Effect of Contract Research Organization Bureaucracy in Clinical Trial Management: A Model From Lung Cancer.

INTRODUCTION: Contract research organization (CRO) support is largely included in clinical trial management, although its effect in terms of time savings and benefit has not yet been quantified. We performed a retrospective multicenter analysis of lung cancer trials to explore differences in term of trial activation timelines and accrual for studies with and without CRO involvement. MATERIALS AND METHODS: Results regarding study timelines from feasibility data to first patient enrollment were collected from 7 Italian thoracic oncology departments. The final accruals (screened/enrolled patients) are reported. We considered CRO/sponsor-administered and CRO-free trials according to who was responsible for the management of the crucial setup phases. RESULTS: Of 113 trials, 62 (54.9%) were CRO-administered, 34 (30.1%) were sponsor-administered, and 17 (15.0%) were CRO-free. The median time from feasibility invitation to documentation obtainment was 151 days in the CRO-administered trials versus 128 in the sponsor-administered and 120 in the CRO-free trials. The time from document submission to contract signature was 142 days in the CRO-administered versus 128 in the sponsor-administered and 132 in the CRO-free trials. The time from global accrual opening to first patient enrollment was 247 days for the CRO-administered versus 194 in the sponsor-administered and 151 in the CRO-free trials. No significant differences were observed in terms of the median overall timeline: 21 months in the CRO-administered, 15 in the sponsor-administered, and 18 months in the CRO-free studies (P = .29). CONCLUSION: Although no statistically significant differences were identified, the results of our analysis support the idea that bureaucratic procedures might require more time in CRO-administered trials than in sponsor-administered and CRO-free studies. This bureaucratic delay could negatively affect Italian patients' screening and enrollment compared with other countries.

Fast and Facile Synthesis of 4-Nitrophenyl 2-Azidoethylcarbamate Derivatives from N-Fmoc-Protected α-Amino Acids as Activated Building Blocks for Urea Moiety-Containing Compound Library.

A fast and facile synthesis of a series of 4-nitrophenyl 2-azidoethylcarbamate derivatives as activated urea building blocks was developed. The N-Fmoc-protected 2-aminoethyl mesylates derived from various commercially available N-Fmoc-protected α-amino acids, including those having functionalized side chains with acid-labile protective groups, were directly transformed into 4-nitrophenyl 2-azidoethylcarbamate derivatives in 1 h via a one-pot two-step reaction. These urea building blocks were utilized for the preparation of a series of urea moiety-containing mitoxantrone-amino acid conjugates in 75-92% yields and parallel solution-phase synthesis of a urea compound library consisted of 30 members in 38-70% total yields.

Assessment of acute oral and dermal toxicity of 2 ethyl-carbamates with activity against Rhipicephalus microplus in rats.

The acute oral and dermal toxicity of two new ethyl-carbamates (ethyl-4-bromophenyl-carbamate and ethyl-4-chlorophenyl-carbamate) with ixodicide activity was determined in rats. The oral LD50 of each carbamate was 300 to 2000 mg/kg, and the dermal LD50 of each carbamate was >5000 mg/kg. Clinically, the surviving rats that had received oral doses of each carbamate showed decreased weight gain (P < 0.05) and had slight nervous system manifestations. These clinical signs were evident from the 300 mg/kg dose and were reversible, whereas the 2000 mg/kg dose caused severe damage and either caused their death or was motive for euthanasia. At necropsy, these rats had dilated stomachs and cecums with diffuse congestion, as well as moderate congestion of the liver. Histologically, the liver showed slight degenerative lesions, binucleated hepatocytes, focal coagulative necrosis, and congestion areas; the severity of the lesions increased with dosage. Furthermore, an slight increase in gamma-glutamyltransferase, lactate dehydrogenase, and creatinine was observed in the plasma. The dermal application of the maximum dose (5000 mg/kg) of each carbamate did not cause clinical manifestations or liver and skin alterations. This finding demonstrates that the carbamates under study have a low oral hazard and low acute dermal toxicity.