natgillin/translations-raw huggingface dataset:
Indledningsvis indsendte ansøgeren data, der sammenlignede bivirkningerne uden nogen statistisk analyse, og der blev anmodet om en statistisk sammenligning.
Initially, the Applicant submitted the data comparing the adverse events without any statistical analysis and a statistical comparison was requested.
Enkeltdosis: OR-estimat: 5,67, 95 % CI [1,12; 28,78] p=0,0371 Flerdosis: OR-estimat: 1,41, 95 % CI [0,97; 2,05] p=0,0716
Single dose: OR estimate: 5.67, 95 % CI [1.12; 28.78] p = 0.0371 Multiple dose: OR estimate: 1.41, 95 % CI [0.97; 2.05] p = 0.0716
Det blev derfor fremført, at specifikke undersøgelser af dermal irritation er påkrævet i henhold til de retningslinjer, der henvises til i det ovenstående.
It was therefore argued that specific dermal irritation studies are required according to the guidelines mentioned above.
Fentanyl er 75-100 gange stærkere end parenteral morfin.
Fentanyl is 75-100 times more potent than parenteral morphine.
Derfor blev det vurderet som sikkert at antage, at yderligere undersøgelser ikke ville bibringe væsentlige nye oplysninger til denne positive sikkerhedsprofil, og derfor burde de undgås af hensyn til dyrevelfærden, som det har været almindelig praksis ved andre europæiske procedurer gennem tiden.
For this reason, it was considered reliable to assume that further investigations would not substantially add to this favourable safety profile and should hence be avoided for reasons of animal welfare as has been common practice in other European procedures in the past.
- Ikkekliniske aspekter
- Non-clinical issues
De medlemsstater, der havde gjort indsigelser, var derfor af den overbevisning, at forskellen ikke kun var statistisk signifikant, men at forskellen også var klinisk relevant.
Therefore, the objecting MS were of the view that the difference was not only statistically significant but that the difference was also considered to be clinically relevant.
Det blev derfor fremført, at de ikke kunne anvendes som understøttelse af en lignende sikkerhedsprofil, som det kræves i retningslinjerne.
It was therefore argued that this could not be used as supportive of a similar safety profile as required by the guideline.
Da der på nuværende tidspunkt ikke findes nogen specifikke europæiske retningslinjer for vurderingen af transdermale systemers lokale tolerabilitet, og set i lyset af den tidligere erfaring med markedsføringstilladelser for flere andre depotplastre i EU, bemærkede CHMP, at hudtolerabilitet altid var blevet vurderet som en del af de farmakokinetiske undersøgelser.
As there is currently no explicit EU guidance available on the evaluation of local tolerability of transdermal systems, and considering previous experience with marketing authorisations of several other transdermal patches in the EU, the CHMP noted that skin tolerability had always been assessed as part of the pharmacokinetic studies.
Ansøgeren erkendte, at der kun er blevet udført ikkekliniske enkeltdosisundersøgelser.
The Applicant acknowledged that only non-clinical single dose studies have been performed.
Disse resultater er blevet bekræftet af en sammenlignelig tolerabilitetsprofil, som er fastlagt gennem kliniske undersøgelser (se nedenfor).
These findings have been corroborated by a comparable tolerability profile determined in clinical studies (see below).
Derfor er de krav, der er indeholdt i disse bestemmelser, blevet betragtet som anbefalinger snarere end deciderede krav af de europæiske medlemsstater og ansøgere.
Consequently, the requirements set in these regulations have been taken rather as recommendations by European Member States and applicants in the past than absolute requirements.
De medlemsstater, der havde gjort indsigelser, var af den opfattelse, at undersøgelsesresultaterne skulle analyseres på ny, fordi irritationsdataene oprindelig ikke var blevet vurderet tilstrækkelig grundigt.
The objecting MS were of the view that the study results needed to be reanalysed because initially the irritation data had not been appropriately assessed.
