Early Access in Oncology: Why Is It Needed?

Timely access to cancer therapies with significant added value is an important expectation for patients and a primary responsibility for every public health service. Over time, collaboration between the pharmaceutical industry and regulatory agencies has made it possible to agree to implement tools in order to accelerate the development and approval of potentially innovative drugs. In Italy, too, several early access tools have been introduced. In June 2018 a panel of experts agreed on the need to simplify and streamline early access assessment criteria and processes. The panel developed a proposal to categorize cancer drugs eligible for early access. In the curative setting, the evaluation of the medical need should take into account both the relapse rate, attributed on the basis of the disease free survival (DFS), and the strength of the recommendations of the Italian Association of Medical Oncology (AIOM) for any therapeutic alternatives already available. The panel then found it appropriate to use the European Society for Medical Oncology (ESMO) criteria for the evaluation of the clinical benefit. The sum of the scores assigned to the three parameters should allow the clinical value of the drug to be defined and, consequently, the priorities for early access to be established. This multiparameter approach can also be adapted to the non-curative setting. The early access process should be reserved for first-in-class drugs and should provide for the recognition of a conditional reimbursement within 60 days, financed by a special fund. The proposal developed by the panel has the objective of starting a proactive discussion with the Italian health authority

Therapeutic Value and Innovation of a Drug and Criteria for Evaluation: A Multidisciplinary Experience in the Veneto Region

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Randomised clinical trial: a leucine-metformin-sildenafil combination (NS-0200) vs placebo in patients with non-alcoholic fatty liver disease

BACKGROUND: Sirtuin 1 (Sirt1) is suppressed in non-alcoholic fatty liver disease (NAFLD), while its' stimulation or overexpression results in reduced disease severity in pre-clinical NAFLD models. Leucine allosterically activates Sirt1 and synergise with other Sirt/AMPK/NO pathway activators. We developed a triple combination of leucine, metformin and sildenafil (NS-0200), which was effective in a mouse model of non-alcoholic steatohepatitis (NASH). AIM: To report the results from a Phase 2, randomised clinical trial of of NS-0200 in 91 subjects with NAFLD (liver fat ≥15% by magnetic resonance imaging-proton-density fat fraction (MRI-PDFF)). METHODS: Subjects were randomised to placebo, low-dose (1.1 g leucine/0.5 g metformin/0.5 mg sildenafil) or high-dose NS-0200 (1.1 g leucine/0.5 g metformin/1.0 mg sildenafil) b.d. for 16 weeks; change in hepatic fat was assessed via MRI-PDFF, and lipid metabolism was assessed via changes in the lipidomic signature. Seventy subjects completed the trial and met a priori compliance criteria. Analyses were conducted on the full cohort and on those with alanine aminotransferase (ALT) values above median (50 U/L; n = 35). RESULTS: In the full cohort, active treatments did not separate from placebo. High dose NS-0200 reduced hepatic fat by 15.7% (relative change from baseline) in the high ALT group (P < 0.005) while low dose NS-0200 and placebo did not significantly change hepatic fat. Lipidomic analysis showed dose-responsive treatment effects in both overall and high ALT cohorts, with significant decreases in metabolically active lipids and up-regulation of fatty acid oxidation. CONCLUSION: These data support further evaluation of high-dose NS-0200 for treating NASH, especially in those with elevated ALT (NCT 02546609)

Association of kidney disease measures with risk of renal function worsening in patients with type 1 diabetes

Background: Albuminuria has been classically considered a marker of kidney damage progression in diabetic patients and it is routinely assessed to monitor kidney function. However, the role of a mild GFR reduction on the development of stage 653 CKD has been less explored in type 1 diabetes mellitus (T1DM) patients. Aim of the present study was to evaluate the prognostic role of kidney disease measures, namely albuminuria and reduced GFR, on the development of stage 653 CKD in a large cohort of patients affected by T1DM. Methods: A total of 4284 patients affected by T1DM followed-up at 76 diabetes centers participating to the Italian Association of Clinical Diabetologists (Associazione Medici Diabetologi, AMD) initiative constitutes the study population. Urinary albumin excretion (ACR) and estimated GFR (eGFR) were retrieved and analyzed. The incidence of stage 653 CKD (eGFR &lt; 60 mL/min/1.73 m2) or eGFR reduction &gt; 30% from baseline was evaluated. Results: The mean estimated GFR was 98 \ub1 17 mL/min/1.73m2 and the proportion of patients with albuminuria was 15.3% (n = 654) at baseline. About 8% (n = 337) of patients developed one of the two renal endpoints during the 4-year follow-up period. Age, albuminuria (micro or macro) and baseline eGFR &lt; 90 ml/min/m2 were independent risk factors for stage 653 CKD and renal function worsening. When compared to patients with eGFR &gt; 90 ml/min/1.73m2 and normoalbuminuria, those with albuminuria at baseline had a 1.69 greater risk of reaching stage 3 CKD, while patients with mild eGFR reduction (i.e. eGFR between 90 and 60 mL/min/1.73 m2) show a 3.81 greater risk that rose to 8.24 for those patients with albuminuria and mild eGFR reduction at baseline. Conclusions: Albuminuria and eGFR reduction represent independent risk factors for incident stage 653 CKD in T1DM patients. The simultaneous occurrence of reduced eGFR and albuminuria have a synergistic effect on renal function worsening

