A strategic reflection for the management and implementation of CAR-T therapy in Spain: an expert consensus paper

CAR-T cell therapy represents a therapeutic revolution in the prognosis and treatment of patients with certain types of hematological cancer. However, they also pose new challenges in the healthcare, regulatory and financial fields. The aim of the RET-A project was to undertake a strategic reflection on the management of CAR-T therapies within the Spanish National Health System, to agree on recommendations that will help to better deal with the new context introduced by these cell therapies in the present and in the future. This think tank involved 40 key agents and opinion leaders. The experts identified three great challenges for implementing advanced therapies in Spain: therapeutic individualisation, with a multidisciplinary approach; acceleration of access times, by minimizing bureaucracy; and increase in the number of centers qualified to manage the CAR-T therapies in the NHS. The experts agreed on the ideal criteria for designating those qualified centers. They also agreed on a comprehensive CAR-T care pathway with the timings and roles which would ideally be involved in each part of the process.

The Emerging Role of Nanosuspensions for Drug Delivery and Stability

: Poor solubility of some medicinal compounds is a serious challenge that can be addressed by using a nano-suspension for improved delivery. The nanoparticles enhance the bioavailability along with the aqueous solubility of the drug, which is accomplished by increasing the active surface area of the drug. The gained attention of the nanosuspension is due to its stabilization facility, which is achieved by polymers, such as polyethylene glycol (PEG), having a particular size range of 10 - 100 nm. Hence, these nanoparticles have the capacity of binding to the targeted with very low damage to the healthy tissues. These are prepared by various methods, such as milling, high-pressure homogenization, and emulsification, along with melt emulsification. Moreover, surface modification and solidification have been used to add specific properties to the advanced therapies as post-processing techniques. For many decades, it has been known that water solubility hampers the bioavailability and not all drugs are water-soluble. In order to combat this obstacle, nanotechnology has been found to be of specific interest. For elevating the bioavailability by increasing the dissolution rate, the methodology of reduction of the associated drug particles into their subsequent submicron range is incorporated. For oral and non-oral administration, these nanosuspension formulations are used for the delivery of drugs.

Changes in Spectral Fluorescence Properties of a Near-Infrared Photosensitizer in a Nanoform as a Coating of an Optical Fiber Neuroport

In this work, we tested a new approach to assess the presence of inflammatory process in the implant area using spectral methods and the technique of fiber fluorescence analysis of photosensitizers in nanoform. First of all, the spectral characteristics of the photosensitizer when interacting with the porous surface of the implant, based on hydroxyapatite under in vitro and in vivo conditions, were determined. Thus, it was shown that spectral characteristics of photosensitizers can be used for judgement on the process of inflammation in the implant area and thus on the local presence of the immunocompetent cells. The analysis was performed at a sufficient depth in the biotissue by using the near-infrared spectral region, as well as two different methods: fiber-based laser spectroscopy and fiber-optic neuroscopy, which served to monitor the process and regular fluorescence diagnosis of the studied area. Fluorescence spectroscopic analysis was performed on experimental animals in vivo, i.e., under conditions of active immune system intervention, as well as on cell cultures in vitro in order to judge the role of the immune system in the interaction with the implant in comparison. Thus, the aim of the study was to determine the relationship between the fluorescence signal of nanophotosensitizers in the near infrared spectral region and its parameters with the level of inflammation and the type of surface with which the photosensitizer interacts in the implant area. Thus, fiber-optic control opens up new approaches for further diagnosis and therapy in the implant area, making immune cells a prime target for advanced therapies.

