Regulatory Considerations for Producing mRNA Vaccines for Clinical Trials.

The approval of clinical trials by the competent authorities requires comprehensive quality documentation on the new drug to be used on the clinical trial participant. In the EU, quality data is summarized as investigational medicinal product dossier (IMPD), in the United States, as investigational new drug (IND) application. For that, several preconditions concerning production, quality control, and assurance have to be fulfilled. Here, specific requirements related to mRNA vaccines are addressed on the basis of European standards.

Quality Control Analysis of Mesenchymal Stem/Stromal Cells During Investigational New Drug Application for GvHD Administration in China.

Graft-versus-host disease (GvHD), including the acute and chronic types (aGvHD, cGvHD), arise as the dominating secondary disease in patients with unsatisfying consequences of allogeneic hematopoietic stem cell transplantation (HSCT). Approximately half of GvHD patients were steroid-resistant, with a two-year overall survival rate lower than 20%. Worse still, there are no standardized criteria for an optimal second-line therapy for steroid-resistant aGVHD patients. Notably, pioneering investigators have highlighted the ameliorative or therapeutic effects of human umbilical cord-derived mesenchymal stem/stromal cells (hUC-MSCs) upon GvHD largely attributed to their unique hematopoietic-supporting and immunomodulatory properties. Of note, quality control (QC) is the prerequisite to assure the safety and quality of hUC-MSCs before investigational new drug (IND) applications and large-scale clinical applications. Herein, we summarize the state-of-the-art updates upon IND-associated QC and clinical trials of hUC-MSCs during allogeneic HSCT in China. Meanwhile, the supervisory policy and medical ethics of current licensed MSC products for GvHD administration and the concomitant opportunities and challenges have also been discussed.

Analysis of secondary pharmacology assays received by the US Food and Drug Administration.

Secondary pharmacology studies are a time-efficient and cost-effective method for determining the safety profile of a potential new drug before it enters human trials. The results of these multi-target screens are commonly submitted with Investigational New Drug (IND) applications, but there currently is little guidance on how such information is presented and which targets are chosen for testing. In this study, we expand on our previous analysis of secondary pharmacology reports by manually curating and analyzing all secondary pharmacology results received by the FDA received as part of an IND submission. A total of 1120 INDs submitted by 480 sponsors between 1999 and October 2020 were included in this study. The overall results were largely consistent with previous internal and external studies, showing that the most tested target in our set was the histamine 1 receptor (tested 938 times), the most hit target was sodium channel site 2 (hit 141 times), and the target with the highest hit percentage was the vesicular monoamine transporter 2 (hit 42.2% of the time). Additionally, this study demonstrated that improvements in the secondary pharmacology submission process, such as changes in formatting and nomenclature, could enhance the utility of these assays for regulatory review, including assisting with identifying the safety liabilities of a drug candidate early in development. This updated data set will allow FDA-industry collaborative working groups to continue developing the best methods for regulatory submission of secondary pharmacology data and evaluate the need for a standard target panel.

Successful regulatory agency interaction - A nonclinical regulatory strategist's perspective.

Regulatory agency interaction occurs from before a candidate drug enters clinical development and all the way to marketing approval and beyond. This paper presents ways to enable successful interaction by avoiding issues, with an emphasis on nonclinical testing aspects. Strategic thinking as to whether an early regulatory agency meeting should occur is discussed and if yes, how to make it a success by generating relevant questions with proper preparation including a robust Briefing Document. Examples of unfavourable regulatory agency feedback during meetings is given which may have been avoided. Similarly, ways for successful regulatory submission in the form of a Clinical Trials Application (CTA) in Europe or an Investigational New Drug (IND) application in the US are considered with examples of comments that can be received from regulatory agencies. At marketing application stage with submission of a Marketing Authorisation Application (MAA) in Europe and a New Drug Application (NDA) or a Biologic License Application (BLA) in the US, a key document is the Nonclinical Overview and suggested content and potential deficiencies are presented to allow avoidance of adverse regulatory agency responses and time delay. Successful regulatory agency interaction involves robust scientific thinking, proper planning and well-written documentation.

Immunogenicity Risk Assessment for Multi-specific Therapeutics.

