The European Regulatory System includes the EMA, the European Commission and the fifty regulatory authorities of the thirty-one countries of the European Economic Area who work with ICH and WHO to ensure compliance with good clinical, manufacturing and distribution practices by manufacturers to provide effective, safe and quality medicines. Directive 2001/83/EC is the reference legislation applicable to all medicinal products produced industrially for human use, as it establishes the set of requirements necessary for the evaluation of an application for a marketing authorisation. In the European Union two authorisation procedures are established: national and community authorisations (centralised, mutual recognition and decentralised procedure). For each type of procedure, the developer can submit complete or simplified applications based on the characteristics of the drug for which approval is requested and following the criteria established by the regulatory authorities. The EMA has seven scientific committees that will assess whether the balance between benefits and risks of the drug is positive for the population as a whole. The CP is divided into several phases: 1) Preliminary activity that allows the applicant to ask the EMA for scientific advice on quality, pre-clinical, clinical and statistical tests to be used; 2) Presentation and validation of the CTD, an essential document to describe the fundamental characteristics of the medicinal product, taking into account the guidelines published by the EMA and the European Commission; 3) Scientific evaluation carried out by the CHMP; 4) The European Commission issues the AIC and transforms the scientific decision of the EMA into a legal standard published in the Official Journal of the European Community; 5) Post-authorisation activities. The key principle of the risk-benefit balance is applied during the development of FDCs (Fixed-dose Drug Combination) consisting of two or more APIs present in the final formulation in a fixed ratio, the approval of which requires evidence of safety and efficacy not only of the individual APIs but also of the combination. FDCs formed from previously authorised APIs will be approved on the basis of bioequivalence with the originators and used in an effective and safe regime of medicinal products with the same API, same dosage and therapeutic indication. A new therapeutic approach is represented by the co-formulations of two or more biological products, which in addition to ensuring the beneficial effects of the combination, require further stability, analytical and production studies as they undergo degradation and activity alteration processes. Among the various analytical methods used by the formulator during the development of an FDC, the computational modelling technique emerges, which allows to identify the optimal design space of the co-formulating by superimposing the stability zones of each protein. Among the case studies reported is the Mabthera subcutaneous formulation, approved through a development program that compared SC and IV formulations, evaluating comparability in terms of efficacy and safety and patient preferences for the route of administration used. One failure was the combination of Eylea with Nesvacumab, as the results of the studies conducted did not provide a sufficient difference in terms of safety and efficacy compared to monotherapy with Eylea alone. In conclusion, despite all the benefits derived from biological FDCs, their development is complex and difficult due to biochemical and biophysical instabilities linked to the activity of the individual components and the competent authority will assess the marketing authorisation through an overall positive risk/benefit balance in favour of the population.
Il Sistema normativo Europeo comprende l’EMA, la Commissione Europea e le cinquanta autorità di regolamentazione dei trentuno paesi dello Spazio Economico Europeo che collaborano con ICH e l’OMS per garantire il rispetto delle buone prassi cliniche, di produzione e di distribuzione da parte delle aziende produttrici utili a fornire farmaci efficaci, sicuri e di qualità. La Direttiva 2001/83/CE rappresenta la normativa di riferimento applicabile a tutti i medicinali prodotti industrialmente destinati all’uso umano, in quanto stabilisce l’insieme dei requisiti necessari per la valutazione di una domanda di AIC. Nell’Unione Europea sono stabilite due procedure autorizzative: autorizzazioni nazionali e comunitarie (procedura centralizzata, di mutuo riconoscimento e la procedura decentrata). Per ogni tipologia di procedura, lo sviluppatore può presentare domande complete o semplificate sulla base delle caratteristiche del farmaco di cui si richiede l’approvazione e seguendo i criteri stabiliti dalle autorità regolatorie. L’EMA dispone di sette comitati scientifici che valuteranno se il bilancio tra benefici e rischi del farmaco risulta complessivamente positivo per la popolazione. La CP si articola in varie fasi:1) Attività preliminare che concede all’applicant di richiedere all’EMA la consulenza scientifica riguardo gli aspetti qualitativi, pre-clinici, clinici e i test statistici da utilizzare;2) Presentazione e validazione del CTD, documento essenziale per descrivere le caratteristiche fondamentali del medicinale, tenendo in considerazione le linee guida pubblicate dall’EMA e dalla Commissione Europea;3) Valutazione scientifica effettuata dal CHMP;4) La Commissione Europea rilascia l’AIC e trasforma la decisione scientifica dell’EMA in una norma legale pubblicata nella Gazzetta Ufficiale della Comunità Europea;5) Attività post autorizzazione. Il principio chiave del bilancio rischi-benefici viene applicato durante lo sviluppo di FDC (Fixed-dose Drug