Analysis of oncological drugs authorised in Spain in the last decade: association between clinical benefit and reimbursement.

BACKGROUND: Our study aimed to assess whether there was a relationship between clinical benefits and reimbursement decisions as well as the inclusion of economic evaluations in  therapeutic positioning reports (IPTs) and to explore factors influencing reimbursement decisions. MATERIALS AND METHODS: We analysed all anti-cancer drugs approved in Spain from 2010 to September 2022. The clinical benefit of each drug were evaluated using the European Society for Medical Oncology Magnitude of Clinical Benefit Scale (ESMO-MCBS) 1.1. The characteristics of these drugs were obtained from the Spanish Agency of Medicines and Medical Devices. Reimbursement status information was obtained using BIFIMED, a web resource available in Spanish and consulted the agreements of the Interministerial Committee on Pricing of Medicines (CIPM). RESULTS: In total, 73 drugs were included involving 197 indications. Almost half of the indications had substantial clinical benefit (49.8% yes vs. 50.3% no). Of the 153 indications with a reimbursement decision, 61 (56.5%) reimbursed indications had substantial clinical benefit compared to 14 (31.1%) of the non-reimbursed (p < 0.01). The median gain of overall survival was 4.9 months (2.8-11.2) for reimbursed indications and 2.9 months (1.7-5) in non-reimbursed (p < 0.05). Only six (3%) indications had an economic evaluation in the IPT. CONCLUSION: Our study revealed that there is a relationship between substantial clinical benefit and the reimbursement decision in Spain. However, we also found that the overall survival gain was modest, and a significant proportion of the reimbursed indications had no substantial clinical benefit. Economic evaluations in IPTs are infrequent and cost-effectiveness analysis is not provided by CIPM.

Ligand and metal-centred reactivity in 2,6-bis(imino)-1,4-dihydropyridinate Zn(II) alkyls: the dual behaviour of an intriguing type of complex.

Dihydropyridines, either free or metal-coordinated, are organic hydride transfer reductants that perform on the same premises as the natural redox cofactor NAD(P)+/NAD(P)H. 1-Bn and 1-Me are alkylzinc complexes containing dihydropyridinate-based pincer ligands that have been synthesized through different routes involving the addition of ZnR2 (R = Bn, Me) to the 2,6-bis(imino)-pyridine and 2,6-bis(imino)-4-Bn-dihydropyridine (iPrBIP and 4-BniPrBIPH2) ligands, respectively. The alkyls complexes 1-R react with fluorinated alcohols RFOH (RF = C6F5 or t-C4F9) yielding isolable fluoroalkoxides 2-F5 and 2-F9, in which the reactive 1,4-dihydropyridinate ligand remains unchanged. The crystal structure of 2-F5 shows the shortest Zn⋯F-C interaction reported so far, involving one of the o-F atoms of the C6F5 group. However, the mechanism of the alcoholysis reactions is not straightforward, as NMR monitoring revealed that acidic RFOH first protonates the dihydropyridine nitrogen, releasing the dihydropyridine base 4-BniPrBIPH2 and a highly reactive Zn(R)(ORF) species that re-captures the dihydropyridine in a subsequent step, eliminating the corresponding alkane (R-H). Depending on the mixing conditions, the pincer dihydropyridinate ligand may undergo aromatization to produce the new Zn(II) dialkoxides 3-F5 and 3-F9 stabilised by a neutral iPrBIP ligand [(4R-iPrBIP)Zn(ORF)2]. These protonation and hydride transfer reactions illustrate the dual reactivity of the pincer 1,4-dihydropyridinate zinc entity.