"The Original Sound": A new non-pharmacological approach to the postnatal stress management of preterm infants

Objective: To evaluate the effect of the exposure to "The Original Sound" (TOS), an original track composed of different sounds such as fetal heartbeat, breathing, blood flow, and ambience sounds, specifically created for this study, on physiological stability of preterm infants during a 10-d hospitalization.Methods: Thirty-four preterm infants (32-37 weeks of gestation) were randomized to receive either TOS or environmental noise. TOS was provided for a 20-min period, three times a day, using two speakers and a MP3 player placed in the cradle. Cardiorespiratory and behavioral parameters were recorded.Results: Heart rate in the treated group was positively correlated with TOS exposure, showing a significant reduction on day 2 and lower values during the first day. A decrease in RR is also recorded on day two in the TOS group, although not significant.Conclusion: This study provides preliminary evidence for short-term improvements in the physiological stability of preterm infants using TOS. Future studies are needed to investigate the potential of this non-pharmacological approach and its clinical relevance to postnatal stress management in neonatal intensive care units

Prezzo, rimborso e accesso ai farmaci in Italia: le proposte di riforma di quattro panel di esperti

Il presente documento illustra i risultati di un lavoro di quattro panel interdisciplinari e multistakeholder (istituti pubblici, ricercatori, industria) sull’accesso al rimborso e la negoziazione dei prezzi dei farmaci nel Servizio sanitario nazionale, realizzato nell’ambito di un seminario residenziale tenutosi in aprile 2019. In particolare, sono stati discussi i temi a) dell’innovatività dei farmaci, con i relativi vantaggi sull’accesso (fondi dedicati, accesso immediato ai mercati regionali, mancata applicazione di scontistiche obbligatorie); b) del processo e dei criteri di negoziazione di prezzo e rimborso per un nuovo farmaco o una nuova indicazione di un farmaco già presente sul mercato; c) della rinegoziazione dei prezzi, in relazione a modifiche del contesto di mercato ed in presenza di nuove evidenze sul profilo di efficacia e sicurezza e d) della gestione di specifici ambiti di complessità negoziale, rappresentati da farmaci caratterizzati da evidenze molto incerte al momento del lancio, dagli accordi di rimborsabilità condizionata, da terapie combinate e da terapie cosiddette one-shot. I suggerimenti forniti dagli esperti vanno nella direzione di un miglioramento dell’attuale assetto regolatorio, più che di una sua modifica sostanziale e presentano elementi di interesse anche in relazione al successivo decreto ministeriale di revisione del sistema di pricing

