Early market access of cancer drugs in the EU.

Patient access to new cancer drugs in the EU involves centralised licensing decisions by regulators as well as reimbursement recommendations in the context of national healthcare systems. Differences in assessment criteria and evidence requirements may result in divergent decisions at central and national levels, ultimately compromising effective access to patients. Early access decisions are particularly challenging due to the limited clinical evidence available to conclude on the benefit-risk and relative (cost-) effectiveness of new high-priced cancer drugs. We describe mechanisms to accelerate approval of promising anticancer drugs that fulfil an unmet medical need, review the experience from the European Medicines Agency, compare timelines and outcomes of reimbursement decisions in major EU markets, and discuss shortcomings of the current system, ongoing initiatives, and future steps to facilitate effective early access.

The future is now: model-based clinical trial design for Alzheimer's disease.

Failures in trials for Alzheimer's disease (AD) may be attributable to inadequate dosing, population selection, drug inefficacy, or insufficient design optimization. The Coalition Against Major Diseases (CAMD) was formed in 2008 to develop drug development tools (DDT) to expedite drug development for AD and Parkinson's disease. CAMD led a process that successfully advanced a clinical trial simulation (CTS) tool for AD through the formal regulatory review process at the US Food and Drug Administration (FDA) and European Medicines Agency (EMA).

From adaptive licensing to adaptive pathways: delivering a flexible life-span approach to bring new drugs to patients.

The concept of adaptive licensing (AL) has met with considerable interest. Yet some remain skeptical about its feasibility. Others argue that the focus and name of AL should be broadened. Against this background of ongoing debate, we examine the environmental changes that will likely make adaptive pathways the preferred approach in the future. The key drivers include: growing patient demand for timely access to promising therapies, emerging science leading to fragmentation of treatment populations, rising payer influence on product accessibility, and pressure on pharma/investors to ensure sustainability of drug development. We also discuss a number of environmental changes that will enable an adaptive paradigm. A life-span approach to bringing innovation to patients is expected to help address the perceived access vs. evidence trade-off, help de-risk drug development, and lead to better outcomes for patients.

Gatekeepers and enablers: how drug regulators respond to a challenging and changing environment by moving toward a proactive attitude.

This article analyzes the role of regulatory authorities in facilitating innovation in the pharmaceutical sector. We describe how regulators are expanding their role to be not only gatekeepers but also enablers of development. They have already responded to the challenging and changing environment by moving toward a proactive attitude beyond evaluation of products, thereby more actively contributing to their development. Regulators have to continuously evolve their knowledge and standards alongside evolution in science. Creation of supportive regulatory frameworks and multistakeholder interaction will help address unmet regulatory needs.

Are women appropriately represented and assessed in clinical trials submitted for marketing authorization? A review of the database of the European Medicines Agency.

OBJECTIVE: There is concern that patients included in trials do not represent the true patient population and women in particular may selectively be excluded. We looked at trial data submitted to the European Medicines Agency (EMEA) by drug companies to achieve marketing authorization in Europe between 2000 and 2003. METHODS: We reviewed the EMEA database and included the main studies for the risk/benefit assessment (pivotal trials) submitted between 2000 and 2003. RESULTS: In pivotal trials submitted to the EMEA there was no, or generally clinically negligible, evidence for gender bias; however, women were underrepresented in hypertension, diabetes and hepatitis B trials, and overrepresented in rheumatoid arthritis and allergic conjunctivitis. CONCLUSIONS: In trials submitted for marketing authorization to the EMEA gender bias was not a serious problem.

The toxicology expert: what is required?

In contrast to many traditional professions, toxicologists form a group with very different backgrounds, i.e. they may have been educated to become medical doctors, veterinarians, pharmacists, chemists, biochemists or biologists. Professional competence can be gained in different ways by candidate toxicologists, and according to the European system, their training can be divided into two parts. (i) Theoretical training on several topics such as analytical methods, organ toxicity, mutagenicity, carcinogenicity can be obtained by attending courses organised by the national societies of toxicology. (ii) Spending several years on active experimental work in the fields of modern toxicology (e.g. analytical methods, toxic and genotoxic mechanisms, reproductive toxicity) is necessary to develop the capability to design and carry out experimental studies and to evaluate one's own and other people's research results. Candidate toxicologists should learn to evaluate data with a strictly scientific 'plausibility above numbers' approach.

