natgillin/translations-raw huggingface dataset:
The high CV may therefore just reflect a sufficiently large difference between the performance of the compared products.
Velik koeficient variacije tako morda odraža dovolj veliko razliko med zmogljivostjo primerjanih zdravil.
The reference product is Reminyl 8mg/16mg and 24mg in the form of prolonged release capsules.
Referenčno zdravilo je Reminyl 8 mg/16 mg in 24 mg v obliki kapsul s podaljšanim sproščanjem.
A single dose study with 24 mg was considered to be acceptable due to the poor tolerability of galantamine in patients and in healthy volunteers, provided that the following multiple dose study was performed, which included the 24 mg dose:
Študija z enim 24-miligramskim odmerkom se je štela za sprejemljivo zaradi slabega prenašanja galantamina pri bolnikih in zdravih prostovoljcih, če je bila izvedena naslednja študija z več odmerki, v katero je bil vključen 24-miligramski odmerek:
The two other ways of calculations (Cpd and Ctrough) were conducted post hoc after it became apparent that prespecified Cminss data did not result in acceptable 90%CI.
Druga načina izračuna (Cpd in Ctrough) sta bila opravljena post hoc potem, ko je postalo jasno, da predhodno določeni podatki za vrednost Cminss ne dajo sprejemljivega 90odstotnega intervala zaupanja.
In addition the CHMP was also of the view that for cholinesterase inhibitors like galantamine, the relationship between administered dose and therapeutic effect is not entirely clear, and for this reason the results from the bioequivalence studies are considered to be of primary importance in this application.
CHMP je tudi menil, da za zaviralce holinesteraze, kot je galantamin, zveza med uporabljenim odmerkom in terapevtskim učinkom ni povsem jasna, zato se šteje, da so rezultati študije biološke enakovrednosti v tej vlogi primarnega pomena.
Furthermore as mentioned previously the Cpd and Ctrough definitions are indeed considered post-hoc, introducing an unacceptable level of bias.
Poleg tega sta omenjeni opredelitvi vrednosti Cpd in Ctrough dejansko obravnavani post hoc, kar uvede nesprejemljivo raven napake.
The three single dose studies were carried out using the 8 and 16mg strengths:
Tri študije z enim odmerkom so bile izvedene z jakostma 8 in 16 mg:
All bioequivalence criteria were fulfilled in this study, except for Cmin, which the Applicant originally calculated as the minimum value recorded during 24 hours at steady-state.
V tej študiji so bila izpolnjena vsa merila biološke enakovrednosti, razen za vrednost Cmin, ki jo je predlagatelj prvotno izračunal kot najmanjšo vrednost, zabeleženo v 24 urah dinamičnega ravnovesja.
A single dose study with the 16 mg dose after a high fat meal Single dose studies with the 8 mg and 16 mg formulations demonstrated bioequivalence with the reference product Reminyl (once daily), not only in the conventional bioequivalence range of 80-125%, but in an even tighter range of 90-111% for both AUCt and Cmax.
Študije z enim odmerkom s formulacijama 8 in 16 mg so dokazale biološko enakovrednost z referenčnim zdravilom Reminyl (enkrat dnevno), vendar ne samo v običajnem razponu biološke enakovrednosti 80-125 odstotkov, ampak celo v ožjem razponu 90-111 odstotkov za vrednost AUCt in Cmax.
Additionally the Applicant also presented as supportive data the peak-trough-fluctuation (%PTF) values for all three strengths and an analysis using repeated measurements of Cmin pd at days 10, 11 and 12 (i.e. at the 24 mg dose) of the multiple dose study.
Poleg tega je predlagatelj kot podporne podatke predložil tudi nihanje med najmanjšo in najvišjo koncentracijo (% PTF) za vse tri jakosti ter analizo s ponovitvami meritev vrednosti Cmin pd 10., 11. in 12. dan (tj. za 24-miligramski odmerek) študije z več odmerki.
As apparent from the protocol, Cmin (defined as minimum drug concentration in the dosing interval) was pre-specified as secondary parameter (descriptive statistics) and descriptive Cmin data had already been reported in the initial submission.