The objective of this manuscript is to provide the reader with a hypothetical case study to present an immunogenicity risk assessment for a multi-specific therapeutic as part of Investigational New Drug (IND) application. In order to provide context for the bioanalytical strategies used to support the multi-specific therapeutic presented herein, the introduction focuses on known immunogenicity risk factors. The subsequent hypothetical case study applies these principles to a specific example HC-12, based loosely on anti-TNFα and anti-IL-17A bispecific molecules previously in development, structured as an example immunogenicity risk assessment for submission to health authorities. The risk of higher incidence and safety impact of anti-drug antibodies (ADA) due to large protein complexes is explored in the context of multi-specificity and multi-valency of the therapeutic in combination with the oligomeric forms of the targets.

Development and investigational new drug application of mesenchymal stem/stromal cells products in China.

Mesenchymal stem/stromal cells (MSCs) have broad application prospects for regenerative medicine due to their self-renewal, high plasticity, ability for differentiation, and immune response and modulation. Interest in turning MSCs into clinical applications has never been higher than at present. Many biotech companies have invested great effort from development of clinical grade MSC product to investigational new drug (IND) enabling studies. Therefore, the growing demand for publication of MSC regulation in China necessitates various discussions in accessible professional journals. The National Medical Products Administration has implemented regulations on the clinical application of MSCs therapy. The regulations for MSCs products as drug have been updated in recent years in China. This review will look over the whole procedure in allogeneic MSC development, including regulations, guidance, processes, quality management, pre-IND meeting, and IND application for obtaining an approval to start clinical trials in China. The review focused on process and regulatory challenges in the development of MSCs products, with the goal of providing strategies to meet regulatory demands. This article describes a path for scientists, biotech companies, and clinical trial investigators toward the successful development of MSC-based therapeutic product.

Aggregation and analysis of secondary pharmacology data from investigational new drug submissions at the US Food and Drug Administration.

Secondary pharmacology studies are utilized by the pharmaceutical industry as a cost-efficient tool to identify potential safety liabilities of drugs before entering Phase 1 clinical trials. These studies are recommended by the Food and Drug Administration (FDA) as a part of the Investigational New Drug (IND) application. However, despite the utility of these assays, there is little guidance on which targets should be screened and which format should be used. Here, we evaluated 226 secondary pharmacology profiles obtained from close to 90 unique sponsors. The results indicated that the most tested target in our set was the GABA benzodiazepine receptor (tested 168 times), the most hit target was adenosine 3 (hit 24 times), and the target with the highest hit percentage was the quinone reductase 2 (NQO2) receptor (hit 29% of the time). The overall results were largely consistent with those observed in previous publications. However, this study also identified the need for improvement in the submission process of secondary pharmacology studies by industry, which could enhance their utility for regulatory purpose. FDA-industry collaborative working groups will utilize this data to determine the best methods for regulatory submission of these studies and evaluate the need for a standard target panel.

Pre-clinical study of IRDye800CW-nimotuzumab formulation, stability, pharmacokinetics, and safety.

BACKGROUND: Epidermal growth factor receptor (EGFR) is a target for cancer therapy as it is overexpressed in a wide variety of cancers. Therapeutic antibodies that bind EGFR are being evaluated in clinical trials as imaging agents for positron emission tomography and image-guided surgery. However, some of these antibodies have safety concerns such as infusion reactions, limiting their use in imaging applications. Nimotuzumab is a therapeutic monoclonal antibody that is specific for EGFR and has been used as a therapy in a number of countries. METHODS: Formulation of IRDye800CW-nimotuzumab for a clinical trial application was prepared. The physical, chemical, and pharmaceutical properties were tested to develop the specifications to determine stability of the product. The acute and delayed toxicities were tested and IRDye800CW-nimotuzumab was determined to be non-toxic. Non-compartmental pharmacokinetics analysis was used to determine the half-life of IRDye800CW-nimotuzumab. RESULTS: IRDye800CW-nimotuzumab was determined to be non-toxic from the acute and delayed toxicity study. The half-life of IRDye800CW-nimotuzumab was determined to be 38 ± 1.5 h. A bi-exponential analysis was also used which gave a t1/2 alpha of 1.5 h and t1/2 beta of 40.8 h. CONCLUSIONS: Here, we show preclinical studies demonstrating that nimotuzumab conjugated to IRDye800CW is safe and does not exhibit toxicities commonly associated with EGFR targeting antibodies.

Regulatory considerations for developing a phase I investigational new drug application for autologous induced pluripotent stem cells-based therapy product.

