Translational Science Interagency Fellowship Projects and Mentors

FDA Mentor Names

Minjun Chen, Ph.D.
Paul Hayashi, M.D.

Position and Organizational Affiliation

Minjun Chen: Staff Fellow, Division of Bioinformatics and Biostatistics, National Center for Toxicological Research (NCTR), FDA

Paul Hayashi: DILI Team Lead, Division of Hepatology and Nutrition, Office of New Drug, Center for Drug Evaluation and Research, FDA

Contact Information (email/telephone)

minjun.chen@fda.hhs.gov/870-543-7057

paul.hayashi@fda.hhs.gov/301-837-7225

NCATS Mentor Names

Ruili Huang, Ph.D.
Menghang Xia, Ph.D.

Position and Organizational Affiliation

Ruili Huang: Tox21 Informatics Team Lead, DPI, NCATS, NIH

Menghang Xia: Tox21 Biology Team Lead, DPI, NCATS, NIH

Contact Information (email/telephone)

huangru@mail.nih.gov/301-827-0944

mxia@mail.nih.gov/301-827-5359

Research Project Summary

One of the major safety risks during clinical drug development is the occurrence of drug-induced liver injury (DILI), which can cause fatal liver failure. It is a top safety reason for drug-candidate failure during clinical trials and has led to more than 50 drugs being withdrawn from the market. Detecting DILI potential as early as possible is critical to public health and efficient drug development. One reason a drug with significant DILI risk can progress to clinical trials and even drug approval is that nonclinical (i.e., animal) tests are often unable to detect the liver injury signal. The scientists at the NCTR developed in silico–based predictive models — such as RO2 and DILI score — which have been used to help FDA reviewers evaluate DILI risk encountered during the review process. Although these models have high specificity, they also have low sensitivity. The Tox21 program has screened ∼8,500 chemicals in more than 70 high-throughput assays at NCATS, generating more than 100 million data points. This large content-rich in vitro data set, together with machine learning technologies, presents an unprecedented opportunity to improve predictive models for better assessing DILI liabilities and supporting the FDA review process.

Proposed Project for the Fellow

We aim to integrate the Tox21 in vitro assay data generated at NCATS with in silico data available at NCTR to improve the performance of DILI prediction models. The fellow will apply machine learning approaches to analyze the in vitro data to identify the assays relevant to DILI prediction. A new predictive model will be developed by integrating the selected in vitro assays with in silico models, such as RO2 and DILI score. Then, the fellow will apply the developed model to assist FDA medical reviewers in their assessment of DILI risk in Investigational New Drug (IND) Application or New Drug Applications (NDA). The fellow will model at least 20 drug candidates with DILI concern observed in clinical trials in the FDA internal database or reported in literature and will work with NCATS scientists to test these compounds using the model-selected in vitro assays. If needed, new assays will be identified or designed to enhance DILI risk assessment.

References

1. Chen M, Borlak J, Tong W. High lipophilicity and high daily dose of oral medications are associated with significant risk for drug-induced liver injury. Hepatology. 2013;58(1);388-396.
2. Chen M, Borlak J, Tong W. A model to predict severity of drug‐induced liver injury in humans. Hepatology. 2016;64(3):931-940.
3. Mishra P, Chen M. Application of “rule-of-two” model to direct-acting antivirals for treatment of chronic hepatitis C: can it predict potential for hepatotoxicity? Gastroenterology.
4. 2017;152(6):1270-1274.
5. Xu T, Ngan D, Ye L, et al. Predictive models for human organ toxicity based on in vitro bioactivity data and chemical structure. Chem. Res. Toxicol. 2020;33(3):731-741.
6. Richard AM, Huang R, Waidyanatha S, et al. The Tox21 10K Compound Library: collaborative chemistry advancing toxicology. Chem. Res. Toxicol. 2021;34(2):189-216.

FDA Mentor Names

Lauren Choi, Pharm.D.
Monisha Billings, D.D.S., M.P.H., Ph.D.