Increased genomic damage in lymphocytes of patients before and after long-term maintenance hemodialysis therapy.

This study investigates spontaneous genomic damage in peripheral lymphocytes of 19 patients with severe end-stage renal disease not enrolled onto a maintenance hemodialysis (MHD) program (creatinine level, 5.4 to 10.5 mg/dL) and 16 long-term MHD patients (111 to 282 months on MHD) and the possible association of genomic damage with the degree of renal insufficiency and duration of MHD. Genomic damage was assessed by evaluating the numbers of micronuclei (MN), which are cytoplasmic DNA-containing structures. The average number of MN in the control group of 23 healthy subjects was 15.3 +/- 4.7 MN/1,000 binucleate (BN) cells. The MN frequencies in the long-term MHD group were significantly greater (44.3 +/- 13.7 MN/1,000 BN) than the control frequencies. A significant increase in MN frequencies (28.2 +/- 9.4 MN/1,000 BN) was also seen in patients with advanced renal failure. The major findings of the study, high MN frequencies in long-term hemodialysis and advanced chronic renal failure patients, may result from decreased DNA repair previously shown and may contribute to the increased cancer incidence in these patients.

Discrimination between genotoxicity and cytotoxicity for the induction of DNA double-strand breaks in cells treated with aldehydes and diepoxides.

The time-dependent dose-response relationships for the induction of DNA double-strand breaks (DSB) assessed by pulsed-field gel electrophoresis (PFGE) and for viability (evaluated by the MTT cytotoxicity test) were investigated in order to discriminate between genotoxic and cytotoxic mechanisms of DNA fragmentation. Cultured human lung epithelial cells (A549) were treated (i) with the aldehydes formaldehyde or glutaraldehyde and (ii) with the DNA-DNA interstrand crosslinkers melphalan, diepoxybutane or diepoxyoctane. Induction of DSB by formaldehyde and glutaraldehyde was seen only after cell viability was reduced to less than about 60% of the control values, indicating that DSB were the consequence of extragenomic damage and viability loss. Melphalan, diepoxybutane and diepoxyoctane induced DSB by a genotoxic mode with concentrations that did not affect cell survival: 8 h after treatment initiation both heat-labile crosslinks and DSB could be detected. Cells were not able to repair the crosslinks induced by diepoxybutane, the crosslinker with the shortest chain length. In contrast, with melphalan and diepoxyoctane, which have a longer crosslinking property considerable repair of crosslinks was observed. The molecular size distribution of the produced DNA fragments supported this mechanistic distinction. The DNA fragments generated by diepoxides were initially large, their concentration decreasing monotonously from 7 Mbp to less than 1 Mbp and were converted to smaller fragments by 72 h in the course of cell death. In contrast, DNA fragments induced by formaldehyde peaked below 1 Mbp, implicating activation of DNA-degrading enzymes.

Advanced glycated albumin impairs protein degradation in the kidney proximal tubules cell line LLC-PK1.

Advanced glycation end-products (AGEs) are assumed to play a major role in the genesis of diabetic nephropathy and other diabetic complications. We studied the potential effect of AGEs on protein turnover and lysosomal proteinase activities in LLC-PK1 cells, a pig kidney proximal tubules cell line. Advanced glycated bovine serum albumin (AGE-BSA) was used as a model of AGEs and its action was compared to that of nonglycated BSA. AGE-BSA but not BSA (50 micromol/l) induced a significant increase in cell volume (BSA: 4870.6 +/- 74.8 fl, AGE-BSA: 5718.0 +/- 20.7 fl, p<0.01). Protein degradation rate was decreased by 13.8% after 48 hrs. incubation with AGE-BSA (p<0.01) while protein synthesis increased by 19,1%, (p<0.01). After incubation with AGE-BSA but not BSA activities of lysosomal cathepsins (B, L+B and H) decreased in a time- and dose-dependent fashion. This decline was neither caused by a shift in lysosomal pH outside the optimal range for cathepsins, nor by a direct inhibitory effect of AGEs modified proteins or peptides but most probably by inhibition of cathepsin B expression as measured by RT-PCR. It is supposed that impaired protease activities participated in decreased protein breakdown and cell enlargement. For the first time our data provide the evidence that AGEs induce hypertrophy of LLC-PK1 cells due to decreased protein breakdown resulting from reduced lysosomal proteinase activities with a concomitant stimulation of protein synthesis.

