Deprescribing anticholinergic medication in the community mental health setting: A quality improvement initiative.

BACKGROUND: Chronic anticholinergic medication (ACM) prescribing with antipsychotics when no longer clinically indicated can lead to serious side effects and adversely impact patient quality of life. OBJECTIVES: Through modifications of previously described deprescribing strategies undertaken in an academic, schizophrenia clinic, this quality improvement (QI) project aimed to bolster ACM deprescription where clinically appropriate among patients with schizophrenia and other psychiatric disorders at a community mental health center. METHODS: A multidisciplinary team involving clinical pharmacists and psychiatrists created web streaming video medical education accredited modules, supplemented by small groups sessions and case consultations, and provided these to psychiatrists and nurse practitioners at a community mental health center over a one-year period. Electronic medical record reports were also generated, highlighting patients who were receiving one of two ACM used in the clinic: benztropine and/or trihexyphenidyl; these were periodically distributed to support appropriate deprescription. Patient education infographic material focused on ACM were also created and deployed. RESULTS: One hundred and twenty-six patients were identified as receiving benztropine or trihexyphenidyl in March 2019. One hundred and six (84%) were on one or both of these medications for at least six months. The mean (±SD) age of the study sample was 53.4 (±12.6) years; a third of the sample was over 60 years. Thirty-seven patients, or 29.4%, had their ACM discontinued or the dosage reduced. Deprescription was not associated with age, sex, race, or diagnosis. Deprescription was not associated with antipsychotic polypharmacy, first versus second generation, or oral versus long acting preparation. CONCLUSIONS: These results suggest that deprescription of ACM in a community mental health center can occur with prescriber education and support. However, results from previous stages of this QI project, where much higher rates of deprescription were demonstrated, indicate the important benefit of more direct clinical pharmacist support and involvement in the process.

Development and regulatory strategies for drug and diagnostic co-development.

At the 5th FDA-Drug Industry Association (DIA) Workshop on 'Pharmacogenomics in Drug Development and Regulatory Decision Making', track four focused on the current thinking and issues in the co-development of therapeutic drugs or biologics, and their companion diagnostic products. Identification and validation of genomic and other biomarkers are becoming important components of drug-development strategies, and recent successes show the power of personalized approaches to change the benefit-risk paradigm for new drugs.

Voluntary exploratory data submissions to the US FDA and the EMA: experience and impact.

Heterogeneity in the underlying mechanisms of disease processes and inter-patient variability in drug responses are major challenges in drug development. To address these challenges, biomarker strategies based on a range of platforms, such as microarray gene-expression technologies, are increasingly being applied to elucidate these sources of variability and thereby potentially increase drug development success rates. With the aim of enhancing understanding of the regulatory significance of such biomarker data by regulators and sponsors, the US Food and Drug Administration initiated a programme in 2004 to allow sponsors to submit exploratory genomic data voluntarily, without immediate regulatory impact. In this article, a selection of case studies from the first 5 years of this programme - which is now known as the voluntary exploratory data submission programme, and also involves collaboration with the European Medicines Agency - are discussed, and general lessons are highlighted.

Towards consensus practices to qualify safety biomarkers for use in early drug development.

Application of any new biomarker to support safety-related decisions during regulated phases of drug development requires provision of a substantial data set that critically assesses analytical and biological performance of that biomarker. Such an approach enables stakeholders from industry and regulatory bodies to objectively evaluate whether superior standards of performance have been met and whether specific claims of fit-for-purpose use are supported. It is therefore important during the biomarker evaluation process that stakeholders seek agreement on which critical experiments are needed to test that a biomarker meets specific performance claims, how new biomarker and traditional comparators will be measured and how the resulting data will be merged, analyzed and interpreted.

Renal biomarker qualification submission: a dialog between the FDA-EMEA and Predictive Safety Testing Consortium.

The first formal qualification of safety biomarkers for regulatory decision making marks a milestone in the application of biomarkers to drug development. Following submission of drug toxicity studies and analyses of biomarker performance to the Food and Drug Administration (FDA) and European Medicines Agency (EMEA) by the Predictive Safety Testing Consortium's (PSTC) Nephrotoxicity Working Group, seven renal safety biomarkers have been qualified for limited use in nonclinical and clinical drug development to help guide safety assessments. This was a pilot process, and the experience gained will both facilitate better understanding of how the qualification process will probably evolve and clarify the minimal requirements necessary to evaluate the performance of biomarkers of organ injury within specific contexts.

Urinary clusterin, cystatin C, beta2-microglobulin and total protein as markers to detect drug-induced kidney injury.

Earlier and more reliable detection of drug-induced kidney injury would improve clinical care and help to streamline drug-development. As the current standards to monitor renal function, such as blood urea nitrogen (BUN) or serum creatinine (SCr), are late indicators of kidney injury, we conducted ten nonclinical studies to rigorously assess the potential of four previously described nephrotoxicity markers to detect drug-induced kidney and liver injury. Whereas urinary clusterin outperformed BUN and SCr for detecting proximal tubular injury, urinary total protein, cystatin C and beta2-microglobulin showed a better diagnostic performance than BUN and SCr for detecting glomerular injury. Gene and protein expression analysis, in-situ hybridization and immunohistochemistry provide mechanistic evidence to support the use of these four markers for detecting kidney injury to guide regulatory decision making in drug development. The recognition of the qualification of these biomarkers by the EMEA and FDA will significantly enhance renal safety monitoring.