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
We are more than our omics Garattini, Silvio
European journal of clinical pharmacology,
07/2020, Letnik:
76, Številka:
7
Journal Article
Recenzirano
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.
Summary 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.
Therapeutic drug and immunogenicity monitoring (TDIM) is increasingly proposed to guide therapy with biologics, characterised by high inter-individual variability of their blood levels, to permit ...objective decisions for the management of non-responders and reduce unnecessary interventions with these expensive treatments. However, TDIM has not yet entered clinical practice partly because of uncertainties regarding the accuracy and precision of enzyme-linked immunosorbent assays (ELISA). Here we report the characterisation of a novel surface plasmon resonance (SPR)-based TDIM, applied to the measurement of serum concentrations of infliximab, an antibody against tumour necrosis factor α (anti-TNFα), and anti-infliximab antibodies. SPR has the obvious advantages of directly detecting and measuring serum antibodies in minutes, avoiding the long incubation/separation/washing/detection steps of the methods proposed so far, reducing complexity and variability. Moreover, drug and anti-drug antibodies can be measured simultaneously. This new method was validated for sensitivity and reproducibility, and showed cost-effectiveness over commercial ELISA kits. This method may be applied to other biotherapeutics. These data pave the way for the development of SPR-based point-of-care devices for rapid on-site analysis.
...the diseases, not the drugs, are the orphans because all drugs are very expensive,3 having marrying this success story (table). ...in some cases, several OMPs are available for the same disease; ...for example, three drugs are licensed for treatment of Gaucher's disease (imiglucerase, velaglucerase alfa, and taliglucerase alfa).15 No evidence favours any one product over the other, and each drug costs about US$200 000 per patient per year. In a landmark departure from previous practice in 2014, the US Senate requested information on developmental costs and numerous other details for sofosbuvir, a drug for radical treatment of hepatitis C virus infection.19 Individual EU member state governments have since increasingly been requesting that industry disclose information about costs incurred during drug development that justify drug prices, but without legal obligations, these requests have largely been evaded. First synthesised in 1869, hydroxyurea has been used for decades in patients with myeloproliferative disorders and is now also indicated for sickle-cell disease.22,23 In the 2017 issue of the British National Formulary, one type of hydroxyurea for myeloproliferative disorders is listed at £0·24 per g, and another type of hydroxyurea for sickle-cell disease is listed at £16·7 per g. Common sense suggests that something must be wrong here.
Biological medicines have improved patients’ outcomes, but their high costs may limit access. Biosimilars, alternatives that have demonstrated high similarity in terms of quality, safety, and ...efficacy to an already licensed originator biological product, could increase competition and decrease prices. Given the expanding number of biosimilars, patients may switch from originator to biosimilar or among biosimilars. Randomized trials and observational studies conducted with multiple biosimilars over many disease areas confirmed the safety and efficacy of switching from originator to biosimilar. This study summarizes evidence on switching between biosimilars for which there are concerns to provide future guidance. A systematic search (MEDLINE, Embase, and Cochrane Library) for studies on anti-TNF agents, assessing clinical efficacy and safety of biosimilar-to-biosimilar switch in chronic inflammatory diseases, was performed. We retrieved 320 records and included 19 clinical studies. One study with historical control compared switching between biosimilars to maintenance of the same biosimilar. Ten were controlled cohort studies comparing switching between two biosimilars vs. switching from originator to a biosimilar or vs. multiple switches. Eight were single-arm cohort studies, where participants switched from one biosimilar to another, and the outcomes were compared before and after the switch. Overall, these studies did not highlight significant concerns in switching between biosimilars. Therefore, switching studies seem difficult to perform and unnecessary with the body of evidence suggesting no real problems in practice coupled with stringent regulatory requirements. Monitoring the use of biosimilars in clinical practice could support clinical decision-making, rational use of biological medicines, and help to further realize possible savings.
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.
