IOTF Mentors: Track 3 and Track 4

While at FDA, fellows will each be assigned a mentor who will be a senior member of FDA scientific review staff. Fellows will be matched with one of the mentors from the list below through a process of mutual selection. Mentors are listed in alphabetical order by last name.

Serge L. Beaucage, Ph.D.

Chief, Laboratory of Biological Chemistry (LBC), Division of Biotechnology Research and Review IV (DBRR IV), Office of Biotechnology Products, Office of Pharmaceutical Quality, Center for Drug Evaluation and Research

serge.beaucage@fda.hhs.gov

240-402-9387

Project Title

Chemical synthesis of oligonucleotides for therapeutic and synthetic biology applications.

Project Summary

This project has important scientific and regulatory implications associated with the detection and treatment of infectious diseases and cancers. Indeed, antisense DNA oligonucleotides, aptamers, and small interfering RNA oligonucleotides (siRNA) have been used in vivo to treat various types of human diseases by altering the expression of disease-causing genes. Furthermore, our research objectives are aimed at minimizing process- and product-related impurities in synthetic nucleic acid sequences intended to be used as nucleic acid-based drugs. This can be achieved through the development of innovative solid supports and unique thermolabile groups for the protection of hydroxyl, amine and phosphate/thiophosphate functions of DNA and RNA sequences. Success in achieving those critical tasks will ensure the highest purity, safety and efficacy of nucleic acid-based drugs intended for pharmaceutical indications. Advances in creative technologies to enable highly efficient solid-phase chemical synthesis and purification of DNA and RNA sequences are essential to the project, particularly in the context of a continuous manufacturing process for nucleic acid-based drugs. First and foremost, the aims of this project are to fulfill the high demand for highly pure synthetic DNA and RNA sequences, which will be used in a variety of therapeutic and synthetic biology applications including chromosomal engineering.

Proposed Project for IOTF Fellow

As mentioned above, the key objectives of the project are to creatively design and implement the use of thermolabile groups to improve the automated solid-phase synthesis and purification of synthetic nucleic acid-based drugs with the intent of minimizing process- and product-related impurities to levels that will not be a safety concern to patients. Basic organic chemistry skills are required for this project given that modification of standard nucleic acid protecting groups are necessary to ensure the production of highly pure nucleic acid sequences. Skills in cell biology might alternatively be required should the IOTF fellow be considering working on the development of methods designed to enhance the cellular delivery of therapeutic DNA and/or RNA sequences as in vitro and in vivo inhibitors of protein-causing disease expression.

Regulatory Activity

The review of incoming pre-Investigational New Drugs (pINDS) and Investigational New Drugs (INDS) submissions, and of the amendments of the currently active INDs, is the responsibility of the LBC. More than 400 active INDs are under review in the LBC; these INDs relate to a plethora of PEGylated and unPEGylated proteins including enzymes and antibodies. In addition, PEGylated and unPEGylated growth factors, erythropoetin-derived products, immunoconjugates, fibroblast and epidermal growth factors, thrombolytic and toxin-fusion proteins are among the active INDs under the jurisdiction of the LBC. The fellow will participate in the regulatory review of pIND and IND submissions. These activities will provide the fellow with a solid regulatory training under the tutelage of review teams dedicated to assessing the quality attributes of therapeutic proteins and enzymes, through a science-based approach.

Nirjal Bhattarai, Ph.D.

Principal Investigator, Gene Transfer and Immunogenicity Branch, Division of Cellular and Gene Therapies, Office of Tissues and Advanced Therapies, Center for Biologics Evaluation and Research, Food and Drug Administration

nirjal.bhattarai@fda.hhs.gov

240-402-6834

Project Title

Assessing Immunogenicity of Products for Gene Therapy and T cell Therapy

Project Summary

Although T cell based cancer immunotherapy has shown a remarkable promise to treat various cancers, patients treated with therapeutic T cells can develop severe inflammatory disease notably cytokine release syndrome (CRS) in part due to activation of bystander immune cells. Furthermore, inflammation has become a critical risk factor in the clinical application of T cell immunotherapy. Immunosuppressive drugs that are used to manage the inflammation associated with T cell therapy also suppress the efficacy of therapeutic T cells. Thus, novel strategies to manage inflammation during T cell immunotherapy are required for their wide spread use against various cancers. The goal of this project is to develop strategies to reduce inflammation associated with T cell immunotherapy for cancer.