Kot je razvidno iz protokola, je bila vrednost Cmin (opredeljena kot najmanjša koncentracija zdravila v odmernem intervalu) predhodno določena kot sekundarni parameter (opisna statistika), o opisnih podatkih vrednosti Cmin pa so že poročali v prvotni vlogi.
If the Cmin values of the test product tend to decrease more than in a reference product, one could also expect lower clinical efficacy of the test product.
Če so vrednosti Cmin za preskušano zdravilo nagnjene k zmanjševanju v večji meri kot za referenčno zdravilo, lahko pričakujemo manjšo klinično učinkovitost preskušanega zdravila.
The CHMP agreed that although there is no explicit recommendation for computing of Cmin for prolonged release products at the present time, recommendations connected to immediate release products cannot be extrapolated to prolonged release products, which differ from immediate release products with respect to the shape of the pharmacokinetic profile.
CHMP se je strinjal, da kljub trenutni odsotnosti izrecnega priporočila za izračun vrednosti Cmin za zdravila s podaljšanim sproščanjem priporočil za zdravila s takojšnim sproščanjem ni možno ekstrapolirati na zdravila s podaljšanim sproščanjem, ki se razlikujejo od zdravil s takojšnim sproščanjem glede oblike farmakokinetičnega profila.
The CHMP was therefore of the view that the risk benefit ratio of Galantamine STADA is negative and that a marketing authorization should not be granted.
CHMP je zato menil, da je razmerje med koristmi in tveganji za zdravilo Galantamine STADA negativno, zato se dovoljenje za promet z zdravilom ne sme odobriti.
The CHMP was of the view that Cmin is considered to be an important rate parameter especially in multiple dose bioequivalence studies, and that demonstration of bioequivalence is of paramount importance.
CHMP je menil, da se vrednost Cmin šteje za pomemben parameter hitrosti, zlasti v študijah biološke enakovrednosti z več odmerki, in da je dokaz biološke enakovrednosti ključnega pomena.
It was clear, that the way for computing Cmin as Cminss was preferred initially, and descriptive statistics for this parameter were submitted in the final study report.
Jasno je bilo, da je bil način izračuna vrednosti Cmin v obliki Cminss prvotno prednostni, v končnem poročilu študije pa je bila predložena opisna statistika za ta parameter.
The Applicant was requested by the CHMP to provide justification for the choice of the method for Cmin calculation in the steady state study and also to discuss which definition of Cmin would best reflect the prolonged release characteristics of the product and allow detection of possible differences between test and reference product.
CHMP je predlagatelja zaprosil, da predloži utemeljitev izbire metode za izračun vrednosti Cmin v dinamičnem ravnovesju ter razpravlja o tem, katera opredelitev vrednosti Cmin bi najbolje odražala značilnost podaljšanega sproščanja zdravila ter omogočila odkrivanje možnih razlik med preskušanim in referenčnim zdravilom.
A study at steady state with the highest strength (24 mg) after gradual dose increase (8 mg and
študija v dinamičnem ravnovesju z največjo jakostjo (24 mg) po postopnem zviševanju odmerka
1) Cminss defined as the lowest concentration on a concentration-time curve at steady-state within one dosing interval including the pre-dose concentration value.
1) Vrednost Cminss opredeljena kot najnižja koncentracija na krivulji koncentracije v odvisnosti od časa v dinamičnem ravnovesju v enem odmernem intervalu, vključno z vrednostjo koncentracije pred odmerkom.
The CHMP concluded that bioequivalence had not been shown and that the pharmacokinetic characteristics suggest inferior performance of Galantamine STADA prolonged release capsules in comparison with the reference product.
Zaključek CHMP je, da biološka enakovrednost ni bila dokazana in da farmakokinetične značilnosti nakazujejo inferiorno zmogljivost zdravila Galantamine STADA kapsule s podaljšanim sproščanjem v primerjavi z referenčnim zdravilom.
3) Cminss defined as the concentration 24 h after the 4th dose immediately before the next dose would be administered (Ctrough)
3) Vrednost Cminss opredeljena kot koncentracija 24 ur po četrtem odmerku tik pred dajanjem naslednjega odmerka (Ctrough).