Retningslinjerne for ikkekliniske undersøgelser af lokal tolerance blev udviklet, før transdermale systemer blev indført.
The guideline on non-clinical investigations of local tolerance was developed before the introduction of transdermal systems.
CHMP vurderede dossieret og de tilgængelige data, herunder de spørgsmål, der var rejst af de berørte medlemsstater, der havde gjort indsigelse.
The CHMP assessed the dossier and the available data, including the issues raised by the objecting CMS.
Fentanyl er blevet markedsført som intravenøs bedøvelse siden 1960'erne.
Fentanyl has been marketed as iv anaesthetic since the 1960s.
Hvis der kan opnås enighed om, at irritationsscorer på eller under 1 er uden klinisk relevans, og at mere end 90 % af de rapporterede forekomster ligger inden for dette godkendte interval, ville det som en følge heraf være fejlagtigt udelukkende at basere beslutningen om en potentiel alvorlig risiko på en lille andel (mindre end 4 % (enkeltdosis) henholdsvis 9 % (flerdosis)) af enheden.
If it can be agreed that irritation scores at or below 1 are without clinical relevance and that more than 90 % of the reported incidences are well within this accepted range, it would consequently be erroneous to base the decision about a potential serious risk solely on a small portion (less than 4 % (SD) respectively 9 % (MD)) of the entity.
BILAG I FORTEGNELSE OVER LÆGEMIDLERNES NAVNE, LÆGEMIDDELFORM, STYRKER, INDGIVELSESVEJ, ANSØGERE, INDEHAVERE AF MARKEDSFØRINGSTILLADELSE I MEDLEMSSTATERNE
ANNEX I LIST OF THE NAMES, PHARMACEUTICAL FORM, STRENGTHS OF THE MEDICINAL PRODUCTS, ROUTE OF ADMINISTRATION, APPLICANT IN THE MEMBER STATES
Det gyldige produktresumé, etiketteringen og indlægssedlen er de endelige versioner, der er opnået under koordinationsgruppens procedure.
The valid Summary of Product Characteristics, labelling and package leaflet are the final versions achieved during the Coordination group procedure.
Det aktive stofs effekt og systemiske tolerabilitet forbliver således uændret.
Hence, efficacy and systemic tolerability of the active substance remains unaffected.
Det er vigtigt at understrege, at ansøgeren genskabte den statistisk signifikante produkteffekt for enkeltdosisundersøgelsen (p=0,0371), mens forskellene for flerdosisundersøgelsen ikke var statistisk signifikante (p=0,0716).
More importantly, the Applicant reproduced the statistically significant product effect for the single dose study (p= 0.0371), whereas for the multiple dose study the differences were not statistically significant (p=0.0716).
De medlemsstater, der havde gjort indsigelser, fremførte, at selv om denne undersøgelse hverken var udformet eller havde tilstrækkelig statistisk styrke til at vurdere tolerabilitetsprofilen, tyder dens resultater på en dårligere sikkerhedsprofil for testproduktet.
The objecting MS argued that although this study was neither designed nor powered to assess the tolerability profile, its results suggest a worse safety profile for the test product.
På grund af den mekaniske belastning under fjernelse af det klæbende lag fra overhuden er irritation uundgåelig, hvorfor en smule hudirritation altid vil forekomme ved gentagen anvendelse af depotplastre.
Due to the mechanical stressing during the detachment of the adhesive layer from the upper skin area, irritation is unavoidable; therefore slight skin irritation is always induced by the repetitive use of transdermal patches.
- Kliniske aspekter
- Clinical issues
Referencelægemidlet er Dorogesic 25-100 µg/h, (MAH Janssen-Cilag, Neuss, Tyskland).
The reference medicinal product is Dorogesic 25 - 100 µg/h, (MAH Janssen-Cilag, Neuss, Germany).
Dette beviser, at selv den visuelt påviste mindre stigning i forekomsterne af hudirritation tydeligvis ikke har nogen indvirkning på lægemiddelstoffets permeabilitet i sammenligning med referencelægemidlet.