Proposed Project for IOTF Fellow

In this lab, fellow will utilize our established model to examine activation of therapeutic T cells in response to cancer antigens, and assess the intracellular signaling of cancer-specific T cells. Previous studies have shown that activated T cells secrete exosomes that induce bystander immune cell activation; however, the mechanism for this remains largely unknown. The IOTF fellow will study the role of exosomes secreted by CAR-T cells in bystander immune cell activation and inflammation associated with T cell immunotherapies. We expect that the knowledge gained from these studies will enhance our understanding of the role of exosomes in inflammation associated with T cell immunotherapy and aid to design safer and more effective cancer specific T cell therapies for future.

Regulatory Activity

The IOTF fellow will participate in the regulatory review of investigational new drug (IND) applications for cell and gene therapy products. Many of these investigational new drug products are for the treatment of cancer. The fellow will also attend office and divisional regulatory meetings, and seminars. All of these activities will provide the fellow with a regulatory training to assess safety and efficacy of cell and gene therapy products.

Ashwinkumar Bhirde, Ph.D.

Project Lead/Research-Review Chemist-CDER/OBP/DBRRII

ashwinkumar.bhirde@fda.hhs.gov

(240) 402-6234

Regulatory Science Priority Area: Evaluating cancer biotherapeutics (e.g., monoclonal antibodies, insulin analogs biosimilars) for stability under relevant stress conditions throughout the drug product life cycle

Running Project Title: Biosimilar Analytics: Biosimilar quality and impacts of container closure systems on particulates/particles

Project Summary

The Office of Biotechnology Products (OBP) in the Office of Pharmaceutical Quality (OPQ) evaluates the quality of biotherapeutic protein biosimilar and originator drug products (DPs). DP quality is impacted by variability in critical quality attributes, such as glycosylation patterns, high molecular weight species, and particles of injectable protein cancer biotherapeutics. The primary objective of this project is to evaluate biosimilar and reference products quality metrics in Insulin and other therapeutic protein drugs like monoclonal antibody DPs. Secondary objective of the project is to understand the impact of container closure systems and develop suitable methods to detect and evaluate particles in therapeutic protein formulations. The results of this project will be to disseminate the findings in peer-reviewed journals, internal/external forums (posters, talks) for stakeholders including drug and instrument manufacturers, and generate training materials for internal review staff. This project has multiple sub-projects and the IOTF can work on either of the project depending on the background and interest.

This project is divided into the following specific sub-projects:
Sub-project 1: OBP evaluates the quality of insulin DPs. OBP assessors and research labs have been working closely together as part of the OBP Insulin Working Group to address potential quality issues related to insulin DPs. Unlike other biotechnology DPs, insulin DPs are predominantly self-administered and potentially gets exposed to real-world stress conditions like agitation etc. This study aims to address regulatory review concerns regarding the stability of insulin biosimilars and originator DPs when using insulin in vials, pens, and pumps, to support insulin product manufacturing, testing and surveillance to ensure the delivery of high-quality insulin drugs. Potential real-world scenarios which may negatively impact insulin DPs including biosimilars quality will be evaluated.

Sub-project 2: Current reference standards to calibrate instruments for cancer therapeutic protein particle detection. However, these reference standards are physically rigid and vary in optical contrast when compared to protein particles which are soft, flexible, and irregular in shape and size. To address this short coming the National Institute of Standards and Technology (NIST) has developed novel proteinaceous particle surrogates as reference standards to help characterize particles in injectable cancer therapeutics. This project will evaluate the suitability of the NIST reference materials for particle detection in cancer drug formulations. In collaboration with NIST and the Office of Testing and Research at FDA, we propose to develop a novel morphologically-directed Raman spectroscopy method to characterize subvisible and visible particles using the NIST standards. The outcomes of this project will help update OBP recommended review practices for particulate matter testing requirements, help enhance the review process for drug applications, and provide support in the modernization efforts and improvements of US Pharmacopeia monographs for particles in protein DP injections.

