FrancophonIA/ELRC3.0 huggingface dataset:
English: Scientific conclusions and grounds for refusal of the variation presented by the European Medicines Agency
Slovenian: Znanstveni zaključki in podlaga za zavrnitev spremembe, ki jo je predstavila Evropska agencija za zdravila
English: • Safety issues
Slovenian: • Vprašanja glede varnosti
English: This is in agreement with the conclusions of the Scientific Advisory Group (SAG) consulted.
Slovenian: To je v skladu z zaključki znanstvene svetovalne skupine, s katero je bilo opravljeno posvetovanje.
English: The applicant presented his rationale in writing and at an oral explanation.
Slovenian: Predlagatelj je predstavil svoja izhodišča v pisni dokumentaciji in ustni obrazložitvi.
English: The CHMP assessed all the detailed grounds for re-examination and argumentations presented by the applicant.
Slovenian: Odbor CHMP je ocenil vse podrobne razloge za ponoven pregled in utemeljitve, ki jih je predložil predlagatelj.
English: Recommendations following re-examination
Slovenian: Priporočila po ponovnem pregledu
English: Summary of the applicant's response to the grounds for re-examination:
Slovenian: Povzetek odgovora predlagatelja za zahtevo za ponoven pregled:
English: However, there are no established methods of analysis that can remedy this after cross-over has occurred.
Slovenian: Vendar ne obstajajo nobene sprejete metode analize, ki lahko to vprašanje rešijo po tem, ko je prišlo do prehoda.
English: However, in this analysis, progressive disease (which suffers of the limitations described above) was included as a deterioration event.
Slovenian: Vendar je bila v to analizo napredujoča bolezen (ki je predmet zgoraj navedenih pomanjkljivosti) vključena kot dogodek poslabšanja.
English: In addition, some assessments may have been influenced by knowledge of progression status.
Slovenian: Poleg tega je na nekatere ocene morda vplivalo poznavanje stanja napredovanja.
English: Disease progression was assessed using adapted Macdonald criteria (Chinot et al., 2013).
Slovenian: Napredovanje bolezni so ocenili po merilih po Macdonaldu (Chinot et al., 2013).
English: This analysis resulted in an estimated benefit of smaller magnitude, based on an analysis that, necessarily but problematically, introduces some informative censoring.
Slovenian: Ta analiza je povzročila ocenjeno korist manjše razsežnosti na podlagi analize, ki nujno, vendar problematično, uvaja nekaj informativnega cenzuriranja.
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.
Slovenian: Te analize je treba tolmačiti previdno, saj ustrezni podatki niso bili zbrani sistematično po napredovanju bolezni in posledični vpliv (morebitno informativnega) cenzuriranja na rezultate ni jasen.
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.
Slovenian: Nazadnje je predlagatelj predložil naknadno analizo po merilih RANO (Wen et al., 2010), ki so trenutni standard v kliničnih preskušanjih.
English: According to this analysis, 84% of the PFS events could be considered unequivocal.
Slovenian: Po podatkih omenjene analize bi lahko 84 % dogodkov preživetja brez napredovanja bolezni šteli za nedvoumne.
English: These apparent responses are not always necessarily indicative of a true antiglioma effect.
Slovenian: Ti očitni odzivi pa ne kažejo nujno na pravi učinek proti gliomu.
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.
Slovenian: Še posebno predlagatelj ni jasno utemeljil, kako so merila, izbrana za izključitev določenih bolnikov ali dogodkov v različnih občutljivostnih analizah, obravnavala odstopanja/negotovosti glede ocene napredovanja.
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.
Slovenian: Čeprav se je predlagatelj strinjal, da so bili omejeni podatki zajeti po času napredovanja bolezni, je zatrjeval, da to ne zmanjša vrednosti podatkov, zajetih s študijo.
English: Other endpoints including corticosteroid use, and sign and symptoms of GMB also need special consideration in light of the nature of the mechanism of bevacizumab.
Slovenian: Druge končne točke, vključno z uporabo kortikosteroidov, ter znake in simptome glioblastoma je treba prav tako posebej obravnavati kar zadeva naravo mehanizma bevacizumaba.
English: Nominally, statistically significant results were retained for some parameters when PD was not counted as a deterioration event.
Slovenian: Nominalno so se statistično pomembni rezultati ohranili za nekatere parametre, kadar se napredujoča bolezen ni štela za dogodek poslabšanja.
English: Changes in corticosteroid use, normally considered indicative for disease progression are confounded by the overlapping physiological effects of corticosteroids and bevacizumab.
Slovenian: Spremembe pri uporabi kortikosteroidov, ki običajno kažejo na napredovanje bolezni, dopolnjujejo prekrivajoči se fiziološki vplivi kortikosteroidov in bevacizumaba.
