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.

Preclinical and clinical pharmacodynamic assessment of L-778,123, a dual inhibitor of farnesyl:protein transferase and geranylgeranyl:protein transferase type-I.

Farnesyl:protein transferase (FPTase) inhibitors were developed as anti-Ras drugs, but they fail to inhibit Ki-Ras activity because Ki-Ras can be modified by geranylgeranyl:protein transferase type-I (GGPTase-I). L-778,123, an inhibitor of FPTase and GGPTase-I, was developed in part because it can completely inhibit Ki-Ras prenylation. To support the clinical development of L-778,123, we developed pharmacodynamic assays using peripheral blood mononuclear cells (PBMCs) to measure the inhibition of prenylation of HDJ2 and Rap1A, proteins that are FPTase- and GGPTase-I substrates, respectively. We validated these assays in animal models and show that inhibition of HDJ2 prenylation in mouse PBMCs correlates with the concentration of FPTase inhibitors in blood. In dogs, continuous infusion of L-778,123 inhibited both HDJ2 and Rap1A prenylation in PBMCs, but we did not detect inhibition of Ki-Ras prenylation. We reported previously results from the first L-778,123 Phase I trial that showed a dose-dependent inhibition of HDJ2 farnesylation in PBMCs. In this report, we present additional analysis of patient samples from this trial and a second Phase I trial of L-778,123, and demonstrate the inhibition of both HDJ2 and Rap1A prenylation in PBMC samples. This study represents the first demonstration of GGPTase-I inhibition in humans. However, no inhibition of Ki-Ras prenylation by L-778,123 was detected in patient samples. These results confirm the pharmacologic profile of L-778,123 in humans as a dual inhibitor of FPTase and GGPTase-I, but indicate that the intended target of the drug, Ki-Ras, was not inhibited.

Cycle Time Metrics for Multisite Clinical Trials in the United States.

Conducting randomized controlled trials entails a prolonged, costly study start-up (SSU) process that may create significant delays. Optimizing the operational aspects of multisite trials requires identifying benchmarks in the SSU process and the potential delays associated with them. We engaged in a collaborative effort to identify and describe key SSU intervals that correspond with necessary procedures and processes for activating multisite clinical trials in the US. After developing definitions for SSU benchmarks and obtaining data from research coordinating entities, we identified factors that were significantly associated with reduced cycle times, including the use of central institutional review boards for study approval and status as a private practice or independent research site. However, small sample sizes and large proportions of missing data hamper the interpretability of our results. Future development of standard measures of SSU efficiency will be critical to analyzing and improving study initiation processes at US research sites.

Quality by Design in Clinical Trials: A Collaborative Pilot With FDA.

The quality of a clinical trial can be assessed by whether the trial meets the needs of its various customers, as well as by its freedom from critical deficiencies or errors. In order to ensure the quality of a clinical trial, it is therefore important to conduct quality planning in parallel with the process to design and prior to the conduct of the trial. Quality planning consists of prospectively establishing quality goals and developing the products and processes required to deliver a quality trial. This article describes the quality planning process conducted by a pharmaceutical sponsor for a clinical trial and the pilot review of the resulting integrated quality management plan by the FDA. This pilot demonstrates the usefulness of this process to enable alignment between sponsors and regulators concerning quality in clinical trials.