Regulatory Activity

The mentor is responsible for primary review of investigational new drug (IND’s) and supplemental biologic licensing applications (sBLA’s). He has in-depth experience in reviewing the chemistry manufacturing and controls of INDs and cross-reference INDs related to monoclonal antibodies etc., The mentor is also deeply involved in the development of regulatory policy including guidance documents, and OBP recommended practices. The IOTF fellow will be fully integrated into an existing team and will be provided with opportunities to participate in training and regulatory review activities related to regulatory submissions. The fellow will spend up to 50% of their time reviewing manufacturing, production, and quality of biotechnology product submissions related to the treatment of cancer and other indications. The fellow will also be exposed to regulatory policy and support working group activities from both a technical and regulatory perspective to gain expertise in the development of regulatory policy. The fellow will also attend lab, branch, divisional, and office level meetings, and may join the mentor at CDER or FDA level meetings to support regulatory or policy decision making, which is often germane to oncology drug products.

Weijie Chen, Ph.D.

Research Physicist, Division of Imaging, Diagnostics, and Software Reliability, CDRH/OSEL

weijie.chen@fda.hhs.gov

(301) 796-2663

Regulatory Science Priority Area: Develop methods and tools to improve and streamline clinical trial design

Project Title

Assessment methodology development for medical image segmentation: from diagnostics to radiation therapy and imaging biomarkers for oncology trials

Project Summary

Artificial intelligence (AI) and machine learning (ML) algorithms are being developed at an ever-increasing pace for medical image segmentation, i.e., identifying the extent of lesions or an organ of interest, in diagnostic/therapeutic devices and imaging biomarker for drug trial applications with tremendous public health impact. Assessment of image segmentation is a key in clinical study endpoints that directly impact regulatory decisions for a broad spectrum of device and drug-trial applications, including image-guided radiation treatment planning, computer-assisted surgical devices, and imaging biomarkers as surrogate endpoints for drug trials. It is widely recognized that a standardized approach to the assessment of image segmentation is lacking [1-3]. Similarly, the agency lacks guidelines and the review of related submissions is challenging, slow and sometimes inconsistent.

In this project, a team of FDA scientists will develop assessment methodologies and tools to help industry as well as FDA reviewers decide on appropriate performance metrics and truthing methods for standardized assessment of image segmentation in diagnostic/treatment devices and drug trial applications. The project will help streamline and accelerate the regulatory review of related products. Depending on the skills and interests of the fellow, we will find a role to be filled in the project above. We are looking for help

* Managing a CT image dataset obtained from a collaborator * Develop or implement (i.e., based on open-source tools) image segmentation algorithms for radiation treatment planning * Work with the mentor and collaborators on the development of assessment methodologies including statistical modeling and analysis methods. * Training and provide technical support for regulatory review of premarket applications that involve AI for image segmentation, especially radiation treatment planning products.

Proposed Project for IOTF fellow

AI based image segmentation for radiation treatment planning

Regulatory Activity

premarket applications involving AI in radiation treatment planning, AI based imaging biomarkers

Rosalie K. Elespuru, Ph.D.

Principal Investigator, Genetic Toxicology Lab, OSEL, Division of Biology, Chemistry and Materials Science (DBCMS) CDRH

rosalie.elespuru@fda.hhs.gov

301-796-0237

Project Title

Genetic Alterations, Cancer Risk, and Translational Diagnostics

Project Summary

Genetic alterations are implicated in the causation of cancer and recently cancer driver mutations (CDMs) have been used as biomarkers for diagnosis of cancer, stratification of patients into treatment groups, and monitors of therapy outcome. For safety assessment (cancer prevention), FDA assesses the capability for DNA interactions of new drugs, device materials, and food additives. In the area of cancer diagnosis and therapy, CDRH regulates genetic and genomic diagnostic devices, expected to be developed for the advent of "personalized medicine". In both aspects a central theme is the analytical capability for detection of rare mutant DNA within a background of normal DNA.

Proposed Project for IOTF Fellow

Exploration of “Comet-chip” for assessment of DNA damage. Comet-Chip is a new tool for monitoring mechanisms of genetic damage that can be used to study cytotoxicity, DNA repair, and DNA damage mechanisms. Relevant medical device applications, such as the actions of metals and nanoparticles will be addressed.

Diagnostics for early cancer detection and therapy monitoring. Detection of mutant DNA in blood and/or exosome RNA in urine or saliva would be the focus. K-RAS codon 12 mutations are a common biomarker for lung and pancreas cancers, and a good model for assessment of diagnostic tools, limits of detection, and human application. Exosomes are a new source of stable nucleic acid biomarkers and can be resourced from less invasive human compartments such as urine and saliva. Experiments would be designed for detection of spiked-in surrogate nucleic acids. Adequate systems development could be followed by an application for early diagnosis and therapy monitoring of pancreatic or lung cancer. This project would define the technical factors affecting detection of rare mutant DNA and/or RNA biomarkers.