Position and Organizational Affiliation

Lauren Choi: Lead Clinical Analyst, Science Policy and Research Team 2, Immediate Office, Office of New Drugs, Center for Drug Evaluation and Research, FDA

Monisha Billings: Epidemiologist, Science Policy and Research Team 2, Immediate Office, Office of New Drugs, Center for Drug Evaluation and Research, FDA

Contact Information (email/telephone)

lauren.choi@fda.hhs.gov/240-402-2897

monisha.billings@fda.hhs.gov/301-796-7365

NCATS Mentor Name

Qian Zhu

Position and Organizational Affiliation

Staff Scientist, Informatics Core, DPI, NCATS

Contact Information (email/telephone)

qian.zhu@nih.gov/301-480-7841

Research Project Summary

Off-label use of drugs in children and adolescents is common and results in significant morbidity. There is limited drug information for the pediatric population. Several studies have reported high rates of off-label (9%–78.7%) use among pediatric patients.^1-3 A literature review by Mason et al. summarized 14 studies that assessed off-label drug use in the pediatric population.⁴ In one included study, as many as 82.6% of pediatric patients received off-label drugs and up to 19.9% developed an adverse drug reaction (ADR) from off-label use.⁴ At times, off-label drugs have been prescribed to children despite contraindications.⁵ These pediatric patients had a significantly higher risk of ADRs (7.3% vs. 1.2%; P <0.01) compared to those treated with an on-label drug.⁵ Another study found that the risk of ADRs more than doubled for pediatric patients with off-label drug use compared to those without (OR: 2.25, 95%; CI, 1.95–2.59).⁶ The risk of ADRs has been shown to increase by 30% for each additional off-label drug exposure.⁶ Studies concluded that improved pharmacovigilance to facilitate drug research and evidence-based prescribing in children is needed. This study proposes to ascertain off-label drug-related serious adverse events (SAEs) — including long-term outcomes — among pediatric patients compared with adults prescribed the same drugs.

Proposed Project for the Fellow

The fellow will engage in a study to elucidate off-label prescribing patterns in the pediatric population and to ascertain the SAEs — including long-term outcomes — among pediatric patients in comparison to adults prescribed these drugs. To this end, a stepwise approach from a high level to a more granular level of assessment will be undertaken. In collaboration with various FDA offices and divisions, the fellow will generate a list of off-label drugs using drug labeling and drug utilization data; ascertain all reported SAEs involving pediatric populations using the FDA Adverse Event Reporting System (FAERS); undertake a granular assessment of the top selected SAEs-drug pairs from Sentinel, with statistical analyses comparing pediatric versus adult populations; characterize these off-label drugs (e.g., new molecular entities, indication, route of administration, etc.); and analyze long-term outcomes. The fellow will access real-world data from NCATS and NIH — which includes the Biomedical Translational Research Information System (BTRIS), NCATS Biomedical Data Translator program, and National COVID Cohort Collaborative (N3C) — to identify and stratify pediatric patient characteristics associated with those SAEs-drug pairs. Natural language processing and machine learning will be utilized at several stages in the study. This study will assess the safety concerns pertaining to off-label drug use in pediatric patients to enhance FDA’s monitoring and pharmacovigilance programs.

References

1. Gore R, Chugh PK, Tripathi CD, et al. Pediatric off-label and unlicensed drug use and its implications. Curr Clin Pharmacol. 2017;12(1):18-25. PMID: 28322168.
2. Shanshal AM, Hussain SA. Off-label prescribing practice in pediatric settings: pros and cons. Systematic Reviews in Pharmacy. 2021;12(1):1267-1275.
3. Allen HC, Garbe MC, Lees J, et al. Off-label medication use in children, more common than we think: a systematic review of the literature. J Okla State Med Assoc. 2018;111(8):776-783.
4. Mason J, Pirmohamed M, Nunn T. Off-label and unlicensed medicine use and adverse drug reactions in children: a narrative review of the literature. Eur J Clin Pharmacol. 2012;68(1):21-28. Epub 2011 Jul 22. PMID: 21779968.
5. Pratico AD, Longo L, Mansueto et al. Off-label use of drugs and adverse drug reactions in pediatric units: a prospective, multicenter study. Curr Drug Saf. 2018;13(3):200-207. PMID: 29921210.
6. Bellis JR, Kirkham JJ, Thiesen S, Conroy EJ, et al. Adverse drug reactions and off-label and unlicensed medicines in children: a nested case-control study of inpatients in a pediatric hospital. BMC Med. 2013;11:238. PMID: 24229060.