Changes in the classification of carcinogenic chemicals in the work area. Section III of the German List of MAK and BAT Values.

Carcinogenic chemicals in the work area are currently classified into three categories in section III of the German List of MAK and BAT Values (list of values on maximum workplace concentrations and biological tolerance for occupational exposures). This classification is based on qualitative criteria and reflects essentially the weight of evidence available for judging the carcinogenic potential of the chemicals. It is proposed that these categories - IIIA1, IIIA2, IIIB - be retained as Categories 1, 2, and 3, to correspond with European Union regulations. On the basis of our advancing knowledge of reaction mechanisms and the potency of carcinogens, these three categories are supplemented with two additional categories. The essential feature of substances classified in the new categories is that exposure to these chemicals does not contribute significantly to risk of cancer to man, provided that an appropriate exposure limit (MAK value) is observed. Chemicals known to act typically by nongenotoxic mechanisms and for which information is available that allows evaluation of the effects of low-dose exposures, are classified in Category 4. Genotoxic chemicals for which low carcinogenic potency can be expected on the basis of dose-response relationships and toxicokinetics, and for which risk at low doses can be assessed are classified in Category 5. The basis for a better differentiation of carcinogens is discussed, the new categories are defined, and possible criteria for classification are described. Examples for Category 4 (1,4-dioxane) and Category 5 (styrene) are presented.

Renal cell cancer correlated with occupational exposure to trichloroethene.

A previous cohort-study in a cardboard factory demonstrated that high and prolonged occupational exposure to trichloroethene (C2HCl3) is associated with an increased incidence of renal cell cancer. The present hospital-based case/control study investigates occupational exposure in 58 patients with renal cell cancer with special emphasis on C2HCl3 and the structurally and toxicologically closely related compound tetrachloroethene (C2Cl4). A group of 84 patients from the accident wards of three general hospitals in the same area served as controls. Of the 58 cases, 19 had histories of occupational C2HCl3 exposure for at least 2 years and none had been exposed to C2Cl4; of the 84 controls, 5 had been occupationally exposed to C2HCl3 and 2 to C2Cl4. After adjustment for other risk factors, such as age, obesity, high blood pressure, smoking and chronic intake of diuretics, the study demonstrates an association of renal cell cancer with long-term exposure to C2HCl3 (odds ratio 10.80; 95% CI: 3.36-34.75).

Acute intoxication with trichloroethene: clinical symptoms, toxicokinetics, metabolism, and development of biochemical parameters for renal damage.

The present study reports on a 17-year-old male who ingested approximately 70 ml trichloroethene (TRI) in a suicide attempt. The patient developed fever, tremor, general motor restlessness, and sinus tachycardia and lost consciousness 5 h after poisoning. After 5 days of intubation under narcosis with forced hyperventilation and diuresis he regained consciousness. During this period blood and urine were collected and TRI and its metabolites were quantified. The highest concentration of TRI in blood was detected 13 h after ingestion. Trichloroethanol and trichloroacetic acid, metabolites of the cytochrome P450-mediated pathway, and N-acetyl-S-(1, 2-dichlorovinyl)-l-cysteine and N-acetyl-S-(2, 2-dichlorovinyl)-l-cysteine from the glutathione-dependent pathway of TRI were quantified in urine samples. Besides these known metabolites in humans, chloroacetic acid and dichloroacetic acid were identified for the first time in urine of a human exposed to TRI. Although the patient exhibited normal levels of glucose and total protein in urine, excretion of alpha1- and beta2-microglobulin as well as beta-NAG was significantly increased. In addition to these typical markers of selective tubule damage, analysis of the urinary protein pattern by SDS-PAGE revealed increased excretion of several low-molecular-mass proteins between 10,000 and 50,000 Da, clearly indicating tubular damage. Based on the elucidated glutathione-dependent mechanism for the nephrotoxicity of TRI, activation of the formed S-conjugates by beta-lyases to reactive intermediates may account for the observed renal effects after a single, high dose of TRI.

Alcohol abuse: potential role in electrolyte disturbances and kidney diseases.

