Regenerative Medicine Combination Products for Devices & Biologics
Regenerative medicine is a dynamic and exciting field that provides hope of restoring, regenerating, repairing, or replacing missing or damaged tissues. The potential medical applications are numerous and varied. Many regenerative medicine products are complex, in that tissue engineering can involve biologic and device combinations, for example, 3-dimensional, cell-scaffold configurations. These novel products represent the confluence of clinical medicine, engineering, and science. The Regenerative Medicine Program is intended to extend and enhance the ability of FDA to regulate regenerative medicine products effectively and to permit the agency to participate in product development proactively, so that safe and effective new products can become available to patients.
The Regenerative Medicine Program in the Commissioner’s Fellowship Program is cross center collaboration between the Center for Biologics Evaluation and Research (CBER) and the Center for Devices and Radiological Health (CDRH). Selected Fellows will be mentored by Preceptors in both the CDRH and CBER.
This project will accept two Fellows. If you would like to apply to this project, list Kenneth J. Cavanaugh on your application. Drs. Durfor and Oh will also receive the applications submitted to Dr. Cavanaugh.
Fellows are trained and participate in biologic and device regulation in both Centers and benefit from the mentoring of senior regulatory scientists from the two Centers. All Fellows in the Regenerative Medicine Program will:
- Participate in and learn the review processes in both CBER and CDRH;
- Participate in FDA working groups such as the cross-center tissue engineering working groups;
- Provide scientific direction for Regenerative Medicine Seminar series;
- Have the potential to perform outreach activities such as writing articles for publication or presenting at public workshops;
- Have exposure to activities such as standards development and collaborations with external organizations (i.e. Multi-agency Tissue Engineering Science Interagency Working Group).
In addition to regulatory work, each Fellow will have the opportunity to develop a unique project under the guidance of the Preceptors listed below. The projects are aimed at assessing current challenges or needs in the field of regenerative medicine, identifying and organizing the relevant applicable resources, and proposing potential solutions. The project outcomes will enhance the clinical development of regenerative medicine products and increase collaboration among CBER, CDRH, and the regulated community.
Bachelor of Chemical Engineering with Minors in Chemistry and Biology, Villanova University
Ph.D. in Bioengineering, University of Pennsylvania
FDA experience – 8 years
Dr. Cavanaugh is the Chief of the Peripheral Vascular Devices Branch (PVDB), Division of Cardiovascular Devices (DCD), Office of Device Evaluation (ODE), Center for Devices and Radiological Health (CDRH), a position he has held since 2008. PVDB is responsible for the pre-market review of all cardiovascular devices used outside the heart and brain, including vascular stents, vascular and endovascular grafts, inferior vena cava filters, and angioplasty catheters. Many of these devices incorporate biologic components (e.g. vascular grafts involving protein coatings or originating from animal tissue) or are combination products involving substantial device and drug components (e.g. drug-eluting stents or drug-coated angioplasty balloons).
From 2003 to 2008, Dr. Cavanaugh was a biomedical engineer and scientific reviewer in PVDB, focusing on the review of carotid and renal artery stents and embolic protection devices, combination products, and delivery systems for cell and gene therapies. He holds a bachelor's degree in chemical engineering with minors in biology and chemistry, and a Ph.D. in bioengineering. His dissertational research focused on lung injury mechanics.
Proposed Research Project for FDA Fellow: (see description in Dr. Durfor's section as Dr. Durfor and Dr. Cavanaugh will co-mentor one fellow)
The applicant should have an advanced degree (Ph.D. , D.V.M or M.D.) with experience in the field of Regenerative Medicine and preclinical testing of biological materials.
Selected Recent Publications:
A Kumar, K Cavanaugh, S Brooks, and B Zuckerman. FDA perspective on objective performance goals and clinical trial design for evaluating catheter-based treatment of critical limb ischemia. J Vasc Surg. 50(6):1474-6 (2009).
B.S. (Chemistry) College of William and Mary
Ph.D. (Bioorganic Chemistry) University of Virginia
Dr. Durfor is an expert regulatory reviewer in the Plastic and Reconstructive Surgery Devices Branch (PRSB), Division of Surgical, Orthopedic and Restorative Devices (DSORD), Office of Device Evaluation (ODE), Center for Devices and Radiological Health (CDRH). Dr. Durfor has served in the Plastic and Reconstructive Surgery Devices Branch of ODE since June 26, 1994. Previously, he was employed, (since November 8, 1988), by the Center for Biologics Evaluation and Research (CBER) and the National Institutes of Health (NIH) within the Public Health Service (PHS). He was also the lead reviewer for the first cellular device products to receive PMA (Apligraf) and HDE (OrCel) approvals.