Personalized cancer prevention: are we ready? It has been known for some time that both genes and environment are factors in human cancer development. In the era of precision medicine, what is the likelihood that we can begin to assess personalized cancer risk, instead of overall cancer risk? Cancers for which genetic, environmental, viral and other associations are well established include colon, liver, head and neck, and lung cancer. This project is a non-lab (or virtual) option for assembling epidemiological and other data on etiological factors affecting specific types of cancer, including those related to metals, radiation, or a rare type of breast implant associated lymphoma.

Regulatory Activity

The PI has 20 plus years of FDA experience in the application of genetic analyses to cancer risk assessment of regulated products and is involved in the broader scientific community as past President of the US society of genetic toxicologists. The fellow would follow product reviews relative to cancer risk (device safety assessment) or cancer diagnostics (precision medicine), involving the CDRH Divisions that regulate Medical Devices or Diagnostic Tests respectively. The former group deals with the safety of 2000 categories of medical devices (cardiac, orthopedic, dental, hospital-based, etc.), while the latter group reviews diagnostic tests, including genetic and other tests used in precision-targeted cancer therapies. The fellow would focus on one or the other type of regulatory review.

Brandon D. Gallas, Ph.D.

Mathematician, Division of Imaging, Diagnostics, and Software Reliability (DIDSR), Office of Science and Engineering Laboratories (OSEL), Center for Devices and Radiological Health (CDRH), FDA

brandon.gallas@fda.hhs.gov

301-796-2531

Regulatory Science Priority Area: Unleashing the Power of Data, Increasing Choice and Competition Through Innovation, Women's Health - Advances in Biomarker Science

Project Title

Digital Pathology

Project Summary

This objective of this project is to support the digital pathology revolution. Imaging devices, image processing tools, artificial intelligence algorithms, visualization packages, and display devices represent a large regulatory portfolio in CDRH that is continuing to expand. CDRH is in perpetual need of new paradigms for the evaluation of these products using reader studies, standardized databases, and modeling. These evaluations must be statistically interpretable, relevant for their intended use, and at reasonable cost. This project will investigate new, improved clinical trial designs and statistical methods, as well as develop and validate data collection and analysis tools, which will lead to more powerful clinical studies of the efficacy of imaging devices for fewer resources.

Proposed Project for IOTF Fellow

We are in the middle of a large multi-organization project in the area of digital pathology and artificial intelligence. Please refer to project publications that describe our work:

A Pathologist-Annotated Dataset for Validating Artificial Intelligence: A Project Description and Pilot Study, https://www.doi.org/10.4103/jpi.jpi_83_20
Development of Training Materials for Pathologists to Provide Machine Learning Validation Data of Tumor-Infiltrating Lymphocytes in Breast Cancer, https://www.doi.org/10.3390/cancers14102467
Pilot study to evaluate tools to collect pathologist annotations for validating machine learning algorithms, https://www.doi.org/10.1117/1.JMI.9.4.047501

Depending on the skills and interests of the fellow, we will find a role to be filled in the project above. We are looking for help

designing and executing reader studies with expert readers to tailor methods to the clinical environment,
working with the multi-stakeholder group to accomplish objectives and disseminate the project goals and accomplishments,
developing mathematical and simulation demonstrations of potential to increase statistical power with new clinical trial designs and analysis methods,
developing microscope hardware and software for the display of digital pathology slides and images and data collection,
designing reader study protocols and analyses and executing them with novice readers and simulated images to demonstrate proof-of-concept under a controlled setting.

Regulatory Activity

Training courses will be offered to the Fellow on the premarket and post-market functions of CDRH, the importance of risk management in evaluating the safety of new medical products (like artificial intelligence and machine learning), how to conduct meetings, technical writing, and writing for sponsors. The Fellow will gain experience with the device approval process used in CDRH through exposure to actual submissions of imaging devices, computer-aided diagnostic (CAD) devices, and others. The fellow will assist in all aspects: the planning of trials, the review process, meeting with sponsors, writing letters to sponsors, and preparing/attending panel meetings.

Kathryn E. King, Ph.D.

