Preparation Technique Affects Recipient Immune Targeting of Autologous Mesenchymal Stem Cells

Fetal bovine serum (FBS) is used for MSC preparation in pre-clinical animal models and veterinary applications, recently in US clinical trials, and for MSC products with current foreign market authorizations. The effect of anti-bovine titers, which are common in animals and humans, has not been investigated. In the equine model, where anti-bovine titers are universally high due to routine vaccination, we evaluated the recipient immune response to autologous MSCs prepared with and without FBS. Preparation of MSCs with FBS resulted in post injection inflammation and antibody mediated cytotoxicity of MSCs when compared to MSCs prepared without FBS. Importantly, synovial MSC concentrations were reduced and LPS induced pain was higher, when FBS was used to prepare MSCs, demonstrating reduced efficacy of FBS prepared MSCs. Fetal bovine serum should no longer be utilized for MSC preparation in pre-clinical study, clinical study, or veterinary applications. The use of FBS in previously reported studies, and in MSC therapeutics with current foreign market authorization, should be considered when interpreting results.

Distinguishing features of current COVID-19 vaccines: knowns and unknowns of antigen presentation and modes of action

COVID-19 vaccines were developed with an unprecedented pace since the beginning of the pandemic. Several of them have reached market authorization and mass production, leading to their global application on a large scale. This enormous progress was achieved with fundamentally different vaccine technologies used in parallel. mRNA, adenoviral vector as well as inactivated whole-virus vaccines are now in widespread use, and a subunit vaccine is in a final stage of authorization. They all rely on the native viral spike protein (S) of SARS-CoV-2 for inducing potently neutralizing antibodies, but the presentation of this key antigen to the immune system differs substantially between the different categories of vaccines. In this article, we review the relevance of structural modifications of S in different vaccines and the different modes of antigen expression after vaccination with genetic adenovirus-vector and mRNA vaccines. Distinguishing characteristics and unknown features are highlighted in the context of protective antibody responses and reactogenicity of vaccines.

South African Regulatory Authority: The Impact of Reliance on the Review Process Leading to Improved Patient Access

Background: The aims of this study were to compare the overall regulatory review timelines achieved by the South African Health Products Regulatory Authority (SAHPRA) in 2020 to the timelines historically achieved by the Medicines Control Council (MCC). This study also aimed to evaluate the regulatory review processes and the good review practices that have been implemented by SAHPRA to support the assessment of new chemical entities and generic product applications for market authorization in the business-as-usual and backlog process streams.Methods: A questionnaire was completed and verified by SAHPRA to describe the structure of the organization, the resources available, the process for regulatory review of new chemical entities and generic products and the level of implementation of good review practices and regulatory decision-making practices for market authorization. Data were collected and analyzed on the overall approval timelines for new chemical entities and generic products registered by SAHPRA in 2020 in the business-as-usual and backlog process streams.Results: A full, independent scientific review was conducted for all new chemical entities and generic product applications in the business-as-usual stream. Facilitated regulatory pathways were introduced for the review of new chemical entities and generic products in the backlog stream. As a result, the timelines for approval of applications in the backlog stream were 68% quicker for both new chemical entities and generics, using facilitated regulatory pathways, such as abridged and verification review models.Conclusion: The comparisons made through this study provided insight into the improvements that have been made through the establishment of SAHPRA and the transition in 2018 from the MCC. The re-engineered processes that have been developed and implemented by SAHPRA to address the backlog in the review of the applications for market authorization have demonstrated a decrease in the overall median approval times. The expansion of these processes into the routine review of medical products will contribute to the enhanced regulatory performance of SAHPRA and patients’ access to new medicines.

