Monitoring the quality of conduct of clinical trials: a survey of current practices.

BACKGROUND: There is a little empirical evidence to determine which, if any, monitoring practices best achieve the goals of trial monitoring set forth in ICH E6 under the variable circumstances of different clinical trial settings. PURPOSE: The purpose of this project was to describe current methods of monitoring clinical trials and to explore the rationale for the use of those methods. METHODS: An electronic survey of known monitoring practices was developed and sent to over 200 organizations involved in conducting clinical research. The survey collected information on institutional demographics, methods of overall study oversight, use of risk-based monitoring and factors that influence assessments of risk, and details on quality assurance and monitoring practices. RESULTS: Seventy-nine organizations completed the survey; our analysis included the 65 organizations that indicated they perform clinical trials. Data from the survey indicate that a wide variety of monitoring practices are currently being employed. Eighty-three percent of respondents use centrally available data to evaluate site performance, but only 12% of respondents always or frequently used centralized monitoring to replace on-site visits. Eighty-seven percent of respondents indicated that they always performed on-site visits. This varied by type of organization, with 31% of academic coordinating centers/cooperative groups/government organizations always performing on-site monitoring visits versus 84% of other organizations. The rationale for using a specific monitoring approach does not appear to be based on empirical evidence. Fifty-four percent of respondents stated that 'usual practice' determined the frequency with which they conducted on-site monitoring visits. LIMITATIONS: The overall response rate to our survey was only 30%; thus, we may not have captured the full variance of current monitoring practices, and our responding sample may not be representative. CONCLUSION: These findings underscore the necessity of research to provide an evidence base for monitoring practice.

Pyrazolinone-piperidine dipeptide growth hormone secretagogues (GHSs). Discovery of capromorelin.

Novel pyrazolinone-piperidine dipeptide derivatives were synthesized and evaluated as growth hormone secretagogues (GHSs). Two analogues, capromorelin (5, CP-424391-18, hGHS-R1a K(i)=7 nM, rat pituicyte EC(50)=3 nM) and the des-methyl analogue 5c (hGHS-R1a K(i)=17 nM, rat pituicyte EC(50)=3 nM), increased plasma GH levels in an anesthesized rat model, with ED(50) values less than 0.05 mg/kg iv. Capromorelin showed enhanced intestinal absorption in rodent models and exhibited superior pharmacokinetic properties, including high bioavailabilities in two animal species [F(rat)=65%, F(dog)=44%]. This short-duration GHS was orally active in canine models and was selected as a development candidate for the treatment of musculoskeletal frailty in elderly adults.

Discovery and biological characterization of capromorelin analogues with extended half-lives.

New tert-butyl, picolyl and fluorinated analogues of capromorelin (3), a short-acting growth hormone secretagogue (GHS), were prepared as part of a program to identify long-acting GHSs that increase 24-h plasma IGF-1 levels. Compounds 4c and 4d (ACD LogD values >or=2.9) displayed extended plasma elimination half-lives in dogs, primarily due to high volumes of distribution, but showed weak GH secretagogue activities in rats (ED(50)s>10 mg/kg). A less lipophilic derivative 4 (ACD LogD=1.6) exhibited a shorter canine half-life, but stimulated GH secretion in two animal species. Repeat oral dosing of 4 in dogs for 29 days (6 mg/kg) resulted in a significant down-regulation of the post dose GH response and a 60 and 40% increase in IGF-1 levels relative to pre-dose levels at the 8- and 24-h post dose time points. Compound 4 (CP-464709-18) has been selected as a development candidate for the treatment of frailty.