Staff Scientist, Laboratory of Molecular Oncology, Division of Biotechnology Products Review and Research 1, Office of Biotechnology Products (OBP), Center for Drug Evaluation and Research (CDER), FDA

kathryn.kingk@fda.hhs.gov

240-402-9634

Project Title

Molecular mechanisms of epithelial neoplasia

Project Summary

The development of monoclonal antibodies for the targeted treatment of solid tumors is a major focus of efforts in the pharmaceutical arena as is evidenced by recent product approvals. An understanding of the molecular mechanisms underlying cancer pathogenesis is critical for the development and regulatory review of such therapies. In the Weinberg laboratory it is our aim to understand the molecular mechanisms involved in cancer pathogenesis by using the murine epidermis as a model system for the study of epithelial cancers. In particular the lab is focused on the p53 family, comprised of p53/p63/p73, which are expressed as multiple protein isoforms. These isoforms can mimic or interfere with one another, and their balance ultimately determines biological outcome in a context-dependent manner. Unlike p53 which is commonly mutated in human tumors, p63, and in particular the deltaNp63 subclass, is often overexpressed in human squamous cell cancers. However, normal levels of p63 expression are critical for normal epidermal development and homeostasis. The aim of the research is to understand the biological impact of dysregulated p63 expression and the molecular mechanisms of action underlying this impact using murine squamous epithelium in both in vitro and in vivo models.

Proposed Project for IOTF Fellow

Fellow will work on a project relating to the characterization of upstream interactions between the p63 and c-Rel pathways, mediation of downstream events, or targets impacted by the overexpression of deltaNp63 that are c-Rel dependent. This work will contribute to the overall research program of the Weinberg lab, which is focused on p63 and interacting pathways in epithelial biology and neoplasia. The fellow should have a good understanding of cancer, cellular and molecular biology. Candidates must have a Ph.D. and/or a M.D. and experience in cellular/molecular biology. The position will be located on the FDA White Oak Campus in Silver Spring, MD. Opportunities to participate in journal clubs and data sharing meetings exist.

Regulatory Activity

Over nearly 30 years monoclonal antibodies have transformed from being solely a research tool to therapeutic agents for treating human disease. Today development of monoclonal antibodies is a major focus of pharmaceutical manufacturers. The Division of Monoclonal Antibodies is responsible for product quality review of antibodies, antibody conjugates, Ig-linked fusion proteins, ScFv, Fab’s and other antibody related proteins including those currently under development for the detection and treatment of solid tumors. The Fellow will be mentored to participate in regulatory responsibilities which may range from pre-IND meeting guidance to Sponsors through post-marketing manufacturing changes. The mentor has a strong interest in cell substrate characterization issues as they relate to biologics manufacturing and the use of emerging molecular methods for virus detection in biologics. Ample additional opportunities for reviewer training are available both at the divisional and office level.

Ross Marklein, Ph.D.

Senior Staff Fellow, CBER/OTP/OCTHT/DCT1/CTTB

ross.marklein@fda.hhs.gov

832-525-7188

Project Title

Identification of manufacturing conditions that enhance cancer targeting capabilities of extracellular vesicles

Project Summary

Anticancer therapeutics can be administered systemically or locally to the diseased tissue to exert their effect; however, a number of challenges must be addressed to facilitate their clinical translation. In the case of widely investigated drug-loaded nanoparticles (NPs), only a small fraction of administered NPs reach the tumor site due to the inability to effectively cross biological barriers and reach the tumor cells directly. Additionally, these NPs can be phagocytosed or cleared by other cells (e.g. monocytes) thus reducing their anticancer effect and potentially requiring higher doses that could ultimately result in undesired harmful effects in terms of toxicity. Efforts to improve the targeting and permeability of NPs through conjugation of specific molecules/motifs has shown promise, but this approach is typically limited to single (or several) factor attachment, which may not be sufficient to ensure the NPs remain stable and efficiently reach the target tumor site. Therefore, identification of more complex, biologically-inspired surface recognition patterns and drug delivery systems could address this critical gap.