This proves that even the visually inspected, slightly increased incidence of skin irritations obviously has no further influence on the permeability of the drug substance, if compared to the reference medicinal product.
Med henblik på at bedømme denne indsigelses anvendelighed overvejede CHMP nedenstående punkter:
In order to assess the applicability of this objection, the CHMP took into account that the subsequent points:
For at klarlægge disse betænkeligheders kliniske relevans og vurdere signifikansen af den statistiske analyse udført af de berørte medlemsstater blev følgende punkter taget i betragtning af CHMP:
To clarify the clinical relevance of these concerns and to assess the significance of the statistical analysis performed by the CMS, the following points were considered by the CHMP:
Dette reservoir er lagt ind mellem det lag, der er i kontakt med huden (donorlaget) og filmen på bagsiden.
This reservoir was introduced between the layer exposed to the skin (donor layer) and the backing film.
Fentanyls smertestillende og beroligende effekt foreslås medieret hovedsagelig gennem µ-opioid-receptorer.
The analgesic and sedative action of fentanyl is proposed to be mediated mainly through µ-opioid-receptors.
Fentanyl er et syntetisk opioidanalgetikum, der hører under piperidinderivaterne, og som er kemisk forbundet med petidin.
Fentanyl is a synthetic opioid analgesic, belonging to the piperidine derivatives, and is chemically related to pethidine.
Den berørte medlemsstat, der havde gjort indsigelser, var dog af den opfattelse, at godkendelsen af lægemidlet Fentrix, depotplastre, kan udgøre en potentiel alvorlig risiko for folkesundheden for så vidt angår ikkeklinisk og klinisk sikkerhed.
However, the objecting Concerned Member State (CMS) considered that the authorisation of this medicinal product Fentrix, transdermal patch, may present a potential serious risk to public health on the grounds of non-clinical and clinical safety.
Tværtimod antydede den visuelle inspektion af dataene en større risiko for hudirritation.
On the contrary, the visual inspection of the data was suggestive of a worse skin irritation potential.
Fentanyl har en høj lipid opløselighed, hvilket gør det velegnet til transdermal indgivelse.
Fentanyl has a high lipid solubility which makes it suitable for transdermal administration.
Når plastret er påsat huden, breder lægemidlet sig i det subkutane væv og danner et reservoir.
Once the patch is applied to the skin the drug diffuses in the subcutaneous tissues and forms a reservoir.
Under udførelsen af denne model blev der fundet statistiske forskelle mellem behandlingerne i begge undersøgelser (enkeltdosisundersøgelsen og flerdosisundersøgelsen), og pointoverslaget over odds ratioen var 8,35 i enkeltdosisundersøgelsen og 1,45 i flerdosisundersøgelsen.
Performing this model, statistically significant differences were found between treatments in both studies (the single dose study and the multiple dose study), and the point estimate of the odds ratio was 8.35 in the single dose study and 1.45 in the multiple dose study.
Disse værdier anses på baggrund af de gængse erfaringer for at være i overensstemmelse med resultaterne for andre generiske plastre indeholdende fentanyl.
From experience, these values were considered to be well in line with the results of other fentanyl generic patches.
McNemartesten blev derefter anvendt til at undersøge, hvorvidt der blev observeret signifikante forskelle mellem testproduktet og referenceproduktet i forhold til antallet af patienter, der led af bivirkninger.
The McNemar test was then used investigating whether significant differences between the test and the reference in the number of patients who suffered adverse events were observed or not.
Det nuværende dobbeltlagsplasters dermale tolerabilitet blev i en ikkeklinisk analyse sammenlignet med referencelægemidlet "Dorogesic 25" hos kaniner som en del af de farmakokinetiske undersøgelser A/PK 02-P012 og A/PK 02-P013.
The dermal tolerability of the current bilayer patch formulation was non-clinically analysed in comparison to the reference product “Dorogesic 25” in rabbits as part of the pharmacokinetic studies A/PK 02-P012 and A/PK 02-P013.
