In May 2004, the European Clinical Trials Directive came into force. The directive made it mandatory for all clinical drug trials to follow the good clinical practice guidance, and it fuelled existing concerns that financial and organisational constraints were making it almost impossible to conduct independent trials not funded by the drug industry. In the accompanying paper, Berendt and colleagues show that the decrease in the number of new clinical trials registered each year in Denmark began well before 2004, and the decrease was similar for independent and industry sponsored trials.1 In 2006, two years after the enforcement of the EU directive, the number of independent trials actually increased. Similar results have been reported in Sweden, Norway, and Italy.2 The consistency of these findings, despite differences in registration and classification systems, supports their validity and generalisability.So can we feel reassured about the future of independent therapeutic research? Certainly, clinical research not sponsored by the industry is alive and active. Yet, if we consider the role that independent researchers should have in directing therapeutic research towards its primary mission-meeting the needs of patients and health systems-the overall picture is more complex. The data above do not tell us how the relevance and potential impact of the independent trials compare with industry sponsored trials. For instance, the Italian data show that phase III trials, multicentre trials, and international trials are less likely to be independent. 2The trials that showed the efficacy of aromatase inhibitors for early, hormone dependent, postmenopausal breast cancer provide an example of how the aims of industry sponsored trials may differ from those of independent trials. These trials compared the use of aromatase inhibitors with the conventional regimen of five years of tamoxifen.3-6 The first published analyses of these trials, which in two cases were interim analyses that led to the premature cessation and unblinding of the trial, were conducted at median follow-ups of 2.2 to 2.7 years. All four trials found that aromatase inhibitors significantly improved disease-free survival, which is a plausible but not validated surrogate end point for overall survival in early breast cancer. 7 In contrast, no significant effect was seen on overall survival.Because early breast cancer has a long natural history and aromatase inhibitors may have delayed effects, decisions on the use of these drugs in this setting should be based on reliable information on their long term efficacy and safety.8 However, crossover of the control group to aromatase inhibitors in all but one 3 of these studies may hamper their ability to provide this information. 8 Furthermore, for ethical reasons, it is no longer acceptable to conduct a trial in which tamoxifen is given for five years as the control. Consequently, despite the inclusion of more than 20 000 patients in the above trials, aromatase inhibitors are being used to treat early breast c...

Background:Fluoropyrimidine drugs are extensively used for the treatment of solid cancers. However, adverse drug reactions are a major clinical problem, often necessitating treatment discontinuation. The aim of this study was to identify pharmacogenetic markers predicting fluoropyrimidine toxicity.Methods:Toxicity in the first four cycles of 5-fluorouracil or capecitabine-based chemotherapy were recorded for a series of 430 patients. The association between demographic variables, DPYD, DPYS, TYMS, MTHFR, CDA genotypes, and toxicity were analysed using logistic regression models.Results:Four DPYD sequence variants (c.1905+1G>A, c.2846A>T, c.1601G>A and c.1679T>G) were found in 6% of the cohort and were significantly associated with grade 3–4 toxicity (P<0.0001). The TYMS 3′-untranslated region del/del genotype substantially increased the risk of severe toxicity (P=0.0123, odds ratio (OR)=3.08, 95% confidence interval (CI): 1.38–6.87). For patients treated with capecitabine, a MTHFR c.1298CC homozygous variant genotype predicted hand–foot syndrome (P=4.1 × 10−6, OR=9.99, 95% CI: 3.84–27.8). The linked CDA c.−92A>G and CDA c.−451C>T variants predicted grade 2–4 diarrhoea (P=0.0055, OR=2.3, 95% CI: 1.3–4.2 and P=0.0082, OR=2.3, 95% CI: 1.3–4.2, respectively).Conclusion:We have identified a panel of clinically useful pharmacogenetic markers predicting toxicity to fluoropyrimidine therapy. Dose reduction should be considered in patients carrying these sequence variants.

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Contrary to previous estimates for a UK population, genetic DPD deficiency accounts for around 19% of cases of severe fluoropyrimidine toxicity. The influence of DPD deficiency is such that toxicity can be avoided by prior testing and appropriate 5-FU dose/regimen alteration.