706 results on '"Investigational New Drug Application"'
Search Results
2. Hematopoietic Stem Cell Gene Therapy for Cystinosis: From Bench-to-Bedside
- Author
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Cherqui, Stephanie
- Subjects
Medical Biotechnology ,Biomedical and Clinical Sciences ,Pediatric ,Clinical Research ,Stem Cell Research ,Orphan Drug ,Transplantation ,Gene Therapy ,Biotechnology ,Rare Diseases ,Kidney Disease ,Stem Cell Research - Nonembryonic - Human ,Genetics ,Regenerative Medicine ,Development of treatments and therapeutic interventions ,5.2 Cellular and gene therapies ,Good Health and Well Being ,Amino Acid Transport Systems ,Neutral ,Animals ,Cystinosis ,Genetic Therapy ,Hematopoietic Stem Cell Transplantation ,Humans ,Kidney ,Lysosomes ,Transplantation ,Homologous ,cystinosis ,CD34(+) hematopoietic stem and progenitor cells ,gene therapy ,pre-clinical studies ,investigational new drug application ,clinical trial ,CD34+ hematopoietic stem and progenitor cells ,Biological sciences ,Biomedical and clinical sciences - Abstract
Cystinosis is an autosomal recessive metabolic disease that belongs to the family of lysosomal storage disorders. The gene involved is the CTNS gene that encodes cystinosin, a seven-transmembrane domain lysosomal protein, which is a proton-driven cystine transporter. Cystinosis is characterized by the lysosomal accumulation of cystine, a dimer of cysteine, in all the cells of the body leading to multi-organ failure, including the failure of the kidney, eye, thyroid, muscle, and pancreas, and eventually causing premature death in early adulthood. The current treatment is the drug cysteamine, which is onerous and expensive, and only delays the progression of the disease. Employing the mouse model of cystinosis, using Ctns-/- mice, we first showed that the transplantation of syngeneic wild-type murine hematopoietic stem and progenitor cells (HSPCs) led to abundant tissue integration of bone marrow-derived cells, a significant decrease in tissue cystine accumulation, and long-term kidney, eye and thyroid preservation. To translate this result to a potential human therapeutic treatment, given the risks of mortality and morbidity associated with allogeneic HSPC transplantation, we developed an autologous transplantation approach of HSPCs modified ex vivo using a self-inactivated lentiviral vector to introduce a functional version of the CTNS cDNA, pCCL-CTNS, and showed its efficacy in Ctns-/- mice. Based on these promising results, we held a pre-IND meeting with the Food and Drug Administration (FDA) to carry out the FDA agreed-upon pharmacological and toxicological studies for our therapeutic candidate, manufacturing development, production of the GMP lentiviral vector, design Phase 1/2 of the clinical trial, and filing of an IND application. Our IND was cleared by the FDA on 19 December 2018, to proceed to the clinical trial using CD34+ HSPCs from the G-CSF/plerixafor-mobilized peripheral blood stem cells of patients with cystinosis, modified by ex vivo transduction using the pCCL-CTNS vector (investigational product name: CTNS-RD-04). The clinical trial evaluated the safety and efficacy of CTNS-RD-04 and takes place at the University of California, San Diego (UCSD) and will include up to six patients affected with cystinosis. Following leukapheresis and cell manufacturing, the subjects undergo myeloablation before HSPC infusion. Patients also undergo comprehensive assessments before and after treatment to evaluate the impact of CTNS-RD-04 on the clinical outcomes and cystine and cystine crystal levels in the blood and tissues for 2 years. If successful, this treatment could be a one-time therapy that may eliminate or reduce renal deterioration as well as the long-term complications associated with cystinosis. In this review, we will describe the long path from bench-to-bedside for autologous HSPC gene therapy used to treat cystinosis.
- Published
- 2021
3. Outpatient Inhaled Nitric Oxide in a Patient with Vasoreactive Idiopathic Pulmonary Arterial Hypertension and COVID-19 Infection
- Author
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Zamanian, Roham T, Pollack, Charles V, Gentile, Michael A, Rashid, Moira, Fox, John Christian, Mahaffey, Kenneth W, and de Jesus Perez, Vinicio
- Subjects
Good Health and Well Being ,Administration ,Inhalation ,Adult ,Betacoronavirus ,COVID-19 ,Coronavirus Infections ,Familial Primary Pulmonary Hypertension ,Female ,Humans ,Investigational New Drug Application ,Nitric Oxide ,Off-Label Use ,Outpatients ,Pandemics ,Pneumonia ,Viral ,SARS-CoV-2 ,Telemedicine ,Walk Test ,Medical and Health Sciences ,Respiratory System - Published
- 2020
4. Most of the Intended Management Changes After 68Ga-DOTATATE PET/CT Are Implemented
- Author
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Calais, Jeremie, Czernin, Johannes, Eiber, Matthias, Fendler, Wolfgang P, Gartmann, Jeannine, Heaney, Anthony P, Hendifar, Andrew E, Pisegna, Joseph R, Hecht, J Randolph, Wolin, Edward M, Slavik, Roger, Gupta, Pawan, Quon, Andrew, Schiepers, Christiaan, Allen-Auerbach, Martin S, and Herrmann, Ken
- Subjects
Biomedical and Clinical Sciences ,Clinical Sciences ,Clinical Research ,Cancer ,Biomedical Imaging ,Clinical Trials and Supportive Activities ,Aged ,Case Management ,Drugs ,Investigational ,Female ,Humans ,Image Processing ,Computer-Assisted ,Investigational New Drug Application ,Male ,Middle Aged ,Neuroendocrine Tumors ,Organometallic Compounds ,Positron Emission Tomography Computed Tomography ,Positron-Emission Tomography ,Prospective Studies ,Radiopharmaceuticals ,Receptors ,Somatostatin ,Surveys and Questionnaires ,neuroendocrine tumors ,somatostatin receptor ,PET/CT ,DOTATATE ,impact on implemented management ,Nuclear Medicine & Medical Imaging ,Clinical sciences - Abstract
In this prospective referring-physician-based survey, we investigated the definite clinical impact of 68Ga-DOTATATE PET/CT on managing patients with neuroendocrine tumors (NETs). Methods: We prospectively studied 130 patients with 68Ga-DOTATATE PET/CT referred for initial or subsequent management decisions (NCT02174679). Referring physicians completed one questionnaire before the scan (Q1) to indicate the treatment plan without PET/CT information, one immediately after review of the imaging report to denote intended management changes (Q2), and one 6 mo later (Q3) to verify whether intended changes were in fact implemented. To further validate the Q3 responses, a systematic electronic chart review was conducted. Results: All 3 questionnaires were completed by referring physicians for 96 of 130 patients (74%). 68Ga-DOTATATE PET/CT resulted in intended management changes (Q2) in 48 of 96 patients (50%). These changes were finally implemented (Q3) in 36 of 48 patients (75%). Q3 responses were confirmed in all patients with an available electronic chart (36/96; 38%). Conclusion: This prospective study confirmed a significant impact of 68Ga-DOTATATE PET/CT on the intended management of patients with NETs (50% of changes) and notably demonstrated a high implementation rate (75%) of these intended management changes.
- Published
- 2017
5. Comparative study of updated clinical trial regulations in india with respect to Australia, Europe, Japan and US
- Author
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Kumar, Devender, Rahi, Shivali, and Rana, Arpana
- Published
- 2021
- Full Text
- View/download PDF
6. Clinical Development of Gene Therapies: The First Three Decades and Counting
- Author
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Larissa Lapteva, Tejashri Purohit-Sheth, Mercedes Serabian, and Raj K. Puri
- Subjects
gene therapy ,Center for Biologics Evaluation and Research ,Office of Tissues and Advanced Therapies ,Investigational New Drug application ,rare diseases ,natural history ,Genetics ,QH426-470 ,Cytology ,QH573-671 - Abstract
In the past three decades the field of gene therapy has made remarkable progress, surging from mere laboratory experiments to US Food and Drug Administration (FDA)-approved products that bring significant reduction in disease burden to patients who previously had no therapeutic options for their serious conditions. Herein, we review the evolution of the gene therapy clinical research landscape and describe the gene therapy product development programs evaluated by the FDA in Investigational New Drug applications received in 1988–2019. We also discuss the clinical development programs of the first six oncolytic and gene therapy products approved in the United States.