Testen tager ikke højde for hændelsernes tidsmæssige udvikling, men kun for, om forsøgspersonen led af bivirkninger i forbindelse med testproduktet, referenceproduktet, begge produkter eller ingen af produkterne.
This test does not take into account the temporal evolution of events - only if the subject suffered adverse events with the test, or with reference, or with both, or with none.
OR-estimaterne ligger tæt på dem, der er rapporteret af de berørte medlemsstater, der havde gjort indsigelse, men er dog ikke helt identiske med dem.
The OR estimates are close to the ones reported by the objecting CMS, although not exactly identical.
Det er en almindeligt anerkendt klinisk realitet, at når det gælder transdermal terapi, er en hudirritationsscore på 1 almindelig og uden videre klinisk relevans.
It is an accepted clinical reality that for transdermal therapy a skin irritation score of 1 is common and without further clinical relevance.
Da det er fastslået, at der ikke er risiko for hudoverfølsomhed ved det aktive stof og alle andre af plastrets hjælpestoffer, hvilket blev bekræftet under kliniske forhold (se nedenfor), kan der ikke forventes at fremkomme flere oplysninger fra yderligere dyreforsøg.
As absence of any sensitising potential is also well-known for the active substance and all other excipients of the patch and could be clinically confirmed (see below), no new information can be reasonably expected from additional studies in animals.
Derfor udførte de berørte medlemsstater, der havde gjort indsigelse, en ny statistisk analyse baseret på en blandet logistisk regressionsmodel, hvor sandsynligheden for at få en bivirkning afhang af både antallet af observationer og behandlinger (faste effekter) og forsøgsperson (som en randomiseret effekt).
Therefore, the objecting CMS performed a new statistical analysis based on a logistic regression mixed model where the likelihood of having an AE depended both on the number of observations and treatments (fixed effects) and subject (as a random effect).
CHMP medtog alle disse aspekter i sine overvejelser og godtog argumentet om, at de tilgængelige kliniske data i tilstrækkelig grad påviser den sammenlignelige lokale tolerabilitet hos Fentrix og Dorogesic.
Taking all these aspects into consideration, the CHMP accepted the argument that the available nonclinical data sufficiently demonstrate the comparable local tolerability of Fentrix and Dorogesic.
Baseret på Kuss' tilgang (Kuss, O.: "How to use SAS for logistic regression with correlated data", SAS User Group International (SUGI) Conference Proceedings 27, Paper 261-27 (2002)) genberegnede ansøgeren den blandede logistiske model i henhold til SAS-proceduren NLMIXED (SAS Version 9.1.3).
SAS User Group International (SUGI) Conference Proceedings 27, Paper 261-27 (2002)), the Applicant recalculated the logistic mixed model using the SAS Procedure NLMIXED (SAS Version 9.1.3).
I hver af de kliniske farmakokinetiske undersøgelser (enkeltdosis- såvel som flerdosisundersøgelsen) bekræftedes det, at for Fentrixplastret var procentdelen af en hudirritationsscore på 0 (ingen irritation), og scoren 1 (minimalt erytem, næsten ikke synligt, scoren beregnes i henhold til FDA's branchevejledning "Skin Irritation and Sensitization Testing of Generic Transdermal Products") nået op på over 90 %.
Each of the clinical pharmacokinetic studies (single dose (SD) as well as multiple dose (MD)), confirmed that for the Fentrix patch, the percentage of skin irritation scores of 0 (no irritation) and score 1 (minimal erythema, barely perceptible, scoring according to the FDA Guidance for industry, Skin Irritation and Sensitization Testing of Generic Transdermal Products) reached more than 90 %.
Enkeltdosisundersøgelse: Den gennemsnitlige score var 0,39 for testproduktet og 0,25 for referenceproduktet.
Single dose study: the mean score for test was 0.39 and 0.25 for the reference.