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).
Slovenian: Čeprav so nadalje razvili merila za oceno standardnega odziva (merila RANO), s katerimi bi zmanjšali to težavo in vplivali na odločitve v zvezi z zdravljenjem, potrditev teh meril kot končnih točk za klinične koristi še poteka (Wen et al., 2010).
English: • Efficacy issues
Slovenian: • Vprašanja glede učinkovitosti
English: Based on the arguments of the applicant and all the supporting data on safety and efficacy, the CHMP re-examined its initial opinion and in its final opinion concluded by majority decision that the efficacy of the above mentioned medicinal product is not sufficiently demonstrated, and, therefore maintains its recommendation for the refusal of the variation of the Marketing Authorisation for the above mentioned medicinal product.
Slovenian: Na podlagi utemeljitev predlagatelja in vseh podpornih podatkov o varnosti in učinkovitosti je odbor CHMP ponovno pregledal svoje prvotno mnenje in z večino sprejel končno mnenje, da učinkovitost zgoraj navedenega zdravila ni bila zadovoljivo dokazana, zaradi česar ostaja pri svojem priporočilu za zavrnitev vloge za spremembo dovoljenja za promet z zdravilom za zgoraj navedeno zdravilo.
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.
Slovenian: Vse dodatne analize ne izključujejo možnosti pomembnega odstopanja, ocenjeni učinek pa ni zadostno zanesljiv, da bi zaključili, da je bila dokazana klinično pomembna terapevtska učinkovitost.
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.
Slovenian: Kar zadeva oceno napredovanja bolezni z magnetnoresonančnim slikanjem je odbor CHMP ostal pri svojem mnenju, da ostaja vpliv uporabe prilagojenih meril v študiji BO21990 nejasen.
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.
Slovenian: Analiza sekundarne končne točke, tj. z zdravjem povezane kakovosti življenja (HRQoL), ni pokazala prednosti dodatka bevacizumaba k standardnemu zdravljenju.
English: • In the absence of established efficacy, a positive benefit-risk balance has not been established.
Slovenian: • zaradi odsotnosti dokazane učinkovitosti pozitivno razmerje med tveganji in koristmi ni bilo dokazano.
English: Similar limitations apply to the determination of performance status.
Slovenian: Podobne pomanjkljivosti veljajo za poslabšanje stanja zmogljivosti.
English: Following the above CHMP opinion, the applicant requested re-examination and submitted on 22 July 2014 its detailed grounds for the request for re-examination of the CHMP opinion recommending the refusal of the granting of the marketing authorisation.
Slovenian: Po zgornjem mnenju odbora CHMP je predlagatelj zahteval ponoven pregled in 22. julija 2014 predstavil podrobne razloge za zahtevo za ponoven pregled mnenja, v katerem je odbor CHMP priporočil zavrnitev vloge za pridobitev dovoljenja za promet z zdravilom.
English: The applicant concluded that despite the obvious flaws and biases of the exploratory survival analyses these analyses indicated a beneficial effect of bevacizumab.
Slovenian: Zato je zaključil, da te analize kljub očitnim napakam in odstopanjem raziskovalnih analiz preživetja kažejo na koristen učinek bevacizumaba.
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.
Slovenian: Bolniki so prejeli 10 mg/kg bevacizumaba vsaka dva tedna v fazi sočasnega zdravljenja in v fazi vzdrževanja ter 15 mg/kg bevacizumaba vsake tri tedne v fazi zdravljenja z enim zdravilom.
English: Radiotherapy and TMZ were administered in line with standard regimens used in the setting of newly diagnosed glioblastoma (Stupp et al., 2005).
Slovenian: Radioterapijo in temozolomid so prejemali skladno s standardnimi režimi zdravljenja novopostavljene diagnoze glioblastoma (Stupp et al., 2005).
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.
Slovenian: Čeprav se je strinjal, da se merila za oceno napredovanja bolezni pri možganskih tumorjih še vedno razvijajo, pa je zatrjeval, da predstavljajo merila, ki so jih uporabili v študiji Avaglio, najbolj napredno in sprejeto tehnologijo v skladu s priporočili strokovnjakov.
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.
Slovenian: Vendar je zaključil, da so pozitivni učinki, ki jih navaja predlagatelj, v glavnem posledica vključitve napredujoče bolezni kot dogodka v te analize in zato ne zagotavljajo neodvisne podpore ali vpogleda v klinične koristi odložitve napredovanja.
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.
Slovenian: Ni bilo dokazano, da je nezmožnost prikaza koristi za celokupno preživetje posledica zdravljenj po napredovanju bolezni (vključno s prehodom na bevacizumab) in ne pomanjkanja učinka.
