Gilbert J. Burckart, Pharm.D.

Associate Director for Regulatory Policy
Office of Clinical Pharmacology
Office of Translational Science
Center for Drug Evaluation and Research
Silver Spring, MD

Background:

Pharm.D.
FDA Experience - 1 year

Research Interests:

Pharmacogenomics of Immunosuppressive Agents, Pediatric Clinical Pharmacology, Membrane Transporters, Biomarkers in Transplantation

Proposed Research Project for FDA Fellow:

Pharmacogenomics and Pharmacometrics of Adverse Effects and Dosing of Anti-Proliferative Agents in Children Following Heart Transplantation

Selected Recent Publications:

1. Burckart GJ, Amur S, Goodsaid FM, Lesko LJ, Frueh FW, Huang SM, Cavaille-Coll M. Qualification of biomarkers for drug development in organ transplantation. American Journal of Transplantation 2008; 8:267-270.
2. Burckart GJ. Pharmacogenomics: the key to improved drug therapy in transplant patients. Clinical Laboratory Medicine 2008; 28:411-422.
3. Girnita DM, Brooks MM, Webber SA, Burckart GJ, Ferrell R, Zdanowicz G, DeCroo S, Smith L, Chinnock R, Canter C, Addonizio L, Bernstein D, Kirklin JK, Naftel D, Girnita AL, Zeevi A. Genetic polymorphisms impact the risk of acute rejection in pediatric heart transplantation: A multi-institutional study. Transplantation 2008; 85:1632-39.
4. Girnita DM, Burckart G, Zeevi A. Effect of cytokine and pharmacogenomic genetic polymorphisms in transplantation. Current Opinion in Immunology 2008; 20:614-25.
5. Wang J, Shaw L, Figurski M, Burckart GJ. The impact of P-glycoprotein and Mrp2 on mycophenolic acid levels in mice. Transplant Immunology 2008; 19:192-196.
6. Frueh FW, Amur S, Mummaneni P, Epstein RS, Aubert RE, DeLuca TM, Verbrugge RR, Burckart GJ, Lesko LJ. Pharmacogenomic biomarkers information in drug labels approved by the United States Food and Drug Administration: prevalence of related drug use. Pharmacotherapy 2008; 28: 992-998.
7. Liu S, Beringer PM, Hidayat L, Rao AP, Louie S, Burckart GJ, Shapiro B. Probenecid, but not cystic fibrosis, alters the total and renal clearance of fexofenadine. Journal of Clinical Pharmacology 2008; 48: 957-65.
8. Huang S-M, Strong JM, Zhang L, Reynolds KS, Nallani S, Temple R, Abraham S, Al Habet S, Baweja RK, Burckart GJ, Chung S, Colangelo P, Frucht D, Green MD, Hepp P, Karnaukhova E, Ko HS, Lee J-I, Marroum PJ, Norden JM, Qiu W, Rahman NA, Sobel S, Stifano T, Thummel K, Wei XX, Yasuda S, Zheng JH, Zhao H, Lesko LJ. New era in drug interaction evaluation: US Food and Drug Administration update on CYP enzymes, transporters and the guidance Process. Journal of Clinical Pharmacology 2008; 48:662-670.

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Edward Cox, M.D., M.P.H. 

Director, Office of Antimicrobial Products (OAP)
Office of New Drugs
Center for Drug Evaluation and Research
10903 New Hampshire Avenue
Silver Spring, MD 

Background:

M.D., Univ. of North Carolina School of Medicine
M.P.H., Johns Hopkins School of Hygiene and Public Health
FDA Experience – 11 years
Medical Officer in the Division of Special Pathogen and Transplant Products
Deputy Director of Office of Antimicrobial Products
Director of Office of Antimicrobial Products
Board Certifications – infectious diseases and internal medicine (ABIM)

Research Interests:

• Antimicrobial drug development
• Issues in clinical trial design
• Antimicrobial resistance

Proposed Research Project for FDA Fellow:

1. Evaluation of the trends over time in antibacterial drug development.
2. Evaluation of factors including economic factors that impact upon decisions to develop or not develop antibacterial drugs.

