European Association of Hospital Pharmacists (EAHP) guidance on the pharmacy handling of in vivo gene therapy medicinal products.

Gene therapy is becoming increasingly prevalent, with new gene therapy medicinal products (GTMPs) being approved for use every year. Hospital pharmacists are expected to prepare and dispense these products, but there is substantial heterogeneity in the availability of up-to-date, practical guidance at a national level in Europe. Many institutions have no or very limited experience in handling GTMPs. As such, there is a need for updated, practical guidance to aid hospital pharmacy teams in developing institutional standard operating procedures (SOPs) for the safe handling of GTMPs across the entire workflow. Here, we present the European Association of Hospital Pharmacists' updated guidance on the handling of GTMPs, developed by a team of recognised experts from around Europe. Each aspect of the GTMP handling process is addressed, including receipt and storage, dispensing and reconstitution, transportation, administration, waste disposal, decontamination of spills and accidental exposure. A series of figures are provided to aid the development of practical workflows. This guidance document is intended as a framework to help develop institutional SOPs and should always be used in conjunction with local regulations.

Implementation and operational management of marketed chimeric antigen receptor T cell (CAR-T Cell) therapy-a guidance by the GoCART Coalition Pharmacist Working Group.

Chimeric Antigen Receptor T cells (CAR-T cells) are a type of Advanced Therapy Medicinal Product (ATMP) classified as ex-vivo (cell-based) gene therapy. CAR-T cells constitute an immunotherapy that works by enabling T cells to specifically recognise cancer cells and destroy them [1]. CAR-T cells are currently licensed to treat certain blood cancers including relapsed or refractory lymphomas, B-cell acute lymphoblastic leukaemia or multiple myeloma [2]. The indications for their use are expanding and are expected to encompass other therapeutic areas. CAR-T cells are used both in children and adults [2]. CAR-T cells are biologic drugs and are therefore more complex than traditional medicinal products. T cells collected from the patient (or donor) are sent to a Good manufacturing Practice (GMP) manufacturing facility where they are genetically modified to contain a chimeric antigen receptor (CAR). This receptor is designed to recognise and target a specific protein on cancer cells. Once manufactured, they are delivered to the hospital where they are administered to the designated patient. Hospital pharmacies are central in the process of ensuring appropriate organisational governance, operational handling, clinical suitability, and pharmacovigilance [1, 3]. The GoCART Coalition Pharmacist working group's mission was to develop standards of care to advance the field of cellular therapies in Europe. The purpose of this document is to provide practical guidance on the implementation and safe operational use of marketed CAR-T cell products within hospital pharmacies primarily throughout Europe. This document outlines the key areas where pharmaceutical expertise should focus and the key considerations for the hospital pharmacy. Countries may have different requirements and there may be variation in practice between hospitals. This document is intended as a guide and the recommendations should be adapted to meet local requirements. This document does not provide clinical information relating to the use of CAR-T cell products. The Summary of medicinal Product Characteristics (SmPC) [4, 5], and national and international clinical guidelines (where in place) should be followed for the most up-to-date clinical management of CAR-T cell patients. An example is the UK "institutional readiness documents" for pharmacy which includes detailed checklists for each stage of the pathway [6]. Spain developed the Plan of Advanced Therapies in the National Health System: CAR medicines published in November 2018 [7], the CAR-T Medicines Management Procedure of the Spanish Society of Hospital Pharmacy [8] or the Hospital pharmacist's roles and responsibilities with CAR-T medicines article published also by the Spanish Oncology group of the Spanish Society of Pharmacy [9]. This guide has been designed to support the implementation of marketed CAR-T products; however, the principles may also be applicable to clinical trials. For CAR-T cell products being used in clinical trials, additional trial regulation and clinical trial protocols must be followed. This document is divided into two sections. Section 1 outlines considerations for hospital pharmacies during the implementation of a CAR-T cell service. Section 2 outlines the key operational considerations for hospital pharmacies in the patient and product pathway.

A randomized clinical trial of histamine 2 receptor antagonism in treatment-resistant schizophrenia.

Histamine has important functions as regulator of several other key neurotransmitters. Patients with schizophrenia have lower histamine H1 receptor levels. Since a case report in 1990 of an effect of the H2 antagonist famotidine on negative symptoms in schizophrenia, some open-label trials have been performed, but no randomized controlled trial. Recently, it was shown that clozapine is a full inverse agonist at the H2 receptor. We performed a researcher-initiated, academically financed, double-blind, placebo-controlled, parallel-group, randomized trial with the histamine H2 antagonist famotidine in treatment-resistant schizophrenia. Thirty subjects with schizophrenia were randomized to have either famotidine (100 mg twice daily, n = 16) or placebo (n = 14) orally, added to their normal treatment regimen for 4 weeks. They were followed up weekly with the Scale for the Assessment of Negative Symptoms (SANS), the PANSS (Positive and Negative Syndrome Scale), and Clinical Global Impression (CGI) Scale. In the famotidine group, the SANS score was reduced by 5.3 (SD, 13.1) points, whereas in the placebo group the SANS score was virtually unchanged (mean change, +0.2 [SD, 9.5]). The difference did not reach statistical significance (P = 0.134) in Mann-Whitney U analysis. However, the PANSS Total score and the General subscore as well as the CGI showed significantly (P < 0.05) greater change in the famotidine group than in the placebo group. No significant adverse effects were observed. This is the first placebo-controlled, randomized clinical trial showing a beneficial effect of histamine H2 antagonism in schizophrenia. H2 receptor antagonism may provide a new alternative for the treatment of schizophrenia.