Proposed Project for IOTF Fellow

Our lab has developed a high throughput, morphological screening tool to assess the effects of different soluble cues on MSC production of extracellular vesicles. The IOTF will use this approach to screen novel 'priming' conditions (i.e. preconditioning) that alter the surface composition of EVs relevant to their ability to recognize cancer surface receptors and facilitate uptake of anticancer therapeutics. The fellow will then investigate how different manufacturing platforms (e.g. flasks vs. bioreactors) impact MSC-EV production and the subsequent cancer uptake/killing bioactivity. Together with other lab members we will associate the observed MSC-EV uptake/killing bioactivity with comprehensive proteomic and metabolomic profiles of the manufactured MSC-EVs. The knowledge gained through completion of this work will provide insight into the effect of manufacturing (soluble priming signals and scale) on MSC-EV bioactivity relevant to cancer treatment, as well as provide a generalizable platform for other EV-based therapeutics for diverse disease applications.

Regulatory Activity

The IOTF fellow will work together with the mentor and participate in the regulatory review of investigational new drug (IND) applications for cell and gene therapy products for the treatment of cancer. Besides the direct mentorship, the fellow will have the opportunity to meet with and discuss other CMC-related challenges to development of cell and gene therapies through participation in consultations and regular lab branch meetings. The fellow will also be able to attend office and divisional regulatory meetings, and research/training seminars. Finally, there will be opportunities for educational outreach as the mentor has relationships with local universities that would greatly benefit from the regulatory science perspective provided by the IOTF fellow in any of the following formats: guest lectures, seminars, and in-person scientific demonstrations. Together, these regulatory activities, combined with the proposed regulatory science project, will provide the fellow with foundational regulatory training to assess safety and efficacy of cell and gene therapy products.

Michael O’Hara, Ph.D.

Deputy Director, Division of Radiological Health, Office of In Vitro Diagnostics and Radiological Health (OIR), Center for Devices and Radiological Health (CDRH), Food and Drug Administration (FDA)

michael.ohara@fda.hhs.gov

301-796-0294

Project Title

Regulatory Requirements for Radiation Oncology (RO)

Project Summary

Like all medical treatments, radiation therapy treatments present both benefits and risk. Approximately 70% of all cancer patients will receive radiation therapy in one form or another. Of these patients, 60% will be treated with curative intent. This therapeutic modality has led to improvements in the treatment of numerous types of cancer. At the same time, it exposes patients to high doses of ionizing radiation (hereafter “radiation”), which elevates a person’s lifetime risk of developing cancer and can cause substantial morbidity. A balanced public health approach seeks to support the benefits of radiation therapy while minimizing the risk.

Patients should receive an optimal radiation dose, with the desired treatment effect on the tumor and sparing of normal tissue. FDA can advance this goal by using our regulatory authority judiciously while also collaborating with the healthcare profession community. FDA and our partners will take steps to:

Identify weaknesses in pre-market regulatory review that affect cleared medical devices;
Increase the level of post-market device failure reporting;
Develop methods to analyze device failure databases;
Promote safe use of radiation therapy devices.

By coordinating these efforts, we can optimize patient exposure to radiation, prevent treatment errors, and thereby reduce radiation-related risk while maximizing the benefits of RO treatment.

Proposed Project for IOTF Fellow

Conduct scientific reviews of radiation therapy devices to determine if changes in pre-market requirements or new post-market programs are necessary to maximize the benefits of radiation therapy with as low as reasonably achievable radiation doses. These reviews will include pre-market assessment of the regulatory data currently necessary to clear radiation therapy devices for clinical markets. The project will review post-market and compliance data from marketed radiation oncology devices to determine if the post-market and compliance issues with these devices can help predict the need for changes in regulatory scrutiny during pre-market evaluation. This project will provide input and direction for the implementation of FDA’s initiative to reduce exposure to radiation through dose reduction efforts related to equipment design and labeling. Regulatory activities related to radiation therapy treatments and regulatory changes for radiopharmaceuticals or chemotherapeutic drugs at FDA’s Center for Drug Evaluation and Research (CDER) will be assessed for impact on clearance of radiation therapy devices and our dose check program. This project will involve working with a team of interdisciplinary scientists to better regulate medical devices for radiation therapy. Also, the Fellow will provide input and direction in the implementation of FDA’s goal of reducing errors in radiation therapy through efforts related to training, equipment design and labeling, and education.

Regulatory Activity

Expected 1 year accomplishments: Learn FDA’s pre-market, post-market and compliance review program for radiation therapy products. Assist in developing and guiding implementation of all aspects of FDA’s action plan for radiation therapy devices, as described above. Develop a monitoring plan and metrics to measure longer term outcomes of FDA’s action plan.

Keith Peden, Ph.D.