Selected Recent Publications:

Overview of recent studies of community-acquired pneumonia. Higgins K, Singer M, Valappil T, Nambiar S, Lin D, Cox E.  Clin Infect Dis. 2008 Dec 1;47 Suppl 3:S150-6.

Perspective piece on antibacterial drug development in News and Analysis. Cox E. Nature Reviews Drug Discovery. January 2007;6(1):12.

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John Z. Duan, Ph.D. 

Biopharmaceutics,
Office of New Drug Quality Assessment
Office of Pharmaceutical Science
Center for Drug Evaluation and Research
Silver Spring, MD

Background:

Ph.D. in Pharmaceutical Science
FDA Experience - 13 years

Research Interests:

Dr. Duan has special interest in biopharmaceutics, especially IVIVC analyses. With his programming expertise, he found that the review practice involved a lot of repetitive activities and one of the solutions he has been pursuing is automation. His current project is developing a review tool for biopharmaceutics review, which will be a collection of modules and each of them is a combination of knowledge base, review template, and training tool for a particular type of biopharmaceutics study. The research project titled “Biopharmaceutics Review Tool Development” is in line with following three key opportunity areas identified in critical path initiatives: Better Evaluation Tools, Harnessing Bioinformatics and Moving manufacturing into the 21st century.

Proposed Research Project for FDA Fellow:

The research project titled “Biopharmaceutics Review Tool Development” may address the following three issues related to review management.

1. Consistency: the review tool will provide quality standardized review for routine biopharmaceutics studies. Standardization, which can effectively use the limited resources, is the key for better and quicker reviews.
2. Training resource: the review tool will provide training tool for reviewers with diverse clinical pharmacology background.
3. Time management: the review tool will save time because reviews of routine studies will be automated.

The review tool will be a knowledge base for standard biopharmaceutics issues. It will be an easy-use, issue-specific, and question-based tool. It will help reviewers to retrieve the relevant parts of the knowledge base in a handy way according the review issues. It will keep review consistency, improve the quality and shorten the review time. It will also be an education tool.

Selected Recent Publications:

1. Clinical Pharmacology and Biopharmaceutics (CPB) ReviewKit Development. John Z Duan, Padmaja Mummaneni, Nu He, Kirk Roy and Chandra Sahajwalla. FDA Science Forum: Transforming the FDA through Bioinformatics. Novermber, 2008. FDA

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Jogarao (Joga) V.S. Gobburu, Ph.D. 

Center for Drug Evaluation and Research
Silver Spring, MD

Background:

FDA Experience - 10 years

Research Interests:

Quantitative Clinical Pharmacology or Pharmacometrics; modeling and simulation of clinical trials; clinical trial design; dose optimization using Pharmacometrics.

Proposed Research Project for FDA Fellow:

1. Quantitative disease models.
2. Modeling and simulation based clinical trial design, especially in pediatrics.

Selected Recent Publications:

1. JVS Gobburu, Gopalakrishnan M. Optimal Dose Finding in Drug Development: Approaches and Regulatory Perspectives in Dose Optimization in Drug Development, Editor Krishna R, Marcel Dekker, 2001.
2. Cohen MH, Johnson JR, Massie T, Sridhara R, McGuinn WD Jr, Abraham S, Booth BP, Goheer MA, Morse D, Chen XH, Chidambaram N, Kenna L, Gobburu JV, Justice R, Pazdur R. Approval summary: nelarabine for the treatment of T-cell lymphoblastic leukemia/lymphoma. Clin Cancer Res. 2006 Sep 15;12(18):5329-35.
3. Jadhav PR, Agerso H, Tornoe CW, Gobburu JV. Semi-mechanistic pharmacodynamic modeling for degarelix, a novel gonadotropin releasing hormone (GnRH) blocker. J Pharmacokinet Pharmacodyn. 2006 Oct;33(5):609-34. Epub 2006 Aug 8.
4. Jadhav PR, Gobburu JV. A new equivalence based metric for predictive check to qualify mixed-effects models. AAPS J. 2005 Oct 7;7(3):E523-31. Review.
5. Bhattaram VA, Booth BP, Ramchandani RP, Beasley BN, Wang Y, Tandon V, Duan JZ, Baweja RK, Marroum PJ, Uppoor RS, Rahman NA, Sahajwalla CG, Powell JR, Mehta MU, Gobburu JV. Impact of pharmacometrics on drug approval and labeling decisions: a survey of 42 new drug applications. AAPS J. 2005 Oct 7;7(3):E503-12. Review.

