Success rates for product development strategies in new drug development.

WHAT IS KNOWN AND OBJECTIVE: While research has examined the likelihood that drugs progress across phases of clinical trials, no research to date has examined the types of product development strategies that are the most likely to be successful in clinical trials. This research seeks to identify the strategies that are most likely to reach the market-those generated using a novel product development strategy or strategies that combine a company's expertise with both drugs and indications, which we call combined experience strategies. METHODS: We evaluate the success of product development strategies in the drug development process for a sample of 2562 clinical trials completed by 406 US pharmaceutical companies. To identify product development strategies, we coded each clinical trial according to whether it consisted of an indication or a drug that was new to the firm. Accordingly, a clinical trial that consists of both an indication and a drug that were both new to the firm represents a novel product development strategy; indication experience is a product development strategy that consists of an indication that a firm had tested previously in a clinical trial, but with a drug that was new to the firm; drug experience is a product development strategy that consists of a drug that the firm had prior experience testing in clinical trials, but with an indication that was new to the firm; combined experience consists of both a drug and an indication that the firm had experience testing in clinical trials. Success rates for product development strategies across clinical phases were calculated for the clinical trials in our sample. RESULTS AND DISCUSSION: Combined experience strategies had the highest success rate. More than three and a half percent (0·036) of the trials that combined experience with drugs and indications eventually reached the market. The next most successful strategy is drug experience (0·025) with novel strategies trailing closely (0·024). Indication experience strategies are the least successful (0·008). These differences are statistically significant. WHAT IS NEW AND CONCLUSION: The primary contribution of this study is that product development strategies combining experience with drugs and indications strategies are the most likely to reach the market, even though they are least common strategy. Therefore, combined experience strategies remain underutilized. The findings also suggest a promising path for pursuing combined experience strategies: gaining expertise with drugs is likely to be a more effective path to gaining the expertise necessary for developing subsequent recombination strategies.

Disturbed vibrotactile sense in finger pulps in patients with Type 1 diabetes--correlations with glycaemic level, clinical examination and electrophysiology.

AIMS: In a cohort of men and women with Type 1 diabetes, prospectively followed for > 20 years, vibrotactile sense in fingers was investigated and related to neurophysiological tests, glycaemic level and clinical score. METHODS: Out of 58 patients, diagnosed at the age of 15-25 years and recruited 1984-1985, 32 patients (13 women, median age 52 years, range 44-75 years; 19 men, median age 52 years, range 39-69 years; median duration 33.5 years, range 21-52 years) accepted follow-up in 2006. Vibration thresholds were measured in finger pulps of index and little fingers bilaterally at seven frequencies and related to results of touch (monofilaments), tactile discrimination (two-point discrimination test), electrophysiology (median nerve function), glycaemic level (HbA(1c) levels since 1984-1985) and a clinical score. RESULTS: Vibrotactile sense was reduced in finger pulps, mainly in men, compared with an age- and gender-matched healthy control group with normal HbA(1c) . Vibration thresholds were increased, particularly at 250 and 500 Hz, in both index and little finger pulps. Touch and tactile discrimination correlated with vibration thresholds, but not with each other or with electrophysiology. HbA(1c) levels (at follow-up or mean values from five follow-ups since recruitment) did not correlate with any nerve function variables. Clinical scores correlated with vibrotactile sense, particularly at higher frequencies (> 125 Hz), but not with total Z-scores of electrophysiology. Duration of disease did not correlate with any variables. CONCLUSIONS: Examination of vibration thresholds in index and little finger pulps may be valuable to detect neuropathy, where thresholds correlate with symptoms and tests.

Relationship between drug plasma concentrations and psychomotor performance after single doses of ethanol and benzodiazepines.

In a placebo controlled, crossover study psychomotor effects of single doses of diazepam, 10 and 20 mg, flunitrazepam, 1 and 2 mg, as well as 0.9 g ethanol/kg body weight were investigated over a time period of 6 h in 12 healthy men. Blood samples were collected simultaneously with the test sessions to determine drug concentrations in plasma or blood. The ethanol dose caused the least performance impairment, followed by 10 mg diazepam. The most pronounced impairment was caused by 2 mg flunitrazepam, whereas 20 mg diazepam and 1 mg flunitrazepam caused intermediate impairment and were approximately equipotent on group level. Considerable interindividual differences with respect to maximal impairment following a particular drug treatment were observed, with poor correlation between individual maximal impairments and individual peak plasma concentrations of the drug. The maximal impairment in simple reaction time following the flunitrazepam treatments occurred earlier relative to the peak plasma concentration of the drug as compared to the diazepam treatments. This may indicate that acute tolerance develops differently for the two drugs.

Simultaneous determination of common benzodiazepines in blood using capillary gas chromatography.