2) Cminss defined as the concentration immediately before the 4th dose (Cpd)
2) Vrednost Cminss opredeljena kot koncentracija tik pred četrtim odmerkom (Cpd).
The presented results of the single multiple dose steady state study demonstrated that Cmin values after the test product are likely to be substantially lower in comparison to the reference product.
Predstavljeni rezultati študije z več odmerki v dinamičnem ravnovesju so pokazali, da so vrednosti Cmin po preskušanem zdravilu verjetno bistveno nižje v primerjavi z referenčnim zdravilom.
In the study protocol of the multiple dose study, AUCT and Cmaxss after the 24 mg dose were proposed as primary parameters (for which bioequivalence was shown in the conventional bioequivalence range), while Cminss was not defined as primary pharmacokinetic parameter.
V študijskem protokolu študije z več odmerki sta bila kot primarna parametra (za katera je bila biološka enakovrednost dokazana v običajnem razponu biološke enakovrednosti) predlagani vrednosti AUCT in Cmaxss po 24-miligramskem odmerku, vrednost Cminss pa ni bila opredeljena kot primarni farmakokinetični parameter.
IS-CV of the single dose studies had been taken into account for the sample size calculation of the multiple dose study and that the study was not powered for the higher IS-CV of Cminss.
Predlagatelj je razložil, da so vrednost IS-CV iz študij z enim odmerkom upoštevali pri izračunu velikosti vzorca za študijo z več odmerki in da študija ni imela zadostne moči za večje vrednosti IS-CV za Cminss.
It was noted that while Cmin and Ctrough should be the same for immediate release products, they usually differ for prolonged release products.
Ugotovljeno je bilo, da se vrednosti Cmin in Ctrough pri zdravilih s podaljšanim sproščanjem običajno razlikujeta, čeprav bi morali biti enaki kot pri zdravilih s takojšnim sproščanjem.
16 mg for 4 days each with dosing after a light meal).
(8 mg in 16 mg za 4 dni z jemanjem zdravila po lahkem obroku).
However the CHMP noted that since the study did not have a replicate design, the IS-CV may in fact also include differences between products and is not true intra-subject CV.
Vendar je CHMP ugotovil, da študija ni imela zasnove s ponavljanjem, zato IS-CV morda dejansko vključuje razlike med zdraviloma in ni prava vrednost koeficienta variacije znotraj preiskovancev.
Furthermore the pooling of the pre-dose concentrations (Cmin) in the steady state study at day 10/11/12 as a proof of bioequivalence instead of standard non-pooled data (replicate design), was not considered to be acceptable by the CHMP.
Poleg tega je CHMP štel za nesprejemljivo združevanje predodmernih koncentracij (Cmin) v študiji dinamičnega ravnovesja 10., 11. in 12. dan kot dokaz biološke enakovrednosti namesto standardnih nezdruženih podatkov (zasnova s ponovitvami).
Strength Pharmaceutical Form Route of administration
Farmacevtska oblika
A single dose study with the 16 mg dose under fasting conditions
študija z enim odmerkom z jakostjo 16 mg pri teščih preiskovancih,
A single dose study with the 8 mg dose under fasting conditions
študija z enim odmerkom z jakostjo 8 mg pri teščih preiskovancih,
Three single dose studies and one steady state study have been conducted to establish bioequivalence of the prolonged release tablets Galantamine STADA in comparison to the reference product Reminyl prolonged release capsules.
Za določitev biološke enakovrednosti tablet s podaljšanim sproščanjem Galantamine STADA v primerjavi z referenčnim zdravilom Reminyl kapsule s podaljšanim sproščanjem so bile izvedene tri študije z enim odmerkom in ena študija v dinamičnem ravnovesju.
The CHMP were of the view that the requirements of this guideline are clear and they are based on the principle that using a derived parameter (such as %PTF) for the pharmacokinetic evaluation decreases the sensitivity to detect a possible difference between products
Smernica za peroralne in transdermalne odmerne oblike z modificiranim sproščanjem (CPMP/EWP/280/96 corr), kjer je navedeno, da za študije dinamičnega ravnovesja velja naslednje: „Ocenjevanje biološke enakovrednosti temelji na vrednostih AUCτ, Cmax in Cmin ob uporabi podobnih statističnih postopkov kot za formulacije s takojšnjim sproščanjem.“ CHMP je menil, da so zahteve te smernice jasne in temeljijo na načelu, da uporaba izpeljanega parametra (kot je % PTF) za farmakokinetično vrednotenje zmanjša občutljivost za odkrivanje možne razlike med zdravili.
