Genotoxicity and Carcinogenicity Testing of Pharmaceuticals

214 Pages·2015·3.041 MB·English

by  Michael J. Graziano, David Jacobson-Kram (eds.)

Michael J. Graziano
David Jacobson-Kram
Editors
Genotoxicity
and Carcinogenicity
Testing of
Pharmaceuticals
Genotoxicity and Carcinogenicity Testing
of Pharmaceuticals

Michael J. Graziano (cid:129) David Jacobson-Kram
Editors
Genotoxicity and
Carcinogenicity Testing
of Pharmaceuticals
Editors
Michael J. Graziano David Jacobson-Kram
Vice- President of Drug Safety Evaluation ToxRox Consulting
Bristol-Myers Squibb McLean
Princeton Virginia
New Jersey USA
USA
ISBN 978-3-319-22083-3 ISBN 978-3-319-22084-0 (eBook)
DOI 10.1007/978-3-319-22084-0
Library of Congress Control Number: 2015954554
Springer Cham Heidelberg New York Dordrecht London
© Springer International Publishing Switzerland 2015
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Edit ors
Mike Graziano has more than 27 years of experience as a toxicologist in the
pharmaceutical industry. He is currently Vice President of Drug Safety Evaluation
at Bristol- Myers Squibb where he is responsible for the nonclinical safety testing
for all drugs within the BMS portfolio. Within the past 6 years, Mike has provided
nonclinical support for eight new drug approvals. Prior to joining BMS in 2003, he
was Director of Anticancer and Antibacterial Toxicology Programs at Pfi zer
Pharmaceutical Research, Ann Arbor, MI, and with Parke-Davis Pharmaceutical
Research Division/Warner-Lambert Company. He is author/co-author of more than
90 scientifi c publications and abstracts, many dealing with the nonclinical safety of
new therapeutic agents. Mike is a member of the IQ DruSafe Leadership Group, the
PhRMA Clinical and Preclinical Development Committee, the EFPIA Preclinical
Safety Development Committee, and HESI. He is also the PhRMA Deputy Topic
Leader for the current ICH S1 Expert Working Group. Mike received a B.S. in
Animal Science from Rutgers University, a M.S. in Veterinary Toxicology from
Louisiana State University, a Ph.D. in Toxicology from the University of Kentucky,
and was a Postgraduate Research Toxicologist at the University of California,
Berkeley. Mike is also a Diplomate of the American Board of Toxicology.
D avid Jacobson-Kram received his PhD in embryology from the University of
Connecticut; he then went on to serve as a staff fellow at the National Institute on
Aging. After leaving N.I.H., Dr. Jacobson-Kram joined the faculty of George
Washington University School of Medicine and then later, Johns Hopkins University
Oncology Center. During this same period he served, on a part-time basis, as a
geneticist in the Offi ce of Toxic Substances at the Environmental Protection Agency
and as Acting Branch Chief in EPA’s Offi ce of Research and Development. Dr.
Jacobson-Kram served as the VP of the Toxicology and Laboratory Animal Health
Division at BioReliance Corporation, a contract testing laboratory from 1988 until
2003. From 2003 until 2014, he served as the Associate Director of Pharmacology
and Toxicology in FDA’s Offi ce of New Drugs. Over the past thirty years, he has
served as principal and co-principal investigator on several N.I.H. grants and
government contracts and published widely in the areas of genetic and molecular
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vi Editors
toxicology. Dr. Jacobson-Kram has served as council member, treasurer, and
c hairman of the Genetic Toxicology Association; executive council member to the
Environmental Mutagen Society; editor of C ell Biology and Toxicology; and a
member of N.I.H. special study sections. In 1996, he became a Diplomate of the
American Board of Toxicology (DABT).
Contents
1 Introduction: An Overview of Industry and Regulatory
Perspectives on the Genotoxic and Carcinogenic
Assessment of Pharmaceuticals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
Michael J. Graziano
2 Chemical Structure-Based and Toxicogenomic Models . . . . . . . . . . . . 13
Lidiya Stavitskaya , Jiri Aubrecht , and Naomi L. Kruhlak
3 Genotoxicity Testing of API . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35
L. L. Custer and M. W. Powley
4 Genotoxic Impurities in Pharmaceuticals . . . . . . . . . . . . . . . . . . . . . . . 55
Peter Kasper and Lutz Müller
5 New and Emerging Genetic Toxicity Tests and Approaches
to Genetic Toxicology Testing. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 75
Patricia A. Escobar , Stephen D. Dertinger , and Robert H. Hefl ich
6 History and Current Regulatory Requirements . . . . . . . . . . . . . . . . . . 95
James S. MacDonald and David Jacobson-Kram
7 Carcinogenicity Testing Strategies for Small Molecules . . . . . . . . . . . 109
Abigail Jacobs and Frank D. Sistare
8 Carcinogenicity of Biopharmaceuticals . . . . . . . . . . . . . . . . . . . . . . . . 125
Maggie Dempster , Kris Siezen , Bas ter Braak , Willem van den Brink ,
Annette Emerenciana , Francesco Bellanti , Ruben G. Duijnhoven ,
Marcel Kwa , and Jan Willem van der Laan
9 Addressing Positive Findings in Carcinogenicity Studies . . . . . . . . . . 159
Todd Bourcier and Denis Roy
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10 Nonclinical Strategies for Investigating Potential Tumor
Signals Detected in Clinical Trials . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 183
Lorrene A. Buckley , Beatriz Silva-Lima , and Mark A. Tirmenstein
Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 205
Contributors
Jiri Aubrecht Drug Safety Research and Development , Pfi zer Inc. , Groton ,
CT , USA
Francesco Bellanti Division of Pharmacology , Leiden Academic Center for Drug
Research , Leiden , The Netherlands
Todd Bourcier , PhD US Food and Drug Administration , Center for Drug
Evaluation and Research , Silver Spring , MD , USA
Lorrene A. Buckley Lilly Research Laboratories, Toxicology and Drug
Disposition , Eli Lilly and Company, Inc. , Indianapolis , IN , USA
L. L. Custer Drug Safety Evaluation , Bristol-Myers Squibb , New Brunswick ,
NJ , USA
Maggie Dempster Safety Assessment , GlaxoSmithKline, LLC. , Philadelphia ,
PA , USA
Stephen D. Dertinger Litron Laboratories , Rochester , NY , USA
Ruben G. Duijnhoven Section on Pharmacovigilance , Medicines Evaluation
Board , Utrecht , The Netherlands
D ivision of Pharmacoepidemiology and Clinical Pharmacology, U trecht Institute
for Pharmaceutical Sciences, Utrecht University , Utrecht , The Netherlands
Annette Emerenciana D ivision of Pharmacology, L eiden Academic Center for
Drug Research , Leiden , The Netherlands
Patricia A. Escobar Merck Research Laboratories , West Point , PA , USA
Michael J. Graziano Drug Safety Evaluation , Bristol-Myers Squibb , Princeton ,
NJ , USA
Robert H. Hefl ich Division of Genetic and Molecular Toxicology , National Center
for Toxicological Research/U.S. Food and Drug Administration (U.S. FDA/NCTR),
Jefferson , AR , USA
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