Chief, Laboratory of DNA Viruses, Division of Viral Products, Office of Vaccines Research and Review, CBER, FDA

keith.peden@fda.hhs.gov

240-402-7312

Project Title

Evaluation of the safety of neoplastic cell substrates for viral vaccine production: Development of assays to assess tumorigenicity and oncogenicity

Project Summary

Vaccines have proven to be the best way to control infectious diseases. Vaccines are needed against such diseases as HIV/AIDS, pandemic influenza, MERS, Ebola virus, and Zika virus. Unfortunately, the current repertoire of cell substrates used to produce vaccines is inadequate and additional cells are needed. The types of cells required to manufacture these new vaccines are always immortal, some are tumorigenic, and some are derived from human tumors. The use of such cells presents regulatory hurdles such as the perceived risks of using cells that were derived from a human cancer to make preventative vaccines for infants and children. Our research attempts to address these concerns by establishing animal models capable of detecting the oncogenic activity of DNA. We have demonstrated that the animals most susceptible to the oncogenic activity of DNA are newborn rats and certain strains of newborn mice. Current work is centered on investigating whether the newborn p53-deficient mouse is as sensitive as other models and whether it has advantages over other rodents.

Proposed Project for IOTF Fellow

While specific projects change depending on progress being made, the general areas of research will be in evaluation of virus detection methodologies, understanding how cells become tumorigenic (which will involve investigating the contribution of epigenetics to tumorigenicity), and evaluating the oncogenicity of DNA in animal models.

Regulatory Activity

Our area of regulation is in viral vaccines against diseases caused by HIV, influenza virus, Ebola virus, Zika virus, and other viruses; our specific areas of responsibility are in product safety and manufacturing as well as in evaluating vaccine effectiveness.

Ashutosh Rao, R.Ph., Ph.D.

Chief, Laboratory of Applied Biochemistry, Division of Biotechnology Review and Research III, Office of Biotechnology Products, Office of Pharmaceutical Quality, Center for Drug Evaluation and Research (CDER), FDA

ashutosh.rao@fda.hhs.gov

240-402-7338

Project Title

Protein oxidation and autophagy in the context of cancer chemotherapy and cardiotoxicity

Project Summary

Our goal is to understand the mechanisms of oxidative stress, protein oxidation and DNA damage in the context of drug quality, safety and efficacy, with an emphasis on cancer chemotherapy and cardiotoxicity. The anthracycline doxorubicin is a critical front-line treatment for primary breast cancer. Unfortunately, doxorubicin and other oncology agents also cause dose-limiting cardiotoxicity. The cardiac damage is thought to result from mitochondrial oxidative stress that causes free radical damage to heart muscle. Previous combination therapies aimed at cardioprotection have used non-specific antioxidants that have failed to show clinical benefit. How autophagy plays a role in such drug resistance is also unclear. We have identified specific proteins that are oxidized under cardiotoxic conditions that could serve as biomarkers of adverse events and targets for cardioprotective drug development. We validated a syngeneic, preclinical animal model for investigating the safety signals from a range of small molecule and biotechnology-derived oncology agents. We apply Next Generation Sequencing technologies to decipher genetic links to the regulation of oxidative stress. Using cellular, animal models and patient-derived samples, we aim to characterize the molecular and genetic pathways by which oxidants and anti-oxidants effect cardiac and tumor biology. Towards this overall goal we have three ongoing, oncology-related projects: (1) elucidate the mechanisms of cell death and autophagy by mitochondrially-targeted redox agents, (2) the application of a syngeneic animal model for studying cardiotoxicity and antitumor efficacy of small molecule and biotechnology derived drugs, and (3) apply Next-Generation Sequencing technology to identify genomic signatures linked to drug-related adverse events.

Proposed Project for IOTF Fellow

The fellow will have the opportunity to pursue one of several research projects based on his/her interest within the context of cancer chemotherapy. Candidates must have a good understanding of cancer biology, biochemistry and molecular biology. Position is located on the main campus of the FDA at White Oak in Silver Spring, MD. The fellow will also have opportunities to interact and collaborate with oncologists and NCI laboratories on specific joint projects. The Fellow will also be expected to participate in regular research meetings and seminars.

Regulatory Activity

The Office of Biotechnology Products regulates a broad range of therapeutic agents such as monoclonal antibodies and cytokines including, but not limited to, oncology products. The fellow will actively participate in the team-based review of investigational new drug applications. The fellow will be expected to attend regulatory training sessions and participate in regulatory meetings.

