The cost of biopharmaceutical R&D: Is biotech different?

The costs of developing the types of new drugs that have been pursued by traditional pharmaceutical firms have been estimated in a number of studies. However, similar analyses have not been published on the costs of developing the types of molecules on which biotech firms have focused. This study represents a first attempt to get a sense for the magnitude of the R&D costs associated with the discovery and development of new therapeutic biopharmaceuticals (specifically, recombinant proteins and monoclonal antibodies [mAbs]). We utilize drug-specific data on cash outlays, development times, and success in obtaining regulatory marketing approval to estimate the average pre-tax R&D resource cost for biopharmaceuticals up to the point of initial US marketing approval (in year 2005 dollars). We found average out-of-pocket (cash outlay) cost estimates per approved biopharmaceutical of $198 million, $361 million, and $559 million for the preclinical period, the clinical period, and in total, respectively. Including the time costs associated with biopharmaceutical R&D, we found average capitalized cost estimates per approved biopharmaceutical of $615 million, $626 million, and $1241 million for the preclinical period, the clinical period, and in total, respectively. Adjusting previously published estimates of R&D costs for traditional pharmaceutical firms by using past growth rates for pharmaceutical company costs to correspond to the more recent period to which our biopharmaceutical data apply, we found that total out-of-pocket cost per approved biopharmaceutical was somewhat lower than for the pharmaceutical company data ($559 million vs $672 million). However, estimated total capitalized cost per approved new molecule was nearly the same for biopharmaceuticals as for the adjusted pharmaceutical company data ($1241 million versus $1318 million). The results should be viewed with some caution for now given a limited number of biopharmaceutical molecules with data on cash outlays, different therapeutic class distributions for biopharmaceuticals and for pharmaceutical company drugs, and uncertainty about whether recent growth rates in pharmaceutical company costs are different from immediate past growth rates. Copyright © 2007 John Wiley & Sons, Ltd.

Influence of megasonic agitation on the electrodeposition of high aspect ratio blind vias

This paper presents preliminary studies in electroplating using megasonic agitation to avoid the formation of voids within high aspect ratio microvias that are used for the redistribution of interconnects in high density interconnection technology in printed circuit boards. Through this technique, uniform deposition of metal on the side walls of the vias is possible. High frequency acoustic streaming at megasonic frequencies enables the decrease of the Nernst diffusion layer down to the sub-micron range, allowing thereby conformal electrodeposition in deep grooves. This effect enables the normally convection free liquid near the surface to be agitated. Higher throughput and better control of the material properties of the deposits can be achieved for the manufacturing of embedded interconnections and metal-based MEMS. For optimal filling performance of the microvias, a full design of experiments (DOE) and a multi-physics numerical simulation have been conducted to analyse the influence of megasonic agitation on the plating quality of the microvias. Megasonic based deposition has been found to increase the deposition rate as well as improving the quality of the metal deposits.

Advanced glycation of fibronectin impairs vascular repair by endothelial progenitor cells: Implications for vasodegeneration in diabetic retinopathy

PURPOSE. Vascular repair by marrow-derived endothelial progenitor cells (EPCs) is impaired during diabetes, although the precise mechanism of this dysfunction remains unknown. The hypothesis for the study was that progressive basement membrane (BM) modification by advanced glycation end products (AGEs) contributes to impairment of EPC reparative function after diabetes-related endothelial injury.

METHODS. EPCs isolated from peripheral blood were characterized by immunocytochemistry and flow cytometry. EPC interactions on native or AGE-modified fibronectin (AGE-FN) were studied for attachment and spreading, whereas chemotaxis to SDF-1 was assessed with the Dunn chamber assay. In addition, photoreactive agent-treated monolayers of retinal microvascular endothelial cells (RMECs) produced circumscribed areas of apoptosis and the ability of EPCs to “endothelialize” these wounds was evaluated.

RESULTS. EPC attachment and spreading on AGE-FN was reduced compared with control cells (P < 0.05–0.01) but was significantly restored by pretreatment with Arg-Gly-Asp (RGD). Chemotaxis of EPCs was abolished on AGE-FN but was reversed by treatment with exogenous RGD. On wounded RMEC monolayers, EPCs showed clustering at the wound site, compared with untreated regions (P < 0.001); AGE-FN significantly reduced this targeting response (P < 0.05). RGD supplementation enhanced EPC incorporation in the monolayer, as determined by EPC participation in tight junction formation and restoration of transendothelial electric resistance (TEER).