Nordkanalstrasse 28 20097 Hamburg Tyskland anvendelse
Nordkanalstrasse 28 20097 Hamburg Germany transdermico
I princippet skulle de ikkekliniske data om lokal tolerance af dobbeltlagsplastret have været suppleret af en analyse af risikoen for overfølsomhed.
In principle, the non-clinical data on local tolerance of the bilayer patch should have been complemented by an analysis of its sensitisation potential.
Ansøgeren erkendte, at der kun er blevet udført ikkekliniske enkeltdosisundersøgelser, til trods for at punkt 4.2 "Dermal tolerance testing" i "Note for Guidance on Non-clinical Tolerance Testing of Medicinal Products" (CPMP/SWP/2145/00) angiver, at dermal tolerance skal testes med enkelte og gentagne doser samt en vurdering af risikoen for overfølsomhed.
The Applicant acknowledged that only non-clinical single dose studies have been performed in spite of the fact that section 4.2 “Dermal tolerance testing” of the Note for Guidance on Non-clinical Tolerance Testing of Medicinal Products (CPMP/SWP/2145/00), indicates that dermal tolerance is tested by a single and repeat dose administration and an evaluation of the sensitising potential.
Begge kliniske farmakokinetiske undersøgelser, enkeltdosis- såvel som flerdosisundersøgelser, bekræftede, at Fentrixplastret generelt er veltolereret på menneskelig hud.
Both clinical pharmacokinetic studies, single dose (SD) as well as multiple dose (MD), confirmed that the Fentrix patch is in general well tolerated when applied to the human skin.
Flerdosisundersøgelse: Antallet af observationer af hudirritation med en score over 1 var 77 for testproduktet og 56 for referenceproduktet, hvor antallet af forsøgspersoner med hudirritation var det samme (26).
Multiple dose study: the number of observations with skin irritation above score 1 was 77 for the test and 56 for the reference, in the same number (26) of subjects with skin irritation.
Plastrets fremherskende bestanddele - hovedsageligt to af klæbestofferne - virkede ikke irriterende på marsvins hud, når de blev testet alene i henhold til retningslinjerne CPMP/SWP/2145/00 og OECD 406 (Buehlermetoden).
However, the predominant constituents of the patch - mainly two of the adhesives, were not found to be sensitive to the skin of guinea pigs when tested alone according to guidelines CPMP/SWP/2145/00 and OECD 406 (Buehler method).
De medlemsstater, der havde gjort indsigelser, mente dog, at hjælpestofferne i denne ansøgning afviger kvalitativt fra referenceproduktets hjælpestoffer, og at ansøgeren havde anvendt enkeltlags- i stedet for dobbeltlagsudgaven af plastret i visse ikkekliniske undersøgelser.
However it was the view of the objecting Member States (MS) that the excipients in this application are qualitatively different to those of the reference product and that the Applicant had used the monolayer instead of the bilayer version of the patch in some non-clinical investigations.
Depotplastret påsættes den intakte hud, hvorved det aktive stof med konstant hastighed afgives til det systemiske kredsløb.
Transdermal patches are applied to intact skin in order to deliver at a constant rate the active substance to the systemic circulation.
Valget af det binære endepunkt ("hudreaktioner > 1") indeholdt behandling (testprodukt over for referenceprodukt) og observation (i timer fra første indgivelse) som faste forklarende variabler og en randomiseret effekt på forsøgspersonerne.
Choosing the binary endpoint ("skin reaction > 1") included treatment (test vs. reference) and observation (in h from first administration) as fixed explanatory variables and a random subject effect.
I undersøgelsen A/PK 02-P013 blev en række hudreaktioner vurderet i overensstemmelse med de aktuelle retningslinjer for enkelte test af dermal tolerance (CPMP/SWP/2145/00) og blev bedømt som negligerbare til let irriterende for både testobjektet og referenceplastret.
In Study A/PK 02-P013, skin reactions were assessed in compliance with existing guidance on single dermal tolerance tests (CPMP/SWP/2145/00) and were rated negligible to slightly irritant for both test item and reference patch.