Sometimes these are so wide that what is judged non-inferior from a statistical point of view might actually be questionable from a clinical point of view.13,14 Unreliable messages from questionable ...methods As with a superiority design in a placebo-controlled trial, evidence of non-inferiority to active comparators might allow drugs onto the market that are in fact less acceptable than those in current clinical use.
Abstract
Measurements of serum concentrations of therapeutic antibodies and anti-drug antibodies (ADA) can support clinical decisions for the management of non-responders, optimizing the therapy. In ...the present study we compared the results obtained by classical ELISA and a recently proposed surface plasmon resonance (SPR)-based immunoassay, in 76 patients receiving infliximab for inflammatory bowel diseases. The two methods indicated very similar serum concentrations of the drug, but there were striking differences as regards ADA. All the sera showing ADA by ELISA (14) also showed ADA by SPR, but the absolute amounts were different, being 7–490 times higher with SPR, with no correlation. Eight patients showed ADA only with SPR, and these ADA had significantly faster dissociation rate constants than those detectable by both SPR and ELISA. The underestimation, or the lack of detection, of ADA by ELISA is likely to reflect the long incubation steps which favor dissociation of the patient’s low-affinity ADA, while the commercial, high-affinity anti-infliximab antibodies used for the calibration curve do not dissociate. This problem is less important with SPR, which monitors binding in real time. The possibility offered by SPR to detect ADA in patients otherwise considered ADA-negative by ELISA could have important implications for clinicians.
Background Gastric-cancer is a heterogeneous type of neoplastic disease and it lacks appropriate therapeutic options. There is an urgent need for the development of innovative pharmacological ...strategies, particularly in consideration of the potential stratified/personalized treatment of this tumor. All-Trans Retinoic-acid (ATRA) is one of the active metabolites of vitamin-A. This natural compound is the first example of clinically approved cyto-differentiating agent, being used in the treatment of acute promyelocytic leukemia. ATRA may have significant therapeutic potential also in the context of solid tumors, including gastric-cancer. The present study provides pre-clinical evidence supporting the use of ATRA in the treatment of gastric-cancer using high-throughput approaches. Methods We evaluated the anti-proliferative action of ATRA in 27 gastric-cancer cell-lines and tissue-slice cultures from 13 gastric-cancer patients. We performed RNA-sequencing studies in 13 cell-lines exposed to ATRA. We used these and the gastric-cancer RNA-sequencing data of the TCGA/CCLE datasets to conduct multiple computational analyses. Results Profiling of our large panel of gastric-cancer cell-lines for their quantitative response to the anti-proliferative effects of ATRA indicate that approximately half of the cell-lines are characterized by sensitivity to the retinoid. The constitutive transcriptomic profiles of these cell-lines permitted the construction of a model consisting of 42 genes, whose expression correlates with ATRA-sensitivity. The model predicts that 45% of the TCGA gastric-cancers are sensitive to ATRA. RNA-sequencing studies performed in retinoid-treated gastric-cancer cell-lines provide insights into the gene-networks underlying ATRA anti-tumor activity. In addition, our data demonstrate that ATRA exerts significant immune-modulatory effects, which seem to be largely controlled by IRF1 up-regulation. Finally, we provide evidence of a feed-back loop between IRF1 and DHRS3, another gene which is up-regulated by ATRA. Conclusions ATRA is endowed with significant therapeutic potential in the stratified/personalized treatment gastric-cancer. Our data represent the fundaments for the design of clinical trials focusing on the use of ATRA in the personalized treatment of this heterogeneous tumor. Our gene-expression model will permit the development of a predictive tool for the selection of ATRA-sensitive gastric-cancer patients. The immune-regulatory responses activated by ATRA suggest that the retinoid and immune-checkpoint inhibitors constitute rational combinations for the management of gastric-cancer. Keywords: All-trans-retinoic-acid, Immune-responses, Gastric-cancer, IRF1, RNA-sequencing
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