Blood samples were extracted with n-butyl acetate, and the extracts analysed by capillary gas chromatography using DB-1 and DB-1701 capillary columns with electron-capture detection. The DB-1701 column was found to give better separation of different benzodiazepines (BZDs). Recoveries ranged from 79 to 98%. Detection limits ranged from 0.005 to 0.015 microM for triazolam and flunitrazepam, and from 0.02 to 0.1 microM for other BZDs. Data on accuracy and precision are given for diazepam, desmethyldiazepam, flunitrazepam and nitrazepam.

Interference with analysis of amphetamine in blood by N-ethylbenzenamine from rubber septums.

When blood stored in glass vials sealed with natural rubber septums was screened for amphetamine, a contaminant was seen. The contamination originated from the rubber septums and was identified by GC/MS as N-ethylbenzenamine. Like amphetamine, N-ethylbenzenamine was extracted from strongly alkaline solutions. N-Ethylbenzenamine and amphetamine chromatographed with the same retention time on a packed Apiezon/KOH column and on nonpolar capillary columns. Separation was achieved on a medium polar capillary column. Trifluoroacetyl derivatives of amphetamine and N-ethylbenzenamine had the same retention time on a packed SP-2250 column, but separated on nonpolar capillary columns. The amounts of N-ethylbenzenamine found were high enough to give rise to significant false positive results if N-ethylbenzenamine was erroneously read as amphetamine. N-Ethylbenzenamine is believed to be formed by thermal decomposition of the vulcanizing agent zinc ethylphenyldithiocarbamate used in rubber production.

Impaired vibrotactile sense at low frequencies in fingers in autoantibody positive and negative diabetes.

Vibration thresholds in index and little finger pulps in subjects with autoantibody [GADA, IA-2A and/or ICA] positive and negative diabetes 20 years after diagnosis were higher than in age-matched controls at low frequencies (8 and 16 Hz), irrespective of HbA1c values, indicating selective impairment of Meissner's corpuscles and/or their innervating axons.

Physico-chemical characterization of indoor/outdoor particulate matter in two residential houses in Oslo, Norway: measurements overview and physical properties--URBAN-AEROSOL Project.

Indoor/outdoor measurements have been performed in the Oslo metropolitan area during summer and winter periods (2002-2003) at two different residential houses. The objective of the measurement study was to characterize, physically and chemically, the particulate matter (PM) and gaseous pollutants associated with actual human exposure in the selected places, and their indoor/outdoor relationship. In this paper, we focus on the PM measurements and examine the relationship between the indoor and outdoor PM concentrations taking into account the ventilation rate, indoor sources and meteorological conditions. The indoor/outdoor measurements indicate the important contribution of the outdoor air to the indoor air quality and the influence of specific indoor sources such as smoking and cooking to the concentration of PM inside houses. However, no specific correlation was found between the indoor/outdoor concentration ratio and the meteorological parameters. This study provides information on the physical characteristics and the relationship of indoor to outdoor concentration of particulate matter in residential houses. Moreover, the parameters that influence this relationship are discussed. The results presented here are specific to the sampled houses and conditions used and provide data on the actual human exposure characteristics which occur in the spatial and temporal scales of the present study.

Hearing impairment in orchestral musicians.

Symphony orchestra musicians from The Royal Danish Theatre (15 females and 80 males) aged 22 to 64 years were audiologically examined to elucidate the presence and the frequency of noise-induced hearing loss among classical musicians. Compared to a reference material (ISO 7029) the median hearing thresholds of the musicians were increased for all age groups. When using hearing sensitivity in one or both ears less than 20 dB HL as a criterion for normality, it was found the 58% of the musicians had a hearing impairment. 50% of the males and 13% of the females showed a typical audiogram with a notched curve at higher frequencies normally attributed to occupational noise exposure. Furthermore, a significantly poorer hearing on the left ear was found at higher frequencies among the violinists. It is concluded that symphonic musicians suffer from hearing impairment and that the impairment might be ascribed to symphonic music.

Health and lifestyle characteristics of professional singers and instrumentalists.

Ninety-one instrumentalists and 51 opera singers of the Royal Theatre in Copenhagen, Denmark, were examined, in order to study the frequency of symptoms from the musculoskeletal system and upper airways. The response rate was 91 per cent. Estimates of odds ratios (OR) with 95 per cent confidence interval were calculated, using multiple logistic regression equations, adjusting for age and gender. The frequency of musculoskeletal complaints was the same in singers and instrumentalists. Musculoskeletal problems were however not identical. Instrumentalists had statistically significantly more symptoms from the arm region than singers, OR = 3.1 (1.02-9.5), P less than 0.05. In contrast, instrumentalists had significantly fewer complaints from hip-, knee- and foot joints than singers, OR = 0.2 (0.07-0.61), P less than 0.001. Singers had significantly more symptoms from mouth, lips or throat than instrumentalists, OR = 4.5 (1.7-11.5), P = 0.002. Both male and female instrumentalists had a higher blood pressure. This difference seemed at least in part to be explained by a higher alcohol intake among instrumentalists. We suggest these differences in life style and health characteristics are likely to be caused by professional, ie occupational, work loads.