Using Conversation Analysis to Examine When Educational Videos Are Introduced in Patient Education

As the seas of advanced therapies have swelled in the last few decades, multiple myeloma patients have been empowered, encouraged, and sometimes required, to engage in their care. We applied a conversation analysis approach to 12 nurse-led education visits (1011 minutes of audio) containing reference to educational videos. We indexed extracts based on whether the nurse or patient first mention the video. Patients oriented toward the video to demonstrate knowledge (n=15; 88%) and clarify information (n=2; 12%). Nurses oriented toward the video either through positive (n=14; 39%), negative (n=13= 36%), or neutral (n=9; 25%) assessments. Videos created opportunities for patients to pursue their topics of interest during in-person visits. Also, nurses often oriented toward the videos pre-emptively to achieve their teaching goals either by acknowledging the patients’ exposure to upcoming information or by positively or negatively assessing the videos in ways that enable them to re-orient talk to educational scripts.

Methodological Characteristics of Clinical Trials Supporting the Marketing Authorisation of Advanced Therapies in the European Union

Several advanced therapy medicinal products (ATMPs) have been approved in the European Union (EU). The aim of this study is to analyse the methodological features of the clinical trials (CT) that supported the marketing authorization (MA) of the approved ATMPs in the EU. A systematic review of the characteristics of pivotal CT of ATMPs approved in the EU until January 31st, 2021 was carried out. A total of 17 ATMPs were approved and 23 CT were conducted to support the MA (median, 1, range, 1–3). Of those studies, 8 (34.78%) were non-controlled and 7 (30.43%) used historical controls. Only 7 (30.4%) were placebo or active-controlled studies. Among all CT, 21 (91.3%) were open-label and 13 (56.52%) had a single-arm design. To evaluate the primary endpoint, 18 (78.26%) studies used an intermediate and single variable. The median (IQR) number of patients enrolled in the studies was 75 (22–118). To date, ATMPs’ approval in the EU is mainly supported by uncontrolled, single-arm pivotal CT. Although there is a trend toward an adaptive or a life cycle approach, a switch to more robust clinical trial designs is expected to better define the benefit and the therapeutic added value of ATMPs.

Cardiogenic shock in Taiwan from 2003 to 2017 (CSiT-15 study)

Background This study investigated temporal trends in the treatment and mortality of patients with cardiogenic shock (CS) in Taiwan in relation to acute myocardial infarction (AMI) accreditation implemented in 2009 and the unavailability of percutaneous ventricular assist devices. Methods Data of patients diagnosed as having CS between January 2003 and December 2017 were collected from Taiwan’s National Health Insurance Research Database. Each case was followed from the date of emergency department arrival or hospital admission for the first incident associated with a CS diagnosis up to a 1-year interval. Measurements included demographics, comorbidities, treatment, mortality, and medical costs. Using an interrupted time-series (ITS) design with multi-level mixed-effects logistic regression model, we assessed the impact of AMI accreditation implementation on the mortality of patients with AMI and CS overall and stratified by the hospital levels. Results In total, 64 049 patients with CS (mean age:70 years; 62% men) were identified. The incidence rate per 105 person-years increased from 17 in 2003 to 25 in 2010 and plateaued thereafter. Average inpatient costs increased from 159 125 points in 2003 to 240 993 points in 2017, indicating a 1.5-fold increase. The intra-aortic balloon pump application rate was approximately 22–25% after 2010 (p = 0.093). Overall, in-hospital, 30-day, and 1-year mortality declined from 60.3%, 63.0%, and 69.3% in 2003 to 47.9%, 50.8% and 59.8% in 2017, respectively. The decline in mortality was more apparent in patients with AMI-CS than in patients with non-AMI-CS. The ITS estimation revealed a 2% lower in-hospital mortality in patients with AMI-CS treated in district hospitals after the AMI accreditation had been implemented for 2 years. Conclusions In Taiwan, the burden of CS has consistently increased due to high patient complexity, advanced therapies, and stable incidence. Mortality declined over time, particularly in patients with AMI-CS, which may be attributable to advancements in AMI therapies and this quality-improving policy.

Inequality of access to advanced therapies for patients with inflammatory arthritis: a postcode lottery?

