The European Medicines Agency's approval of new medicines for type 2 diabetes.

Since 2005, more than 40 new medicines for the treatment of type 2 diabetes have been introduced on the market. These consist of 15 new active substances establishing three new classes of non-insulin products, and several new or modified insulin products and combinations. The approval of these products in Europe is regulated via the centralized procedure at the European Medicines Agency. Demonstration of benefit with regard to improved glucose control remains the principal outcome required from confirmatory studies to demonstrate efficacy. For the majority of these new medicines approved since 2005, cardiovascular outcome trials have now been completed, and have invariably supported the cardiovascular safety of these products. In some of these trials additional important benefits have been observed, for instance, a reduction in major adverse cardiovascular events and improvement of renal outcome. The existing regulatory framework and the continuous adaption of regulatory requirements to emerging developments will continue to guide the approval of new products in the future.

Extrapolation in the development of paediatric medicines: examples from approvals for biological treatments for paediatric chronic immune-mediated inflammatory diseases.

The European Union (EU) Paediatric Regulation requires that all new medicinal products applying for a marketing authorisation (MA) in the EU provide a paediatric investigation plan (PIP) covering a clinical and non-clinical trial programme relating to the use in the paediatric population, unless a waiver applies. Conducting trials in children is challenging on many levels, including ethical and practical issues, which may affect the availability of the clinical evidence. In scientifically justified cases, extrapolation of data from other populations can be an option to gather evidence supporting the benefit-risk assessment of the medicinal product for paediatric use. The European Medicines Agency (EMA) is working on providing a framework for extrapolation that is scientifically valid, reliable and adequate to support MA of medicines for children. It is expected that the extrapolation framework together with therapeutic area guidelines and individual case studies will support future PIPs. Extrapolation has already been employed in several paediatric development programmes including biological treatment for immune-mediated diseases. This article reviews extrapolation strategies from MA applications for products for the treatment of juvenile idiopathic arthritis, paediatric psoriasis and paediatric inflammatory bowel disease. It also provides a summary of extrapolation advice expressed in relevant EMA guidelines and initiatives supporting the use of alternative approaches in paediatric medicine development.

The European Medicines Agency review of pixantrone for the treatment of adult patients with multiply relapsed or refractory aggressive non-Hodgkin's B-cell lymphomas: summary of the scientific assessment of the committee for medicinal products for human use.

On May 10, 2012, the European Commission issued a conditional marketing authorization valid throughout the European Union for pixantrone for the treatment of adult patients with multiply relapsed or refractory aggressive non-Hodgkin's B-cell lymphoma (NHL). Pixantrone is a cytotoxic aza-anthracenedione that directly alkylates DNA-forming stable DNA adducts and cross-strand breaks. The recommended dose of pixantrone is 50 mg/m(2) administered on days 1, 8, and 15 of each 28-day cycle for up to 6 cycles. In the main study submitted for this application, a significant difference in response rate (proportion of complete responses and unconfirmed complete responses) was observed in favor of pixantrone (20.0% vs. 5.7% for pixantrone and physician's best choice, respectively), supported by the results of secondary endpoints of median progression-free and overall survival times (increase of 2.7 and 2.6 months, respectively). The most common side effects with pixantrone were bone marrow suppression (particularly of the neutrophil lineage) nausea, vomiting, and asthenia. This article summarizes the scientific review of the application leading to approval in the European Union. The detailed scientific assessment report and product information, including the summary of product characteristics, are available on the European Medicines Agency website (http://www.ema.europa.eu).

Prognostic factors and survival in 324 patients with pancreatic endocrine tumor treated at a single institution.

PURPOSE: Unequivocal pathologic markers for the prognosis of pancreatic endocrine tumors are often lacking. Suggestions for prognostic guidance include the WHO classification. Recently, a tumor-node-metastasis (TNM) staging system was proposed. We evaluate this system, as well as assess other potential prognostic factors such as tumor Ki67, size, endocrine syndrome, heredity, body mass index (BMI), and plasma chromogranin A, in a large patient material treated at a single institution. EXPERIMENTAL DESIGN: A total of 324 patients with pancreatic endocrine tumor, consecutively diagnosed and treated at a tertiary referral center, were retrospectively evaluated. Median follow-up was 54 months (range, 1-423 months). Patient and tumor data were extracted from medical records. Univariate and multivariate analyses were done to recognize factors of prognostic value. RESULTS: The median overall survival was 99 months (95% confidence interval, 81-117). Five- and 10-year survival rates were 64% and 44%, respectively. In univariate analysis, TNM stage, radical surgery, WHO classification, nonfunctioning tumor, Ki67 > or = 2%, chromogranin A > or = 3 times the upper normal limit, BMI < 20 kg/m2, sporadic tumor, tumor size, and referral from our primary uptake area had a significant prognostic effect. In multivariate analysis, TNM stage, WHO classification, radical surgery, and Ki67 > or = 2% retained their significance. Having a nonfunctioning tumor was not an independent marker of poor prognosis and neither was heredity. CONCLUSIONS: The recently suggested TNM staging system emerged as a useful clinical tool.