- Published
- 2020
- Full Text
- View/download PDF
7. Regulation of Regenerative Medicine Products
- Author
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Gee, Adrian P., COHEN, IRUN R., Series Editor, LAJTHA, ABEL, Series Editor, LAMBRIS, JOHN D., Series Editor, PAOLETTI, RODOLFO, Series Editor, Rezaei, Nima, Series Editor, Schmuck, Eric G., editor, Hematti, Peiman, editor, and Raval, Amish N., editor
- Published
- 2018
- Full Text
- View/download PDF
8. Regulation and status of herbal medicine clinical trials in Korea
- Author
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Boram Lee, Yujin Choi, Pyung-Wha Kim, Changsop Yang, and Myeong Soo Lee
- Subjects
Herbal medicine ,Clinical trial ,Investigational new drug application ,IND ,Miscellaneous systems and treatments ,RZ409.7-999 - Abstract
Background: Herbal medicine has been used frequently in Korean medicine. We aimed to summarize the relevant regulations for herbal medicine clinical trials and to analyze their current status in the Republic of Korea. Methods: We searched for legislation to find regulations on herbal medicine clinical trials. Additionally, the websites of the Korean Ministry of Food and Drug Safety (KMFDS) and Clinical Research Information Service (CRIS) were searched to investigate the current status of them. Results: To conduct herbal medicine clinical trials for new drugs or previously approved drugs outside of indications, investigational new drug (IND) approval should be obtained from the KMFDS. For clinical trials of herbal medicines that have been used for more than 3 years with 200 cases at the clinical trial institution, nonclinical data can be exempted from IND approval. Total 95 and 108 herbal medicine clinical trials from the KMFDS and CRIS websites were analyzed. The number of clinical trials showed an increasing trend each year, as did KMFDS-regulated clinical trials. Recently, three clinical trials targeting new herbal formulations frequently used in Korean medicine institutions have been approved based on relevant regulations. Conclusion: We confirmed that herbal medicine clinical trials are managed through strict regulations, which can ensure the safe and effective use of herbal medicine. Despite strict regulations, attempts to accumulate evidence through clinical trials for herbal medicine are increasing. High-quality clinical trials should be conducted to develop new drugs that reflect the clinical setting using relevant regulations, evaluate the efficacy and safety of the drugs, and strengthen insurance coverage.
- Published
- 2021
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9. INDs for PET Molecular Imaging Probes—Approach by an Academic Institution
- Author
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Mosessian, Sherly, Duarte-Vogel, Sandra M, Stout, David B, Roos, Kenneth P, Lawson, Gregory W, Jordan, Maria C, Ogden, Amanda, Matter, Cheryl, Sadeghi, Saman, Mills, George Q, Schelbert, Heinrich R, Radu, Caius G, Czernin, Johannes, Couto, Marcelo, and Phelps, Michael E
- Subjects
Pharmacology and Pharmaceutical Sciences ,Biomedical and Clinical Sciences ,Biotechnology ,Bioengineering ,Biomedical Imaging ,Academies and Institutes ,Animals ,Cytarabine ,Drug Approval ,Drugs ,Investigational ,Female ,Humans ,Male ,Molecular Imaging ,Molecular Probes ,Positron-Emission Tomography ,Rats ,Sprague-Dawley ,United States ,United States Food and Drug Administration ,PET probes ,Investigational New Drug application ,FDA regulations ,Cost-effective ,Clinical trial ,Physiology ,Clinical Sciences ,Nuclear Medicine & Medical Imaging ,Clinical sciences - Abstract
We have developed an efficient, streamlined, cost-effective approach to obtain Investigational New Drug (IND) approvals from the Food and Drug Administration (FDA) for positron emission tomography (PET) imaging probes (while the FDA uses the terminology PET drugs, we are using "PET imaging probes," "PET probes," or "probes" as the descriptive terms). The required application and supporting data for the INDs were collected in a collaborative effort involving appropriate scientific disciplines. This path to INDs was successfully used to translate three [(18) F]fluoro-arabinofuranosylcytosine (FAC) analog PET probes to phase 1 clinical trials. In doing this, a mechanism has been established to fulfill the FDA regulatory requirements for translating promising PET imaging probes from preclinical research into human clinical trials in an efficient and cost-effective manner.
- Published
- 2014
10. Regulatory Considerations for Producing mRNA Vaccines for Clinical Trials.
- Author
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Schmid A
- Subjects
- Humans, RNA, Messenger genetics, United States, Investigational New Drug Application, Vaccines, Synthetic, Clinical Trials as Topic, mRNA Vaccines, Quality Control
- Abstract
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., (© 2024. The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature.)
- Published
- 2024
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- View/download PDF
11. Hematopoietic Stem Cell Gene Therapy for Cystinosis: From Bench-to-Bedside
- Author
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Stephanie Cherqui
- Subjects
cystinosis ,CD34+ hematopoietic stem and progenitor cells ,gene therapy ,pre-clinical studies ,investigational new drug application ,clinical trial ,Cytology ,QH573-671 - Abstract
Cystinosis is an autosomal recessive metabolic disease that belongs to the family of lysosomal storage disorders. The gene involved is the CTNS gene that encodes cystinosin, a seven-transmembrane domain lysosomal protein, which is a proton-driven cystine transporter. Cystinosis is characterized by the lysosomal accumulation of cystine, a dimer of cysteine, in all the cells of the body leading to multi-organ failure, including the failure of the kidney, eye, thyroid, muscle, and pancreas, and eventually causing premature death in early adulthood. The current treatment is the drug cysteamine, which is onerous and expensive, and only delays the progression of the disease. Employing the mouse model of cystinosis, using Ctns−/− mice, we first showed that the transplantation of syngeneic wild-type murine hematopoietic stem and progenitor cells (HSPCs) led to abundant tissue integration of bone marrow-derived cells, a significant decrease in tissue cystine accumulation, and long-term kidney, eye and thyroid preservation. To translate this result to a potential human therapeutic treatment, given the risks of mortality and morbidity associated with allogeneic HSPC transplantation, we developed an autologous transplantation approach of HSPCs modified ex vivo using a self-inactivated lentiviral vector to introduce a functional version of the CTNS cDNA, pCCL-CTNS, and showed its efficacy in Ctns−/− mice. Based on these promising results, we held a pre-IND meeting with the Food and Drug Administration (FDA) to carry out the FDA agreed-upon pharmacological and toxicological studies for our therapeutic candidate, manufacturing development, production of the GMP lentiviral vector, design Phase 1/2 of the clinical trial, and filing of an IND application. Our IND was cleared by the FDA on 19 December 2018, to proceed to the clinical trial using CD34+ HSPCs from the G-CSF/plerixafor-mobilized peripheral blood stem cells of patients with cystinosis, modified by ex vivo transduction using the pCCL-CTNS vector (investigational product name: CTNS-RD-04). The clinical trial evaluated the safety and efficacy of CTNS-RD-04 and takes place at the University of California, San Diego (UCSD) and will include up to six patients affected with cystinosis. Following leukapheresis and cell manufacturing, the subjects undergo myeloablation before HSPC infusion. Patients also undergo comprehensive assessments before and after treatment to evaluate the impact of CTNS-RD-04 on the clinical outcomes and cystine and cystine crystal levels in the blood and tissues for 2 years. If successful, this treatment could be a one-time therapy that may eliminate or reduce renal deterioration as well as the long-term complications associated with cystinosis. In this review, we will describe the long path from bench-to-bedside for autologous HSPC gene therapy used to treat cystinosis.
- Published
- 2021
- Full Text
- View/download PDF
12. Investigator Responsibilities in Clinical Research.
- Author
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Feehan, Amy K. and Garcia-Diaz, Julia
- Subjects
- *
MEDICAL research personnel , *PROSECUTION , *CLINICAL trials , *FEDERAL regulation , *EMPLOYEE training - Abstract
Background: Clinical trials are an integral part of translating new basic science research into therapeutics. It is crucial for those who run clinical trials to realize the gravity of their responsibilities as principal investigators. Methods: This review focuses on the relevant investigator responsibilities under the Code of Federal Regulations Title 21, the contents of Form 1572, FDA inspections, and methods to improve compliance. Results: While responsibility for day-to-day study activities can be delegated to outside entities and to study staff, a clinical principal investigator who has signed US Food and Drug Administration (FDA) Form 1572 is held responsible for noncompliance and misconduct by anyone working on the study. Depending on the infraction, consequences can range from a publicly posted warning letter by the FDA to criminal prosecution and fines or imprisonment. Conclusion: Investigators are not only responsible for producing high-quality, meaningful, scientific research, but they are also responsible for maintaining public trust. If the principal investigator acts with integrity and provides training and oversight of employees, FDA inquiries should go smoothly. Following good clinical practice standards for clinical research will result in quality data collection and facilitate the analysis and publication process. [ABSTRACT FROM AUTHOR]
- Published
- 2020
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13. Overview of Chemistry, Manufacturing, and Controls (CMC) for Pluripotent Stem Cell-Based Therapies
- Author
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Van Deusen, Amy Lynnette, McGary, Michael Earl, Turksen, Kursad, Series editor, and Childers, Martin K., editor
- Published
- 2016
- Full Text
- View/download PDF
14. Expanded access to investigational drugs in psychiatry: A systematic review.
- Author
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Vermeulen, Stefan F., Polak, Tobias B., and Bunnik, Eline M.