FDA Mentor Names

Zhichao Liu, Ph.D.
Qi Liu, Ph.D.

Position and Organizational Affiliation

Zhichao Liu: Technical lead at AI Research Force, Division of Bioinformatics and Biostatistics, National Center for Toxicological Research, FDA

Qi Liu: Associate Director for Innovation and Partnership, Office of Clinical Pharmacology/Office of Translational Sciences, Center for Drug Evaluation and Research, FDA

Contact Information (email/telephone)

zhichao.liu@fda.hhs.gov/870-543-7909

qi.liu@fda.hhs.gov/301-796-1568

NCATS Mentor Name

Gregory T. Tawa, Ph.D.

Position and Organizational Affiliation

Modeling and Informatics Lead, Therapeutic Development Branch, DPI, NCATS, NIH

Contact Information (email/telephone)

gregory.tawa@nih.gov/301-827-7177 or 240-550-0749

Research Project Summary

Most rare diseases have a genetic etiology and affect a small proportion of the population, but are severe and life-threatening. Although rare diseases are themselves infrequent, collectively they are a common occurrence. There are more than 7,000 rare diseases according to the European Organization for Rare Diseases statistics. However, fewer than 600 treatment options are available. Artificial intelligence (AI) has changed the landscape of biomedical fields and provides a unique solution to unravel the hidden information from different biological profiles. Building an AI-powered drug repositioning framework to prioritize approved or investigational drugs for rare diseases would provide a comprehensive solution to facilitate rare disease therapy development. Ultimately, the goal would be to leverage the AI-powered framework, along with wet-lab verification, to evaluate drugs for the treatment of rare diseases.

Proposed Project for the Fellow

The fellow will explore different AI-based approaches to assess comprehensively the potential for approved and investigational drugs to be used as treatments for rare diseases (e.g., Noonan syndrome). The fellow will assist in the development of an AI-based drug repurposing framework that includes biological data curation and preprocessing, deep-learning algorithm deployment, and web-based platform construction. The fellow will receive instruction in current FDA rare disease regulations and application of AI in a regulatory setting to better position the developed framework for FDA use. Furthermore, the fellow will work closely with NIH mentors to establish experimental protocols to evaluate the efficacy of repurposing candidates derived from the AI-powered drug repurposing framework. The long-time collaboration between FDA and NCATS on projects of this kind has an established record of high productivity (see the relevant joint publications of PIs from FDA and NCATS). The fellow will gain valuable expertise by curating data, developing AI solutions, developing wet-lab protocols, and publishing results. The FDA and NCATS will benefit by further expanding upon the historical success of their joint collaborations.

Relevant Publications

1. Liu Z, Chen X, Roberts R, Huang R, Mikailov M, Tong W. Unraveling gene fusions for drug repositioning in high-risk neuroblastoma. Front Pharmacol. 2021;12:608778.
2. Zhu L, Roberts R, Huang R, et al. Drug repositioning for Noonan and Leopard syndromes by integrating transcriptomics with a structure-based approach. Front Pharmacol. 2020;11:927.
3. Delavan B, Roberts R, Huang R, Bao W, Tong W, Liu Z. Computational drug repositioning for rare diseases in the era of precision medicine. Drug Discov Today. 2018;23(2):382-394.
4. Liu Z, Zhu L, Roberts R, Tong W. Toward clinical implementation of next-generation sequencing-based genetic testing in rare diseases: where are we? Trends Genet. 2019;35(11):852-867.

FDA Mentor Name

Ashutosh Rao, Ph.D.

Position and Organizational Affiliation

Chief of the Laboratory of Applied Biochemistry, Co-Chair of the Center for Excellence in Tumor Biology, Silvio O. Conte Senior Biomedical Research and Biomedical Product Assessment Service Expert, Office of Biotechnology Products, Center for Drug Evaluation and Research, FDA

Contact Information (email/telephone)

ashutosh.rao@fda.hhs.gov/240-402-7338

NCATS Mentor Name

Juan J. Marugan, Ph.D.

