Regulatory framework for advanced therapy medicinal products in Europe and United States

Advanced therapy medicinal products (ATMPs) are a fast-growing field of innovative therapies. The European Union (EU) and the United States (US) are fostering their development. For both regions, ATMPs fall under the regulatory framework of biological products, which determines the legal basis for their development. Sub-classifications of advanced therapies are different between regions, while in EU, there are four major groups, i.e., gene therapy, somatic cell therapy, tissue-engineered therapies, and combined advanced therapies; in US, the sub-classification covers two major groups of products, i.e., gene therapy and cellular therapy. The inclusion criteria that define a gene therapy are equivalent in both regions, and the exclusion criteria are directly related to the indications of the product. In the EU, there is a clear differentiation between cell- and tissue-based products regarding their classification as advanced therapies or coverage by other legal frameworks, whereas in US, there is a broader classification about whether or not these products can be categorized as biologic products. Both in EU and in US, in order to classify a cell- or a tissue-based product as an advanced therapy, it must be ensured that the processing of the cells implies a manipulation that alters their biological characteristics, although the term of manipulation in US differentiates between structural and non-structural cells and tissues. The regulatory terminology used to define ATMPs and their sub-classification reveals some differences between EU and US

Early Access to Medicines: Use of Multicriteria Decision Analysis (MCDA) as a Decision Tool in Catalonia (Spain)

Early access to medicines allows the prescription of a medicine before it is available in the public formulary to patients with severe or rare diseases with high unmet needs who have no authorised therapeutic alternatives available. In this context, consistent decision making is difficult, and a systematic assessment procedure could be useful to tackle complex situations and guarantee the equity of medicines' access. A multidisciplinary panel (MP) conducted four workshops to develop an early access framework based on a reflective multiple criteria decision analysis (MCDA). A set of 12 criteria was agreed: eight quantitative (severity of disease, urgency, efficacy, safety, internal and external validity, therapeutic benefit and plausibility) and four qualitative (therapeutic alternative, existence of precedents, management impact and costs). Quantitative criteria were weighted using a five-point scale. The relative importance of quantitative criteria had mean weights from 4.7 to 3.6, showing its relevance in the decisions. The framework was tested using two case studies, and reliability was assessed by re-test. The re-test revealed no statistical differences, indicating the consistency and replicability of the framework developed. MCDA may help to structure discussions for heterogeneous treatment requests, providing predictability and robustness in decision making involving sensitive and complex situations

Implementing reflective multicriteria decision analysis (MCDA) to assess orphan drugs value in the Catalan Health Service (CatSalut)

Background: orphan medicines show some characteristics that hinder the evaluation of their clinical added value. The often low level of evidence available for orphan drugs, together with a high budget impact and an incremental cost-effectiveness ratio many times higher than drugs used for non-orphan diseases, represent challenges in their appraisal and effective access to clinical use. In order to explore how to handle these hurdles, the Catalan Health Service (CatSalut) began an initiative on a multidimensional assessment of drugs value during the appraisal process. Reflective multicriteria decision analysis (MCDA) using analytical methods was chosen, since it may help to standardise and contextualize all the relevant data related with the drug that could contribute to a decision. The aim of the study was to determine whether the implementation of reflective MCDA methodology could support the decision-making process about orphan medicines in the context of CatSalut. Methods: the assessment and decision-making process for orphan drugs in the Programa d'Harmonització Farmacoterapeutica (PHF) of CatSalut was prioritized to test the implementation of the reflective MCDA both a qualitative and quantitatively. A staged approach was used with the following main steps: selection and structuration of quantitative criteria (Core Model) and qualitative criteria (Contextual Tool), framework scoring and assessment of three orphan drug case studies. This proof-of-concept would grant a continued refinement of the methodology and, if and when validated, its potential integration to other therapeutic areas of the PHF. Results: the final framework was composed by 10 quantitative criteria (Core Model) and 4 qualitative criteria (Contextual Tool) according to the PHF goals being the most important criteria "disease severity", "unmet need", "comparative effectiveness" and "comparative safety /tolerability". The matrix developed for the case studies served as a guide for the selection of the essential information that the decision-makers were expected to include in a framework. The reflective discussion was considered the most relevant phase of the approach to support inputs for health decision-making processes reflecting both drug value and place in therapy. Conclusions: the study showed that reflective MCDA methodology could be implemented to complement the decision-making process in CatSalut, as an aid to determine the clinical added value for orphan medicines. MCDA provided transparency and a structured discussion during the committee meetings, thus increasing transparency and predictability of the relevant items supporting the agreements adopted on orphan drugs access

Caracterització i regulació transcripcional del gen "pfkfb3"