Endocrine pancreatic tumors with glucagon hypersecretion: a retrospective study of 23 cases during 20 years.

BACKGROUND: Glucagon-secreting endocrine pancreatic tumor is a rare disease, hence controlled studies on clinical management are lacking. In an attempt to assess the efficacy of diagnostic and therapeutic measures in patients with glucagonoma, a retrospective study was performed using the archives of a tertiary care center. PATIENTS AND METHODS: Records from 340 patients with endocrine pancreatic tumors were reassessed and 23 patients with malignant endocrine pancreatic tumor and elevated plasma glucagon levels were identified. RESULTS: About 7% of patients with histologically verified tumors fullfilled our criteria for glucagonoma. Only 22% of these patients had developed diabetes prior to the diagnosis of glucagonoma. Seventy eight percent had metastatic disease to the liver at diagnosis. Necrolytic migratory erythema was diagnosed or clinically suspected in 52%. Somatostatin receptor scintigraphy was positive in 95%. Nineteen patients received chemotherapy at some point, in 18 cases streptozotocin and 5 FU. With this treatment, objective radiological responses were seen in 50% of evaluable patients. Other treatment modalities used were interferon, somatostatin analogs, hepatic artery embolization, radio-frequency ablation of liver metastases, and radiolabeled somatostatin analogs. During the study period, 11 patients died at a median of 80 months from diagnosis whereas 11 patients are still alive after a median follow up of 52 months. One patient was lost to follow-up. CONCLUSIONS: Glucagonomas represent 7% of our comprehensive referral material of endocrine pancreatic tumors. Necrolytic migratory erythema was a common finding (52%) and diabetes less frequent at presentation than previously reported. Tumors were positive on somatostatin receptor scintigraphy and objective responses were seen to chemotherapy.

Temozolomide as monotherapy is effective in treatment of advanced malignant neuroendocrine tumors.

PURPOSE: A retrospective analysis of the toxicity and efficacy of temozolomide in advanced neuroendocrine tumors. EXPERIMENTAL DESIGN: Thirty-six patients with advanced stages of neuroendocrine tumor (1 gastric, 7 thymic and 13 bronchial carcinoids, 12 pancreatic endocrine tumors, 1 paraganglioma, 1 neuroendocrine foregut, and 1 neuroendocrine cecal cancer) were treated with temozolomide (200 mg/m(2)) for 5 days every 4 weeks. Patients had previously received a mean of 2.4 antitumoral medical regimens. Tumor response was evaluated radiologically according to the Response Evaluation Criteria in Solid Tumors every 3 months on an intent-to-treat basis. The circulating tumor marker plasma chromogranin A was also assessed. The expression of O(6)-methylguanine DNA methyltransferase, an enzyme implicated in chemotherapy resistance, was studied by immunohistochemistry (n=23) and compared with response to temozolomide. RESULTS: Median overall time to progression was 7 months (95% confidence interval, 3-10). Radiologic response was seen in 14% of patients and stable disease in 53%. Side effects were mainly hematologic; 14% experienced grade 3 or 4 thrombocytopenia (National Cancer Institute toxicity criteria). Ten patients had tumors with O(6)-methylguanine DNA methyltransferase immunoreactivity in <10% of nuclei, whereas four patients showed radiologic responses. CONCLUSIONS: Temozolomide as monotherapy had acceptable toxicity and antitumoral effects in a small series of patients with advanced malignant neuroendocrine tumors and four of these showed radiologic responses.

Evaluation of a scoring scheme, including proinsulin and the apolipoprotein B/apolipoprotein A1 ratio, for the risk of acute coronary events in middle-aged men: Uppsala Longitudinal Study of Adult Men (ULSAM).