- Subjects
- *
DRUG accessibility , *INVESTIGATIONAL drugs , *PEOPLE with mental illness , *PSYCHIATRY , *DRUGS - Abstract
• Some patients with serious mental illness have exhausted all approved treatments. • Patients with treatment-resistance cannot always participate in clinical trials. • Expanded access allows prescription of investigational drugs, outside of trials. • Globally, only fourteen expanded access programs were ever conducted in psychiatry. • Treatment resistant patients may not (always) be supplied investigational drugs. Some psychiatric patients have exhausted all approved treatment options. Numerous investigational drugs are currently being developed and tested in clinical trials. However, not all patients can participate in clinical trials. Expanded access programs may provide an opportunity for patients who cannot participate in clinical trials to use investigational drugs as a therapeutic option outside of clinical trials. It is unknown to what extent expanded access occurs in psychiatry. We conducted a systematic literature search on PubMed, Embase, and PscyInfo, with additional information from ClinicalTrials.gov, the WHO International Clinical Trials Registry Platform and FDA/EMA approvals, in order to find all expanded access programs ever conducted, globally, in the field of psychiatry. This resulted in a total of fourteen expanded access programs ever conducted in psychiatry. Given the prevalence of psychiatric disorders, the activity in clinical research in psychiatry, the regulatory framework enabling expanded access, and the impact of psychiatric disorders on patients, their families, and society, we had expected a higher utilization of expanded access. We propose that the psychiatric community, with pharmaceutical industry, should consider establishing and optimizing expanded access programs. [ABSTRACT FROM AUTHOR]
- Published
- 2023
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- View/download PDF
15. Regulatory Considerations
- Author
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Cha, Karen J., Crommelin, Daan J. A., Editor-in-chief, Lipper, Robert A., Editor-in-chief, Wang, Jeffrey, editor, Shen, Wei-Chiang, editor, and Zaro, Jennica L., editor
- Published
- 2015
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16. Regulatory characteristics and pivotal study design of US Food and Drug Administration approval of drugs for major vs. minor cancer.
- Author
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Yamashita, Kenji, Kaneko, Masayuki, and Narukawa, Mamoru
- Subjects
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TUMOR classification , *ACCESS to information laws , *CLINICAL drug trials , *EXPERIMENTAL design , *MARKETING , *ORPHAN drugs , *TIME , *TUMORS , *INFORMATION resources , *GOVERNMENT programs , *GOVERNMENT regulation , *DRUG approval , *DISEASE incidence , *CONTENT mining , *DESCRIPTIVE statistics , *INVESTIGATIONAL drugs - Abstract
Purpose: We aimed to investigate the regulatory approval of drugs for cancers by the US Food and Drug Administration based on the cancer type (major vs. minor), including the use of expedited development programs and duration from Investigational New Drug application (IND) to marketing approval. Methods: From publicly available records and through a Freedom of Information Act request, we gathered data to evaluate regulatory characteristics and pivotal study design for 115 anticancer drug approvals between 2012 and 2017 and the data were analyzed based on cancer incidence (major vs. minor cancers) and how expedited programs, orphan drug designation, and pivotal study design contribute to expedited approval was studied. Results: Drugs targeting minor cancers more frequently (67%; P = 0.0155) utilized breakthrough therapy designation and/or accelerated approval, both of which significantly contributed to expedited drug approval (median time from IND to approval, 6.4 years; P = 0.0008, 6.2 years; P < 0.0001). Drug approvals for pivotal study design without a comparator arm took significantly less time from IND to approval (median time from IND to approval, 6.2 years; P < 0.0001). Conclusions: Drugs targeting minor cancers have frequently utilized the expedited development programs; thus, efficiently shortening time to approval. As many of such drugs are approved based on non-comparative pivotal studies, meticulous evaluation and follow-up should be performed for such drugs after their approval. [ABSTRACT FROM AUTHOR]
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- 2019
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17. Quantitative systems pharmacology: Landscape analysis of regulatory submissions to the US Food and Drug Administration
- Author
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David G. Strauss, Yaning Wang, Jane P. F. Bai, Hao Zhu, Justin C. Earp, Jeffry Florian, and Rajanikanth Madabushi
- Subjects
United States Food and Drug Administration ,Computer science ,Research ,Articles ,RM1-950 ,Investigational New Drug Application ,Network Pharmacology ,Percentage distribution ,Data science ,United States ,Article ,Food and drug administration ,Drug Development ,Drug development ,Modeling and Simulation ,Scientific domain ,Humans ,Landscape analysis ,Pharmacology (medical) ,Therapeutics. Pharmacology ,License ,Systems pharmacology - Abstract
Quantitative systems pharmacology (QSP) has been proposed as a scientific domain that can enable efficient and informative drug development. During the past several years, there has been a notable increase in the number of regulatory submissions that contain QSP, including Investigational New Drug Applications (INDs), New Drug Applications (NDAs), and Biologics License Applications (BLAs) to the US Food and Drug Administration. However, there has been no comprehensive characterization of the nature of these regulatory submissions regarding model details and intended applications. To address this gap, a landscape analysis of all the QSP submissions as of December 2020 was conducted. This report summarizes the (1) yearly trend of submissions, (2) proportion of submissions between INDs and NDAs/BLAs, (3) percentage distribution along the stages of drug development, (4) percentage distribution across various therapeutic areas, and (5) nature of QSP applications. In brief, QSP is increasingly applied to model and simulate both drug effectiveness and safety throughout the drug development process across disease areas.
- Published
- 2021
18. Current status of therapeutic alternatives for COVID-19: A narrative review
- Author
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M. Akova and A. T. Aslan
- Subjects
Microbiology (medical) ,Ledipasvir ,medicine.medical_specialty ,Daclatasvir ,Sofosbuvir ,business.industry ,Cobicistat ,Reviews ,Nitazoxanide ,Investigational New Drug Application ,Clinical trial ,chemistry.chemical_compound ,Infectious Diseases ,chemistry ,Expanded access ,medicine ,Intensive care medicine ,business ,medicine.drug - Abstract
Since December 2019, severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection has exploded and led to a global crisis. Currently, the global case numbers topped 200 million, and toll of dead exceeded 4 million around the world. The pathogenesis of coronavirus disease 2019 (COVID-19) is driven by two processes. During the first stage of the infection that lasts around 5-7 days, replication of SARS-CoV-2 occurs. In the second stage, the disease may progress due to an exaggerated inflammatory response leading to tissue damage. Therefore, it is anticipated that antiviral agents would be effective during the early phase of the disease, while immunomodulator agents are likely to be more beneficial in the second stage of COVID-19. This basic concept of disease development led to explore several antiviral and immunomodulator agents for the treatment of COVID-19. Currently, remdesivir is the only available Food and Drug Administration-approved antiviral agent for the treatment of COVID-19. However, some other agents have been approved by various mechanisms, including Emergency Use Authorizations, Emergency Investigational New Drug applications, compassionate use or expanded access programs. In addition, a variety of repurposed agents that were approved for other indications are being investigated for the treatment of COVID- 19 in clinical trials. A myriad of publications including randomized controlled trials (RCTs) are emerging continuously and are accessible as peer-reviewed, pre-print and press release formats. Considering the critical importance of RCTs in generating evidence and providing further guidance on COVID-19 treatment, we herein reviewed only RCTs and meta-analyses. The discussion includes antiviral agents (hydroxychloroquine, lopinavir/ritonavir, remdesivir, favipiravir and ivermectin) and, various immunomodulatory drugs (corticosteroids, tocilizumab, baricitinib, and IL-1 inhibitors). Other investigational therapies including darunavir/cobicistat, umifenovir, sofosbuvir/daclatasvir, sofobuvir/ledipasvir, ribavirin, nitazoxanide and interferon-based regimens were not evaluated due to insufficient data on the efficacy and safety of these agents.
- Published
- 2021
19. Cellular and Molecular Mechanisms of Nephropathic Cystinosis.
- Author
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Levtchenko, Elena N. and Levtchenko, Elena N.
