
Danish: CHMP konkluderede imidlertid, at de positive virkninger, der påberåbes af ansøgeren, hovedsagelig skyldes medregning af sygdomsprogression som hændelse i analyserne og derfor ikke tilstrækkeligt underbygger eller belyser de kliniske fordele ved at forsinke progressionen.
English: Concerning overall survival, the CHMP acknowledged that no OS benefit had been observed in Study BO21990, a finding consistent with the result of the RTOG 0825 trial.
Danish: For total overlevelse konstaterede CHMP, at der ikke er iagttaget nogen fordel i total overlevelse i undersøgelse BO21990, hvilket er i overensstemmelse med resultatet af undersøgelse RTOG 0825.
English: Clinical relevance of PFS: The applicant considered that Avaglio study used a variety of validated and reliable measures to assess the clinical status that captured the patient's perspective (health-related quality of life [HRQOL]), neurocognitive function (Mini Mental Status Examination [MMSE]), and functional status (Karnofsky Performance Status [KPS]).
Danish: Den kliniske relevans af progressionsfri overlevelse: Ansøgeren fandt, at Avaglioundersøgelsen anvendte en række forskellige validerede og pålidelige målinger til vurdering af den kliniske status, som inddrog patientens synsvinkel (helbredsrelateret livskvalitet, neurokognitiv funktion (Mini Mental Status Examination (MMSE)) og funktionel status (Karnofsky Performance Status (KPS)).
English: In conclusion, as the clinical relevance of the efficacy results is uncertain, and the benefit-risk balance of bevacizumab as an add-on therapy to standard of care for newly diagnosed glioblastoma is considered negative.
Danish: Som konklusion er den kliniske relevans af resultaterne vedrørende virkning usikker, og benefit/risk-forholdet for bevacizumab som tillæg til standardbehandling af nydiagnosticeret glioblastom anses for negativt.
English: No new safety signals with bevacizumab were observed in study BO21990, but there was a higher incidence of Grade 3 and 4 AEs, SAEs, non-progression deaths, and discontinuations of treatment in the bevacizumab group.
Danish: Der blev ikke iagttaget nye sikkerhedssignaler med bevacizumab i undersøgelse BO21990, men i bevacizumab-gruppen var der højere forekomst af bivirkninger af grad 3 og 4, alvorlige bivirkninger, dødsfald uden progression samt seponering af behandlingen.
English: Key post-hoc sensitivity analyses that took into account the concerns raised by the CHMP on the reliability of the imaging technique to detect disease progression excluded patients 1) with potential or confirmed pseudo-progression, 2) with possible pseudo-progression in the Pl+RT/T arm and possible pseudo-response in the Bv+RT/T arm and 3) with PFS < Day 93 to avoid any potential impact of pseudo-progression and post-radiation imaging changes at the first disease assessment.
Danish: De vigtigste post hoc-følsomhedsanalyser til imødegåelse af CHMP's betænkeligheder vedrørende pålideligheden af billeddannelsesteknik til påvisning af sygdomsprogression udelukkede patienter 1) med potentiel eller bekræftet pseudoprogression, 2) med mulig pseudoprogression i Pl+RT/T-armen og mulig pseudorespons i Bv+RT/T-armen og 3) med progressionsfri overlevelse < dag 93.
English: Reliability of PFS: The applicant considered that the robustness and reliability of the primary analysis of PFS was confirmed in a number of predefined and post-hoc sensitivity analyses.
Danish: Pålideligheden af progressionsfri overlevelse: Ansøgeren fandt, at robustheden og pålideligheden af den primære analyse af progressionsfri overlevelse bekræftedes af en række analyser, dels prædefinerede, dels post hoc.
English: It has not been established that the most likely cause for the failure to demonstrate an OS benefit is confounded by post-progression treatments (including crossover to bevacizumab) rather than lack of an effect.
Danish: Det er ikke sandsynliggjort, at den manglende påvisning af en fordel i total overlevelse i højere grad end manglende virkning skyldes konfundering som følge af behandlinger foretaget efter sygdomsprogression (herunder overkrydsning til bevacizumab).
English: The analyses of the secondary endpoint health-related quality of life (HRQoL) did not show an advantage of addition of bevacizumab to standard treatment.