PRSB reviews 510(k)s, IDEs, HDEs and PMAs seeking approval for devices for: wound healing (e.g., acute burn wounds and chronic ulcers) and soft tissue repair (e.g., facial, peritoneal and lung tissues) as well as several biological and drug products containing device materials through InterCenter consults. Many of these devices contain components composed of physiological materials (e.g., cells, proteins and polysaccharides) or biosynthetic (e.g., in situ crosslinking or polymerizing) materials. Dr. Durfor's experience includes regulation of mammalian cell culture products and in situ polymerizing medical devices, research on protein structure/function, and considerable exposure to clinical trial design issues (e.g., from 200-2001 he served as the Chairman of the InterCenter Clinical Wound Healing Group). He is currently the CDRH expert on “the chemistry and manufacturing of biosynthetic, cellular and tissue-derived medical devices for soft tissue repair.”
Proposed Research Project for FDA Fellow and Applicant Requirements:
Previously, Commissioner’s Fellows evaluated the existing methods for performing such studies in soft tissue material (i.e., Dr. Caitilin Hamilin – class 2008) and orthopedic applications (Katherine Kavlock-Class 2009). A related assessment is being performed for systems that deliver cellular and cell/scaffold constructs (Dr. James Bertram – Class 2009). It is clear however, that standard approaches for evaluating biocompatibility testing may not be appropriate or informative for regenerative medicine products (or in situ –polymerizing devices), e.g., see C. Durfor’s Staff College Presentations entitled “Biocompatibility Evaluation of Biotechnology Products.” This is because xenogenic cells or extracelluar matrix may be present on the former class of products and the chemical/physical composition may change in the later class of devices. Recognition of this issue led CDRH to submit (and receive Critical Path funding) for a program that reevaluated the biocompatibility testing for devices in contact with neurological tissue.
The proposed Fellow will: 1) draw upon the results of Drs. Hamilin and Kavlock’s Fellowship projects in preclinical testing for hard and soft tissue materials, respectively, (as well as the findings of other Fellows when appropriate), 2) review the data available for investigational and approved medical devices and biologics and 3) their own research experience in the field of Regenerative Medicine to determine the following issues for cell/scaffold products and novel medical devices components (e.g., in situ-polymerizing and/or physiological materials):
- Under what conditions will the current methods of evaluating biocompatibility provide meaningful and sufficient data.
- What criteria should be met so that meaningful and sufficient biocompatibility/preclinical data can be based on published literature of similar products (and hence reduce the need for animal studies).
- Under what conditions and how should sample preparation methods be modified to provide more accurate evaluation of biocompatibility (e.g., studies on components rather than a final product; tests performed on animal-derived constructs rather then the proposed human-product; studies with final product rather than extracts; or studies with reagents and reaction intermediates in addition to final products).
- Under what conditions might additional / new tests be considered to augment the current biomaterial biocompatibility test methods (e.g., in addition to L929 fibroblast cytotoxicity perhaps monitoring metabolic activity or using the quantitative microscopy techniques published by Dr. John T. Elliott (NIST) and others that are under consideration as ASTM standards).
A major aspect of evaluating medical devices and Biological cell / scaffold constructs prior to initiating clinical studies or completing biocompatibility studies (i.e., ISO-10993, Biological Evaluation of Medical Devices Part-1: Evaluation and Testing, and http://www.fda.gov/cdrh/g951.html).
Selected Recent Publications:
- Lyle DB, Shallcross JC, Durfor CN, Hitchins VM, Breger JC, Langone JJ,, “Screening biomaterials for stimulation of nitric oxide-mediated inflammation,” J Biomed Mater Res A. 2008 May 15;90A(1):82-93.
- C. Witten, A. Batra, C.N. Durfor, S.L. Hilbert, D.S. Kaplan, D. Fink, D. Lavoire, E. Mahler and R. McFarland, “Overview of FDA Regulatory Process,” in Principles of Regenerative Medicine, A. Atala, R. Lanza, J. Thomson and R. Nerem (editors), Amsterdam, Academic Press, Elsevier, 2008
- KJ.B. Hellman, R.R. Solomon, C. Gaffey, C. N. Durfor and J.G. Bishop. Regulatory Considerations, pp 915-927, Principles of Tissue Engineering, 2nd Ed., R.P. Lanza, R. Langer and J. Vacanti (editors), San Diego, Academic Press, 2000.
- K.B. Hellman, E. Knight, and C.N. Durfor. Tissue Engineering: Product Applications and Regulatory Issues, pp. 341-366, Frontiers in Tissue Engineering, Charles W. Patrick, Antonio G. Mikos, and Larry V. McIntire (editors), Amsterdam, Elsevier Science, 1998.
- C.N. Durfor. Biotechnology Biomaterials: A Global Regulatory Perspective for Tissue Engineered Products: Summary Report and Future Directions. Tissue Engineering, 3(1), 115-120, 1997.
Steven S. Oh, Ph.D.