Position and Organizational Affiliation

Group Leader, Early Translation Branch, NCATS, NIH

Contact Information (email/telephone)

maruganj@mail.nih.gov/301-480-9857

Research Project Summary

Autophagy, as a fundamental stress sensor mechanism in cells, must be modulated properly. Too little or too much triggers cell death. Alterations in autophagy associated with cancer could facilitate tumor progression or drug resistance. This alteration in autophagy progressively induces a loss of mitochondrial function, reduction of oxidative phosphorylation, and upregulation of glycolysis — a hallmark of tumor progression and epithelial-mesenchymal transition (EMT). Autophagy-dependent cancer cells are highly glycolytic, and they have characteristics of cancer stem cells. Dr. Marugan has disclosed several PIP4Kgamma allosteric modulators able to upregulate autophagy in several cells. These molecules induce a conformation in PIP4Kgamma similar to the one induced by short chain ceramides, and therefore have potential for antitumoral activity. Direct inhibitors of mTOR (like Rapamycin) and activators of direct AMP-activated protein kinase (AMPK) also will result in an upregulation of autophagy.

In this sense, it is possible that, depending on the mutations or the stage of the cancer (early stage or highly evolved), cells might respond better to inducers or inhibitors of autophagy. Our proposal would like to study these questions in a systematic manner to understand these alterations in autophagy observed in cancer cells and see if these mechanisms are able to promote or impair autophagy and impact their growth and viability using cells at different stages (e.g., early, metastatic, and stem cancer cells).

Proposed Project for the Fellow

The fellow will evaluate the effect of autophagy modulators with well-known mechanisms — such as activators (e.g., mTOR inhibitors, AMPK agonists, PIP4Kgamma inhibitors, metformin, mitoQ) or inhibitors (e.g., hydroxyquinoline, lysosomotropic agents, ULK1 inhibitors, mTORC1 activator) — and impact the growth and viability of breast and pancreatic cancer cells at different stages of tumorgenesis (e.g., early-stage cancer, metastasis, and cancer stem cells). The fellow also will be involved in the synthesis and scale up of selected molecules for pharmacokinetic and efficacy studies in relevant rodent models of cancer (xenograph and/or immunocompetent).

Relevant Publications

1. Biel TG, Aryal B, Gerber MH, Trevino JG, Mizuno N, Rao VA. Mitochondrial dysfunction generates aggregates that resist lysosomal degradation in human breast cancer cells. Cell Death Dis. 2020;11(6):460. Available from: https://pubmed.ncbi.nlm.nih.gov/32541677/

FDA Mentor Names

Alexandre Ribeiro
Kevin Ford

Position and Organizational Affiliation

Staff Fellow, Division of Applied Regulatory Science, Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, FDA

Contact Information (email/telephone)

alexandre.ribeiro@fda.hhs.gov/412-894-6755

kevin.ford@fda.hhs.gov/202-510-7090

NCATS Mentor Name

Marc Ferrer, Ph.D.

Position and Organizational Affiliation

Director, 3-D Tissue Bioprinting Laboratory, DPI, NCATS, NIH

Contact Information (email/telephone)

ferrerm@mail.nih.gov/240-515-4118

Research Project Summary

Kidney organoids derived from induced pluripotent stem cells (iPSCs), like the type developed by the Freedman Lab at the University of Washington or developed with the BioPearl Cyprio technology, are being evaluated at NCATS and the Center for Drug Evaluation and Research (CDER) as novel 3-D cellular platforms for the potential of predicting drug metabolism and drug efficacy/toxicity. These platforms contain different cell types within structures that represent kidney tissue complexity and function, affording them great potential for drug metabolism and nephrotoxicity assessments.

Proposed Project for the Fellow

The fellow will work toward the evaluation and characterization of an iPSC-derived kidney organoid platform as a 3-D cellular system with enhanced physiology that can be assayed to predict drug metabolism and efficacy/toxicity in a normal versus polycystic kidney disease (PKD) cellular background. At the FDA and NCATS, the fellow will learn the protocols for kidney organoid production in a 96- or 384-well plate format. At the FDA, the fellow will test the ability to evaluate drug metabolism with compounds that are known substrates for renal cytochrome P450 (CYP) and UDP-glucuronosyltransferase (UGT) enzymes using liquid chromatography–mass spectrometry assays established at CDER. Research on evaluating drug toxicity that targets the renal interstitium also will be planned for the next research phase. At NCATS, the fellow will help develop a cell imaging–based assay to establish efficacy effect of compounds on PKD phenotypes and study the toxic effect of compounds on normal and PKD models. In addition to imaging extracellular matrix components for screening drug-induced defects in the renal insterstitium, cell viability assays will be performed — such as CellTiterGlo and live/dead fluorescence assays — and organoid structure will be analyzed from brightfield images. Altogether, interpretation of toxicity and efficacy results as predictive of clinical effects will take into consideration information on drug metabolism.