Danish: Analyserne af det sekundære endepunkt, helbredsrelateret livskvalitet, viste ingen fordel af bevacizumab som tillæg til standardbehandling.
English: The applicant provided an additional post-hoc PFS analysis where all progressions exclusively based on non-index lesions were not regarded as a PFS event.
Danish: Ansøgeren fremlagde en supplerende post hoc-analyse af progressionsfri overlevelse, hvor alle de progressioner, der udelukkende baseret var på ikke indicerede forandringer, ikke blev betragtet som hændelser knyttet til progressionsfri overlevelse.
English: The primary analysis of PFS showed a statistically significant difference in favour of bevacizumab (HR 0.64, 95%CI 0.55-0.74; p<0.0001).
Danish: Den primære analyse af progressionsfri overlevelse viste statistisk signifikant forskel i bevacizumabs favør (HR 0,64, 95 % SI [0,55; 0,74], p<0,0001).
English: The applicant did not convincingly show that the sensitivity analyses performed were able to mitigate the risk of systematic biases in the evaluation of PFS and were adequate to provide sufficient reassurance that bevacizumab produces a PFS increase of clinically important magnitude.
Danish: Ansøgeren har ikke overbevisende godtgjort, at de udførte følsomhedsanalyser kunne afbøde risikoen for systematiske skævheder i vurderingen af progressionsfri overlevelse eller var tilstrækkelige til at sikre, at bevacizumab bevirker en klinisk betydningsfuld forlængelse af progressionsfri overlevelse.
English: Study methodology including imaging and disease assessment criteria: The applicant considered that the pivotal study (Avaglio) was designed using standard methodology in GBM for the assessment of tumour growth and followed the current clinical practice.
Danish: Undersøgelsens metodologi, herunder kriterierne for vurdering af billeddannelse og sygdom: Ansøgeren fandt, at hovedundersøgelsen (Avaglio) var tilrettelagt med standardmetoder til vurdering af tumorvækst ved glioblastoma multiforme og fulgte den nuværende kliniske praksis.
English: According to the applicant, the KPS results showed a delay in time to definitive deterioration in KPS in favour of bevacizumab irrespective of whether PD was included (pre-specified) or excluded (exploratory) as an event.
Danish: Ifølge ansøgeren sås en forlængelse af tiden til definitiv forværring af KPS til i bevacizumabs favør uanset om progressiv sygdom blev medtaget (præspecificeret) eller blev udelukket (orienterende) som en hændelse.
English: The analysis OS showed no statistically significant difference in survival time between the bevacizumab arm and the placebo arm (HR 0.89, 95% CI 0.75-1.07, p=0.2135).
Danish: Analyserne af total overlevelse viste ingen statistisk signifikant forskel i overlevelsestid mellem bevacizumab og placeboarmen (HR 0,89, 95 % SI [0,75; 1,07], p=0,2135).
English: Thus, the CHMP maintained the view that it was not possible to estimate with sufficient confidence the magnitude of the gain in tumour control provided by bevacizumab when added to standard of care.
Danish: CHMP fastholdt derfor, at det ikke med tilstrækkelig sikkerhed kan beregnes, hvor stor en forøgelse af tumorkontrol der opnås med bevacizumab som tillæg til standardbehandling.
English: • The efficacy of bevacizumab in combination with radiotherapy and temozolomide for the treatment of adult patients with newly diagnosed glioblastoma has not been sufficiently demonstrated;
Danish: • at virkningen af bevacizumab i kombination med strålebehandling og temozolomid til behandling af voksne patienter med nydiagnosticeret glioblastom ikke er tilstrækkeligt påvist, og
English: The observed efficacy results in study BO21990 were overall consistent with the results reported from another trial investigating the effect of bevacizumab in glioblastoma (RTOG0825), i.e., no effect on OS, no benefit in terms of HRQoL, and possibly even a detriment in neurocognitive functioning (as suggested in study RTOG0825).
Danish: De iagttagne resultater for virkning i undersøgelse BO21990 svarede overvejende til dem, der beskrives fra en anden undersøgelse af virkningen af bevacizumab ved glioblastom (RTOG0825), dvs. ingen virkning på samlet overlevelse, ingen fordel i helbredsrelateret livskvalitet, og muligvis endda skadelig virkning på kognitiv funktion (som undersøgelse RTOG0825 tyder på).