However the CHMP highlighted Section 5 of the current CPMP Note for Guidance on Modified Release Oral and Transdermal Dosage Forms (CPMP/EWP/280/96 corr), which states that the following applies for the steady state study:
Vendar je CHMP poudaril 5. razdelek trenutno veljavnega dokumenta CPMP
Whereas
Jakost
Cminss and peak-trough fluctuation (PTF) were considered as secondary parameters as well as all pharmacokinetic parameters for the other two dosage strengths The multiple dose study was designed to mirror clinical conditions by up-titration of all three doses.
Za drugi dve jakosti so bili obravnavani vsi farmakokinetični parametri.
EU Number
EU Številka
Invented name Strength
Izmišljeno ime Jakost
London, 24 January 2008 Doc.
London, 24. januar 2008 Sklic dok.
If you are in a clinical trial or compassionate use programme and need more information about your treatment, contact the doctor who is giving it to you.
Če ste vključeni v klinično preizkušanje ali program sočutne uporabe ter potrebujete več podatkov o zdravljenju, se obrnite na zdravnika, ki vam je predpisal zdravljenje.
The letter from the company notifying the EMEA of the withdrawal of the application is available here.
Dopis podjetja, s katerim je bila EMEA obveščena o umiku vloge, je na voljo tukaj.
QUESTIONS AND ANSWERS ON THE WITHDRAWAL OF THE MARKETING APPLICATION for SINEREM
VPRAŠANJA IN ODGOVORI GLEDE UMIKA VLOGE ZA DOVOLJENJE ZA PROMET za zdravilo
The application was at day 175 when the company withdrew.
Podjetje je umaknilo vlogo na 175. dan.
What are the consequences of the withdrawal for patients undergoing clinical trials / compassionate use programmes with Sinerem?
Kakšne so posledice umika za bolnike, ki sodelujejo v kliničnih preizkušanjih/programih sočutne uporabe zdravila Sinerem?
After the CHMP had assessed the responses from the company to a list of questions, there were still some unresolved issues outstanding.
Ko je CHMP ocenil odgovore podjetja na seznam vprašanj, je nekaj vprašanj še vedno ostalo nerešenih.
There was one main study of the effectiveness of Sinerem, involving a total of 271 patients with pelvic cancers.
Izvedli so eno glavno študijo učinkovitosti zdravila Sinerem, ki je vključevala skupaj 271 bolnikov z rakom v medeničnem predelu.
The very small size of the particles allows them to be carried in the body, and to enter the lymphatic system.
Zelo majhna velikost delcev jim omogoča, da se prenašajo po telesu in da vstopijo v limfni sistem.
How far into the evaluation was the application when it was withdrawn?
Kako daleč je bil postopek ocenjevanja vloge ob umiku vloge?
What documentation did the company present to support its application to the CHMP?
Katero dokumentacijo je podjetje predložilo CHMP v podporo svoji vlogi?
The effects of Sinerem were first tested in experimental models before being studied in humans.
Učinki zdravila Sinerem so bili najprej preizkušeni s pomočjo izkustvenih modelov, nato pa so jih raziskali pri ljudeh.
The company informed the CHMP that compassionate use programmes using Sinerem are ongoing and will be reconsidered accordingly.
Podjetje je CHMP obvestilo, da programi sočutne uporabe zdravila Sinerem potekajo in bo o njih ponovno razmislilo skladno z navedenim.
Active substance: Superparamagnetic iron oxide nanoparticles stabilised with dextran and sodium citrate
Zdravilna učinkovina: Superparamagnetni nanodelci železovega oksida, stabilizirani z dekstranom in natrijevim citratom
Based on the review of the initial documentation, the CHMP prepares a list of questions at day 120, which is sent to the company.
Na podlagi pregleda začetne dokumentacije CHMP na 120. dan pripravi seznam vprašanj, ki ga pošlje podjetju.