Det hastighedskontrollerende trin i forbindelse med absorptionstiden for lægemidlet er typisk hudens permeabilitet.
The rate controlling step of drug absorption is commonly the permeation through the skin.
Det nuværende dobbeltlagsplaster afviger kun fra de tidligere enkeltlagsplastre i kraft af det ekstra reservoirlag.
The current bilayer patch differs from the earlier monolayer formulation only by the additional insertion of a reservoir layer.
Teknologien med fentanyldepotplastre er blevet anvendt til klinisk smertelindring siden 1991.
The transdermal fentanyl patch technology has been used clinically to provide analgesia since 1991.
På baggrund af biotilgængelighedsundersøgelserne blev det påvist, at Fentrixplastrene er sammenlignelige med referencelægemidlet Dorogesic SMAT.
Based on the bioequivalence studies, Fentrix patches have confirmed comparability to the reference medicinal product, Dorogesic SMAT.
I dag anvendes fentanyl i udbredt grad som bedøvende og smertestillende middel.
Today fentanyl is extensively used as an anaesthetic and analgesic.
Derfor blev det fremført, at der også bør tages højde for de ikkekliniske undersøgelser af enkeltlagsudgaven, når den lokale tolerabilitet vurderes.
For this reason, it was argued that the non-clinical studies testing the monolayer version should also be accounted for when the local tolerability is assessed.
Begrundelsen for dette var, at vurderingen af den lokale tolerance efter gentagne doser var blevet udført under flerdosisbioækvivalensundersøgelsen hos mennesker.
The justification for this was that the evaluation of the local tolerance after repeat dose administration had been carried out during the multiple dose bioequivalence study in humans.
- Det blev betragtet som rimeligt og etisk at vurdere hudtolerabilitet for depotplastre indeholdende opioider som en del af sammenlignende biotilgængelighedsundersøgelser.
- it was considered to be reasonable and ethical to assess skin tolerability of opioid containing transdermal patches as part of comparative bioavailability studies
Det afgørende donorlag er dog fuldstændig identisk i enkeltlags- og dobbeltlagsplastrene.
Nevertheless, the crucial donor layer has the identical composition in both monolayer and bilayer patches.
Ansøgerens begrundelse var, at vurderingen af den lokale tolerance efter gentagne doser er blevet udført under flerdosisbioækvivalensundersøgelsen hos mennesker.
The Applicant's justification was that the evaluation of the local tolerance after repeat dose administration has been carried out during the multiple dose bioequivalence study in humans.
I den statistiske analyse udført af de berørte medlemsstater, der havde gjort indsigelse, er kun en lille procentdel af forekomsterne af hudirritation, beregnet til 3,28 % (enkeltdosis)/8,46 % (flerdosis) for Fentrixplastret og 0,64 % (enkeltdosis)/5,93 % (flerdosis) for referenceplastret,
In the statistical analysis performed by the objecting CMS, only a small percentage of incidences of skin irritations, calculated as 3.28 % (SD)/8.46%(MD) for the Fentrix patch and 0.64 % (SD)/5.93%(MD) for the reference patch, have been included to evaluate the comparability of the safety profile.
Referencemedlemsstaten vurderede, at det var rimeligt og etisk at vurdere hudtolerabilitet for depotplastre indeholdende opioider som en del af sammenlignende biotilgængelighedsundersøgelser.
The RMS considered it to be reasonable and ethical to assess skin tolerability of opioid containing transdermal patches as part of comparative bioavailability studies.
Den er omkring 17 timer for fentanyl efter transdermal indgivelse sammenlignet med parenterale lægemidler og lægemidler, der indgives via slimhinderne, hvor den er på syv timer.
Therefore, the elimination half-life is longer compared to other administration routes, with about 17 h for fentanyl after transdermal administration, compared to parenteral and transmucosal administered drug of 7 h. The release of the drug from the patch is controlled without membrane.