1 A total of three hundred and nineteen new chemical entities (NCEs) were investigated in man for the first time between 1964 and 1985 by seven UK‐owned pharmaceutical companies. The majority (96.2%), were self‐originated by the UK company or one of its overseas subsidiaries. 2 There was an increase in the number of NCEs investigated each year in man, doubling from an average of 12 per year up to 1980, to over 20 per year between 1981 and 1985. The majority of first drug evaluations in human volunteers were carried out in the UK (92.2%), in contrast to evaluation of new medicines in patients, where 42.9% were first tested outside the UK. 3 The majority of NCEs evaluated in man (78%), were in four therapeutic classes: anti‐infectives (32%), anti‐allergics (22%), drugs acting on the central nervous system (13%) and cardiovascular system agents (11%). 4 By the end of 1985, 49 (15.4%) of these NCEs had been marketed in the UK and 198 (62.0%) discontinued from further development. The main reasons for termination were inappropriate pharmacokinetics in man (39.4%), and lack of clinical efficacy (29.3%). 5 Average development times increased from less than 2 years between 1964 and 1965, to around 8 years in the 1980s with a consequent reduction in the effective patent life.

Several quantitative RBA methods are available that could be used to help lessen concern over subjective drug assessments and to help guide authorities toward more objective and transparent decision-making. When evaluating a new drug therapy, we recommend the use of multiple RBA approaches across different therapeutic indications and treatment populations in order to bound the risk-benefit profile.

The initial identification of the ALK gene, expressed as C-terminal part of the transforming fusion protein NPM-ALK in the t(2;5)(p23;q35) lymphoma-associated chromosomal translocation, revealed a novel receptor tyrosine kinase (RTK). In order to expand the knowledge on ALK expression in the human system, we examined a panel of human cell lines for ALK expression and found that transcription is completely repressed in cell lines of entodermal origin (0/21). Furthermore, full length receptor expression is absent in cell lines of the hematopoietic system with the exception of t(2; 5)-associated anaplastic large cell lymphomas lines (ALCL), which are known to express chimeric NPM-ALK mRNA. Cell lines established from solid tumors of ectodermal origin, including melanoma and breast carcinoma, exhibited widespread mRNA expression of the ALK receptor at a broad range (53/64), an association which was found to be strongest in cell lines derived from neuroblastoma (6/6), glioblastoma (8/8) as well as in cell lines established from Ewing sarcoma (4/4) and retinoblastomas (2/2). Because of the reported involvement of neutrophin tyrosine kinase receptors in autocrine differentiation in neuroblastomas, we analyzed cell lines positive for full length or chimeric ALK protein for the presence of phoshotyrosine residues within the intracellular region of ALK. While the constitutive activation of chimeric NPM-ALK molecules could be shown, no evidence was found for induced or constitutively activated ALK receptors in neuroblastoma, melanoma or breast carcinoma cell lines. Although the receptor could be shown to be consistently expressed with exclusive specificity in tissues developed from the ectoderm, our results do not support any involvement of ALK in the stimulation of tumorigenic cell growth or differentiation so far, indicating that ALK expression is a physiologic rather than a pathologic phenomenon. © 2002 Wiley-Liss, Inc. Key words: receptor tyrosine kinase; ALK, translocation; t(2;5)(p23; q35); ALCL; tumor cell linesThe genesis of lymphoproliferative disorders and of solid tumors is caused in part by chromosomal translocations, when new hybrid genes are generated and the expression of the fusion gene products possess severe oncogenic properties. 1 Anaplastic large cell lymphoma (ALCL) is associated with a (2;5)(p23;q35) chromosomal translocation, 2 which fuses the gene encoding the ALK receptor tyrosine kinase localized at 2p23 with the housekeeping gene nucleophosmin (NPM) at 5q35. 3 The resultant hybrid gene harbors the NH 2 -terminus of NPM linked to the entire intracytoplasmatic portion of ALK encoding a constitutively activated 80 kDa nuclear phosphoprotein, 4 which could be shown to be sufficient for malignant transformation of murine fibroblasts in vitro or for induction of transplantable lymphoma in mice. 5,6 Recently, a number of investigations have shown that genes other than NPM could provide similar structural and functional prerequisites, since different ALK products have been identified in cases of ALCLs as...

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Although this study only provided an indirect measure of medication usage, it demonstrated that a less frequent dosing regimen significantly improved levels of both compliance and persistence; however, even on weekly regimens bisphosphonate usage remains sub-optimal thereby reducing the clinical benefits.