High-energy devices in different surgical settings: lessons learnt from a full health technology assessment report developed by SICE (Società Italiana di Chirurgia Endoscopica).

BACKGROUND: The present paper aims at evaluating the potential benefits of high-energy devices (HEDs) in the Italian surgical practice, defining the comparative efficacy and safety profiles, as well as the potential economic and organizational advantages for hospitals and patients, with respect to standard monopolar or bipolar devices. METHODS: A Health Technology Assessment was conducted in 2021 assuming the hospital perspective, comparing HEDs and standard monopolar/bipolar devices, within eleven surgical settings: appendectomy, hepatic resections, colorectal resections, cholecystectomy, splenectomy, hemorrhoidectomy, thyroidectomy, esophago-gastrectomy, breast surgery, adrenalectomy, and pancreatectomy. The nine EUnetHTA Core Model dimensions were deployed considering a multi-methods approach. Both qualitative and quantitative methods were used: (1) a systematic literature review for the definition of the comparative efficacy and safety data; (2) administration of qualitative questionnaires, completed by 23 healthcare professionals (according to 7-item Likert scale, ranging from - 3 to + 3); and (3) health-economics tools, useful for the economic evaluation of the clinical pathway and budget impact analysis, and for the definition of the organizational and accessibility advantages, in terms of time or procedures' savings. RESULTS: The literature declared a decrease in operating time and length of stay in using HEDs in most surgical settings. While HEDs would lead to a marginal investment for the conduction of 178,619 surgeries on annual basis, their routinely implementation would generate significant organizational savings. A decrease equal to - 5.25/-9.02% of operating room time and to - 5.03/-30.73% of length of stay emerged. An advantage in accessibility to surgery could be hypothesized in a 9% of increase, due to the gaining in operatory slots. Professionals' perceptions crystallized and confirmed literature evidence, declaring a better safety and effectiveness profile. An improvement in both patients and caregivers' quality-of-life emerged. CONCLUSIONS: The results have demonstrated the strategic relevance related to HEDs introduction, their economic sustainability, and feasibility, as well as the potentialities in process improvement.

Scientific and ethical issues in add-on designs for antidiabetic drugs.

This editorial describes the clinical trials related to antidiabetic drugs, most of them following an "add-on" design of where the new drug is added to metformin and the comparative arm is metformin plus placebo. Many drugs are already approved for therapy following this design; the authors believe that it is unethical to continue this trend because it makes it impossible to stratify the many antidiabetic drugs according to their efficacy and toxicity.

Quality, efficacy, safety-it is not enough!

There is a need of comparative studies to understand the differences in term of efficacy and safety of drugs with different mechanisms of action but similar therapeutic indications. This requires changes in the European Legislation of criteria for drug approval.

Food advertising during children's television programmes in Italy.

OBJECTIVE: Previous studies from European countries noted that food products promoted on TV for children did not comply with international guidelines, including the World Health Organization European Nutrient Profile Model (WHO-ENPM) and the EU Pledge Nutrition Criteria (EU-PNC, an initiative developed by leading food companies). We aim to provide new data from Italy. DESIGN: Evaluation of Italian TV advertisements. Data on nutritional values for food product advertised were compared with nutritional standards issued by the WHO-ENPM and the EU-PNC. SETTING: In total, 180 h of TV programmes from six Italian channels, 2016-2017. PARTICIPANTS: Eight hundred and ten consecutive advertisements during children's programmes. RESULTS: Out of 810 advertisements, 90 (11·1 %) referred to food products. Among these, 84·5 % of the foods promoted did not meet the WHO-ENPM and 55·6 % the EU-PNC guidelines. Advertisements promoting sweet and salty snacks (i.e. ≥ 70 % of all foods) v. other food products showed higher non-compliance with both the WHO-ENPM (OR: 73·8; 95 % CI: 4·09, 1330) and the EU-PNC (OR: 9·21; 95 % CI: 2·82, 30·1). CONCLUSIONS: In Italy, most food advertisements during children's programmes are not compliant with European nutritional standards. Almost all the advertisements for snacks do not meet international guidelines. As the WHO-ENPM guidelines do not propose standards for all the food products, including meals, there is an urgent need to define independent and easy-to-read guidelines for food advertisements targeting children. As a first step towards the complete ban of food advertisements targeting children recommended by other researchers, these guidelines should be enforced by all the TV broadcasts.

The MIMIC Study: Prognostic Role and Cutoff Definition of Monocyte-to-Lymphocyte Ratio and Lactate Dehydrogenase Levels in Metastatic Colorectal Cancer.