BACKGROUND: In recent years, the importance of circulating levels of proinsulin and apolipoproteins as risk factors for myocardial infarction (MI) has been highlighted. The aims of the current study were to investigate whether introduction of these new markers of coronary risk could improve the performance of a risk prediction score and to compare this new score with traditional scoring schemes, such as the Framingham Study and the Prospective Cardiovascular Munster (PROCAM) Study schemes. METHODS: From 1970 to 1973 all 50-year-old men in Uppsala, Sweden, were invited to participate in a health survey aimed at identifying risk factors for cardiovascular disease (the Uppsala Longitudinal Study of Adult Men [ULSAM] cohort). The current study investigated metabolic characteristics at baseline and the incidence of fatal and nonfatal MI (n = 251) during 28.7 years of follow-up in 1108 men who were free of coronary heart disease at baseline. RESULTS: The risk prediction score was derived from one half of the population sample from the ULSAM cohort and included systolic blood pressure, smoking, family history of MI, serum proinsulin, and the ratio between apolipoprotein B and apolipoprotein A1. The score was highly predictive for future MI (hazard ratio, 1.77 for a 1 SD increase; 95% CI, 1.49 to 2.10, P <.0001) in the other half of the population that was not used for generating the score. The ULSAM score performed slightly better than the Framingham and PROCAM scores (evaluated as areas under the receiver operating curves; Framingham, 61%; PROCAM, 63%; ULSAM, 66%; P =.08). CONCLUSIONS: A risk prediction score for MI including proinsulin and the ratio between apolipoprotein B and apolipoprotein A1 was developed in middle-aged men. This score was highly predictive for future fatal and nonfatal MI and proved to be at least as good as the Framingham and the PROCAM scores, being based on traditional risk factors.

Cardiovascular risk factors for stable angina pectoris versus unheralded myocardial infarction.

BACKGROUND: Ischemic heart disease can vary substantially in its clinical presentation. Some patients have acute myocardial infarction (MI) without any previous signs of myocardial ischemia, whereas other patients may have stable angina pectoris for years without periods of acute unstability. This study compared baseline risk factors between subjects in whom stable angina pectoris developed and subjects in whom unheralded fatal or nonfatal MI developed during the follow-up period. METHODS: In 1970 to 1973, all 50-year-old men in Uppsala, Sweden, were invited to participate in a health survey aimed at identifying risk factors for cardiovascular disease. The present study is a nested case-control study of subjects who were free of coronary heart disease (CHD) at baseline and who then underwent revascularization (percutaneous transluminal coronary angioplasty or coronary artery bypass grafting) because of angina pectoris without preceding MI (n = 70) or in whom fatal or nonfatal MI developed without prior known CHD (n = 372) during the period until 1998. RESULTS: In multivariate Cox proportional hazard models, low-density lipoprotein and high-density lipoprotein levels (protective) were significant independent risk factors for stable angina pectoris demanding revascularization, whereas smoking, diastolic blood pressure, serum proinsulin levels, and serum lipid levels were significant independent predictors of subsequent unheralded MI. When comparing hazard ratios (HR), significantly higher HR for diastolic blood pressure (1.40 vs 1.00, for 1 SD increase) and serum proinsulin (1.82 vs1.20, for 1 SD increase) were found in the group in which unheralded MI developed than in the group with stable angina pectoris. CONCLUSIONS: Serum lipid levels were important risk factors for the development of both stable and acute coronary heart disease. In addition, proinsulin levels and blood pressure were independent predictors of unheralded MI only, which suggests that these factors are involved in thrombosis, plaque rupture, or both.

Increase in blood glucose concentration during antihypertensive treatment as a predictor of myocardial infarction: population based cohort study.

OBJECTIVE: To investigate the impact of an increase in blood glucose on the risk of developing myocardial infarction, with particular emphasis on people taking antihypertensive drugs. DESIGN: Prospective population based cohort study. SETTING: Uppsala, Sweden. PARTICIPANTS: 1860 men who had participated in 1970-3 at age 50 in a health survey aimed at identifying risk factors for cardiovascular disease and were re-examined at age 60 and then followed for 17.4 years. MIN OUTCOME MEASURE: Myocardial infarction after age 60. RESULTS: The incidence of myocardial infarction was significantly higher in men treated for hypertension than in those without such treatment (23% v 13.5%, P<0.0001). Participants who developed myocardial infarction after the age of 60 (n=253) showed a significantly larger increase in blood glucose between age 50 and 60 than did those without myocardial infarction. In multivariate Cox proportional hazard models increase in blood glucose was an independent risk factor for myocardial infarction (P=0.0001) in men receiving antihypertensive treatment at age 60 (n=291, mainly beta blockers and thiazide diuretics) but not in those without such treatment. The impact of increase in blood glucose declined after inclusion of serum proinsulin concentrations at baseline but was still significant. A significant interaction existed between proinsulin concentration (a marker of insulin resistance) at baseline and antihypertensive treatment on increase in blood glucose. CONCLUSIONS: Increase in blood glucose between the ages of 50 and 60 and baseline proinsulin concentration were important risk factors for myocardial infarction in men receiving antihypertensive treatment, indicating that both an insulin resistant state and the metabolic impact of beta blockers and diuretics increase the risk of myocardial infarction.