- Subjects
Medicine ,Pharmacology ,3-dimensional models ,CD34+ hematopoietic stem and progenitor cells ,CTNS-pathogenic variants ,apoptosis ,arterial spin labelling ,autophagy ,azoospermia ,biomarkers ,bone ,bone-muscle wasting ,cell and animal models ,cell model ,central nervous system ,chitotriosidase ,clinical course ,clinical trial ,cortical atrophy ,cysteamine ,cystine ,cystine blood level ,cystinosis ,disulfiram ,endocytosis ,endolysosome ,epithelial cell differentiation ,fertility ,fibroblast growth factor 23 ,fractures ,galectin-3 ,gene therapy ,genotype ,histopathology ,history ,hollow fiber membrane ,homeostasis ,hypogonadism ,infantile nephropathic cystinosis ,inflammasome ,interleukins ,investigational new drug application ,kidney ,kidney progenitors ,kidney proximal tubule ,leptin ,lysosomal storage disease ,lysosomal storage diseases ,lysosomal storage disorder ,macrophages ,mice ,mitochondrial distress ,mouse model ,nephropathic cystinosis ,newborn screening ,newborn screening for cystinosis ,novel therapies ,osteoclast ,osteoclasts ,pre-clinical studies ,programmed cell death ,proximal tubular cells ,sclerostin ,therapeutic monitoring ,treatment strategies for cystinosis ,zebrafish - Abstract
Summary: Nephropathic cystinosis (MIM # 219800) is a rare autosomal recessive disorder caused by mutations in the lysosomal cystine transporter cystinosin, encoded by the CTNS gene (17p13.2). This devastating condition initially affects kidneys and subsequently many other organs including eyes, thyroid, pancreas, muscles, and brain. While lysosomal cystine storage is a key feature of the disease and the main target of current therapy, recent groundbreaking research has revealed that cystinosin has diverse functions in cells, being involved in vesicle trafficking, energy homeostasis, and cell death mechanisms. These discoveries deepen our insights into the mechanisms of cystinosis and of lysosomal biology in general. In this Special Issue dedicated to the pioneer of cystinosis research Dr. Jerry Schneider, we highlight the state-of-the-art understanding of cellular and molecular mechanisms of various disease features, opening new horizons for innovative treatment strategies for cystinosis and potentially other lysosomal storage diseases.
20. Plasmid Vaccines and Therapeutics: From Design to Applications
- Author
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Manthorpe, Marston, Hobart, Peter, Hermanson, Gary, Ferrari, Marilyn, Geall, Andrew, Goff, Blake, Rolland, Alain, Schaffer, David V., editor, and Zhou, Weichang, editor
- Published
- 2005
- Full Text
- View/download PDF
21. CONVALESCENT PLASMA THERAPY FOR COVID-19 PATIENTS: REGULATORY GUIDANCE ON COLLECTION, TESTING, PROCESSING, STORAGE, DISTRIBUTION, AND CLINICAL TRIALS
- Author
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Kamla Pathak, Devender Pathak, Amit Porwal, and Ramakant Yadav
- Subjects
Pharmacology ,Protocol (science) ,2019-20 coronavirus outbreak ,medicine.medical_specialty ,Convalescent plasma ,Coronavirus disease 2019 (COVID-19) ,business.industry ,Pharmaceutical Science ,Investigational New Drug Application ,Clinical trial ,Medicine ,Distribution (pharmacology) ,Pharmacology (medical) ,Observational study ,business ,Intensive care medicine - Abstract
Convalescent plasma can be transfused to patients suffering from the same infection or for preparing immunoglobulin concentrates. Plasma obtained from recovered patients can be a valuable alternative during the COVID-19 pandemic for supporting its treatment within a randomized or case-control clinical trials or observational studies of plasma transfusion and for preparing plasma-derived biological products. WHO Blood Regulators Network highlighted that a systematic approach for collecting convalescent plasma from patients recovered from COVID-19 could provide a useful intervention. Structured clinical trials can be used to assess safety and effectiveness of convalescent plasma. The convalescent plasma therapy is still in the experimental stage and is currently not included in the interim clinical guidelines of WHO. However, an emergency investigational new drug application (eIND) process has been induced to ensure the availability of COVID-19 convalescent plasma to the patients with severe or life-threatening COVID-19 conditions. USFDA is regularly amending its guidance as new results, and best practices are emerging. The write-up provides an overview of convalescent plasma, from a regulatory considerations viewpoint, systematic workflow protocol, and a cross-section of clinical trials underway.
- Published
- 2021
22. Analysis of secondary pharmacology assays received by the US Food and Drug Administration
- Author
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Christina Scott, Andrew Dodson, Muriel Saulnier, Kevin Snyder, and Rebecca Racz
- Subjects
Pharmacology ,United States Food and Drug Administration ,Vesicular Monoamine Transport Proteins ,Humans ,Drugs, Investigational ,Investigational New Drug Application ,Toxicology ,United States ,Histamine - Abstract
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.
- Published
- 2022
23. Clinical development of a poly(2-oxazoline) (POZ) polymer therapeutic for the treatment of Parkinson’s disease – Proof of concept of POZ as a versatile polymer platform for drug development in multiple therapeutic indications.
- Author
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Moreadith, Randall W., Viegas, Tacey X., Bentley, Michael D., Harris, J. Milton, Fang, Zhihao, Yoon, Kunsang, Dizman, Bekir, Weimer, Rebecca, Rae, Brendan P., Li, Xiuling, Rader, Christoph, Standaert, David, and Olanow, Warren
- Subjects
- *
DRUG development , *PARKINSON'S disease treatment , *OXAZOLINE , *IMMUNOGLOBULINS , *DRUG delivery systems , *DRUG administration - Abstract
The potential of poly (2-oxazoline) or POZ to be a versatile and broad based platform for drug delivery with wide utility in multiple therapeutic areas has long been recognized by experts in the field. This feature article provides a case study which describes the chemistry and preclinical studies underlying the Investigational New Drug Application for SER-214, a POZ conjugate of rotigotine, for the treatment of Parkinson’s disease. We report the chemistry, preclinical safety and pharmacology, and the early clinical safety, tolerability and pharmacokinetic data from the Phase I study in patients. SER-214 utilizes a POZ polymer and proprietary custom linker technology to deliver a sustained dose of rotigotine over a period of seven days following a single subcutaneous administration – a result not observed by any other polymer approach that we are aware of. As such, this candidate drug has the promise to be a major advancement in the treatment of Parkinson’s disease. Furthermore, this feature article also highlights the versatility of the POZ polymer platform (POZ™) to deliver cancer drugs by actively targeting cancer cells. Preclinical data reported in this feature showcase the polymer’s attributes in facilitating targeted delivery with folic acid and antibody targeting agents (ADCs). The ability of POZ to reliably delivery large payloads of anticancer drugs is of particular importance when pursuing low-receptor-density targets on the cancer cell. The data presented in this feature, much of it for the first time, establish the broad utility of the POZ polymer platform in drug development. Together with its ease of manufacture, ability to attach drugs to the polymer, and ability to administer an appropriate dose to patients, the results underscore the need to further explore and expand the untapped potential of POZ for the development of new therapeutics for unmet medical needs. [ABSTRACT FROM AUTHOR]
- Published
- 2017
- Full Text
- View/download PDF
24. Analysis of Development Time of New Drugs Developed by Korean Domestic Companies
- Author
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Jeongyeon Cho and Lee, Sang Won
- Subjects
Drug development ,Drug approval ,General Medicine ,Investigational New Drug Application ,Business ,Marketing ,Pharmaceutical sciences ,Drug industry - Published
- 2020
25. An Analysis of Antibacterial Drug Development Trends in the United States, 1980–2019
- Author
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John Farley, Nidhi Dheman, Edward Cox, Nicole M. Mahoney, Michael Lanthier, and Thushi Amini
- Subjects
0301 basic medicine ,Microbiology (medical) ,Drug ,medicine.medical_specialty ,medicine.drug_class ,media_common.quotation_subject ,030106 microbiology ,03 medical and health sciences ,0302 clinical medicine ,Drug Development ,Internal medicine ,medicine ,Humans ,030212 general & internal medicine ,Antibacterial drug ,Drug Approval ,media_common ,United States Food and Drug Administration ,business.industry ,Drugs, Investigational ,Investigational New Drug Application ,biochemical phenomena, metabolism, and nutrition ,Quinolone ,United States ,Anti-Bacterial Agents ,Infectious Diseases ,Drug development ,Median time ,Investigational Drugs ,business - Abstract
We present a longitudinal analysis of investigational new drug applications (INDs) for new, systemic antibacterial drugs under active development between 1980 and 2019, evaluating the characteristics of these investigational drugs and the outcomes of these drug development programs. The number of INDs in active development declined by two-thirds, from 39 active INDs at its peak in 1987 to a low 13 in 2001, with decreased development of new cephalosporin, quinolone, and macrolide drugs and reduced participation from large pharmaceutical firms. Antibacterial drug development activity rebounded substantially from 2002 to 2009, primarily led by involvement of small pharmaceutical companies. As of 31 December 2019, the number of active INDs has declined to an 11-year low, and the number of antibacterial INDs initiated with the US Food and Drug Administration during 2010–2019 was lower than any of the previous 3 decades. Antibacterial drug development programs initiated in the 1980s and 1990s had high success rates, with >40% of INDs obtaining marketing approval, in a median time of about 6 years from IND receipt to approval. For drug development programs initiated between 2000 and 2009, we found that IND-to-approval rates reduced to 23%, with median development times for approved antibacterial drugs increasing to 8.2 years. The majority of INDs in development as of 31 December 2019 come from already established drug classes, most in early stages of development, and few are sponsored by large pharmaceutical companies.