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H.M. James Hung, Ph.D. 

Division of Biometrics I
Office of Biostatistics, Office of Translational Science
Center for Drug Evaluation and Research
Silver Spring, MD

Research Interests:

Throughout his 20+ years with CDER of FDA, Dr. Hung has been conducting extensive research on factorial design trials, utility of p-value distribution, adaptive design/analysis, non-inferiority trials, and multi-regional trials. His research was supported by a number of CDER RSR funds. In addition to research, Dr. Hung has been contributing to several FDA/CDER working groups such as non-inferiority guidance group, adaptive design guidance group.

Proposed Research Project for FDA Fellow:

Working with Dr. Hung, the fellow will participate in biostatistical research relevant to regulatory science, particularly in the areas of clinical trial design/analysis methodology and the statistical principle for interpretation of scientific evidence to help enhance drug development programs. In particular, the innovative designs such as non-inferiority design and adaptive design that deviate greatly from the conventional clinical trial designs have a great many of challenges and controversies in terms of the methods for statistical inference and logistic issues. Multi-regional clinical trials have become reality and been faced with the serious problems of interpretability of trial results because of large regional differences seen in many regulatory applications. There is a dire need of research to enhance trial design for minimizing regional differences. Future directions of research in these areas include assessment of utility and pitfalls of these trial designs, management of trial conduct and data quality issues.

Selected Recent Publications:

1. Hung, H.M.J., Wang, S.J., O';Neill, R (2007). "Statistical considerations fortesting multiple endpoints in group sequential or adaptive clinical trials", Journal of Biopharmaceutical Statistics 17, 1201-1210.
2. Hung, H.M.J., Wang, S.J., O'Beill, R. (2007). "Non-inferiority trials", Encyclopedia of Clinical Trials, John Wiley & Sons.
3. Hung, H.M.J., Wang, S.J., O'Neill, R (2007). "Issues with statistical risks for testing methods in noninferiority trial without a placebo arm", Journal of Biopharmaceutical Statistics 17, 201-213.
4. Hung, H.M.J. (2007). "Some considerations in use of adaptive design in global clinical trial program", Japan's Critical Path Opportunities - Advanced and
5. Global Drug Development Techniques, the 7th Kitasato University – Harvard School of Public Health Symposium, Ed. by M. Takeuchi and S. Lagakos, 193-202.
6. Hung, H.M.J. (2006). Discussion on "Adaptive clinical trial designs: ready for prime time?" 2004 Workshop jointly sponsored by FDA and Harvard-MIT
7. Division of Health Science and Technology, Statistics in Medicine 26, 3313-3314.
8. Hung, H.M.J., O'Neill, R., Wang, S.J., Lawrence, J. (2006). "A regulatory view on adaptation/flexible clinical trial design", Biometrical Journal 48, 565-573.
9. Hung, H.M.J., Wang, S.J., O'Neill, R. (2006). "Methodological issues with adaptation of clinical trial design", Pharmaceutical Statistics 5, 99-107.
10. Hung, H.M.J., Wang, S.J., O'Neill, R. (2005). "A regulatory perspective on choice of margin and statistical inference issue in non-inferiority trials", Biometrical Journal 47, 28-36.
11. Hung, H.M.J., Wang, S.J., Tsong, Y., Lawrence, J., O'Neill, R.T. (2003), "Some fundamental issues with non-inferiority testing in active controlled clinical trials", Statistical in Medicine 22, 213-225.