Objectives Advanced therapies (AT) including biologics, biosimilars and JAK inhibitors have dramatically improved the quality of life of patients with Rheumatoid arthritis (RA), Psoriatic Arthritis (PsA) and Axial spondyloarthritis (axSpA). Evidence-based criteria for prescribing these drugs in England and Wales is formulated by the National Institute for Health and Care Excellence (NICE) through Health Technology Appraisals (HTAs) and guidelines with the aim of providing equitable access to AT for patients with severe or resistant disease. Similar bodies exist in some, but not all European countries with disparities in AT access between countries in AT access for RA. We examined whether this disparity was mirrored in England for RA, PsA and axSpA despite the NHS in England and Wales being legally obliged to provide funding for AT recommended by NICE’s HTA board, through commissioning bodies, Clinical Commissioning Groups (CCGs). Methods We requested AT pathways from CCGs in England. Where these were not available, individual hospital Trusts were contacted using Freedom of Information (FOI) requests. Results We found marked variability in the way that CCGs in England interpret NICE guidance. We found 41, 29 and 25 different pathways for RA, PsA and axSpA respectively. Similar disparities existed with sequential prescribing where one AT did not work, with limits on numbers of sequential AT in 54%, 59% and 59% of CCGs for RA, PsA and axSpA respectively, with these limits being different for the same condition between CCGs. Conclusion While patients at identical stages of their disease course should have access to the same NICE approved AT, we found this is not the case for large parts of England. Inequality of access was found between regions mirroring the variability which occurs between countries throughout Europe. Harmonisation of access needs to be addressed by policymakers, ensuring fairness in the way that clinicians and patients can access AT.

P.042 Dopamine Dysregulation Syndrome in Parkinson’s Disease and its Management with Advanced Therapies

Background: Dopamine Dysregulation Syndrome (DDS) is an adverse non-motor complication of dopamine replacement therapy in Parkinson’s Disease. The current literature on DDS is limited, and it remains underdiagnosed and challenging to manage. Methods: We performed a retrospective chart review and classified patients according to risk factors that have been identified in the literature, UPDRS scores, intervention and outcome. Univariate analyses were performed to quantify these characteristics. Results: Prior psychiatric illness was identified in 70% of patients, impulse control disorder in 89% and substance abuse in 3.7%. Interventions included reduction of dopamine therapy (88.9%), deep brain stimulation (DBS) of the subthalamic nucleus (STN, 48.1%) or globus pallidus interna (GPi, 7.4%), and levodopa-carbidopa intestinal gel (LCIG) infusion (11.1%). Baseline UPDRS IV before treatment and MDS III after treatment were not significant between intervention groups (p=0.09 and p=0.13 respectively). Overall 88.9% patients improved at follow up, with medication only (75%), STN DBS (100%), GPi DBS (100%) and LCIG (33%). Relapse rate was 18.2%, in the STN group only. Conclusions: Our results suggest that GPi DBS, in concurrence with dopaminergic medication reduction, is the most effective intervention. STN DBS might be also beneficial although the associated medications reduction causes DDS relapse in a subgroup of patients.

Venous Leg Ulcers: Advanced Therapies and New Technologies

The prevalence of venous leg ulcers (VLUs) differs between 1.5% and 3% in the general population. The challenge in treating VLUs is common recurrence. Moreover, VLUs can be resistant to healing, despite appropriate treatment. In these cases, advanced wound therapies should be considered. The number of new technologies, applied in VLUs treatment, has increased in the last years. These therapies include biophysical interventions such as ultrasound therapy, electrical stimulations, electromagnetic therapy, or phototherapy. Furthermore, stem cell therapies, biologic skin equivalents, platelet-rich plasma therapy, oxygen therapies, anti-TNF therapy, or negative pressure wound therapy are advanced venous ulcer therapeutic methods that may support the standard of care. Medical devices, such as a muscle pump activator, or intermittent pneumatic compression device, may be especially useful for specific subgroups of patients suffering from VLUs. Some of the above-mentioned technologies require broader evidence of clinical efficacy and are still considered experimental therapies in dermatology.