What were the reasons given by the company to withdraw the application?
Kakšni so bili razlogi podjetja za umik vloge?
What was the recommendation of the CHMP at that time?
Kakšno je bilo takrat mnenje CHMP?
It contains extremely small particles of iron oxide (nanoparticles).
Zdravilo vsebuje izjemno majhne delce železovega oksida (nanodelci).
These are part of the lymphatic system, a network of structures in the body involved in body defence (immune system).
Bezgavke predstavljajo del limfnega sistema, mrežo telesnih struktur, ki sodeluje pri obrambi telesa (imunski sistem).
This should help making a difference between normal lymph nodes that contain macrophages and therefore magnetic particles, and lymph nodes that are invaded with cancer cells and contain fewer macrophages and fewer magnetic particles.
Zaradi tega bi morala obstajati razlika med normalnimi bezgavkami, ki vsebujejo makrofage in s tem tudi magnetne delce, ter bezgavkami, v katere so prodrle rakaste celice ter imajo zato manj makrofagov in manj magnetnih delcev.
Following the CHMP's opinion, it usually takes around 2 months for the European Commission to grant a licence.
Ko CHMP izda mnenje, Evropska komisija v približno 2 mesecih izda dovoljenje.
Once the company has supplied responses to the questions, the CHMP reviews them and may, before giving an opinion, ask any remaining questions at day 180.
Ko podjetje pripravi odgovore na vprašanja, jih CHMP pregleda in pred izdajo mnenja lahko na 180. dan zaprosi podjetje še za odgovore na dodatna vprašanja.
On 13 December 2007, Guerbet officially notified the Committee for Medicinal Products for Human Use (CHMP) that it wishes to withdraw its application for a marketing authorisation for Sinerem, intended for diagnostic use for the characterisation of lymph nodes visualised by MRI (magnetic resonance imaging) in the evaluation of primary tumour spread in pelvic cancers.
Podjetje Guerbet je 13. decembra 2007 obvestilo Odbor za zdravila za uporabo v humani medicini (CHMP), da želi umakniti svojo vlogo za dovoljenje za promet z zdravilom Sinerem, ki je namenjeno za uporabo v diagnostiki za karakterizacijo bezgavk, ki postanejo vidne s slikanjem z magnetno resonanco pri ocenjevanju razširitve primarnih tumorjev pri raku v medeničnem predelu.
The patients then had an operation to remove the lymph nodes, and the results of the scans were compared by three different specialist readers to the results obtained when looking at the lymph nodes under a microscope to see if they contained any cancer cells.
Bolniki so nato prestali operacijo za odstranitev bezgavk, rezultate slikanj pa so trije različni specialisti primerjali z rezultati pregledov bezgavk pod mikroskopom, da bi ugotovili morebitno prisotnost rakastih celic.
Sinerem is a powder to be made up into a solution for infusion (drip into a vein).
Zdravilo Sinerem je prašek, ki se uporablja za pripravo suspenzije za infundiranje (vnašanje po kapljicah v veno).
The active substance in Sinerem is iron oxide in the form of nanoparticles in a clear, colloidal (jellylike) solution of dextran, a type of sugar.
Zdravilna učinkovina v zdravilu Sinerem je železov oksid v obliki nanodelcev v bistri, koloidni (gelu podobni) raztopini dekstrana, ki je vrsta sladkorja.
Therefore, at the time of the withdrawal, the CHMP's view was that the benefits of Sinerem as a diagnostic agent in the characterisation of lymph nodes in patients with pelvic cancer had not been sufficiently demonstrated and any benefits did not outweigh the identified risks.
Zato je bil v času umika CHMP mnenja, da koristi zdravila Sinerem kot diagnostičnega sredstva za karakterizacijo bezgavk bolnikov z rakom v medeničnem predelu niso zadostno dokazane in da morebitne koristi niso večje od znanih tveganj.
What is Sinerem?
Kaj je zdravilo Sinerem?
When a cancer is in the process of spreading, the cancer cells travel within the lymphatic system, and can be detected in the lymph nodes.
Kadar je rak v stadiju širjenja, rakaste celice potujejo po limfnem sistemu, zaradi česar jih lahko odkrijemo v bezgavkah.