Relevant Publications

1. Cruz NM, Song X, Czerniecki SM, et al. Organoid cystogenesis reveals a critical role of microenvironment in human polycystic kidney disease. Nat Mater. 2017;16(11):1112-1119. doi: 10.1038/nmat4994
2. Czerniecki SM, Cruz NM, Harder JL, et al. High-throughput screening enhances kidney organoid differentiation from human pluripotent stem cells and enables automated multidimensional phenotyping. Cell Stem Cell. 2018;22(6):929-940.e4. doi: 10.1016/j.stem.2018.04.022.

FDA Mentor Names

Elliot Rosen, M.S.
Ashutosh Rao, Ph.D.

Position and Organizational Affiliation

Elliot Rosen: Biologist, Office of Biotechnology Products, Office of Pharmaceutical Quality, Center for Drug Evaluation and Research, FDA

Ashutosh Rao: SBRBPAS Expert, Office of Biotechnology Products, Office of Pharmaceutical Quality, Center for Drug Evaluation and Research, FDA

Contact Information (email/telephone)

elliot.rosen@fda.hhs.gov/240-402-7353

ashutosh.rao@fda.hhs.gov/240-402-7338

NCATS Mentor Name

Haksong Jin, Pharm.D.

Position and Organizational Affiliation

Team Lead, CMC, Drug Product Formulation and Manufacturing, DPI, NCATS, NIH

Contact Information (email/telephone)

haksong.jin@nih.gov/301-827-0920

Overall Research Summary

Although proteins are very important in biological cells and play critical roles in numerous diseases, protein drug products face many challenges in maintaining the physiochemical and biological stability of the active ingredient in the chosen formulation environment and/or container with diluents. The research will focus on how to predict drivers of stability and improve the stability of protein drug products, especially in the in-use clinical setting prior to and during human administration.

Proposed Project for the Fellow

The fellow will review and identify the critical quality attributes that drive the stability of currently marketed protein drug products. The issues will be analyzed and assessed for risk to quality and safety, and a study plan will be carefully designed to triage and test potential conditions that improve stability. Relevant examples of protein drug products and their formulations will be modified to improve the stability by investigating compatibility with a wide range of delivery systems and diluent systems. The outcomes and learnings from this project will support the identification of key drivers of stability and improvements in strategies for future protein drug product development.

Relevant Publications

1. Kryndushkin D, Rao VA. Comparative effects of metal-catalyzed oxidizing systems on carbonylation and integrity of therapeutic proteins. Pharm. Res. 2016 Feb;33(2), 526–539.
2. Kryndushkin D, Wu WW, Venna R, Norcross MA, Shen RF, Rao VA. Complex nature of protein carbonylation specificity after metal-catalyzed oxidation. Pharm. Res. 2017 Apr;34(4):765–779.
3. Rao VA. Perspectives on engineering biobetter therapeutic proteins with greater stability in inflammatory environments. In: Rosenberg A and Demeule B, editors. Biobetters: protein engineering to approach the curative. New York: Springer; 2015. p. 183-202.
4. FDA.gov. Spotlight on CDER Science [Internet]. 2018 June 12. Available from: https://www.fda.gov/drugs/news-events-human-drugs/fda-researchers-explore-fundamental-chemical-reaction-could-threaten-quality-therapeutic-protein

FDA Mentor Name

Carole Sourbier, Ph.D.

Position and Organizational Affiliation

Principal Investigator, Office of Biotechnology Products, Office of Pharmaceutical Quality, Center for Drug Evaluation and Research, FDA

Contact Information (email/telephone)

carole.sourbier@fda.hhs.gov/240-505-4430 or 240-402-7407

NCATS Mentor Name

Ewy Mathé, Ph.D.