Related References:

Rao VA. Targeting mitochondrial fission to trigger cancer cell death. Cancer Research. 2019 Dec 15, 79(24):6074-6075.
Heinzl GA, Lai L, Rao VA. Differentiating the Effects of Oxidative Stress Tests on Biopharmaceuticals. Pharm Res. 2019 May 17;36(7):103.
Pokrzywinski KL, Biel TG, Rosen ET, Bonanno JL, Aryal B, Mascia F, Moshkelani D, Mog S, Rao VA. Doxorubicin-induced cardiotoxicity is suppressed by estrous-staged treatment and exogenous 17β-estradiol in female tumor-bearing spontaneously hypertensive rats. Biol Sex Differ. 2018.
Aryal B, Rao VA. Specific protein carbonylation in human breast cancer tissue compared to adjacent healthy epithelial tissue. PLoS One. 2018.
Biel TG, Rao VA. Mitochondrial dysfunction activates lysosomal-dependent mitophagy selectively in cancer cells. Oncotarget. 2017.
Aryal B, Jeong J, Rao VA. Doxorubicin-induced carbonylation and degradation of cardiac myosin binding protein C promote cardiotoxicity. Proc Natl Acad Sci U S A. 2014.

SBRBPAS Expert, Office of Biotechnology Products (OBP), Office of Pharmaceutical Quality (OPQ), Center for Drug Evaluation and Research, Food and Drug Administration

Baolin.Zhang@fda.hhs.gov

240-402-6740

Regulatory Science Priority Area: Improve product manufacturing, testing, and surveillance to help ensure the availability of high-quality drugs

Project Title

Bioassays for biotechnology products

Project Summary

Bioassays or potency assays are a critical component of quality control strategies for biotechnology products, including monoclonal antibodies (mAbs), bispecific antibodies (BsAbs), and antibody-drug conjugates (ADCs). Dr. Zhang’s laboratory has a track record of research and regulatory expertise in the development of bioassays for biotechnology products and other complex drug products. Currently, the Lab is working to develop functional bioassays for therapeutic antibodies indicated for treatment of cancer and COVID-19. The bioassay research aligns with the Agency’s regulatory mission to ensure product quality and manufacturing consistency, thus facilitating evaluation or development of FDA-regulated products and supports regulatory decision-making and policy development.

Proposed Project for IOTF fellow

The Fellow will join in a multidisciplinary research team to develop and validate novel bioassays for therapeutic antibodies (mAbs, BsAbs, ADCs). This includes assessing the functional impacts of variability in critical product quality attributes (CQAs) - especially those resulting from glycosylation and aggregation of antibody products regulated by FDA.

Regulatory Activity

The Office of Biotechnology Products (OBP) regulates a broad array of biotechnology products (e.g., recombinant proteins, monoclonal antibodies, bispecific antibodies, antibody-drug conjugates, biosimilars, combination products). The Fellow will actively participate in the team-based review of INDs and BLAs and their respective amendments and supplements.

References

Alexis Dean, Shen Luo, Julianne Twomey, and Baolin Zhang (2021) Targeting cancer with antibody-drug conjugates: Promises and Challenges, mAbs, 13:1, DOI: 10.1080/19420862.2021.1951427
Alexis Dean, William Bozza, Julianne Twomey, Shen Luo, Ancy Nalli, and Baolin Zhang (2021) The fight against COVID-19: Striking a balance in the renin-angiotensin system. Drug Discovery Today, DOI: 10.1016/j.drudis.2021.04.006
Julianne Twomey and Baolin Zhang (2021) Cancer immunotherapy update: FDA approved checkpoint inhibitors and companion diagnostics. The AAPS Journal, 23:39. DOI: 10.1208/s12248-021-00574-0.
Julianne Twomey, Shen Luo, Alexis Dean, William Bozza, Ancy Nalli, and Baolin Zhang (2020) COVID-19 update: The race to therapeutic development. Drug Resistance Updates. 52, 100733.

Shen Luo, Keisha McSweeney, Tao Wang, Silvia M. Bacot, Gerald M. Feldman & Baolin Zhang (2020) Defining the right diluent for intravenous infusion of therapeutic antibodies, mAbs, 12:1, DOI: 10.1080/19420862.2019.1685814