BACKGROUND: Monocyte-to-lymphocyte ratio (MLR) and lactate dehydrogenase (LDH) levels are circulating biomarkers that provide information about tumor-related inflammation and immune suppression. This study aimed to evaluate the prognostic role of MLR and LDH in metastatic colorectal cancer (mCRC). MATERIAL AND METHODS: This multicentric study analyzed a consecutive cohort of 528 patients with mCRC treated in 2009-2017. The whole population was randomly divided in training and validation cohort. The first was used to identify a threshold for MLR and to create the prognostic model with MLR and MLR-LDH combined (group 1: MLR-LDH low; group 2: MLR or LDH high; group 3: MLR-LDH high). The second cohort was used to validate the model. RESULTS: At the median follow-up of 55 months, median overall survival (OS) was 22 months. By multivariate analysis, high MLR >0.49 (hazard ratio [HR], 2.37; 95% confidence interval [C.I.], 1.39-4.04), high LDH (HR, 1.73; 95% C.I., 1.03-2.90) in the first model, group 2 (HR, 2.74; 95% C.I.; 1.62-4.66), and group 3 (HR, 3.73; 95% C.I., 1.94-7.18) in the combined model, had a worse prognosis in terms of OS. These data were confirmed both in the validation set and then in the whole cohort. CONCLUSION: MLR and LDH are circulating cost-effective biomarkers, readily available in clinical practice, that can be useful for predicting the prognosis of patients with mCRC. IMPLICATIONS FOR PRACTICE: High monocyte-to-lymphocyte ratio (MLR) and lactate dehydrogenase (LDH) levels could be a sign of a tumor's recruitment of suppressive and inflammatory cells worsening prognosis of different types of cancer, including colorectal cancer (CRC). Currently, no data are available for metastatic CRC regarding a cutoff definition for MLR or the prognostic impact of MLR and MLR-LDH combined. The present study showed in the training cohort and confirmed in the validation and whole cohort that MLR is a reliable and independent laboratory biomarker, which is easy to use, to predict clinical outcomes in patients with mCRC. Moreover, MLR and composite MLR-LDH could potentially result in an incremental improvement in the prognostic value of these biomarkers, being used as stratification tools for patients with mCRC.

Food and Drug Administration vs European Medicines Agency: Review times and clinical evidence on novel drugs at the time of approval.

The Food and Drug Administration (FDA) and European Medicines Agency (EMA) now have expedited review procedures for new drugs. We compared the review times of medicines licensed by the 2 agencies and explored differences in the evidence submitted. In 2015-2017 the FDA licensed 113 drugs, 66 of which reached Europe. The median review time was longer at the EMA than FDA and was shorter for drugs undergoing FDA-expedited programmes compared to the same drugs approved by the EMA through the standard procedure. We identified differences regarding the evidence submitted to the 2 regulators for 7 drugs. The greater use of expedited programmes by the FDA and administrative time at the European Commission mainly explain the later access of new drugs to the European market. The additional evidence submitted to the EMA is generally scant and limited to a few drugs.

We are more than our omics.

Today, personalized medicine is essentially based on individual "omics." However there is a need to integrate this approach with a number of data such as pharmacokinetics, optimal dose and duration of drug treatments, age and gender differences, and drug interactions, which are relevant in terms of benefits and risks but are frequently unknown. This requires independent research that should be supported by governments in order to make personalized medicine a reality.

Clinical evidence supporting the marketing authorization of biosimilars in Europe.

PURPOSE: To review the marketing authorization of biosimilars and provide a critical analysis of the pivotal trials supporting their approval by the European Medicines Agency (EMA). METHODS: EMA website to identify the biosimilars approved up to July 2019 and the European Public Assessment Report for information on pivotal trial design, duration, intervention and control, primary outcome, data on immunogenicity, and comparability margins. RESULTS: The EMA has approved 55 biosimilars (62% in 2017-2019) of 16 biologic products, used in several clinical indications. Some biosimilars were licensed as multiple products, with different commercial names, by the same or different companies. The comparability exercise and subsequent approval of 49/55 (89%) biosimilars were based on one or more pivotal phase III trials testing their clinical efficacy. In all, biosimilars were approved on the basis of 55 trials, mostly phase III (42/55, 76%) assessing clinical efficacy; these were mainly equivalence trials (31/55, 56%). The pivotal phase III trials assessed surrogate measures of clinical effect, and 71% reported immunogenicity data. CONCLUSION: Analysis of the approval of biosimilars in Europe depicts a complex and heterogeneous scenario. The requirement for showing similarity in terms of clinical efficacy and safety provides a robust demonstration of comparable clinical outcomes but lays a burden on biosimilar manufacturers and may delay the introduction of the drugs. The development, licensing, and monitoring of biosimilars would benefit from new strategies to accelerate access to these drugs while reducing uncertainties about their use in practice.

Determinants of choice in offering drug holidays during first-line therapy for metastatic colorectal cancer.