Interfacing Science, Literature, and the Humanities

It aims to investigate the relationship (links, affinities, differences, questions and problems) between the sciences and the humanities in order to question the very idea of \u2018influence\u2019 (or \u2018mutual influences\u2019) in favour of a more dynamic idea of \u2018INTERFACING\u2019. Therefore, a fundamental point of departure is to acknowledge the isomorphism of the two fields, recalling that they have often developed new models and strategies of investigation into complex scientific and cultural (artistic, literary) phenomena at the same time, simultaneously responding to their own actuality and societal matrices. This idea of isomorphism is no longer linked to the traditional ideas of \u2018cause\u2019 and \u2018effect\u2019, but instead implies simultaneity and not consequentiality. It is not always one of the two fields that influences or conditions the other one: isomorphism implies joint discoveries, as both domains tend to develop, at the same time, new investigative models which become, in turn, analogical mirrors of a world in constant progress. This idea leads us to view the sciences and the humanities together, because their mutual interfacing can trigger new, dynamic fields of knowledge in new contexts. Even in the more specific domain of literature or critical theory, the very idea of \u2018influence\u2019 has now become obsolete, to the point of being truly discredited in some circles. As a consequence, other possible paradigms have begun to emerge, following the development of new societal conditions, such as globalisation, changing political assets and the development of new \u2018mediascapes\u2019. In such a shifting context, the idea of \u201cinterface/interfacing\u201d (derived, as is well known, from the new ICT world) seems to offer a suitable paradigm triggering new heuristic implications. Also, the very idea of \u2018interfacing\u2019 leads to the interesting concept of \u2018complexity\u2019, itself a metaphor implying exchange, mutual interlinking and, above all, to the concept of \u2018networking\u2019, that is of new strategies for looking at and therefore rendering the world now in progress. Strategically, to pursue the idea of interfacing between the sciences and the humanities can lead a grasp of new implications underpinning the making of the new Europe, as well as to a development of possible guidelines suggesting new ways to conceive and assess the status of research, the idea of \u2018progress\u2019 and the questions of evolving identities for a reality (Europe) which aims to play a leading role in the international panorama. Among the ideas underpinning this new proposal, there is the one that views the gaps between the humanities and the sciences as an artificial construction articulated during the 19th century, and consolidated by the middle of the 20th century; a construction which is increasingly seen as an anachronism in the 21st century. In the two previous centuries, in fact, theories of education were developed around the ideas of distinction and choice: humanities on the one hand, sciences on the other hand. On the contrary, today students are asking for new educational models, reflecting the complexity and interplay of a world characterised by a different understanding of knowledge and, especially, by the rapid development of new societal matrices. We are facing a constantly evolving cultural situation and this is a fact that both domains have to acknowledge. There are already some positive responses, and, as noted above, also the previous ETNP ACUME has been exploring joint research projects. Among the most interesting examples there are, for instance, new university programs in medical schools, faculties of engineering and other scientific branches which are offering specific courses in literature, arts, philosophy, as well as courses encouraging creativity. On the other side, there are examples of positive applications of scientific research and knowledge in the humanities: from more practical applications, such as the creation of new disciplines within the humanities (e.g. the case of the \u2018Humanistic Informatics\u2019; the creation of new infrastructures, e-archives, new databases, etc.), to new theoretical developments combining theories of literature/criticism and scientific models of investigation (from \u2018field theory\u2019, to chaos theory, to fractal theories, etc.). Other interesting examples come from the social sciences, which have been playing a pivotal role in developing new lines of research and new concepts capable of breaking down barriers and encouraging interdisciplinary approaches. The case of anthropology is, in this regard, quite an exemplary one: take the case of the application, in this field, of the scientific idea of \u2018thick description\u2019 to analyse culture tout court, a broad and complex concept which nevertheless interfaces the two domains. Following similar patterns, in the last two decades scholars in the humanities have started to reconsider the very idea of \u2018literary phenomena\u2019, with literature no longer perceived as a closed system, but instead as a complex one, a network of events, therefore triggering a new understanding of \u2018zeitgeist\u2019. In such a shifting environment, inevitably the links between scientific discoveries and literary and artistic experiments are reconsidered not just as linear and sequential phenomena: they are, instead, interlinked and convergent

Therapeutic Value and Innovation of a Drug and Criteria for Evaluation: A Multidisciplinary Experience in the Veneto Region

Defining therapeutic innovation is a key point to determine the price of newly marketed drugs; however, a pre-requisite for an appropriate management of innovation is that some general rules have been identified to recognize the therapeutic value of any pharmacological agent. These issues are a matter of debate for Regulatory Agencies and for the scientific community as well.Cost-effectiveness principles still represent the main approach to quantify the economic value of a drug based on its clinical effectiveness, and QALYs still represent the main tool to compare outcomes across different therapeutic areas. The main problem in this area is represented by the difficulty in translating general principles into practical decisions. Factors that still hamper the application of the value-based approach include organizational constraints (e.g. drug fixed budgets), the lack of familiarity with cost-effectiveness by most decision-makers, and the history of local decisions

Drugs price and reimbursement regulation: comparators, endpoints and role of the cost-effectiveness

This document illustrates the results of a discussion of two multi-disciplinary expert panels on pricing and reimbursement of medicines. Experts work in different organizations. The discussion focused on comparator(s), endpoint(s), negotiation of prices of new medicines and/or indications to include in the List 648, as well as the role of cost-effectiveness in the price and reimbursement negotiation. The debate took place during the fourth edition of the Seminari di Mogliano, organized on the 30th of September/1st of October, 2021. The two panels agreed on a general need to enhance interaction among the different stakeholders, in the early assessment and negotiation phases, and to increase the transparency/reproducibility of the decisions taken. The experts have also emphasized the need (i) to improve clarity in the evaluation of additional therapeutic value and the place in therapy with respect to comparators and how comparators are identified; (ii) to create work groups to identify the most appropriate endpoint(s), for each therapeutic area and level of unmet needs; (iii) to provide for a systematic use of cost-effectiveness when an added therapeutic value is delivered by a new medicine. With regard to the 648 List, the experts advocated for an overall reorganization of the current rules governing the special uses of drugs