[cat] Els resultats que es presenten en aquesta memòria aporten informació que ens permet donar un pas més en el coneixement de la regulació transcripcional del gen pfkfb3 i conseqüentment de la via glucolítica. En primer lloc, hem localitzat els elements de resposta de HIF-1 al promotor del gen i hem observat que aquests eren essencials per a la resposta a la hipòxia en cèl·lules de glioblastoma humà (T98G) i en fibroblasts embrionaris de ratolí (mEF). Seguidament, hem corroborat la implicació de la progesterona en la regulació del gen pfkfb3, que inicialment havien descrit Hamilton i col·laboradors {Hamilton, 1997 #93}. Hem posat de manifest l'augment d'expressió d'uPFK-2 i del seu mRNA en cèl·lules de càncer de mama (T47D) incubades amb la hormona. A més a més, hem determinat que aquest increment era degut a l'acció dels receptors de progesterona (PR, progesterone receptors). Hem localitzat una possible seqüència consens per aquests receptors (PRE, progesterone response element) al promotor del gen pfkfb3, però encara no hem pogut demostrar si el paper que exerceix la progesterona en la regulació d'aquest gen és a nivell transcripcional o a nivell d'estabilització del seu mRNA. Per comprovar els resultats obtinguts en cèl·lules aïllades, hem estudiat la regulació del gen pfkfb3 in vivo, utilitzant com a model d'experimentació animal la soca de ratolins C57/BL6. Els hem tractat amb STZ i hem observat l'increment d'expressió del mRNA del gen pfkfb3, d'uPFK-2, i de la concentració de Fru-2,6-P2 en el fetge d'animals diabètics. Paral·lelament, hem realitzat l'estudi de la regulació transcripcional del promotor del gen pfkfb3, in vivo, utilitzant la tècnica de transferència gènica per hidrodinàmia. Els resultats obtinguts demostren l'augment de la transcripció del gen en el fetge dels ratolins diabètics en condicions de dejuni. A més, hem realitzat estudis immunohistoquímics dels fetges diabètics i controls, demostrant que l'expressió del gen pfkfb3 es produeix principalment en els hepatòcits proliferants de la zona perivenosa del fetge dels ratolins diabètics. També hem estudiat les vies de senyalització que porten a l'augment d'expressió del gen pfkfb3, demostrant que la via PI3K/Akt/mTOR (activa en aquestes cèl·lules altament proliferants) hi té un paper essencial. Aquests resultats obtinguts sobre la regulació del gen pfkfb3, juntament amb els que ja s'havien descrit {Hamilton, 1997 #93}; {Chesney, 1999 #96}; {Atsumi, 2002 #110}; {Riera, 2002 #113}; {Minchenko, 2002 #144}; {Riera, 2003 #114}; {Bando, 2005 #102}; {Telang, 2006 #106}, ens confirmen la importància que té el fenotip glucolític en les cèl·lules proliferants o tumorals. El gen pfkfb3 controla la síntesi de la Fru-2,6-P2 que, com s'ha explicat a la introducció, és l'activador al·lostèric més potent de l'enzim PFK-1. Per tant, podem considerar que el gen pfkfb3 és clau per a la regulació de la via glucolítica, de manera que el seu augment d'expressió en diferents tipus de cèl·lules proliferants i tumorals condueix a l'activació d'aquesta via i, conseqüentment, afavoreix el canvi cap a un fenotip glucolític

Implementing reflective multicriteria decision analysis (MCDA) to assess orphan drugs value in the Catalan Health Service (CatSalut)

Background: orphan medicines show some characteristics that hinder the evaluation of their clinical added value. The often low level of evidence available for orphan drugs, together with a high budget impact and an incremental cost-effectiveness ratio many times higher than drugs used for non-orphan diseases, represent challenges in their appraisal and effective access to clinical use. In order to explore how to handle these hurdles, the Catalan Health Service (CatSalut) began an initiative on a multidimensional assessment of drugs value during the appraisal process. Reflective multicriteria decision analysis (MCDA) using analytical methods was chosen, since it may help to standardise and contextualize all the relevant data related with the drug that could contribute to a decision. The aim of the study was to determine whether the implementation of reflective MCDA methodology could support the decision-making process about orphan medicines in the context of CatSalut. Methods: the assessment and decision-making process for orphan drugs in the Programa d'Harmonització Farmacoterapeutica (PHF) of CatSalut was prioritized to test the implementation of the reflective MCDA both a qualitative and quantitatively. A staged approach was used with the following main steps: selection and structuration of quantitative criteria (Core Model) and qualitative criteria (Contextual Tool), framework scoring and assessment of three orphan drug case studies. This proof-of-concept would grant a continued refinement of the methodology and, if and when validated, its potential integration to other therapeutic areas of the PHF. Results: the final framework was composed by 10 quantitative criteria (Core Model) and 4 qualitative criteria (Contextual Tool) according to the PHF goals being the most important criteria "disease severity", "unmet need", "comparative effectiveness" and "comparative safety /tolerability". The matrix developed for the case studies served as a guide for the selection of the essential information that the decision-makers were expected to include in a framework. The reflective discussion was considered the most relevant phase of the approach to support inputs for health decision-making processes reflecting both drug value and place in therapy. Conclusions: the study showed that reflective MCDA methodology could be implemented to complement the decision-making process in CatSalut, as an aid to determine the clinical added value for orphan medicines. MCDA provided transparency and a structured discussion during the committee meetings, thus increasing transparency and predictability of the relevant items supporting the agreements adopted on orphan drugs access