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).
Slovenian: Dokazovanje učinkovitosti je temeljilo na randomiziranem, dvojno slepem, s placebom nadzorovanem, multicentričnem preskušanju III. faze (študija BO21990, „AVAglio“) bevacizumaba, temozolomida in radioterapije (faza sočasnega zdravljenja), čemur so sledila preskušanja bevacizumaba in temozolomida (faza vzdrževanja), bevacizumaba (faza zdravljenja z enim zdravilom) in placeba, temozolomida (TMZ) in radioterapije, placeba in temozolomida ter nato še placeba pri bolnikih z novopostavljeno diagnozo glioblastoma (GBM).
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;
Slovenian: • učinkovitost bevacizumaba v kombinaciji z radioterapijo in temozolomidom za zdravljenje odraslih bolnikov z novopostavljeno diagnozo glioblastoma ni bila zadovoljivo dokazana;
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.
Slovenian: V času napredovanja bolezni so podatki kazali težnjo za poslabšanje funkcijskega stanja in z zdravjem povezane kakovosti življenja v primerjavi z ocenami pred napredovanjem bolezni, kar poudarja klinični pomen odloga do napredovanja bolezni za bolnika.
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.
Slovenian: Metodologija študije, vključno z merili za slikanje in oceno bolezni: predlagatelj je menil, da je bila ključna študija (Avaglio) zasnovana z uporabo standardne metodologije pri glioblastomu za oceno rasti tumorja in da je študija sledila trenutni klinični praksi.
English: The median PFS was estimated to be 10.6 months in the bevacizumab arm and 6.2 months in the placebo arm.
Slovenian: Mediana preživetja brez napredovanja bolezni je bila ocenjena na 10,6 meseca v skupini, ki je prejemala bevacizumab, in 6,2 meseca v skupini, ki je prejemala placebo.
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.
Slovenian: Zanesljivost preživetja brez napredovanja bolezni: predlagatelj je menil, da je bila robustnost in zanesljivost primarne analize preživetja brez napredovanja bolezni potrjena v številnih predhodno določenih in naknadnih občutljivostnih analizah.
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.
Slovenian: V študiji Avaglio so prospektivno uporabili več strategij, da bi zmanjšali možnost napačnega tolmačenja magnetnoresonančnega slikanja, vključno z uporabo algoritma za določanje navideznega napredovanja.
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.
Slovenian: Predlagatelj je predložil dodatno naknadno analizo preživetja brez napredovanja bolezni, pri kateri vsa napredovanja bolezni, ki so temeljila izključno na neindeksnih lezijah, niso bila obravnavana kot dogodek preživetja brez napredovanja bolezni.
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%).
Slovenian: V tem preskušanju so poročali tudi o nekoliko večji incidenci arterijskih trombemboličnih dogodkov (5,0 %), zlasti ishemičnih kapi, kot pri prejšnjih preskušanjih z bevacizumabom (do 3,8 % v kombinaciji z različnimi kemoterapijami) in večji kot pri skupini, ki je prejemala placebo (1,6 %).
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.
Slovenian: Znanstvena svetovalna skupina je izpostavila tudi dolgo preživetje, ki so ga zabeležili pri številnih bolnikih z zgodnjim napredovanjem bolezni, in zaključila, da je bila ta ugotovitev kontraintuitivna in morda nadalje kaže na pomanjkanje klinične pomembnosti meril za presojanje o preživetju brez napredovanja bolezni, uporabljenih v tej študiji.
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.
Slovenian: Kar zadeva celokupno preživetje je CHMP potrdil, da v študiji BO21990 niso zabeležili nobene koristi za celokupno preživetje, kar je skladno z rezultati preskušanja RTOG 0825.
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.
Slovenian: Kar zadeva klinične izide je predlagatelj predlagal, da se lahko oceni samo vzdrževanje kakovosti življenja do časa napredovanja bolezni, s čimer se odbor CHMP strinja.
English: Furthermore, it was unclear to what extent HRQoL data collection could have been influenced by knowledge of the response status.
Slovenian: Nadalje ni bilo jasno, v kolikšnem obsegu je lahko na zbiranje podatkov o z zdravjem povezani kakovosti življenja vplivalo poznavanje stanja odziva.
English: The most frequent toxicity associated with the bevacizumab treatment group were gastrointestinal (nausea, constipation, vomiting), alopecia, fatigue, thrombocytopenia, headache and hypertension.
Slovenian: Najpogostejši toksični učinki, ki so jih zabeležili pri skupini, ki je prejemala bevacizumab, so bili učinki na prebavila (navzeja, zaprtje, bruhanje), alopecija, utrujenost, trombocitopenija, glavobol in hipertenzija.