- Published
- 2020
26. Deployment of convalescent plasma for the prevention and treatment of COVID-19
- Author
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Aaron A.R. Tobian, Jeffrey P. Henderson, Andrew Pekosz, Camille M. van Buskirk, Louis M. Katz, Eric A. Gehrie, Wayne T. Nicholson, Eldad A. Hod, Nigel Paneth, Beth H. Shaz, Jeffrey L. Winters, Paul G. Auwaerter, Michael J. Joyner, Amy Wesolowski, Hua Shan, Evan M. Bloch, David J. Sullivan, David L. Thomas, Brenda J. Grossman, Liise Anne Pirofski, Shmuel Shoham, Arturo Casadevall, Jeffrey A. Bailey, Bruce S. Sachais, Lewis Pollack, Steven L. Spitalnik, and Bryan Lau
- Subjects
0301 basic medicine ,medicine.medical_specialty ,Pneumonia, Viral ,Blood Donors ,Review ,Antibodies, Viral ,Risk Assessment ,Immunomodulation ,Betacoronavirus ,03 medical and health sciences ,0302 clinical medicine ,Pandemic ,medicine ,Global health ,Humans ,Investigational New Drug Application ,Intensive care medicine ,Pandemics ,COVID-19 Serotherapy ,SARS-CoV-2 ,United States Food and Drug Administration ,Viral Epidemiology ,business.industry ,Immunization, Passive ,COVID-19 ,Outbreak ,General Medicine ,medicine.disease ,United States ,Clinical trial ,030104 developmental biology ,030220 oncology & carcinogenesis ,Middle East respiratory syndrome ,Coronavirus Infections ,business ,Risk assessment ,Viral load - Abstract
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.
- Published
- 2020
27. Investigator Responsibilities in Clinical Research
- Author
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Julia Garcia-Diaz and Amy K. Feehan
- Subjects
drugs–investigational ,0301 basic medicine ,government regulation ,business.industry ,investigational new drug application ,Principal (computer security) ,General Medicine ,Investigational New Drug Application ,Public relations ,Reviews and Contemporary Updates ,Clinical trial ,research personnel ,03 medical and health sciences ,Misconduct ,030104 developmental biology ,0302 clinical medicine ,Clinical research ,Good clinical practice ,Public trust ,Medicine ,disclosure ,business ,Imprisonment ,030217 neurology & neurosurgery - Abstract
Background: Clinical trials are an integral part of translating new basic science research into therapeutics. It is crucial for those who run clinical trials to realize the gravity of their responsibilities as principal investigators. Methods: This review focuses on the relevant investigator responsibilities under the Code of Federal Regulations Title 21, the contents of Form 1572, FDA inspections, and methods to improve compliance. Results: While responsibility for day-to-day study activities can be delegated to outside entities and to study staff, a clinical principal investigator who has signed US Food and Drug Administration (FDA) Form 1572 is held responsible for noncompliance and misconduct by anyone working on the study. Depending on the infraction, consequences can range from a publicly posted warning letter by the FDA to criminal prosecution and fines or imprisonment. Conclusion: Investigators are not only responsible for producing high-quality, meaningful, scientific research, but they are also responsible for maintaining public trust. If the principal investigator acts with integrity and provides training and oversight of employees, FDA inquiries should go smoothly. Following good clinical practice standards for clinical research will result in quality data collection and facilitate the analysis and publication process.
- Published
- 2020
28. Drug Exposure to Establish Pharmacokinetic–Response Relationships in Oncology
- Author
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Belén P. Solans, María J. Garrido, and Iñaki F. Trocóniz
- Subjects
Drug ,Oncology ,medicine.medical_specialty ,media_common.quotation_subject ,MEDLINE ,Antineoplastic Agents ,Models, Biological ,030226 pharmacology & pharmacy ,03 medical and health sciences ,0302 clinical medicine ,Pharmacotherapy ,Drug Development ,Pharmacokinetics ,Neoplasms ,Internal medicine ,medicine ,Humans ,Pharmacology (medical) ,Investigational New Drug Application ,media_common ,Pharmacology ,Clinical Trials as Topic ,Critical perspective ,Dose-Response Relationship, Drug ,business.industry ,Pharmacometrics ,Patient Care Management ,Treatment Outcome ,Drug development ,Area Under Curve ,030220 oncology & carcinogenesis ,Safety ,Oncology drugs ,business - Abstract
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.
- Published
- 2019
29. The Regulatory Evaluation of Vaccines for Human Use
- Author
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Norman W. Baylor
- Subjects
Drug ,Immunogen ,business.industry ,Drug discovery ,Synthetic antigen ,media_common.quotation_subject ,Investigational New Drug Application ,Disease ,Biotechnology ,03 medical and health sciences ,0302 clinical medicine ,Immune system ,Human use ,030225 pediatrics ,Medicine ,030212 general & internal medicine ,business ,media_common - Abstract
A vaccine is an immunogen, the administration of which is intended to stimulate the immune system to result in the prevention, amelioration, or therapy of any disease or infection (US Food and Drug Administration. Guidance for Industry: content and format of chemistry, manufacturing, and controls information and establishment description information for a vaccine or related product). A vaccine may be a live attenuated preparation of microorganisms, inactivated (killed) whole organisms, living irradiated cells, crude fractions, or purified immunogens, including those derived from recombinant DNA in a host cell, conjugates formed by covalent linkage of components, synthetic antigens, polynucleotides (such as the plasmid DNA vaccines), living vectored cells expressing specific heterologous immunogens, or cells pulsed with immunogen. Vaccines are highly complex products that differ from small molecule drugs because of the biological nature of the source materials such as those derived from microorganisms as well as the various cell substrates from which some are derived. Regardless of the technology used, because of their complexities, vaccines must undergo extensive characterization and testing. Special expertise and procedures are needed for their manufacture, control, and regulation. The Food and Drug Administration (FDA) is the National Regulatory Authority (NRA) in the United States responsible for assuring quality, safety, and effectiveness of all human medical products, including vaccines for human use.The Center for Biologics Evaluation and Research (CBER) within the US FDA is responsible for overseeing the regulation of therapeutic and preventative vaccines against infectious diseases. Authority for the regulation of vaccines resides in Section 351 of the Public Health Service Act and specific sections of the Federal Food, Drug, and Cosmetic Act (FD&C). Vaccines are regulated as biologics and licensed based on the demonstration of safety and effectiveness. The vaccine development process can be divided into two major categories: those events that are not under the regulatory authority of the FDA and are exploratory in nature and those events that are subject to regulatory authority by the FDA. Exploratory events or research and development cover basic research drug discovery processes that occur before the sponsor submits an investigational new drug application (IND) to the FDA. There are four main stages of vaccine development under the purview of regulatory authorities: preclinical, clinical (IND), licensing, and post-licensure. Throughout their life cycle from preclinical evaluation to post-licensure lot release testing, vaccines are subject to rigorous testing and oversight by manufacturers and NRAs. In this chapter an overview of the regulatory evaluation and testing requirements for vaccines is presented.
- Published
- 2021
30. Successful regulatory agency interaction - A nonclinical regulatory strategist's perspective
- Author
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Paul Baldrick
- Subjects
Europe ,Marketing ,Government Agencies ,Interprofessional Relations ,Humans ,General Medicine ,Investigational New Drug Application ,Toxicology ,Drug Approval - Abstract
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.