Background: 'Drug holidays' (DH) for metastatic colorectal cancer (mCRC) were introduced to preserve quality of life. We studied factors associated to a DH offer in first line. Materials & methods: We retrospectively analyzed 754 consecutive patients treated with chemotherapy for mCRC in two Italian institutions between 2005 and 2017. Associations between baseline clinical-pathological factors and DH (56 or more days of treatment interruption) were investigated. Results: In 754 patients, previous metastasectomy, previous thermoablation and previous surgery of primary tumor were independently associated with DH. Excluding procedures or clinical trials: primary rectal cancer and resection of primary tumor were significantly associated to DH. Conclusions: DH was offered to patients with lower burden of disease, but further investigations are needed to safely guide a holiday strategy.

Metformin Use Is Associated With Longer Progression-Free Survival of Patients With Diabetes and Pancreatic Neuroendocrine Tumors Receiving Everolimus and/or Somatostatin Analogues.

BACKGROUND & AIMS: Metformin seems to have anticancer effects. However, it is not clear whether use of glycemia and metformin affect outcomes of patients with advanced pancreatic neuroendocrine tumors (pNETs). We investigated the association between glycemia and progression-free survival (PFS) of patients with pNETs treated with everolimus and/or somatostatin analogues, as well as the association between metformin use and PFS time. METHODS: We performed a retrospective analysis of 445 patients with advanced pNET treated at 24 medical centers in Italy from 1999 through 2015. Data on levels of glycemia were collected at time of diagnosis of pNET, before treatment initiation, and during treatment with everolimus (with or without somatostatin analogues), octreotide, or lanreotide. Diabetes was defined as prior or current use of glycemia control medication and/or fasting plasma glucose level ≥ 126 mg/dL, hemoglobin A1c ≥ 6.5% (48 mmol/L), or a random sample of plasma glucose ≥ 200 mg/dL (11.1 mmol/L), with reported classic symptoms of hyperglycemia or hyperglycemic crisis. Patients were assigned to groups based on diagnosis of diabetes before or during antitumor therapy. PFS was compared between patients with vs without diabetes. Among patients with diabetes, the association between metformin use and PFS was assessed. We performed sensitivity and landmark analyses to exclude patients who developed diabetes while receiving cancer treatment and to exclude a potential immortal time bias related to metformin intake. RESULTS: PFS was significantly longer in patients with diabetes (median, 32.0 months) than without diabetes (median, 15.1 months) (hazard ratio for patients with vs without diabetes, 0.63; 95% confidence interval, 0.50-0.80; P = .0002). PFS of patients treated with metformin was significantly longer (median PFS, 44.2 months) than for patients without diabetes (hazard ratio for survival of patients with diabetes receiving metformin vs without diabetes, 0.45; 95% confidence interval, 0.32-0.62; P < .00001) and longer than for patients with diabetes receiving other treatments (median PFS, 20.8 months; hazard ratio, 0.49; 95% confidence interval, 0.34-0.69; P < .0001). In multivariable analysis, adjusted for other factors associated with outcomes, metformin was associated with longer PFS but level of glycemia was not. Metformin was associated with increased PFS of patients receiving somatostatin analogues and in those receiving everolimus, with or without somatostatin analogues. Sensitivity and landmark analyses produced similar results. CONCLUSIONS: In a retrospective study of patients with pNETs, we found a significant association between metformin use and longer PFS.

Benefits, benefits, once more benefits... with no risk? Stop overlooking the harms of medicines.

Consideration of drug benefits and harms is asymmetric. Approval of drugs is mainly based on efficacy, while the assessment of their safety is left to post-marketing commitments or spontaneous reporting. Benefits are overestimated as a result of pharmaceutical companies' advertisements, the paucity of independent information, and the scant understanding of the effectiveness of medicines in real life. Polypharmacy in older adults-even during the last period of their life-reflects the tendency to assign priority to efficacy and overlook harms, although nobody knows what happens when three or more drugs are given chronically. Medical journals and public research funding projects do not pay enough attention to drug toxicity. We call for a sense of purpose by all those involved in medicine to tackle this problem. European and national agencies and health authorities should promote and support independent information and experimental and clinical studies on drug toxicity. Information should rely not just on spontaneous reporting but also on active pharmacovigilance. The benefit-harm profile of drugs should be periodically reviewed in the light of toxic effects that come to light over the years. Potential interactions within polytherapies should be sought by re-assessing the pharmacokinetics and pharmacodynamics of their components.

Can systematic reviews contribute to regulatory decisions?

