Benjamin Fisher, Ph.D. and April Marrone, Ph.D.
|Benjamin Fisher, PhD|
Division of Reproductive, Gastro-renal, Urological
Office of Device Evaluation (ODE)
Center for Devices and Radiological Health (CDRH)
The Division of Reproductive, Gastro-Renal, and Urological Devices (DRGUD) reviews a wide variety of medical devices such as biliary stents, contraceptive devices, organ preservation equipment, endoscopes, and obesity treatment devices. DRGUD also provides subject matter expertise on its regulated devices to support other offices in CDRH (e.g., Office of Compliance and Office of Surveillance and Biometrics). Benjamin (Ben) Fisher is
currently the Director of DRGUD within CDRH/ODE. Ben began his toxicology career in 1978 working with the Bureau of Radiological Health (now CDRH) where his initial training focused on the assessment of ultrasound-induced developmental and behavioral toxicology. During his tenure at FDA, his training continued in mammalian teratology and he attended the University of Maryland where he received his BS and MS in developmental biology. Ben received his PhD in developmental genetics from the George Washington University where his research utilized mammalian whole embryo culture to evaluate alterations in embryonic gene expression as biomarkers of exposure and toxicity, and their utility in predicting skeletal anomalies. Ben left the FDA in 1998 for a distinguished career in industry. During his industrial career, Ben was a Principal Scientist and Study Director Manager at Covance Laboratories where he was responsible for the design, conduct, and interpretation of preclinical developmental and reproductive toxicology (DART) and juvenile toxicology studies. In addition, he provided oversight to the developmental and reproductive toxicology program at Covance-Vienna. Ben returned to CDRH in 2010, as the Deputy Director of the Division of Biology, providing oversight to the toxicology programs within the Office of Science and Engineering Laboratories.
The Gastroenterology Devices Branch (GEDB) is responsible for the regulatory review of premarket submissions and investigational device exemptions submitted to CDRH/ODE to promote the safety and efficacy of FDA cleared and approved devices and to ensure reasonable safety of participants in clinical device investigations. As a lead reviewer in GEDB, April Marrone conducts scientific regulatory review and provides chemistry consults to other lead reviewers. April is also interested in promoting improvement in product manufacturing and quality through developing device specific FDA guidance, creating review tools to ensure consistency and quality in device review, and publishing external manuscripts on topics relevant to the FDA and industry on topics in the gastroenterology, endoscopy, and bariatric surgery device space. April has served as DRGUD’s representative on the Medical Device User Fee Act IV (MDUFA IV) working group, spearheaded moving FDA guidance on marketing submissions for biliary stents through CDRH, and participated in reclassification efforts for certain types of contraceptive devices. April has served as mentor to new reviewers and has instructed Reviewer Certification Program courses.
Prior to joining CDRH/ODE in November of 2014, April was a Commissioner Fellow at FDA’s National Center for Toxicology Research (NCTR), and has served on the Commissioner Fellowship Program (CFP) Advisory Board. During her tenure at the NCTR, April did research to develop novel epigenetic approaches to safely assess the safety and carcinogenicity of FDA regulated products. Prior to joining the FDA, April was a post-doctoral scientist at the University of Pittsburgh, Children’s Hospital of Pittsburgh where she studied epigenetic regulation of congenital kidney disease in a mouse model. April also completed post-doctoral training at the Max Planck Institute for Biophysical Chemistry where she studied genetic and epigenetic regulation of neuromuscular disease.
Proposed Research Project for FDA Fellow
The proposed project has three specific objectives:
1) Develop review tools and contribute to the scientific body of literature on biliary self- expanding metallic stents (SEMS)
2) Develop FDA guidance on obesity treatment devices and contribute to the scientific body of literature
3) Assist in premarket review of devices regulated by ODE/DRGUD/GEDB.
