Polish regulatory system regarding ATMP hospital exemptions.

Introduction: This article explains the current regulatory system in Poland regarding Advanced Therapy Medicinal Products given under Hospital Exemptions (ATMP-HE). Methods: The relevant sections of Polish legislation are translated into English and their interaction is described. Results: We analyze the impact of these regulations from the perspective of three stakeholder groups: manufacturers, physicians, and patients. Amendments enacted between 2018 and 2023 have substantially changed Polish implementation of the ATMP-HE pathway. In Poland, most ATMP-HE treatments have been therapies employing Mesenchymal Stromal Cells (MSC). Discussion: Comparison to other European countries shows that Poland is within the mainstream of EU practices regarding ATMP-HE implementation. One notable issue is that Poland has relatively low per capita spending on healthcare, and ATMP-HE in Poland must be funded from outside the government healthcare system. Conclusions. The original intention of the legislation that created ATMP-HE was to allow access to experimental therapies for patients with unmet needs. It remains to be seen if that mission can be fulfilled amidst conflicting pressures from various stakeholder groups.

Systematic review and meta-analysis of cell therapy for COVID-19: global clinical trial landscape, published safety/efficacy outcomes, cell product manufacturing and clinical delivery.

During the pandemic of severe respiratory distress syndrome coronavirus 2 (SARS-CoV2), many novel therapeutic modalities to treat Coronavirus 2019 induced disease (COVID-19) were explored. This study summarizes 195 clinical trials of advanced cell therapies targeting COVID-19 that were registered over the two years between January 2020 to December 2021. In addition, this work also analyzed the cell manufacturing and clinical delivery experience of 26 trials that published their outcomes by July 2022. Our demographic analysis found the highest number of cell therapy trials for COVID-19 was in United States, China, and Iran (N=53, 43, and 19, respectively), with the highest number per capita in Israel, Spain, Iran, Australia, and Sweden (N=0.641, 0.232, 0,223, 0.194, and 0.192 trials per million inhabitants). The leading cell types were multipotent mesenchymal stromal/stem cells (MSCs), natural killer (NK) cells, and mononuclear cells (MNCs), accounting for 72%, 9%, and 6% of the studies, respectively. There were 24 published clinical trials that reported on infusions of MSCs. A pooled analysis of these MSC studies found that MSCs provide a relative risk reduction for all-cause COVID-19 mortality of RR=0.63 (95% CI 0.46 to 0.85). This result corroborates previously published smaller meta-analyses, which suggested that MSC therapy demonstrated a clinical benefit for COVID-19 patients. The sources of the MSCs used in these studies and their manufacturing and clinical delivery methods were remarkably heterogeneous, with some predominance of perinatal tissue-derived products. Our results highlight the important role that cell therapy products may play as an adjunct therapy in the management of COVID-19 and its related complications, as well as the importance of controlling key manufacturing parameters to ensure comparability between studies. Thus, we support ongoing calls for a global registry of clinical studies with MSC products that could better link cell product manufacturing and delivery methods to clinical outcomes. Although advanced cell therapies may provide an important adjunct treatment for patients affected by COVID-19 in the near future, preventing pathology through vaccination still remains the best protection to date. We conducted a systematic review and meta-analysis of advanced cell therapy clinical trials as potential novel treatment for COVID-19 (resulting from SARS-CoV-2 coronavirus infection), including analysis of the global clinical trial landscape, published safety/efficacy outcomes (RR/OR), and details on cell product manufacturing and clinical delivery. This study had a 2-year observation interval from start of January 2020 to end of December 2021, including a follow-up period until end of July to identify published outcomes, which covers the most vivid period of clinical trial activity, and is also the longest observation period studied until today. In total, we identified 195 registered advanced cell therapy studies for COVID-19, employing 204 individual cell products. Leading registered trial activity was attributed to the USA, China, and Iran. Through the end of July 2022, 26 clinical trials were published, with 24 out of 26 articles employing intravenous infusions (IV) of mesenchymal stromal/stem cell (MSC) products. Most of the published trials were attributed to China and Iran. The cumulative results from the 24 published studies employing infusions of MSCs indicated an improved survival (RR=0.63 with 95% Confidence Interval 0.46 to 0.85). Our study is the most comprehensive systematic review and meta-analysis on cell therapy trials for COVID-19 conducted to date, clearly identifying the USA, China, and Iran as leading advanced cell therapy trial countries for COVID-19, with further strong contributions from Israel, Spain, Australia and Sweden. Although advanced cell therapies may provide an important adjunct treatment for patients affected by COVID-19 in the future, preventing pathology through vaccination remains the best protection.

