The Danish model for the quick and safe implementation of infliximab and etanercept biosimilars.

PURPOSE: A rapidly increasing use of biological drugs has led to substantial costs. Shift to biosimilars enables considerable reduction of these costs without jeopardizing the treatment of patients, but most countries have extensive possibilities of untapped cost-savings. The aim of this study was to describe the Danish quick and near-complete implementation of the two first TNF inhibitor biosimilars (infliximab and etanercept). METHODS: We shed light on the considerations and experiences made during the implementation, and present key figures from the implementation. RESULTS: The infliximab biosimilar constituted 90.6% of the total amount of infliximab four months following patent expiration of the biooriginator. Similar results were seen for etanercept biosimilar. Substantial cost reductions were experienced in the way that e.g. the infliximab-shift reduced cost by two thirds. CONCLUSION: We believe that a thorough preparation and an organizational setting supporting the implementation is crucial for the successful implementation. This same implementation model will be used for future biosimilars.

Progression-free survival in oncology: Caveat emptor!

Overall survival (OS) is the undisputed gold standard efficacy end-point in cancer drug trials. It is with growing concern that we observe how progression-free survival (PFS) gains ground as surrogate end-point in its place. PFS has appeal because it is resource-efficient, but it has severe shortcomings. Our concern is that uncritical use of PFS will harm the evidence-based evaluation of cancer drugs when considering them for standard use in publicly financed health care systems. PFS is only valid as a surrogate end-point for OS if it correlates strongly with OS and if the cancer drug being investigated has the same effect on PFS and OS such that effects on one predict effects on the other. The latter might be less obvious than the former but is no less critical. Research indicates that in a majority of cases, correlation between surrogate end-points and OS is of medium strength or lower. PFS is therefore unreliable as a surrogate for OS. We do not find it justified to use PFS as surrogate for OS without first having assessed its validity. Stakeholders who take part in evaluating cancer drugs considered for standard use in a health care system must be particularly vigilant about this issue to minimize the risk of introducing cancer drugs that have an unacceptable cost-risk-benefit profile.

Endogenous glucose production increases in response to metformin treatment in the glycogen-depleted state in humans: a randomised trial.

AIMS/HYPOTHESIS: Metformin is believed to reduce glucose levels primarily by inhibiting hepatic glucose production. Recent data indicate that metformin antagonises glucagon-dependent glucose output, suggesting that compensatory mechanisms protect against hypoglycaemia. Here, we examined the effect of metformin on glucose metabolism in humans after a glycogen-depleting fast and the role of reduced-function alleles in OCT1 (also known as SLC22A1). METHODS: In a randomised, crossover trial, healthy individuals with or without reduced-function alleles in OCT1 were fasted for 42 h twice, either with or without prior treatment with 1 g metformin twice daily. Participants were recruited from the Pharmacogenomics Biobank of the University of Southern Denmark. Treatment allocation was generated by the Good Clinical Practice Unit, Odense University Hospital, Denmark. Variables of whole-body glucose metabolism were assessed using [3-(3)H]glucose, indirect calorimetry and measurement of substrates and counter-regulatory hormones. The primary outcome was endogenous glucose production (EGP). RESULTS: Thirty-seven individuals were randomised. Thirty-four completed the study (12 had none, 13 had one and nine had two reduced-function alleles in OCT1). Three were excluded from the analysis because of early dropout. Metformin significantly stimulated glucose disposal rates and non-oxidative glucose metabolism with no effect on glucose oxidation. This increase in glucose utilisation was explained by a concomitant increase in glycolytic flux and accompanied by increased EGP, most likely mediated by increased plasma lactate, glucagon and cortisol levels. There was no effect of reduced-function OCT1 alleles on any of these measures. All individuals completed the glycogen-depleting fast without hypoglycaemia. CONCLUSIONS/INTERPRETATION: Metformin stimulates glycolytic glucose utilisation and lactate production in the glycogen-depleted state. This may trigger a rise in glucose counter-regulatory hormones and subsequently an increase in EGP, which protects against hypoglycaemia. TRIAL REGISTRATION: ClinicalTrials.gov NCT01400191 FUNDING: Danish Research Council for Health and Disease (0602-02695B) and Odense University Hospital Free Research Fund, 2012.