Combination) formati da due o più API presenti nella formulazione finale in un rapporto fisso, la cui approvazione richiede prove di sicurezza ed efficacia non solo dei singoli API ma anche prove relative alla combinazione. Gli FDC formati da API precedentemente autorizzati, saranno approvati sulla base della bioequivalenza con gli originatori e utilizzati in un regime efficace e sicuro di medicinali con gli stessi API, stesso dosaggio e indicazione terapeutica. Un nuovo approccio terapeutico, è rappresentato dalle coformulazioni di due o più prodotti biologici, che oltre a garantire gli effetti benefici della combinazione, richiedono ulteriori studi di stabilità, analitici e di produzione in quanto subiscono processi di degradazione e alterazione dell’attività. Tra i vari metodi analitici utilizzati dal formulatore durante lo sviluppo di un FDC, emerge la tecnica della modellazione computazionale che permette di identificare lo spazio di progettazione ottimale della coformulazione attraverso la sovrapposizione delle zone di stabilità di ciascuna proteina. Tra i case studies riportati è presente il Mabthera formulazione sottocutanea, approvato attraverso un programma di sviluppo che confrontava le formulazioni SC e IV, valutando la comparabilità in termini di efficacia e sicurezza e le preferenze del paziente per la via di somministrazione utilizzata. Un fallimento è stata la combinazione di Eylea con Nesvacumab, in quanto i risultati degli studi condotti non hanno fornito una differenza sufficiente in termini di sicurezza ed efficacia rispetto alla monoterapia con solo Eylea.
IL SISTEMA NORMATIVO EUROPEO. CASE STUDY: FIXED DOSE DRUG COMBINATIONS
SCANZANO, MARIA LEONARDA RITA
2019/2020
Abstract
The European Regulatory System includes the EMA, the European Commission and the fifty regulatory authorities of the thirty-one countries of the European Economic Area who work with ICH and WHO to ensure compliance with good clinical, manufacturing and distribution practices by manufacturers to provide effective, safe and quality medicines. Directive 2001/83/EC is the reference legislation applicable to all medicinal products produced industrially for human use, as it establishes the set of requirements necessary for the evaluation of an application for a marketing authorisation. In the European Union two authorisation procedures are established: national and community authorisations (centralised, mutual recognition and decentralised procedure). For each type of procedure, the developer can submit complete or simplified applications based on the characteristics of the drug for which approval is requested and following the criteria established by the regulatory authorities. The EMA has seven scientific committees that will assess whether the balance between benefits and risks of the drug is positive for the population as a whole. The CP is divided into several phases: 1) Preliminary activity that allows the applicant to ask the EMA for scientific advice on quality, pre-clinical, clinical and statistical tests to be used; 2) Presentation and validation of the CTD, an essential document to describe the fundamental characteristics of the medicinal product, taking into account the guidelines published by the EMA and the European Commission; 3) Scientific evaluation carried out by the CHMP; 4) The European Commission issues the AIC and transforms the scientific decision of the EMA into a legal standard published in the Official Journal of the European Community; 5) Post-authorisation activities. The key principle of the risk-benefit balance is applied during the development of FDCs (Fixed-dose Drug Combination) consisting of two or more APIs present in the final formulation in a fixed ratio, the approval of which requires evidence of safety and efficacy not only of the individual APIs but also of the combination. FDCs formed from previously authorised APIs will be approved on the basis of bioequivalence with the originators and used in an effective and safe regime of medicinal products with the same API, same dosage and therapeutic indication. A new therapeutic approach is represented by the co-formulations of two or more biological products, which in addition to ensuring the beneficial effects of the combination, require further stability, analytical and production studies as they undergo degradation and activity alteration processes. Among the various analytical methods used by the formulator during the development of an FDC, the computational modelling technique emerges, which allows to identify the optimal design space of the co-formulating by superimposing the stability zones of each protein. Among the case studies reported is the Mabthera subcutaneous formulation, approved through a development program that compared SC and IV formulations, evaluating comparability in terms of efficacy and safety and patient preferences for the route of administration used. One failure was the combination of Eylea with Nesvacumab, as the results of the studies conducted did not provide a sufficient difference in terms of safety and efficacy compared to monotherapy with Eylea alone. In conclusion, despite all the benefits derived from biological FDCs, their development is complex and difficult due to biochemical and biophysical instabilities linked to the activity of the individual components and the competent authority will assess the marketing authorisation through an overall positive risk/benefit balance in favour of the population.È consentito all'utente scaricare e condividere i documenti disponibili a testo pieno in UNITESI UNIPV nel rispetto della licenza Creative Commons del tipo CC BY NC ND.
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https://hdl.handle.net/20.500.14239/11809