Risk-Based Monitoring: Key Conditions in Collaboration Between Contract Research Organization and Sponsor.

Although risk-based monitoring (RBM) high-level definitions and processes are similar across the pharmaceutical industry, the practical implementation, organizational structures, naming of documents and processes, system capabilities, etc. can be different from company to company. Through an alliance-level relationship, Janssen, PAREXEL, and IQVIA have gained experience and developed best practices with RBM operational deployment, particularly regarding RBM setup and collaboration between sponsor and contract research organization (CRO). As part of the operational strategy, Janssen, PAREXEL, and IQVIA jointly developed an outsourcing manual to consistently guide trial delivery. The outsourcing manual recently adopted policies and implementation guidelines for RBM. Clarity around roles and responsibilities as well as a good understanding of system capabilities and data flows, especially where there are shared systems between the sponsor and CRO, are found to be key success factors. Besides possible organizational changes and the development of mutual processes and system capabilities, the human element is not to be underestimated. Managing the changes in processes and change in mind set within both the sponsor and CRO organization is crucial to successful implementation of RBM, and our experience in this regard forms the basis of this paper.

Cerebrospinal fluid glutamine, tryptophan, and tryptophan metabolite concentrations in dogs with portosystemic shunts.

OBJECTIVE: To determine whether glutamine (GLN), tryptophan (TRP), and tryptophan metabolite concentrations are higher in cerebralspinal fluid (CSF) dogs with naturally occurring portosystemic shunts (PSS), compared with control dogs. ANIMALS: 11 dogs with confirmed PSS and 12 control dogs fed low- and high-protein diets. PROCEDURE: Cerebrospinal fluid and blood samples were collected from all dogs. Serum and CSF concentrations of GLN, alanine, serine, TRP, 5-hydroxyindoleacetic acid (5-HIAA), and quinolinic acid (QUIN) were measured. RESULTS: Cerebrospinal fluid concentrations of GLN, TRP, and 5-HIAA were significantly higher in PSS dogs, compared with control dogs fed high- or low-protein diets. Cerebrospinal fluid QUIN concentration was significantly higher in PSS dogs, compared with control dogs fed the low-protein diet. Serum QUIN concentration was significantly lower in PSS dogs, compared with control dogs fed either high- or low-protein diets. CONCLUSIONS AND CLINICAL RELEVANCE: An increase in CNS GLN concentration is associated with high CSF concentrations of TRP and TRP metabolites in dogs with PSS. High CSF 5-HIAA concentrations indicate an increased flux of TRP through the CNS serotonin metabolic pathway, whereas high CSF QUIN concentrations indicate an increased metabolism of TRP through the indolamine-2,3-dioxygenase pathway. The high CSF QUIN concentrations in the face of low serum QUIN concentrations in dogs with PSS indicates that QUIN production from TRP is occurring in the CNS. High concentrations of QUIN and other TRP metabolites in the CNS may contribute to neurologic abnormalities found in dogs with PSS and hepatic encephalopathy.