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).
Slovenian: Zabeleženi rezultati učinkovitosti v študiji BO21990 so bili na splošno skladni z rezultati iz drugega preskušanja, v katerem so preučevali vpliv bevacizumaba na glioblastom (RTOG0825), tj. brez vpliva na celokupno preživetje, brez koristi na z zdravjem povezano kakovost življenja in morda celo poslabšanje nevrokognitivnega delovanja (kot je bilo predlagano v študiji RTOG0825).
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.
Slovenian: Iz ključnih naknadnih občutljivostnih analiz, ki so upoštevale zadržke, ki jih je izrazil odbor CHMP v zvezi z zanesljivostjo tehnike slikanja za namene odkrivanja napredovanja bolezni, so izključili 1) bolnike s morebitnim ali potrjenim navideznim napredovanjem, 2) bolnike z morebitnim navideznim napredovanjem v skupini, ki je prejemala placebo v kombinaciji z radioterapijo in temozolomidom, in morebitnim navideznim odzivom v skupini, ki je prejemala bevacizumab v kombinaciji z radioterapijo in temozolomidom, ter 3) bolnike s preživetjem brez napredovanja bolezni < 93 dni, da bi se izognili kakršnemu koli morebitnemu vplivu navideznega napredovanja ali sprememb slikanja po obsevanju pri prvi oceni bolezni.
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.
Slovenian: Splošni zaključek o učinkovitosti bevacizumaba v takšnih primerih je, da kliničnega pomena zabeleženega vpliva na preživetje brez napredovanja bolezni ni mogoče določiti in da ustreznega vpliva ni bilo mogoče ugotoviti na podlagi katere kole druge klinično pomembne končne točke.
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]).
Slovenian: Klinični pomen preživetja brez napredovanja bolezni: predlagatelj je menil, da so v študiji Avaglio uporabili več potrjenih in zanesljivih ukrepov za oceno kliničnega stanja, s katero so zajeli vidik bolnika (z zdravjem povezano kakovost življenja [HRQOL]), nevrokognitivno delovanje (kratek preizkus spoznavnih sposobnosti [KPSS]) in funkcijsko stanje (indeks kliničnega stanja po Karnofskyju [KPS]).
English: The number of PD events may have been overestimated in the placebo arm and underestimated in the bevacizumab arm.
Slovenian: Število dogodkov napredujoče bolezni bi lahko bilo preveliko v skupini, ki je prejemala placebo, in premajhno v skupini, ki je prejemala bevacizumab.
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.
Slovenian: Klinični pomen rezultatov učinkovitosti torej ostaja negotov, razmerje med tveganji in koristmi za bevacizumab kot dodatno zdravljenje k standardnemu zdravljenju novopostavljene diagnoze glioblastoma pa se šteje za negativno.
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).
Slovenian: Analiza celokupnega preživetja ni pokazala nobene statistično pomembne razlike v času preživetja med skupino, ki je prejemala bevacizumab, in skupino, ki je prejemala placebo (razmerje ogroženosti 0,89, 95-odstotni interval zaupanja 0,75−1,07; p = 0,2135).
English: Overall conclusion on grounds for re-examination
Slovenian: Splošni zaključek na podlagi ponovnega pregleda
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).
Slovenian: Primarna analiza preživetja brez napredovanja bolezni je pokazala statistično pomembno razliko v korist bevacizumaba (razmerje ogroženosti 0,64, 95-odstotni interval zaupanja 0,55−0,74; p < 0,0001).
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.
Slovenian: Odbor CHMP je zato ostal pri svojem mnenju, da ni bilo mogoče z zadostno gotovostjo oceniti razsežnosti povečanja nadzora nad tumorjem, ki ga povzroča dodatek bevacizumaba k standardnemu zdravljenju.
English: Due to these reasons, the clinical relevance of the observed difference in the primary analysis of PFS is unknown.
Slovenian: Zato klinični pomen zabeležene razlike v primarni analizi preživetja brez napredovanja bolezni ni znan.
English: Absence of OS benefit: According to the applicant, the use of subsequent lines of therapy, that often included bevacizumab, may have confounded the result.
Slovenian: Odsotnost koristi za celokupno preživetje: po mnenju predlagatelja je lahko na rezultate vplivala uporaba posledičnih zdravljenj, ki so pogosto vključevala bevacizumab.
English: Thus, with the evidence provided, the efficacy of bevacizumab has not been convincingly demonstrated.
Slovenian: Učinkovitost bevacizumaba zato ni bila prepričljivo dokazana na podlagi predloženih dokazov.