The present review summarizes the current knowledge on the multiple effects of alcohol overconsumption on the kidney function as well as on water, electrolyte and acid-base homeostasis. In contrast to the well known transitory diuretic effects, the overall long-term effect of chronic alcohol overconsumption is water and salt retention with expansion of extracellular volume. Furthermore, depletion of magnesium, phosphate and calcium is also frequently found in alcohol-dependent patients. These electrolyte disturbances may be associated with the alcohol-induced hypoparathyroidism and parathyroid hormone resistance of the skeletal muscle as well as with the decrease of serum osteocalcin. Metabolic acidosis with lower arterial blood pH and plasma bicarbonate concentrations was revealed in alcoholic patients upon admission and a significant correlation between chronic alcohol overconsumption and increased incidence of hyperuricemia and gout attacks was also reported. Alcohol seems to have dual effects on the blood pressure. Increased blood pressure was demonstrated in men above 80 g and in women above 40 g ethanol consumption daily. In contrast, young adults consuming only 10 to 20 g per day had lower blood pressure than the abstinent group indicating a J-curve relationship. This is in line with the lowered risk for coronary heart disease associated with regular consumption of small alcohol amounts. The mechanisms responsible for the association between alcohol overconsumption and postinfectious glomerulonephritis have not been elucidated yet. Finally severe alcohol abuse predisposes to acute renal failure and seems to be associated with the general catabolic effects.

Cancer in end-stage renal disease: potential factors involved -editorial-.

Increased incidence of cancer at various sites is observed in patients with end-stage renal disease (ESRD). In particular, lymphomas and carcinomas of the kidney, prostate, liver and uterus show an enhanced prevalence in these subjects compared with the general population. A multitude of factors directly or indirectly associated with the renal disease and the treatment regimens may contribute to the increased tumor formation in these patients. Impaired function of the immune system and of DNA repair mechanisms as well as reduced antioxidant defense, accumulation of carcinogenic compounds partly due to reduced renal elimination as well as chronic infections and inflammations are found more frequently in patients with ESRD compared with the general population and may act in concert to accelerate malignant transformation and tumor formation.

S-(1,2-dichlorovinyl)-L-cysteine-induced dedifferentiation and p53 gene mutations in LLC-PK1 cells: a comparative investigation with S-(2-chloroethyl)cysteine, potassium bromate, cis-platinum and styrene oxide.

Exposure of cultured renal (LLC-PK1) cells for 7 weeks to non-cytotoxic concentrations of S-(1,2-dichlorovinyl)-L-cysteine had resulted in the induction of morphologically and biochemically dedifferentiated clones, which retained their altered properties after removal of the chemical. In this study we investigated by polymerase chain reaction-single strand conformational polymorphism (PCR-SSCP) analysis and direct sequencing if S-(1,2-dichlorovinyl)-L-cysteine-induced LLC-PK1 clones display mutations in the p53 gene in comparison with wild-type clones. In addition, the characteristics of S-(1,2-dichlorovinyl)-L-cysteine-induced clones were compared with clones induced by carcinogens/metabolites of carcinogens with different mechanisms of action: (i) The potent alkylating agent and bacterial mutagen chloroethylcysteine, the key metabolite of the carcinogen dichloroethane; (ii) potassium bromate, a nephrocarcinogen inducing reactive oxygen species, which give rise to the formation of 8OHdG and DNA strand-breaks; (iii) cis-platinum, a bifunctional cross-linking agent and strand-break inducer and (iv) styrene oxide, the main intermediate metabolite of styrene, an epoxide whose carcinogenicity is thought to be based on cytotoxicity. Three essential markers of the physiological integrity and renal tubule origin of the wild-type LLC-PK1 cells were disrupted in all chemical-derived clones: (i) the polarisation of the plasma membrane into a luminal and basolateral part; (ii) the sodium-dependent glucose uptake and (iii) the pH-dependent ammonia production. Compared with the wild-type clones, poly(ADP-ribosyl)ation, a posttranslational modification of nuclear proteins, was clearly increased in clones induced by S-(1,2-dichlorovinyl)-L-cysteine, potassium bromate and cis-platinum. These clones displayed also band shifts of p53 exon 7, indicating mutations, which were confirmed by sequencing: a double mutation consisting of a base substitution followed by one base insertion in the case of S-(1,2-dichlorovinyl)-L-cysteine and potassium bromate and a base substitution in the case of cis-platinum. The base insertions both lead to the formation of the stop codon UGA resulting in loss of protein function.