NIMble innovation - a networked model for public antibiotic trials

Antibiotic research and development (R&D) is at an inflection point. Faced with ongoing problems with commercial innovation, we argue for a networked public approach to sustainably moving promising compounds through clinical trials. We propose a global public infrastructure of institutes tasked with 1) conducting all trial stages up to market authorization, including small-scale compound production; 2) negotiating licensing agreements for global production and distribution by industry partners; 3) using public purchasing agreements or subscription models to ensure commercially viable drug production at equitable prices. We invite stakeholders to consider our Networked Institute Model’s (NIM) benefits for unblocking the antibiotic pipeline.

Moving somatic gene editing to the clinic: routes to market access and reimbursement in Europe

Somatic gene editing (SGE) holds great promise for making genetic therapy possible for many monogenic conditions very soon. Is our current system of European market authorization and reimbursement ready for the expected tsunami of gene therapies? At a recent workshop of the Netherlands ZonMw consortium on ethical, legal, and social implications of personalized medicine, we discussed the current possibilities for bringing new gene therapies to the clinic. In Europe, it is not yet clear whether the route via the European medicines agency as an advanced therapy medicinal product is the most appropriate for evaluation of highly personalized SGE applications, although this may optimally guarantee safety and effectiveness. Compassionate use may ensure faster access than the centralized procedure but does not stimulate the commercial development of products. Prescription to named patients may only provide adequate access for single patients. Temporary authorization of use may allow access to medication half a year before formal market authorization has been granted, but may also have large budget impacts. Magistral compounding under a hospital exemption may be an attractive solution for rare, tailor-made applications at an acceptable price. To approve local experimental use of a therapy on a case-by-case basis may be fast, but does not guarantee optimal safety, effectiveness, and broad implementation. We argue that alternative routes should be considered for products developed for a market of large groups of patients versus unique personalized treatments. A balance between scientific evidence for safety and effectiveness, affordability, and fast access may demand a range of alternative solutions.

Liposomal Nanosystems in Rheumatoid Arthritis

Rheumatoid arthritis (RA) is an autoimmune disease that affects the joints and results in reduced patient quality of life due to its chronic nature and several comorbidities. RA is also associated with a high socioeconomic burden. Currently, several available therapies minimize symptoms and prevent disease progression. However, more effective treatments are needed due to current therapies’ severe side-effects, especially under long-term use. Drug delivery systems have demonstrated their clinical importance—with several nanocarriers present in the market—due to their capacity to improve therapeutic drug index, for instance, by enabling passive or active targeting. The first to achieve market authorization were liposomes that still represent a considerable part of approved delivery systems. In this manuscript, we review the role of liposomes in RA treatment, address preclinical studies and clinical trials, and discuss factors that could hamper a successful clinical translation. We also suggest some alterations that could potentially improve their progression to the market.

Infliximab use in the Netherlands: Uptake and characteristics of originator and biosimilars over time

Aims: The objective of this retrospective cohort study was to provide an overview of the utilization of originator and biosimilar infliximab in the Netherlands. Methods: All infliximab dispensings were selected from the PHARMO In-patient Pharmacy Database from 2002-2018. Descriptive analyses were performed in order to characterise initiators and to describe switching patterns over time. Results: Overall, 3,840 patients with 61,274 infliximab dispensings were identified. 2,496 patients initiated an originator infliximab and 777 patients initiated a biosimilar infliximab. Overall, 57% of the patients was female and mean age was 43.2 years. Both originators and biosimilars were mostly prescribed by gastroenterologists, followed by internists and rheumatologists. After market authorization of the first biosimilar the proportion of new patients initiating the biosimilar increased from 39% in 2015 to 91% in 2018. Out of 704 patients eligible for switching 34% switched. Among switchers, the proportion of females was 60% and mean age at index was 45.1 years. Among non-switchers, 55% was female and mean age was 39.8 years. The median time to switch was 1.7 years and switchers were most frequently initiated on infliximab by a rheumatologist (42%), while non-switchers were most frequently initiated by a gastroenterologist (42%). Conclusions: The results of this large population-based cohort show an increase in biosimilar initiation in daily clinical practice. The number of switchers remains relatively low as non-medical switch is not encouraged in the Netherlands.