- Published
- 2021
31. Convection-Enhanced Delivery of a First-in-Class Anti-β1 Integrin Antibody for the Treatment of High-Grade Glioma Utilizing Real-Time Imaging
- Author
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Chibueze D. Nwagwu, Gabriela Bukanowska, Amanda V. Immidisetti, Anne-Marie Carbonell, and Michael A Vogelbaum
- Subjects
Oncology ,CD29 ,medicine.medical_specialty ,medicine.drug_class ,Pharmaceutical Science ,Phases of clinical research ,lcsh:RS1-441 ,Monoclonal antibody ,Article ,lcsh:Pharmacy and materia medica ,03 medical and health sciences ,0302 clinical medicine ,β1 integrin ,Internal medicine ,convection enhanced delivery ,ITGB1 ,Medicine ,Distribution (pharmacology) ,business.industry ,glioblastoma ,clinical trial ,Investigational New Drug Application ,biochemical phenomena, metabolism, and nutrition ,Clinical trial ,monoclonal antibody ,Tumor progression ,030220 oncology & carcinogenesis ,Biomarker (medicine) ,OS2966 ,business ,030217 neurology & neurosurgery ,high-grade glioma - Abstract
Introduction: OS2966 is a first-in-class, humanized and de-immunized monoclonal antibody which targets the adhesion receptor subunit, CD29/&beta, 1 integrin. CD29 expression is highly upregulated in glioblastoma and has been shown to drive tumor progression, invasion, and resistance to multiple modalities of therapy. Here, we present a novel Phase I clinical trial design addressing several factors plaguing effective treatment of high-grade gliomas (HGG). Study Design: This 2-part, ascending-dose, Phase I clinical trial will enroll patients with recurrent/progressive HGG requiring a clinically indicated resection. In Study Part 1, patients will undergo stereotactic tumor biopsy followed by placement of a purpose-built catheter which will be used for the intratumoral, convection-enhanced delivery (CED) of OS2966. Gadolinium contrast will be added to OS2966 before each infusion, enabling the real-time visualization of therapeutic distribution via MRI. Subsequently, patients will undergo their clinically indicated tumor resection followed by CED of OS2966 to the surrounding tumor-infiltrated brain. Matched pre- and post-infusion tumor specimens will be utilized for biomarker development and validation of target engagement by receptor occupancy. Dose escalation will be achieved using a unique concentration-based accelerated titration design. Discussion: The present study design leverages multiple innovations including: (1) the latest CED technology, (2) 2-part design including neoadjuvant intratumoral administration, (3) a first-in-class investigational therapeutic, and (4) concentration-based dosing. Trial registration: A U.S. Food and Drug Administration (FDA) Investigational New Drug application (IND) for the above protocol is now active.
- Published
- 2021
32. Investigational New Drug Applications for Cell Therapy Products
- Author
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Bambi Grilley
- Subjects
Clinical trial ,medicine.medical_specialty ,Biosafety ,Clinical research ,Ongoing review ,business.industry ,medicine ,Investigational New Drug ,Investigational New Drug Application ,Intensive care medicine ,business ,Institutional review board ,Adverse effect - Abstract
Clinical trials being conducted in the USA that utilize cellular therapy products require review from the Food and Drug Administration (FDA) and at least one Institutional Review Board (IRB). Additionally, if the cellular product includes a gene transfer component, the trial will also require review by at least one Institutional Biosafety Committee (IBC). Each of these entities not only requires initial review but also has requirements for ongoing review of the clinical trial including amendments, adverse events, and an annual report. Failure to obtain proper regulatory review of clinical trials can have serious consequences including loss of funding, inability to publish, and restrictions in the ability to engage in further clinical research. It is important to note that these types of trials are regulated differently throughout the world and that if a study is to be conducted outside of the USA, a thorough review of regulations governing that country will be required. This chapter reviews the process for submitting an Investigational New Drug application to the FDA.
- Published
- 2021
33. Immunogenicity Risk Assessment for Multi-specific Therapeutics
- Author
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Joleen T. White, Mark A. Kroenke, Eris Bame, Seema Kumar, and Mark Milton
- Subjects
Pharmacology toxicology ,Pharmaceutical Science ,Context (language use) ,Review Article ,Computational biology ,Risk Assessment ,Antibodies ,Bispecific therapeutic ,Risk Factors ,Antibodies, Bispecific ,Humans ,Medicine ,Investigational New Drug Application ,Multi-specific therapeutic ,Tumor Necrosis Factor-alpha ,Oligomeric target ,business.industry ,Incidence ,Anti-drug antibody ,Immunogenicity ,Interleukin-17 ,Investigational New Drug ,Anti-Drug Antibody ,business ,Risk assessment ,Immunogenicity risk assessment - Abstract
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.
- Published
- 2021
34. Development and investigational new drug application of mesenchymal stem/stromal cells products in China
- Author
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Zhongchao Han, Jialun Wang, Zhao Qinjun, and Han Zhibo
- Subjects
China ,Medicine (General) ,Stromal cell ,Quality management ,Concise Reviews ,Mesenchymal Stem Cell Transplantation ,Regenerative Medicine ,adult stem cells ,Regenerative medicine ,clinical translation ,R5-920 ,Investigational New Drug Application ,cell transplantation ,mesenchymal stem cells ,QH573-671 ,Concise Review ,Mesenchymal stem cell ,Investigational New Drug ,Cell Differentiation ,Cell Biology ,General Medicine ,cellular therapy ,Clinical trial ,Mesenchymal Stem Cells ,Engineering ethics ,Business ,Cytology ,Developmental Biology ,Adult stem cell - Abstract
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.
- Published
- 2021
35. Quality Control Analysis of Mesenchymal Stem/Stromal Cells During Investigational New Drug Application for GvHD Administration in China.
- Author
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Wang A, Zhang L, Zhao M, and Yu H
- Subjects
- Humans, Investigational New Drug Application, Immunomodulation, Graft vs Host Disease therapy, Hematopoietic Stem Cell Transplantation, Mesenchymal Stem Cells, Mesenchymal Stem Cell Transplantation
- Abstract
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., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)
- Published
- 2023
- Full Text
- View/download PDF
36. FDA Drug Regulation: Investigational New Drug Applications
- Author
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E. Bike Su Oner, Sergio R. Labra, and Shelly Fehr
- Subjects
Drug ,business.industry ,media_common.quotation_subject ,Medicine ,Investigational New Drug Application ,Pharmacology ,business ,media_common - Published
- 2021
37. Upsetting the apple CAR‐T (chimeric antigen receptor T‐cell therapy) ‐ sustainability mandates USA innovation
- Author
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Jeremy Pantin and Minoo Battiwalla
- Subjects
medicine.medical_specialty ,medicine.medical_treatment ,Antigens, CD19 ,Receptors, Antigen, T-Cell ,Cancer therapy ,Immunotherapy, Adoptive ,03 medical and health sciences ,0302 clinical medicine ,Antigen ,Neoplasms ,Humans ,Medicine ,Intensive care medicine ,Biological Products ,Receptors, Chimeric Antigen ,United States Food and Drug Administration ,business.industry ,Cancer ,Hematology ,Immunotherapy ,Investigational New Drug Application ,medicine.disease ,United States ,Chimeric antigen receptor ,030220 oncology & carcinogenesis ,Chimeric Antigen Receptor T-Cell Therapy ,Car t cells ,business ,030215 immunology - Abstract
Seldom has a medical advance in cancer therapy been as pivotal as the advent of chimeric antigen receptor (CAR)-T-cell immunotherapy. While the first applications targeted the CD19 antigen on lymphoid malignancies, the incredible specificity of these 'living drugs', curative potential and generalisability to other targets have richly justified their declaration as 2019's breakthrough of the year by Science magazine. Two CAR-T products, Yescarta (axicabtagene ciloleucel) and Kymriah (tisagenlecleucel) were Food and Drug Administration (FDA)-approved in the USA in late 2017, with the FDA commissioner Scott Gottlieb heralding 'a new frontier in medical innovation with the ability to reprogram a patient's own cells to attack a deadly cancer'. Building upon early enthusiasm, nearly 1000 cell- and gene-therapy investigational new drug applications are pending with the FDA, which expects to review and approve between 10 and 20 such treatments annually by 2025. Despite the enormous promise and urgent unmet need fulfilled by CAR-T cells, the real-world adoption of the two FDA-approved treatments has been slow.
- Published
- 2020
38. Freedom of Information Act Access to an Investigational New Drug Application
- Author
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Noel Southall
- Subjects
Pharmacology ,Protocol (science) ,Freedom of information ,business.industry ,Agency (sociology) ,Internet privacy ,Investigational New Drug ,Pharmacology (medical) ,Business ,Investigational New Drug Application ,Translational science ,Repurposing ,Public interest - Abstract
We report our experience working with the US Food and Drug Administration (FDA) to obtain access to an abandoned investigational new drug (IND) application and subsequent application documents submitted by Hoffman-La Roche, Inc. to the agency. Contrary to others’ experience and in response to our specific request, FDA provided the IND application number and 464 pages of relevant material, including the initial pharmacology review by the agency and an annual report consisting of an investigational drug brochure, clinical study protocol and amendments and detailing clinical experience with drug treatment. It may be possible to bring application files of additional drugs previously submitted to the agency into the public record to help bolster repurposing efforts and realize our shared public interest in benefiting from previous human clinical studies.