INTRODUCTION: The new call on independent research on drugs issued in October 2016 by the Italian Medicines Agency (AIFA) explicitly reported that proposals based on systematic reviews were not admissible, and no justification or explanation for this choice was given. Prompted by this policy decision, here, we briefly discuss the potential usefulness of systematic reviews in responding to regulatory needs. First, systematic reviews, by collecting, analysing and critically appraising all relevant studies on a specific topic, may be used by different stakeholders as a basis for making clinical and policy recommendations, including regulatory recommendations. Second, systematic reviews may advance knowledge as primary clinical research does. Third, systematic reviews may be particularly useful to detect signals of unknown adverse effects. Fourth, systematic reviews may be used to identify knowledge gaps. PROPOSAL: Systematic reviews may simultaneously produce new findings and summarize existing knowledge, with the potential of informing regulatory decisions more pragmatically and more rapidly than other research designs. We suggest that national and international calls on independent research on drugs should not put primary clinical research against systematic reviews, as it implies a focus on the methods instead of on the questions being asked. As most calls only broadly define the research areas and the topics to be covered, we argue that it should be up to the applicant to make a proposal on which design provides the most valid and useful answer, and up to the assessors to carefully check the validity, feasibility and relevance of such a proposal.

General Practitioners and Dentists: A Call for Action Against Tobacco.

INTRODUCTION: To investigate the frequency of advice to quit smoking received by the Italian population from general practitioners (GP) and dentists, we analyzed a cross-sectional study. METHODS: A face-to-face survey was conducted in 2014 on 3052 individuals, representative of the general Italian population aged 15 years or more. RESULTS: During the previous year, 89% of individuals (82% of smokers) reported that they had visited a GP while 71% (67% of smokers) had visited a dentist. Among smokers, 25% reported that they had received advice to quit smoking from their GP, and 26% from their dentist. Advice by GPs was less frequently received by smokers with higher education (multivariate odds ratios (OR) were 0.48 for intermediate and 0.38 for high as compared to low education), and more frequently by heavy smokers (≥15 cigarettes/day; OR = 1.78), those with intention to quit (OR = 2.59), with previous quit attempts (OR = 2.09), and those aware of the existence of smoking cessation services (OR = 1.59). Advice by dentists was more frequently received by smokers aged 25-44 years (OR = 3.55 compared to those aged 15-24) and those with an intention to quit (OR = 2.46). Among Italian current smokers, 32% reported that their GP and 17% that their dentist was a current smoker. The corresponding figures among young smokers were 40% and 26%, respectively. CONCLUSION: Healthcare providers have the potential to become a key reference point in the fight against smoking. However, before acting, GPs and dentists should set a good example: those who smoke should urgently quit or at least refrain from smoking during working hours. IMPLICATIONS: GPs and dentists, reaching the large majority of Italian smokers, can make a major contribution in the fight against tobacco. Future studies are needed to investigate possible reasons of the apparently high smoking prevalence among GPs, in order to develop tailored smoking cessation interventions for healthcare providers.

Trials, Regulation and tribulations.

INTRODUCTION: Regulation EU 536/2014 EU introduces a separation between two parts (technical-scientific aspects and locally relevant ethical aspects) in the assessment of applications for approval of trials and provides for each 'Member State concerned' to arrive at 'one single decision' regarding the application for authorisation to conduct a trial. PROPOSALS: The Regulation should be implemented in such a way as to avoid a separation between scientific assessment and ethical assessment; guarantee the absence of conflicts of interest in the institutions responsible for decision-making; promote efficiency on the part of ethics committees. In particular, (i) it is not appropriate to assess Parts I and II of the application for approval to conduct a trial separately (scientific soundness is the principal requisite for ethical soundness); (ii) conflicts of interest should be avoided, especially as regards links with the national authority responsible for drugs regulation; (iii) decision-making in each state should be the responsibility of a single coordinating ethics committee divided into sections specialising in different therapeutic fields; (iv) local committees affiliated to institutions where trial participants are recruited should be able to interact with the coordinating committee, provide consultation services-including on issues of clinical ethics-and promote training in the field of biomedical ethics.

How to increase value and reduce waste when research priorities are set.

The increase in annual global investment in biomedical research--reaching US$240 billion in 2010--has resulted in important health dividends for patients and the public. However, much research does not lead to worthwhile achievements, partly because some studies are done to improve understanding of basic mechanisms that might not have relevance for human health. Additionally, good research ideas often do not yield the anticipated results. As long as the way in which these ideas are prioritised for research is transparent and warranted, these disappointments should not be deemed wasteful; they are simply an inevitable feature of the way science works. However, some sources of waste cannot be justified. In this report, we discuss how avoidable waste can be considered when research priorities are set. We have four recommendations. First, ways to improve the yield from basic research should be investigated. Second, the transparency of processes by which funders prioritise important uncertainties should be increased, making clear how they take account of the needs of potential users of research. Third, investment in additional research should always be preceded by systematic assessment of existing evidence. Fourth, sources of information about research that is in progress should be strengthened and developed and used by researchers. Research funders have primary responsibility for reductions in waste resulting from decisions about what research to do.