When exposed to the action of an external magnet as during an MRI scan, the particles become magnetic, and they can be seen more easily on the scan image.
Če se ti delci izpostavijo delovanju zunanjega magneta, kot med slikanjem z magnetno resonanco, se delci namagnetijo, tako da se jih lahko bolje vidi na sliki, dobljeni s slikanjem z magnetno resonanco.
The main concern of the CHMP was that the effectiveness of Sinerem in enhancing the images seen in the MRI scan had not been shown.
Glavni zadržki CHMP so bili, da učinkovitost zdravila Sinerem pri ojačevanju slik, dobljenih s slikanjem z magnetno resonanco, ni bila dokazana.
Based on the review of the data and the company's response to the CHMP list of questions at the time of the withdrawal, the CHMP had some concerns and was of the provisional opinion that Sinerem could not have been approved for diagnostic use for the characterisation of lymph nodes visualised by MRI (magnetic resonance imaging) in the evaluation of primary tumour spread in pelvic cancers.
Na podlagi pregleda podatkov in odgovorov podjetja na seznam vprašanj, ki jih je zastavil CHMP, je imel Odbor v času umika vloge zadržke in bil začasnega mnenja, da za zdravilo Sinerem ni mogoče odobriti dovoljenja za diagnostične namene za karakterizacijo bezgavk, ki postanejo vidne s slikanjem z magnetno resonanco pri ocenjevanju razširitve primarnih tumorjev pri raku v medeničnem predelu.
It was to be used as a ‘contrast agent' to help make internal body structure more visible on the scan.
Zdravilo bi se uporabljalo kot „kontrastno sredstvo”, ki na diagnostični sliki poudari notranje telesne strukture.
How is Sinerem expected to work?
Kako naj bi zdravilo Sinerem delovalo?
Pelvic cancers are cancers affecting organs in the lower abdomen, such as the prostate gland, the bladder, the womb or the cervix.
Rakasta obolenja v medeničnem predelu prizadenejo organe spodnjega dela trebuha, kot so prostata, sečni mehur, maternica ali maternični vrat.
There were inconsistencies between readers regarding any improvement Sinerem may have brought in detecting cancer spread in lymph nodes during an MRI scan, and Sinerem could not therefore be considered as useful in the management of patients with such conditions.
Med strokovnjaki, ki so razlagali slike, ni bilo skladnosti glede morebitnih izboljšav, ki bi jih zdravilo Sinerem lahko imelo pri odkrivanju širjenja raka v bezgavkah med slikanjem z magnetno resonanco, zaradi česar Odbor zdravila Sinerem ni mogel šteti za uporabnega pri zdravljenju bolnikov s takimi stanji.
What was Sinerem expected to be used for?
Za kaj naj bi se zdravilo Sinerem uporabljalo?
Sinerem was to be used in patients with pelvic cancers.
Zdravilo Sinerem naj bi se uporabljalo pri bolnikih z rakom v medeničnem predelu.
Once in the lymphatic system, the nanoparticles are taken up by a certain type of immune system cell called ‘macrophages' within the lymph nodes.
Nanodelce po vstopu v limfni sistem v bezgavkah vsrkava vrsta celic imunskega sistema, ki jih imenujemo „makrofagi”.
The patients underwent two MRI scans to detect any cancer cells in their lymph nodes, one with Sinerem and one without.
Bolnike so dvakrat slikali z magnetno resonanco, da bi ugotovili prisotnost rakastih celic v njihovih bezgavkah, pri čemer so eno slikanje opravili z zdravilom Sinerem, drugo pa brez zdravila.
Sinerem was to be used to see if the cancer was spreading, by helping visualise the patients' lymph nodes.
Zdravilo Sinerem bi se uporabljalo za ugotavljanje morebitnega širjenja raka, in sicer kot pomoč pri prikazovanju bezgavk bolnikov.
Sinerem was to be used as a diagnostic agent in patients undergoing an MRI scan.
Zdravilo Sinerem je bilo namenjeno za uporabo kot diagnostično sredstvo pri bolnikih med slikanjem z magnetno resonanco.
30 May 2013 EMA/318380/2013
25. julij 2013 EMA/318380/2013