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Baolin Zhang, Ph.D. 

Principal Investigator
Division of Therapeutic Proteins
Office of Biotechnology Products
US FDA Center for Drug Evaluation and Research
Bethesda, MD

Background:

FDA experience – 8 years

Research Interests:

Drug resistance is a major obstacle in cancer therapy. We study how chemotherapies kill cancer cells with particular interest in the identification of molecular alterations rendering tumor resistance. Our goal is to identify biomarkers for predicting tumor responsiveness to different types of cancer therapies. The acquired information will aid FDA scientists in making more informed review decisions with respect to drug safety, efficacy, and dosing. In addition to being a Principal Investigator of a laboratory, I am a quality reviewer for protein drug products in treating cancer and other diseases.

Proposed Research Project for FDA Fellow:

The Fellow will join an FDA Critical Path program to develop a novel apoptosis assay for measuring the potency of anticancer therapeutics. Most cancer therapies are intended to kill cancer cells by inducing apoptosis. However, the potency assays for evaluating these products are generally cell viability/cytotoxicity assays that do not distinguish growth inhibition from apoptosis and other forms of cell death. The use of a single validated assay by different manufacturers will allow comparison of the specific activities of different drugs. It can be used to complement cell viability assays to provide a more informative measure of the cytotoxicity of a drug/biologic. The Fellow will also gain regulatory experience in the review of therapeutic protein products by participating in the review process as a part of an interdisciplinary team.

Selected Recent Publications:

1. Yaqin Zhang and Baolin Zhang (2008) TRAIL-resistance of breast cancer cells is associated with constitutive endocytosis of death receptor-4 and -5. Mol. Cancer Res. 6(12):1861-71.
2. Yaqin Zhang, Leslie Rivera Rosado, Sun Y. Moon, and Baolin Zhang (2008) D4-GDI knockdown inhibits growth and invasive behavior in MDA-MB-231 cells by activation of Rac-dependent p38 and JNK signaling. J. Biol. Chem., manuscript under revision.
3. Di Sun, Duo Xu, and Baolin Zhang (2006) Rac signaling in tumorigenesis and as target for anticancer drug development. Drug Resistance Updates, 9, 274-287.
4. Baolin Zhang (2006) Rho GDP dissociation inhibitors as potential targets for anticancer treatment. Drug Resistance Updates. 9, 134-141.
5. Yaqin Zhang and Baolin Zhang (2006) D4-GDI, a Rho GTPase regulator, promotes breast cancer cell invasiveness. Cancer Res. 66 (11), 5592-5598.
6. Baolin Zhang, Yaqin Zhang, Marie C. Dagher, and Emily Shacter (2005) Rho GDP Dissociation Inhibitor protects cancer cells against drug-induced apoptosis. Cancer Res. 65 (14), 6054-6062.
7. Baolin Zhang, Yaqin Zhang, Emily Shacter, and Yi Zheng (2005) Mechanism of the guanine nucleotide exchange reaction of Ras GTPase – Evidence for a GTP/GDP displacement model. Biochemistry, 44 (7), 2566-2576.
8. Baolin Zhang, Yaqin Zhang, and Emily Shacter (2004) Rac1 inhibits apoptosis in human lymphoma cells by stimulating Bad Phosphorylation on Ser-75. Mol. Cell Biol. 24 (14), 6205-6214.
9. Baolin Zhang, Yaqin Zhang, and Emily Shacter (2003) Caspase-3-mediated inactivation of Rac GTPases promotes drug-induced apoptosis in human lymphoma cells. Mol. Cell Biol. 23, 5716-25.
10. Baolin Zhang, Yuan Gao, Sun Yong Moon, Yaqin Zhang, and Yi Zheng (2001) Oligomerization of Rac1 GTPase mediated by the carboxyl terminal polybasic domain. J. Biol. Chem., 8958-8967.

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