Team Lead, Device and Combination Product
Division of Cellular and Gene Therapies
Office of Cellular, Tissue and Gene Therapies
Center for Biologics Evaluation and Research
Ph.D., University of Michigan
Postdoctoral Fellowship, Johns Hopkins University School of Medicine and Massachusetts Institute of Technology
Faculty, Tufts University School of Medicine
FDA Experience – Since 2007
Dr. Oh serves as Team Lead for device evaluation in the Division of Cellular and Gene Therapies. His areas of regulatory expertise include device-biologic combination products, tissue engineered products, and medical devices with regenerative or therapeutic indications. He provides leadership in reaching various regulatory decisions on products submitted for marketing, clinical investigation, or classification. He also actively participates in policy development and staff training for these combination products as well as devices that produce biologic as the output. Dr. Oh spent some time in CDRH serving as a visiting review scientist from CBER. This unique experience has been crucial to Dr. Oh’s understanding and appreciation of balanced approaches to biologic and device regulation. Upon returning to CBER from CDRH, Dr. Oh has founded Device Biologics Interest Group (DBIG) in 2008 providing a forum to regulatory staff in CBER and CDRH to learn and exchange ideas about regulations, policies, standards, technologies, and review practices applicable to devices and device-biologic combination products. He continues in the effort to harmonize scientific review practices and standards for combination products and devices regulated by CBER and CDRH.
Proposed Research Project for Multi-Center Fellowship in Regenerative Medicine:
Devices used at the patient point of care to process autologous biologic material are becoming increasingly prevalent, particularly in the field of regenerative medicine. A similar type of devices may often have multiple intended uses with varying therapeutic indications. In some cases, a device may produce a biologic output that is a therapeutic product, but the same device could also be used to prepare a clinical sample for an in vitro diagnostic test. These devices may be regulated either in CBER or CDRH. Devices processing biologics at point of care raise unique questions such as: a) Is device control alone sufficient to ensure the quality of the biologic output of the device needed for the device to be safe and effective? b) What kinds of controls and testing are necessary to ensure the device performs adequately for a given intended use and/or clinical indication?
To address these important regulatory questions, the fellow would review the scientific literature to identify the relevant scientific questions that need to be addressed during device development. In addition, the fellow will review and summarize FDA policies in this area. This effort would provide perspectives on the critical information that should be addressed in development for device manufacturing biologics at point of care. An important outcome of the project may be a set of recommendations or white paper discussing the controls necessary to ensure biologic product quality. In addition, these recommendations could provide basis for future FDA guidance documents.
Ph.D. in biology or M.S. in Biomedical engineering (plus 3+ years of research experience) and relevant experience in regenerative medicine.
Selected Recent Publications:
- Lee MH, Arcidiacono JA, Bilek AM, Wille JJ, Hamill CA, Wonnacott KM, Wells MA, Oh SS. Considerations for Tissue Engineered and Regenerative Medicine Product Development Prior to Clinical Trials in the United States. Tissue Eng Part B Rev. 2010, 16, 41-54.
- Li X, Chen H, Oh SS, Chishti AH, A Presenilin-like protease associated with Plasmodium falciparum micronemes is involved in erythrocyte invasion. Mol Biochem Parasito. 2008, 158, 22-31.
- Kariuki MM, Li X, Yamodo I, Chishti AH, Oh SS. Two P. falciparum merozoite proteins binding to erythrocyte band 3 form a direct complex. Biochem Biophys Res Commun 2005, 338, 1690-1695.
- Oh SS, Chishti AH. Host receptors in malaria merozoite invasion. Curr Top Microbiol Immunol 2005, 295, 203-232.
- Li X, Chen H, Oo TH, Daly TM, Bergman LW, Liu SC, Chishti AH, Oh SS. A co-ligand complex anchors Plasmodium falciparum merozoites to the erythrocyte invasion receptor band 3. J Biol Chem 2004, 279, 5765-5771.
- Goel VK, Li X, Chen H, Liu SC, Chishti AH, Oh SS. Band 3 is a host receptor binding merozoite surface protein-1 during the Plasmodium falciparum invasion of erythrocytes. Proc Natl Acad Sci, USA 2003, 100, 5164-5169.
- Hanspal M, Goel VK, Raphael P, Oh SS, Chishti AH. Erythrocyte calpain is dispensable for malaria parasite invasion and growth. Mol Biochem Parasitol 2002, 122, 226-228.
- Lutchman M, Kim AC, Cheng L, Whitehead IP, Oh SS, Hanspal M, Boukharov AA, Hanada T, Chishti AH. Dematin interacts with the Ras-guanine nucleotide exchange factor Ras-GRF2 and modulates mitogen-activated protein kinase pathways. Eur J Biochem 2002, 269, 638-649.
- Voigt S, Hanspal M, LeRoy PJ, Zhao PS, Oh SS, Chishti AH, Liu SC. The cytoadherence ligand Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) binds to the P. falciparum knob-associated histidine-rich protein (KAHRP) by electrostatic interactions. Mol Biochem Parasitol 2000 110, 423-428.
- Oh SS, Voigt S, Fisher D, Yi SJ, LeRoy PJ, Derick LH, Liu SC, Chishti AH. Plasmodium falciparum erythrocyte membrane protein 1 is anchored to the spectrin-actin junction and knob associated histidine-rich protein in the erythrocyte skeleton. Mol Biochem Parasitol 2000 108, 237-247.