- Published
- 2019
39. Regulatory characteristics and pivotal study design of US Food and Drug Administration approval of drugs for major vs. minor cancer
- Author
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Masayuki Kaneko, Kenji Yamashita, and Mamoru Narukawa
- Subjects
medicine.medical_specialty ,Orphan Drug Production ,Breakthrough therapy ,Antineoplastic Agents ,Minor (academic) ,030226 pharmacology & pharmacy ,Food and drug administration ,Orphan drug ,03 medical and health sciences ,0302 clinical medicine ,Neoplasms ,Internal medicine ,medicine ,Drug approval ,Humans ,Pharmacology (medical) ,030212 general & internal medicine ,Drug Approval ,Pharmacology ,United States Food and Drug Administration ,business.industry ,Incidence ,Cancer ,General Medicine ,Investigational New Drug Application ,medicine.disease ,Anticancer drug ,United States ,Research Design ,business - Abstract
We aimed to investigate the regulatory approval of drugs for cancers by the US Food and Drug Administration based on the cancer type (major vs. minor), including the use of expedited development programs and duration from Investigational New Drug application (IND) to marketing approval. From publicly available records and through a Freedom of Information Act request, we gathered data to evaluate regulatory characteristics and pivotal study design for 115 anticancer drug approvals between 2012 and 2017 and the data were analyzed based on cancer incidence (major vs. minor cancers) and how expedited programs, orphan drug designation, and pivotal study design contribute to expedited approval was studied. Drugs targeting minor cancers more frequently (67%; P = 0.0155) utilized breakthrough therapy designation and/or accelerated approval, both of which significantly contributed to expedited drug approval (median time from IND to approval, 6.4 years; P = 0.0008, 6.2 years; P
- Published
- 2019
40. Quality Control and Nonclinical Research on CAR-T Cell Products: General Principles and Key Issues
- Author
-
Yan Huo, Lei Yu, Yonghong Li, and Junzhi Wang
- Subjects
Environmental Engineering ,General Computer Science ,Materials Science (miscellaneous) ,General Chemical Engineering ,medicine.medical_treatment ,Cell ,Energy Engineering and Power Technology ,02 engineering and technology ,010402 general chemistry ,Bioinformatics ,01 natural sciences ,Cell therapy ,Cancer immunotherapy ,Antigen ,medicine ,business.industry ,General Engineering ,Investigational New Drug Application ,021001 nanoscience & nanotechnology ,Chimeric antigen receptor ,0104 chemical sciences ,Genetically modified organism ,Clinical trial ,medicine.anatomical_structure ,lcsh:TA1-2040 ,lcsh:Engineering (General). Civil engineering (General) ,0210 nano-technology ,business - Abstract
Adoptive cell therapy using chimeric antigen receptor T (CAR-T) cells, which is a promising cancer immunotherapy strategy, has been developing very rapidly in recent years. CAR-T cells are genetically modified T cells that can specifically recognize tumor specific antigens on the surface of tumor cells, and then effectively kill tumor cells. At present, exciting results are being achieved in clinical applications of CAR-T cells for patients with hematological malignancies. The research and development of CAR-T cells for various targets and for the treatment of solid tumors have become a hot topic worldwide, so an increasing number of investigational new drug applications (INDAs) and new drug applications (NDAs) of CAR-T cell products are expected to be submitted in future. The quality control and nonclinical research of these products are of great significance in ensuring the safety and effectiveness of these products; however, they also present great challenges and difficulties. This article discusses the general principles of and key issues regarding the quality control and nonclinical research of CAR-T cell products based on their product characteristics and on relevant guidelines for gene and cell therapy products. Keywords: Chimeric antigen receptor T cells, Quality control, Nonclinical research, Safety, Efficacy, Clinical trials, Cancer immunotherapy
- Published
- 2019
41. Significant differences on submission lag following regulation reform for registration of novel therapeutic drugs in Taiwan
- Author
-
I-Chen Sun
- Subjects
0301 basic medicine ,Time Factors ,Lag ,Subsidiary ,Taiwan ,Antineoplastic Agents ,Accounting ,Orphan drug ,03 medical and health sciences ,0302 clinical medicine ,Neoplasms ,Humans ,Pharmacology (medical) ,Investigational New Drug Application ,New drug application ,Pharmacology ,Government ,business.industry ,Drugs, Investigational ,Certificate ,Clinical trial ,Product (business) ,030104 developmental biology ,Clinical Trials, Phase III as Topic ,Oncology ,030220 oncology & carcinogenesis ,business - Abstract
Drug lag, which delays patients' access to medicinal products, is typically associated with pharmaceutical regulations. To shorten drug lag, health authorities may establish new policies to liberalize the regulations, a step that is important in countries, such as Taiwan, with consumer demand for imported novel therapeutic agents. Taiwan's government enacted Articles 38-1 and 38-2 of Regulations for Registration of Medicinal Products to relax the regulatory barriers for new drug submission, thus conditionally exempting the requirement for the Certificate of Pharmaceutical Product (CPP). This study examined whether the enacted regulations reduce submission lag by analyzing the time gap of submission between Taiwan and the United States during 2014-2017. The results indicated that the enacted regulations substantially affected submission lag. Submission lag was significantly shorter for applications not requiring a CPP than those requiring one CPP, which in turn was significantly shorter than those requiring two CPPs. This conclusion can be applied to biological, chemical, non-orphan, and oncology drugs and also applications filed by subsidiary companies, but not orphan drugs and applications filed by contract agents. Among applications requiring one CPP, oncology drugs showed the shortest submission lag. Certain factors, such as clinical studies recruiting over-threshold Taiwanese participants and those performed before the submission of new drug application in the United States, may shorten submission lag. In summary, this study justifies the policy of the exemption from CPP requirements, which supports the hypothesis that relaxing regulatory barriers can reduce submission lag in Taiwan.
- Published
- 2019
42. Aggregation and analysis of secondary pharmacology data from investigational new drug submissions at the US Food and Drug Administration
- Author
-
Rebecca Racz, Daniel P. Russo, Muriel Saulnier, Christina Scott, Kevin Mi, Andrew Dodson, and Kevin Snyder
- Subjects
Pharmacology ,Drug Industry ,business.industry ,United States Food and Drug Administration ,Phases of clinical research ,Investigational New Drug ,Drugs, Investigational ,Toxicology ,Regulatory Submission ,United States ,Food and drug administration ,Drug development ,Pharmaceutical Preparations ,Medicine ,Investigational New Drug Application ,business ,Pharmaceutical industry - Abstract
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.
- Published
- 2021
43. Pre-clinical study of IRDye800CW-nimotuzumab formulation, stability, pharmacokinetics, and safety
- Author
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Darien Toledo, Ayman El-Sayed, Wendy Bernhard, Carolina Gonzalez, Angel Casacó, John F. DeCoteau, Kris Barreto, Humphrey Fonge, Clarence Ronald Geyer, and Raja Solomon Viswas
- Subjects
Male ,0301 basic medicine ,Oncology ,Cancer Research ,Immunoconjugates ,Indoles ,Mice ,Investigator’s brochure ,0302 clinical medicine ,Drug Stability ,Surgical oncology ,Neoplasms ,Medicine ,Investigational New Drug Application ,Epidermal growth factor receptor ,Clinical Trials as Topic ,medicine.diagnostic_test ,biology ,Benzenesulfonates ,Optical Imaging ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,ErbB Receptors ,IRDye800CW ,Surgery, Computer-Assisted ,Positron emission tomography ,030220 oncology & carcinogenesis ,Female ,Antibody ,Nimotuzumab ,Half-Life ,Research Article ,medicine.drug ,medicine.medical_specialty ,medicine.drug_class ,EGFR ,Near-infrared fluorescence imaging ,Antibodies, Monoclonal, Humanized ,Monoclonal antibody ,lcsh:RC254-282 ,03 medical and health sciences ,Pharmacokinetics ,Cell Line, Tumor ,Internal medicine ,Toxicity Tests, Acute ,Genetics ,Animals ,Humans ,Image-guided surgery ,business.industry ,Drugs, Investigational ,Xenograft Model Antitumor Assays ,Clinical trial ,030104 developmental biology ,biology.protein ,business - Abstract
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.
- Published
- 2021
44. Turning genes into medicines—what have we learned from gene therapy drug development in the past decade?
- Author
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Katherine A. High
- Subjects
0301 basic medicine ,Science ,Genetic enhancement ,education ,MEDLINE ,General Physics and Astronomy ,Single gene ,02 engineering and technology ,Biologics ,Bioinformatics ,General Biochemistry, Genetics and Molecular Biology ,Cell therapy ,03 medical and health sciences ,Gene therapy ,Drug Development ,Humans ,Medicine ,Investigational New Drug Application ,lcsh:Science ,Drug Approval ,Gene ,Clinical Trials as Topic ,Multidisciplinary ,Drug discovery ,United States Food and Drug Administration ,business.industry ,Comment ,Genetic Therapy ,General Chemistry ,021001 nanoscience & nanotechnology ,United States ,030104 developmental biology ,Drug development ,lcsh:Q ,0210 nano-technology ,business - Abstract
Gene and cell therapy products approved over the past decade in Europe and North America have provided new therapeutic options for single gene disorders and for hematologic malignancies. Lessons learned, and limitations identified, are reviewed.