The first objective is aimed at facilitating the medical device review process and improving review quality and consistency in biliary SEMS device submissions. Biliary SEMS are Class II devices that require a 510(k) marketing submission. The Gastroenterology Device Branch (GEDB) developed a guidance document, that when finalized, will provide recommendations to industry on how to present data to demonstrate that a new biliary SEMS for palliation of malignancies is as safe and effective as a biliary SEMS that is already available on the market. One goal of the first objective is to incorporate the recommendations in the guidance document into review tools specific to biliary SEMS to aid in 510(k) premarket review of these devices
The FDA has recently been challenged with premarket submissions requesting that the indication of use (IFU) for biliary SEMS be expanded to include the treatment of benign biliary strictures. Treatment of benign strictures is different from palliation of malignant strictures because symptoms associated with benign strictures should resolve following successful treatment making stent removal necessary. This presents the clinical question, could these stents potentially migrate out of the biliary tree causing adverse events and can they be removed following successful treatment. Currently there is little data that the FDA can leverage to address risks that pertain to SEMS for long-term stricture resolution following biliary stent removal. Therefore, another goal of the first objective is to conduct a comprehensive literature review of clinical studies evaluating the use, effectiveness, and adverse events associated with SEMS for benign biliary strictures. A summary of the literature review is intended to be submitted for peer-reviewed publication. This documentation will better educate the GEDB team and industry on the risks and benefits of SEMS for treatment of benign biliary strictures.
GEDB also regulates medical devices intended to treat obesity. Obesity has recently been recognized as a disease with multiple associated morbidities; this is an exciting, relatively new device space, and devices intended to treat obesity are highly variable in their design and mechanism of action. The diversity of these devices presents challenges to FDA on how to make consistent recommendations to industry in an effort to design the most appropriate clinical studies. In 2013, the FDA published a benefit-risk paradigm for clinical trial design of obesity devices, but recent innovative advances in this device space require FDA to revisit and update the paradigm. The second objective of this project is to summarize the regulatory history and current submission status of FDA regulated devices for the treatment of obesity (e.g., technology vs effective weight loss vs adverse events). This work will support GEDB efforts in updating the current benefit-risk paradigm and provide industry with guidance on
clinical trial design. Additionally, guidance on clinical trial design for obesity treatment devices would aid the FDA and industry in ensuring quality evidence is collected to support marketing applications.
The third objective of this project is to provide GEDB with additional resources in medical device review of premarket submissions. A significant amount of knowledge can be gained through evaluation of products via premarket review. Combining the efforts in developing objectives 1 and 2, the aim of the third objective is to develop the fellow’s knowledge in the application of regulatory science. This in turn, will support the personal and professional development of the Commissioner’s fellow.
• Ph.D. in biological/physical sciences and/or biomedical engineering
• Knowledge in gastrointestinal biology (preferred but not required)
• Strong skills in scientific and technical analyses
• Ability to understand regulations of medical devices
• Familiarity with or willingness to learn how to create macros using Microsoft Word
• Documented history of excellent writing and communication skills
Selected Recent Publications
1. A. Marrone, M. Antonino, J. Silverstein, M. Betz, P. Venkataraman-Rao, M. Golding, D.
Cordray, J. Cooper (2016) The regulatory perspectives on endoscopic devices for obesity. Gastrointestinal Endoscopy Clinics of North America (accepted for publication)
2. A. Marrone, V. Tryndyak, F. A. Beland, I. P. Pogribny (2015) MicroRNA responses to the genotoxic carcinogens aflatoxin B1 and benzo[a]pyrene in human HepaRG cells. Toxicol Sci, 149(2):496-502. Doi: 10.1093/toxscikfv253
3. A. Marrone, A. Yatsenko, H. Shcherbata (2014) “Perceptive-Executive-Mechanism of miRNA based buffering of the Cobblestone-Lissencephaly-associated ECM receptor Dystroglycan via its alternative 3’UTR in the Drosophila brain”, Nature Communications, doi: 10.1038/ncomms5906
4. A. Marrone, F. Beland, I. Pogribny (2014) “Non-coding RNA response to xenobiotic exposure: indicator of toxicity and carcinogenicity”, Expert Opinion on Drug Metabolism and Toxicology, 10(10):1409-22. doi: 10.1517/17425255.2014.954312
5. A. Marrone, D. Stolz, S. Bastacky, D. Kostka, A. Bodnar, J. Ho (2014) “miR-17~92 is required for nephrogenesis and renal function”, J Am Soc Nephrol. 25(7): 1440-52. doi: 10.1681/ASN.2013040390