Induced pluripotent stem cells (iPSC)-based therapies have been hailed as the future of regenerative medicine because of their potential to provide treatment options for most degenerative diseases. A key promise of iPSC-based therapies is the possibility of an autologous transplant that may engraft better in the longer-term due to its compatibility with the patient's immune system. Despite over a decade of research, clinical translation of autologous iPSC-based therapies has been slow-partly due to a lacking pre-defined regulatory path. Here, we outline regulatory considerations for developing an autologous iPSC-based product and challenges associated with the clinical manufacturing of autologous iPSCs and their derivatives. These challenges include donor tissue source, reprogramming methods, heterogeneity of differentiated cells, controls for the manufacturing process, and preclinical considerations. A robust manufacturing process with appropriate quality controls and well-informed, prospectively designed preclinical studies provide a path toward successful approval of autologous iPSC-based therapies.

Considerations on chemistry, manufacturing, and control of stem cell products for Investigational New Drug application in China.

Tremendous progress has been made in recent years to produce functional cells for cell therapy products. Hundreds of clinical trials of stem cell products (SCPs) have shown promising therapeutic potential worldwide, including the products derived from human pluripotent stem cells (hPSCs), adult stem cells and mesenchymal stem cells (MSC). Before starting a clinical trial, comprehensive chemistry, manufacturing and control (CMC) study is required to assure the safety and quality consistency of SCPs. The heterogeneity of stem cell products arises from the variability in the donor tissues, isolation of cells and differentiation processes, and appropriate testing approaches are needed to characterize and release SCPs. Here we summarize the regulatory considerations of CMC study in Investigational New Drug (IND) application of SCPs in China based on the current knowledge, and they will be updated in the future with the advance of stem cell biology and regulatory science.

Treatment of Coronavirus Disease 2019 (COVID-19) Patients with Convalescent Plasma.

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2, has spread globally, and no proven treatments are available. Convalescent plasma therapy has been used with varying degrees of success to treat severe microbial infections for >100 years. Patients (n = 25) with severe and/or life-threatening COVID-19 disease were enrolled at the Houston Methodist hospitals from March 28, 2020, to April 14, 2020. Patients were transfused with convalescent plasma, obtained from donors with confirmed severe acute respiratory syndrome coronavirus 2 infection who had recovered. The primary study outcome was safety, and the secondary outcome was clinical status at day 14 after transfusion. Clinical improvement was assessed on the basis of a modified World Health Organization six-point ordinal scale and laboratory parameters. Viral genome sequencing was performed on donor and recipient strains. At day 7 after transfusion with convalescent plasma, nine patients had at least a one-point improvement in clinical scale, and seven of those were discharged. By day 14 after transfusion, 19 (76%) patients had at least a one-point improvement in clinical status, and 11 were discharged. No adverse events as a result of plasma transfusion were observed. Whole genome sequencing data did not identify a strain genotype-disease severity correlation. The data indicate that administration of convalescent plasma is a safe treatment option for those with severe COVID-19 disease.

Deployment of convalescent plasma for the prevention and treatment of COVID-19.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the cause of coronavirus disease 2019 (COVID-19), has spurred a global health crisis. To date, there are no proven options for prophylaxis for those who have been exposed to SARS-CoV-2, nor therapy for those who develop COVID-19. Immune (i.e., "convalescent") plasma refers to plasma that is collected from individuals following resolution of infection and development of antibodies. Passive antibody administration through transfusion of convalescent plasma may offer the only short-term strategy for conferring immediate immunity to susceptible individuals. There are numerous examples in which convalescent plasma has been used successfully as postexposure prophylaxis and/or treatment of infectious diseases, including other outbreaks of coronaviruses (e.g., SARS-1, Middle East respiratory syndrome [MERS]). Convalescent plasma has also been used in the COVID-19 pandemic; limited data from China suggest clinical benefit, including radiological resolution, reduction in viral loads, and improved survival. Globally, blood centers have robust infrastructure for undertaking collections and constructing inventories of convalescent plasma to meet the growing demand. Nonetheless, there are nuanced challenges, both regulatory and logistical, spanning donor eligibility, donor recruitment, collections, and transfusion itself. Data from rigorously controlled clinical trials of convalescent plasma are also few, underscoring the need to evaluate its use objectively for a range of indications (e.g., prevention vs. treatment) and patient populations (e.g., age, comorbid disease). We provide an overview of convalescent plasma, including evidence of benefit, regulatory considerations, logistical work flow, and proposed clinical trials, as scale-up is brought underway to mobilize this critical resource.

Iguratimod as an alternative induction therapy for refractory lupus nephritis: a preliminary investigational study.