Position and Organizational Affiliation

Director of Informatics, DPI, NCATS, NIH

Contact Information (email/telephone)

ewy.mathe@nih.gov/301-402-8953

Research Project Summary

This project aims to predict the efficacy of immune checkpoint Inhibitors (ICIs) and to support the analytical similarity assessment of prospective biosimilars. The metabolic crosstalk between tumor cells and their microenvironment supports tumor growth by providing ample nutrients and an immunosuppressed environment. By activating the immune system, ICIs are changing the metabolic surrounding of tumors, which may lead to a metabolic adaptation. Therefore, the metabolic effect of ICIs on the tumors and the microenvironment could be reflective of their efficacy and could be used as a tool to characterize and compare prospective biosimilars. Indeed, several ICIs will be coming off-patent in 2024–2026 and will become reference products. It is therefore critical to have a clear understanding of the role of the metabolic effect of ICIs on their efficacy and function to facilitate the analytical similarity assessment of this class of products.

Proposed Project for the Fellow

The fellow will perform translational research approaches at both FDA and NCATS sites to predict the efficacy of immune checkpoint inhibitors and to facilitate the analytical similarity assessment of prospective biosimilars. Generation and preparation of samples, real-time metabolic assays, cell-based and biochemical assays, and other in vitro and in vivo assays required to support the analytical similarity assessment of a biotechnology product will be performed at FDA. Multi-omics profiling, computational analyses, interpretation of untargeted metabolomics and RNAseq raw data sets, and participation in the analysis of publicly available data sets from patients treated with immune checkpoint inhibitors will be performed at NCATS. In addition, while at FDA, the fellow will gain experience in diverse aspects of the regulatory review of biotechnology products and will have access to formal regulatory trainings. The fellow also will participate in the office and division regulatory activities.

Relevant Publications

1. Yoon SJ, Lee CB, Chae SU, Jo SJ, Bae SK. The comprehensive “omics” approach from metabolomics to advanced omics for development of immune checkpoint inhibitors: potential strategies for next generation of cancer immunotherapy. Int. J. Mol. Sci. 2021;22(13):6932. Available from: https://doi.org/10.3390/ijms22136932
2. Beger R, Schmidt MA, Kaddurah-Daouk R. Current concepts in pharmacometabolomics, biomarker discovery, and precision medicine. Metabolites. 2020;10(4):129. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7241083/
3. Lim AR, Rathmell WK, Rathmell JC. The tumor microenvironment as a metabolic barrier to effector T cells and immunotherapy. eLife. 2020;9:e55185. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7200151/

FDA Mentor Name

Wendy Weinberg, Ph.D.

Position and Organizational Affiliation

Senior Investigator and Chief, Laboratory of Molecular Oncology, Office of Biotechnology Products, Office of Pharmaceutical Quality, Center for Drug Evaluation and Research, FDA

Contact Information (email/telephone)

wendy.weinberg@fda.hhs.gov/240-447-1819

NCATS Mentor Name

James Inglese, Ph.D.

Position and Organizational Affiliation

Principal Investigator, Assay Development and Screening Technology Laboratory, DPI, NCATS, NIH

Contact Information (email/telephone)

jinglese@mail.nih.gov/301-827-5348

Research Project Summary

Biotechnology products are a rapidly growing sector of drug development, with a large portion targeting oncology indications. Cell-based bioassays are a critical aspect of regulatory review of biotechnology products for product characterization and release testing, and to maintain product safety and efficacy following manufacturing changes. Required under 21 CFR 610.10, these assays serve as a measure of product potency and are ideally designed to reflect a product’s mechanism of action. The goal of this study is to develop a robust, sensitive, and specific cell–based bioassay capable of detecting inhibition of NF-kB/c-Rel activity in a cellular model of head and neck squamous cell cancers (HNSCC).

Proposed Project for the Fellow

Optimal bioassay design and proper validation are critical aspects of control strategies for biotechnology products. NF-kB/c-Rel is coordinately expressed with the p53 homologue p63 in HNSCC and mediates growth and malignant conversion of p63-expressing keratinocytes in preclinical models. The fellow will develop a cell-based bioassay capable of detecting drug interference of nuclear translocation/retention of NF-kB/c-Rel in a cellular model of HNSCC. The assay will be used to enable quantitative high-throughput screening of a small-molecule drug library for drug repurposing to address therapeutic strategies for HNSCC demonstrating c-Rel activation in patients resistant to a class of NF-kB inhibitors that has been shown to differentially suppress RelA but not the other subunits. The drug screening can be done both alone and in the presence of specific licensed therapeutic antibodies to identify synergistic pathways. Findings from this drug screening can be extended to pharmacological studies of mechanism of action of candidate drugs. The fellow also will be trained in biotechnology product quality review principles — including using this assay as a training tool for mastering principles of assay validation — and will participate in regulatory reviews of protein products, gaining exposure to review processes from pre-investigational new drug submissions through licensure and post-approval changes.