6-phosphofructo-2-kinase (pfkfb3) gene promoter contains hypoxia-inducible factor-1 binding sites necessary for transactivation in response to hypoxia

The up-regulation of glycolysis to enhance the production of energy under reduced pO(2) is a hallmark of the hypoxic response. A key regulator of glycolytic flux is fructose-2,6-bisphosphate, and its steady state concentration is regulated by the action of different isozymes product of four genes (pfkfb1-4). pfkfb3 has been found in proliferating cells and tumors, being induced by hypoxia. To understand the organization of cis-acting sequences that are responsible for the oxygen-regulated pfkfb3 gene, we have studied its 5'-flanking region. Extensive analysis of the 5' pfkfb3 promoter sequence revealed the presence of putative consensus binding sites for various transcription factors that could play an important role in pfkfb3 gene regulation. These DNA consensus sequences included estrogen receptor, hypoxia response element (HRE), early growth response, and specific protein 1 putative binding sites. Promoter deletion analysis as well as putative HREs sequences (wild type and mutated) fused to a c-fos minimal promoter unit constructs demonstrate that the sequence located from -1269 to -1297 relative to the start site is required for hypoxia-inducible factor 1 (HIF-1) induction. The effective binding of HIF-1 transcription factor to the HREs at -1279 and -1288 was corroborated by electrophoretic mobility shift assay and biotinylated oligonucleotide pull-down. In addition, HIF-1alpha null mouse embryo fibroblasts transfected with a full-length pfkfb3 promoter-luciferase reporter construct further demonstrated that HIF-1 protein was critically involved for hypoxia transactivation of this gene. Altogether, these results demonstrate that pfkfb3 is a hypoxia-inducible gene that is stimulated through HIF interaction with the consensus HRE site in its promoter region

Pricing of oral generic cancer medicines in 25 European countries; findings and implications

Introduction: There are appreciable concerns among European health authorities with growing expenditure on cancer medicines and issues of sustainability. The enhanced use of low cost generics could help. Aims: Consequently, there is a need to comprehensively document current and future arrangements regarding the pricing of generic cancer medicines across Europe, and whether these are indication specific, as well as how this translates into actual prices to provide future direction. Methodology: Mixed method approach with qualitative research among senior health authority personnel and their advisers. Quantitative research via health authority databases to ascertain current prices for oral cancer medicines that had lost their patent and the influence of population size and economics on prices. Results: 25 European countries participated. Currently we see (a) variable approaches to the pricing of generic cancer medicines, which will continue; (b) no concerns with substitution for oral generic cancer medicines; (c) substantial price reductions versus originators for generic capecitabine (up to -93.1%), generic imatinib (up to -97.8%) and generic temozolomide (up to -80.7%). Prices for oncology medicines are not indication specific, and are not affected by population size although influenced by pricing approaches. There have also been price increases for some non-patented cancer medicines following manufacturer changes although now stabilising. Conclusion: The considerable price reductions seen for some generics means health authorities should further encourage the use of generic oncology medicines when they become available to fund increased volumes and new valued cancer medicines. Countries are also starting to address price increases for generics following changes in the manufacture

Potential approaches for the pricing of cancer medicines across Europe to enhance the sustainability of healthcare systems and the implications

Introduction: There are growing concerns among European health authorities regarding increasing prices for new cancer medicines, prices not necessarily linked to health gain and the implications for the sustainability of their healthcare systems. Areas covered: Narrative discussion principally among payers and their advisers regarding potential approaches to the pricing of new cancer medicines. Expert opinion: A number of potential pricing approaches are discussed including minimum effectiveness levels for new cancer medicines, managed entry agreements, multicriteria decision analyses (MCDAs), differential/tiered pricing, fair pricing models, amortization models as well as de-linkage models. We are likely to see a growth in alternative pricing deliberations in view of ongoing challenges. These include the considerable number of new oncology medicines in development including new gene therapies, new oncology medicines being launched with uncertainty regarding their value, and continued high prices coupled with the extent of confidential discounts for reimbursement. However, balanced against the need for new cancer medicines. This will lead to greater scrutiny over the prices of patent oncology medicines as more standard medicines lose their patent, calls for greater transparency as well as new models including amortization models. We will be monitoring these developments