- Published
- 2020
45. Considerations on chemistry, manufacturing, and control of stem cell products for Investigational New Drug application in China
- Author
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Jiaqi Lu and Wei Wei
- Subjects
0301 basic medicine ,Pluripotent Stem Cells ,Quality Control ,China ,Chemistry, Pharmaceutical ,Cell- and Tissue-Based Therapy ,Bioengineering ,Computational biology ,Applied Microbiology and Biotechnology ,Cell therapy ,03 medical and health sciences ,0302 clinical medicine ,Humans ,Regulatory science ,030212 general & internal medicine ,Investigational New Drug Application ,Induced pluripotent stem cell ,Drug Approval ,Pharmacology ,General Immunology and Microbiology ,Mesenchymal stem cell ,Investigational New Drug ,Cell Differentiation ,Mesenchymal Stem Cells ,General Medicine ,030104 developmental biology ,Stem cell ,Biotechnology ,Adult stem cell - Abstract
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.
- Published
- 2020
46. Regulation and status of herbal medicine clinical trials in Korea: a narrative review
- Author
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Boram, Lee, Yujin, Choi, Pyung-Wha, Kim, Changsop, Yang, and Myeong Soo, Lee
- Subjects
Clinical trial ,IND ,food and beverages ,Review Article ,Herbal medicine ,complex mixtures ,Investigational new drug application - Abstract
Background Herbal medicine has been used frequently in Korean medicine. We aimed to summarize the relevant regulations for herbal medicine clinical trials and to analyze their current status in the Republic of Korea. Methods We searched for legislation to find regulations on herbal medicine clinical trials. Additionally, the websites of the Korean Ministry of Food and Drug Safety (KMFDS) and Clinical Research Information Service (CRIS) were searched to investigate the current status of them. Results To conduct herbal medicine clinical trials for new drugs or previously approved drugs outside of indications, investigational new drug (IND) approval should be obtained from the KMFDS. For clinical trials of herbal medicines that have been used for more than 3 years with 200 cases at the clinical trial institution, nonclinical data can be exempted from IND approval. Total 95 and 108 herbal medicine clinical trials from the KMFDS and CRIS websites were analyzed. The number of clinical trials showed an increasing trend each year, as did KMFDS-regulated clinical trials. Recently, three clinical trials targeting new herbal formulations frequently used in Korean medicine institutions have been approved based on relevant regulations. Conclusion We confirmed that herbal medicine clinical trials are managed through strict regulations, which can ensure the safe and effective use of herbal medicine. Despite strict regulations, attempts to accumulate evidence through clinical trials for herbal medicine are increasing. High-quality clinical trials should be conducted to develop new drugs that reflect the clinical setting using relevant regulations, evaluate the efficacy and safety of the drugs, and strengthen insurance coverage.
- Published
- 2020
47. Treatment of COVID-19 Patients with Convalescent Plasma in Houston, Texas
- Author
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Hampton C, Chavez-East C, Todd N. Eagar, Prasanti Yerramilli, John Rogers, Taryn A Eubank, Gregory C. Ippolito, Layne Pruitt, Dey M, James M. Musser, Concepcion C. Cantu, David Joseph, Mary R. Schwartz, Andre C. Maranhao, Randall J. Olsen, Paul A. Christensen, David W. Bernard, Christopher Leveque, Brian Castillo, Eric Salazar, Faisal Masud, Scott Wesley Long, Talley C, Matthew Ojeda Saavedra, Williams G, Ahmed Shehabeldin, Madiha Ashraf, Karen D. Thomas, Bevin Valdez Lopez, Jian Chen, Katharine G. Dlouhy, Sishir Subedi, Jason J. Lavinder, Katherine K. Perez, and Jimmy Gollihar
- Subjects
Adult ,Male ,medicine.medical_specialty ,Convalescent plasma ,Coronavirus disease 2019 (COVID-19) ,Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ,Pneumonia, Viral ,Clinical scale ,Disease ,Article ,World health ,Betacoronavirus ,Young Adult ,Internal medicine ,Humans ,Medicine ,Investigational New Drug Application ,Adverse effect ,Pandemics ,COVID-19 Serotherapy ,Aged ,Whole Genome Sequencing ,SARS-CoV-2 ,business.industry ,Immunization, Passive ,COVID-19 ,Treatment options ,Middle Aged ,Texas ,Female ,Coronavirus Infections ,business - Abstract
BackgroundCOVID-19 disease, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-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 more than 100 years.MethodsPatients (n=25) with severe and/or life-threatening COVID-19 disease were enrolled at the Houston Methodist hospitals from March 28 – April 14, 2020. Patients were transfused with convalescent plasma obtained from donors with confirmed SARS-CoV-2 infection and had been symptom free for 14 days. The primary study outcome was safety, and the secondary outcome was clinical status at day 14 post-transfusion. Clinical improvement was assessed based on a modified World Health Organization 6-point ordinal scale and laboratory parameters. Viral genome sequencing was performed on donor and recipient strains.ResultsAt baseline, all patients were receiving supportive care, including anti-inflammatory and anti-viral treatments, and all patients were on oxygen support. At day 7 post-transfusion with convalescent plasma, nine patients had at least a 1-point improvement in clinical scale, and seven of those were discharged. By day 14 post-transfusion, 19 (76%) patients had at least a 1-point improvement in clinical status and 11 were discharged. No adverse events as a result of plasma transfusion were observed. The whole genome sequencing data did not identify a strain genotype-disease severity correlation.ConclusionsThe data indicate that administration of convalescent plasma is a safe treatment option for those with severe COVID-19 disease. Randomized, controlled trials are needed to determine its efficacy.
- Published
- 2020
48. Regulatory considerations for developing a phase I investigational new drug application for autologous induced pluripotent stem cells-based therapy product
- Author
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Kapil Bharti, Balendu Shekhar Jha, and Mitra Farnoodian
- Subjects
0301 basic medicine ,Cellular differentiation ,Donor tissue ,Induced Pluripotent Stem Cells ,GLP ,Bioinformatics ,Regenerative Medicine ,Concise Reviews ,Regenerative medicine ,Transplantation, Autologous ,03 medical and health sciences ,0302 clinical medicine ,Medicine ,Humans ,Investigational New Drug Application ,lcsh:QH573-671 ,Induced pluripotent stem cell ,phase I clinical trial ,lcsh:R5-920 ,Manufacturing process ,business.industry ,lcsh:Cytology ,Concise Review ,GMP ,Treatment options ,Cell Differentiation ,Cell Biology ,General Medicine ,030104 developmental biology ,IND ,preclinical work ,business ,lcsh:Medicine (General) ,Reprogramming ,030217 neurology & neurosurgery ,Developmental Biology - Abstract
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., Regulatory considerations for developing a phase I investigational new drug application for an autologous induced pluripotent stem cells‐based therapy.
- Published
- 2020
49. Assessing Animal Models of Bacterial Pneumonia Used in Investigational New Drug Applications for the Treatment of Bacterial Pneumonia
- Author
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John Farley, Ursula Waack, and Edward A. Weinstein
- Subjects
medicine.medical_specialty ,Databases, Factual ,Antitubercular Agents ,Design elements and principles ,Food and drug administration ,03 medical and health sciences ,In vivo ,Pneumonia, Bacterial ,Clinical endpoint ,medicine ,Animals ,Humans ,Experimental Therapeutics ,Pharmacology (medical) ,Investigational New Drug Application ,Intensive care medicine ,Pharmacology ,0303 health sciences ,Immune status ,United States Food and Drug Administration ,030306 microbiology ,business.industry ,Bacterial pneumonia ,Drugs, Investigational ,biochemical phenomena, metabolism, and nutrition ,medicine.disease ,United States ,Disease Models, Animal ,Infectious Diseases ,business ,Pneumonia (non-human) - Abstract
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.
- Published
- 2020
50. Iguratimod as an alternative induction therapy for refractory lupus nephritis: a preliminary investigational study
- Author
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Qing Dai, Ran Wang, Qiong Fu, Liangjing Lu, Ping Ye, Chunmei Wu, Qingran Yan, Fang Du, Chunde Bao, Min Dai, and Yuening Kang
- Subjects
Adult ,Male ,0301 basic medicine ,medicine.medical_specialty ,Refractory lupus nephritis ,lcsh:Diseases of the musculoskeletal system ,Adolescent ,Drug Resistance ,Lupus nephritis ,Salvage therapy ,Induction therapy ,Iguratimod ,Cohort Studies ,Young Adult ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Maintenance therapy ,Refractory ,Prednisone ,Internal medicine ,medicine ,Humans ,Investigational New Drug Application ,Adverse effect ,Salvage Therapy ,030203 arthritis & rheumatology ,Sulfonamides ,business.industry ,Remission Induction ,Induction Chemotherapy ,Middle Aged ,medicine.disease ,Lupus Nephritis ,Treatment Outcome ,030104 developmental biology ,chemistry ,Chromones ,Rheumatoid arthritis ,Female ,lcsh:RC925-935 ,business ,Immunosuppressive Agents ,Research Article ,medicine.drug - Abstract
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.
- Published
- 2020
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