Table 7.

Proposed solutions for the improvement of a development plan aiming for regulatory approval

Challenge	Solution
MSC and MSC-derived secretome	MSC obtained and characterized according to the criteria of the International Society of Cell & Gene Therapy [91]. Tissue factor and hemocompatibility assessment [105] to be included for the evaluation of the product suitability for intravenous use MSC-derived extracellular vesicles isolated according to the guidelines of the International Society for Extracellular Vesicles [92] MSC-derived conditioned medium characterized for the presence of extracellular vesicles and for the contents of soluble biologically active factors [92, 93]. Optimization of formulation and manufacturing [120] Scalable production according to the current Good Clinical Manufacturing guidelines Evaluation of the potency of the product (e.g., immunomodulatory/immunosuppressive properties assessed by mixed lymphocyte reaction) Dose estimated on the basis of preclinical studies or previous pilot clinical studies
Characteristic of the clinical trials	Prospective, randomized, double-blind, or open-label placebo-controlled two-arm studies in hospitalized patients with severe and critical COVID-19 and influenza Concomitant therapies with antivirals, glucocorticoids, and other immunomodulators and antiinflammatory agents according to current guidelines Sample size calculated to detect significant differences for the selected primary efficacy outcome
Functional and biochemical parameters indicating the need for add-on therapy	Patients showing rapidly increasing oxygen needs and systemic inflammation despite treatment with antivirals, immunomodulators, and antiinflammatory agents according to current guidelines Use of the Hyperinflammation Syndrome score at enrollment [113, 114] Recording and monitoring of C-reactive protein, D-dimers, interleukin-6, serum ferritin concentrations, soluble urokinase plasminogen activator receptor, and leukocyte counts [106, 110–112]
Main outcome measures	All-cause mortality at day 28 and at hospital discharge Clinical progression assessed daily by using the WHO Clinical Progression Scale [106]
Secondary outcomes	Length of stay in ICU Need for intubation Length of stay in the hospital Changes in biochemical parameters (C-reactive protein, D-dimers, interleukin-6, serum ferritin concentrations, soluble urokinase plasminogen activator receptor, leukocyte counts) Organ dysfunction score Pulmonary function at 1, 6, 12 months Radiological findings Tolerability and adverse events Viral burden assessed by quantitative real-time polymerase chain reaction
Clinical data recording and reporting	According to the Good Clinical practice guidelines
Data for economic analysis	Recording of costs and resource use

COVID-19 coronavirus disease 2019, ICU intensive care unit, MSC mesenchymal stem/stromal cell, WHO World Health Organization