Relevant Publications

1. King KE, Ponnamperuma RM, Allen C, et al. The p53 homologue ΔNp63α interacts with the Nuclear Factor-κB pathway to modulate epithelial cell growth. Cancer Research. 2008;68(13):5122-5131.
2. Inglese J, Johnson RL, Simeonov A, et al. High-throughput screening assays for the identification of chemical probes. Nature Chemical Biology. 2007;3:466-479.

FDA Mentor Name

Baolin Zhang, Ph.D.

Position and Organizational Affiliation

Senior Investigator, Biologics CMC Leader, HHS SBRBPAS Expert, Office of Biotechnology Products, Office of Pharmaceutical Quality, Center for Drug Evaluation and Research, FDA

Contact Information (email/telephone)

baolin.zhang@fda.hhs.gov/240-402-6740

NCATS Mentor Name

Wei Zheng, Ph.D.

Position and Organizational Affiliation

Group Leader, Therapeutic Development Branch, DPI, NCATS, NIH

Contact Information (email/telephone)

wzheng@mail.nih.gov/301-827-5722

Research Project Summary

Many medications (e.g., therapeutic monoclonal antibodies [mAbs]) are administered to patients through intravenous (IV) infusion. This involves dilution of the medication into a diluent (e.g., saline or 5% dextrose) followed by continuous delivery into a patient’s bloodstream. The diluent(s) must be compatible with specific product formulations to ensure product stability and patient safety; for instance, 5% dextrose is prohibited for use with Herceptin, Avastin, and Remicade as stipulated on product labels.^1-3 Using wrong diluents can cause product aggregation, which may trigger infusion reactions and other adverse events. The current industry practices focus on assessing product stability upon dilution into a diluent in vitro (known as in-use stability testing). However, there is a gap in the knowledge of product stability at the blood-IV interface where drug molecules directly interact with diluent and blood components. The FDA laboratory has shown that several mAbs formulations are susceptible to forming insoluble aggregates with plasma proteins when mixed with 5% dextrose in vitro.^4,5 The work highlights the importance of assessing compatibility of product formulations with IV diluents and human plasma during product development.

Proposed Project for the Fellow

The FDA-NCATS fellow will join a multidisciplinary team of research and regulatory scientists in investigating the impacts of product formulations on product safety during IV infusion. The fellow will explore translational approaches to improve assessment of product quality for IV administration, which may include development of in vitro assay systems to simulate the dynamic nature of bloodstream, use of animal models to monitor infusion reactions, and analyses of clinical adverse events associated with specific products to advance understanding of the link between product formulations and clinical safety. The fellow will compile data from FDA reviews of Investigational New Drug (IND) Application and Biologic License Application (BLA) submissions for infusion reactions and adverse events and perform meta-analysis of the data to assess patterns of toxicity in association with critical formulation characteristics, such as pH, ionic strength, surfactant, and additive. The fellow also will receive training in current procedures for FDA review of regulatory submissions under INDs and BLAs, with a focus on assessment of product quality (chemistry, manufacturing and control (CMC)). The work will be performed jointly in the FDA and NCATS laboratories.

Relevant Publications

1. Herceptin prescribing information (2019). Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/103792s5345lbl.pdf
2. Avastin prescribing information (2019). Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/125085s331lbl.pdf
3. Remicade prescribing information (2018). Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/103772s5385lbl.pdf
4. Luo S, Zhang B. Dextrose-mediated aggregation of therapeutic monoclonal antibodies in human plasma: Implication of isoelectric precipitation of complement proteins. mAbs. 2015;7(6):1094-1103.
5. Luo S, McSweeney M, Wang T, Bacot S, Feldman G, Zhang B. Defining the right diluent for intravenous infusion of therapeutic antibodies. mAbs. 2020;12(1):e1685814.