OBJECTIVES: Iguratimod, a novel immunomodulatory agent for rheumatoid arthritis, has been shown to be effective against murine lupus. The aim of this study was to make a preliminary evaluation of the efficacy and safety of iguratimod as salvage therapy in patients with refractory lupus nephritis (LN). METHODS: We enrolled eligible patients with refractory LN, which we defined as having failed or relapsed on at least two immunosuppressant agents. After enrollment, we substituted iguratimod (25 mg twice daily) for their previous immunosuppressant agents without increasing the dose of steroids. The primary outcome was complete/partial remission (PR/CR) at week 24. Patients who achieved remission continued iguratimod as maintenance therapy over an extended follow-up. RESULTS: The study cohort comprised 14 patients with refractory LN, 10 of whom had recent treatment failure and 4 repeated relapses with inadequate initial responses. At enrollment, none of the patients had detectable evidence of extra-renal involvement. The median prednisone dosage was 10 mg/d (IQR 0-10 mg/day). Thirteen patients were eligible for response evaluation, with one patient missed. The renal response rate was 92.3% (12/13) at week 24, with 38.5% (5/13) achieving CR and 53.8% (7/13) achieving PR. We then continued to follow up the responding patients for up to 144 weeks. Twenty-five percent of the patients (3/12) had renal relapse after initial PR. The estimated glomerular filtration rate of all patients maintained stable during follow-up. One patient had a severe adverse reaction (anemia) but recovered fully after stopping iguratimod. CONCLUSIONS: Our study supports the potential of iguratimod for treatment of refractory LN. Iguratimod could be a promising candidate drug for this condition.

Assessing Animal Models of Bacterial Pneumonia Used in Investigational New Drug Applications for the Treatment of Bacterial Pneumonia.

Animal models of bacterial infection have been widely used to explore the in vivo activity of antibacterial drugs. These data are often submitted to the U.S. Food and Drug Administration to support human use in an investigational new drug application (IND). To better understand the range and scientific use of animal models in regulatory submissions, a database was created surveying recent pneumonia models submitted as part of IND application packages. The IND studies were compared to animal models of bacterial pneumonia published in the scientific literature over the same period of time. In this review, we analyze the key experimental design elements, such as animal species, immune status, pathogens selected, and route of administration, and study endpoints.

Scientific and Regulatory Approach to Botanical Drug Development: A U.S. FDA Perspective.

The United States FDA has received over 800 botanical investigational new drug applications (IND) and pre-IND meeting requests (PIND) in the years preceding 2018. The current data show that indications for submitted INDs cover nearly every review division of the FDA. Despite increasing global interest in the investigation of botanical mixtures as drug products, only two botanical new drug applications (NDA) have been approved in the U.S.: Veregen in 2006 and Fulyzaq (also known as Mytesi) in 2012. Given botanicals' chemical and biological complexity, efforts in characterizing their pharmacology, demonstrating therapeutic efficacy, and ensuring quality consistency remain scientific and regulatory challenges. The FDA published a revised Botanical Drug Development Guidance for Industry document in December 2016 to address developmental considerations for late-phase trials and to provide recommendations intended to facilitate botanical drug development. Herein, we present an analysis of botanical INDs showing their variety of botanical raw materials (e.g., coming from different geographic regions, single vs multiple herbs), the varied levels of previous human experience, and therapeutic areas, as well as provide an overview of experience and challenges in reviewing botanical drugs.

Drug Exposure to Establish Pharmacokinetic-Response Relationships in Oncology.

In the oncology field, understanding the relationship between the dose administered and the exerted effect is particularly important because of the narrow therapeutic index associated with anti-cancer drugs and the high interpatient variability. Therefore, in this review, we provide a critical perspective of the different methods of characterising treatment exposure in the oncology setting. The increasing number of modelling applications in oncology reflects the applicability and the impact of pharmacometrics on all phases of the drug development process and patient management as well. Pharmacometric modelling is a worthy component within the current paradigm of model-based drug development, but pharmacometric modelling techniques are also accessible for the clinician in the optimisation of current oncology therapies. Consequently, the application of population models in a hospital setting by generating close collaborations between physicians and pharmacometricians is highly recommended, providing a systematic means of developing and assessing model-based metrics as 'drivers' for various responses to treatments, which can then be evaluated as predictors for treatment success. Characterising the key determinants of variability in exposure is of particular importance for anticancer agents, as efficacy and toxicity are associated with exposure. We present the different strategies to describe and predict drug exposure that can be applied depending on the data available, with the objective of obtaining the most useful information in the patients' favour throughout the full drug cycle. Therefore, the objective of the present article is to review the different approaches used to characterise a patient's exposure to oncology drugs, which will result in a better understanding of the time course of the response and the magnitude of interpatient variability.