CONCLUSIONS. AGE-modification of vascular substrates impairs EPC adhesion, spreading, and migration; and alteration of the RGD integrin recognition motif plays a key role in these responses. The presence of AGE adducts on BM compromises repair by EPC with implications for vasodegeneration during diabetic microvasculopathy.

Photosensitiser delivery for photodynamic therapy. Part 2: systemic carrier platforms

Background: The treatment of solid tumours and angiogenic ocular diseases by photodynamic therapy (PDT) requires the injection of a photosensitiser (PS) to destroy target cells through a combination of visible light irradiation and molecular oxygen. There is currently great interest in the development of efficient and specific carrier delivery platforms for systemic PDT. Objective: This article aims to review recent developments in systemic carrier delivery platforms for PDT, with an emphasis on target specificity. Methods: Recent publications, spanning the last five years, concerning delivery carrier platforms for systemic PDT were reviewed, including PS conjugates, dendrimers, micelles, liposomes and nanoparticles. Results/conclusion: PS conjugates and supramolecular delivery platforms can improve PDT selectivity by exploiting cellular and physiological specificities of the targeted tissue. Overexpression of receptors in cancer and angiogenic endothelial cells allows their targeting by affinity-based moieties for the selective uptake of PS conjugates and encapsulating delivery carriers, while the abnormal tumour neovascularisation induces a specific accumulation of heavy weighted PS carriers by enhanced permeability and retention (EPR) effect. in addition, polymeric prodrug delivery platforms triggered by the acidic nature of the tumour environment or the expression of proteases can be designed. Promising results obtained with recent systemic carrier platforms will, in due course, be translated into the clinic for highly efficient and selective PDT protocols.

Voodoo Institution or Entrepreneurial University? Spin-off Companies, the Entrepreneurial System and Regional Development in the UK

University spin-off companies occupy a prominent position in both government and university policies and aspirations for the commercialization of university research for economic benefit at regional and national levels. However, most university spin-off companies start small and remain small, reflecting founder aspirations, capabilities, and resource endowments. Based on detailed analysis of university spin-offs in Northern Ireland, it is concluded that these companies are technology lifestyle businesses not dynamic high-growth potential start-ups, and it is suggested that the prominence given to spin-offs in the analysis of technology transfer and in discussions of the economic impacts of universities is misplaced.

The rate of return on equity across industrial sectors on the British stock market, 1825-70

This article assesses the contribution of the various industrial sectors to the growth of the British equity market in the 1825–70 period. It also provides estimates of the rates of return on these industrial sectors in this period. The article then proceeds to examine whether differences in rates of return across the various sectors can be explained by risk or other financial factors. One of the main findings is that the relatively high rates of return in the banking, insurance, and miscellaneous sectors appear to be in some measure explained by the presence of extended liability and uncalled capital.

Intrinsic variability in the detection of micrometastases in lymph nodes for re-staging of colorectal cancer: effect of individual markers and tissue samples

In this study, we investigated whether (a) carcinoembryonic antigen (CEA), cytokeratin-20 (CK-20) and guanylyl cyclase C (GCC) are clinically useful markers for the molecular detection of submicroscopic metastases in colorectal cancer (CRC) and (b) whether overexpression of CEA, CK-20 and GCC can be reliably detected in formalin-fixed, paraffin-embedded tissues as well as frozen lymph nodes. We studied 175 frozen lymph nodes and 158 formalin-fixed, paraffin-embedded lymph nodes from 28 cases of CRC. CEA or CK-20 or GCC-specific polymerase chain reaction (PCR) was carried out on mRNA transcripts extracted from the nodal tissues. Ten out of I I Dukes' B CRC cases had detectable CEA and CK-20 while 6 out of 11 Dukes' B CRC cases had detectable GCC. In general, the difference of re-staged cases when comparing frozen and paraffin-embedded samples was marked; the only statistically significant correlation between frozen and paraffin tissue was for the CEA marker. Our results indicated a high incidence (>50%) of detecting micrometastases in histologically-negative lymph nodes at the molecular level. (C) 2003 Elsevier Science Ltd. All rights reserved.

Indirect comparisons of treatments based on systematic reviews of randomised controlled trials

Randomised controlled trials are the most effective way to differentiate between the effects of competing interventions. However, head-to-head studies are unlikely to have been conducted for all competing interventions.