First decade of clinical trials and published studies with mesenchymal stromal cells from umbilical cord tissue.

Aim: This is the first analysis of both clinical trials and published studies that employ umbilical cord mesenchymal stromal cells, for the decade 2007-2017. Materials & methods: Searching international databases, we found 178 registered trials and 98 publications. Results: Among the registered clinical trials, 20% have resulted in publications so far. Among the publications, 18% report safety and 74% report some form of improvement. Between 36 and 45% of the publications do not report aspects of the cell manufacturing, including isolation method, culture medium or number of culture passages. Conclusion: Analyses that link trials with publications can elucidate factors that promote study completion and publication. More full disclosure of cell manufacturing is needed to evaluate the efficacy of mesenchymal stromal cell isolated from umbilical cord tissue (UC-MSC) products.

Regulations on cell therapy products in China: a brief history and current status.

This report describes changes to cell therapy research and clinical practice in China as a result of guidelines from the central government finalized at the end of 2017. The tables list Chinese authorities and regulations on human cells for medical research over the years 1993-2018. Under the new regulations, cell therapy products (CTPs) are treated like drugs, in alignment with policy in the USA and European Union. At civil institutions in China, there are now two pathways for human clinical trials: research versus pharmaceutical development. At the end of 2018, trials of CTPs were only authorized at 114 approved hospitals. It is hoped that the new policies will help CTPs developed in China gain acceptance by health regulators in the west.

Lifetime probabilities of hematopoietic stem cell transplantation in the U.S.

Healthcare policies regarding hematopoietic stem cell transplantation (HSCT) must address the need for the procedure as well as the availability of stem cell sources: bone marrow, peripheral blood, or umbilical cord blood (UCB). However, data with respect to the lifetime probability of undergoing HSCT are lacking. This study was undertaken to estimate the latter probability in the United States (U.S.), depending on age, sex, and race. We used data from the Center for International Blood and Marrow Transplant Research, the U.S. Surveillance, Epidemiology and End Results Program, and the U.S. Census Bureau and calculated probabilities as cumulative incidences. Several scenarios were considered: assuming current indications for autologous and allogeneic HSCT, assuming universal donor availability, and assuming broadening of HSCT use in hematologic malignancies. Incidences of diseases treated with HSCT and of HSCTs performed increase with age, rising strongly after age 40. Among individuals older than 40, incidences are higher for men than for women. The lifetime probabilities of undergoing HSCT range from 0.23% to 0.98% under the various scenarios. We conclude that, given current indications, the lifetime probability of undergoing autologous or allogeneic HSCT is much higher than previously reported by others and could rise even higher with increases in donor availability and HSCT applicability.

The first decade of advanced cell therapy clinical trials using perinatal cells (2005-2015).

AIM: The first review of advanced cell therapy trials with perinatal cells. MATERIALS & METHODS: We compiled 281 clinical trials of advanced cell therapy with perinatal cells that were registered in 2005-2015. RESULTS: The most common cell source in these trials is cord blood, but the cell type that provides the mechanism of action in the majority of trials is mesenchymal stem/stromal cells. We analyze trends among the 15 parameters we compiled for these trials. CONCLUSION: Advanced cell therapy with perinatal cells is a new field that covers a wide range of diagnoses but where most of the trials are early Phase. Researchers in different countries tend to work with a preferred cell source and cell type.