Current Topics in Nonclinical Drug Development

Pritam S. Sahota, Global ToxPath LLC, Kennewick, Washington, USA,has extensive experience in toxicologic pathology and drug developmentwithin the framework of nonclinical safety assessment of pharmaceuticals.Dr. Sahota was previously Executive Director and Head of Pathology,Preclinical Safety, at Novartis Pharmaceuticals, East Hanover, New Jersey.He obtained his veterinary medicine (BVSc) and veterinary pathologydegrees (MSc and PhD) from Punjab Agricultural University, India. Heis a diplomate of the American Board of Toxicology. After receiving hisPhD in 1976, he started working as a toxicologic pathologist at DawsonResearch Corporation (DRC), Orlando, Florida, a contract research organizationinvolved in the preclinical safety evaluation of drugs and chemicals.At DRC, he received increasing responsibility over the next 10 years(toxicologic pathologist, senior toxicologic pathologist, and scientific director).As a scientific director, he was responsible for the scientific aspects ofpathology as well as toxicology at DRC. While working briefly for DynamacCorporation, Research Triangle Park, North Carolina (1986–1987), he conductedretrospective scientific audits of 23 NTP carcinogenicity studies andparticipated in discussions with the representatives of NTP, FDA, and EPAto review the results of scientific audits of over 200 NTP carcinogenicitystudies. In 1987, he joined Ciba-Geigy Pharmaceuticals in New Jersey asHead/Manager of pathologists in preclinical safety and was also responsiblefor establishing pathology peer review, quality control, and schedulingsystems. He continued to work primarily in this position with increasingresponsibilities at Ciba-Geigy and then Novartis Pharmaceuticals (afterCiba-Sandoz merger in 1997) to become director and eventually ExecutiveDirector and Head of pathology. During this time, he also served as an internationalproject team representative for a number of successfully marketedCNS, immunosuppression, diabetes, and cardiovascular drugs, includingDiovan, which eventually became one of the 15 all-time, best-selling prescriptiondrugs. He also held an adjunct academic appointment of AssistantProfessor at the University of Medicine and Dentistry, New Jersey, for8 years. He successfully led several global preclinical safety initiatives atNovartis, including patient centricity, review of best practices in cardiotoxicityand ocular toxicity, as well as evaluation of rodent carcinogenicitypotential based on noncarcinogenicity data to minimize future delays inregulatory submissions. Since retirement from Novartis Pharmaceuticalsin 2012, Dr Sahota has been the President of Global ToxPath LLC locatedin Kennewick, WA, USA (Toxicologic Pathology Consultancy). As lead editor,he published the following books with CRC Press/Taylor & Francis:(1) Toxicologic Pathology: Nonclinical Safety Assessment (First Edition,2013); (2) Toxicologic Pathology: Nonclinical Safety Assessment (SecondEdition, 2018); (3) The Illustrated Dictionary of Toxicologic Pathology andSafety Science (First Edition, 2019); (4) CT-NCDD: Volume 1 (due to bepublished in 2020); (5) Road to Greatness (due to be published in 2020);(6) Toxicologic Pathology: A Primer (due to be published in 2021); and(7) Toxicologic Pathology: An Atlas (due to be published in 2022).Philip Bentley is a principal consultant at Toxicodynamix InternationalLLC. He studied biochemistry at the University of Hull, UK, graduatingwith a BSc in 1970 and a PhD in 1974. He had postdoctoral fellowships atthe Universities of Basel, Switzerland, and Mainz, Germany. His postdoctoralresearch centered upon formation and inactivation of reactive metabolitesand the enzymes involved in the metabolism of foreign compounds. In1979, he joined the Investigative Toxicology group (known as Cell Biology)in the Toxicology Department of Ciba-Geigy, Basel, Switzerland, andremained with the company, later Novartis, until 2014. In these 35 years,he held various management positions in Europe and the United Stateswith responsibility for Investigative Toxicology; Drug Metabolism; DrugMetabolism and Toxicology; Preclinical Safety Europe; Drug Metabolismand Pharmacokinetics; Toxicology/Pathology United States; PreclinicalSafety United States; and Global Preclinical Safety. In these positions, hecontributed to the registration of more than 45 marketed drug products andthe preparation of several hundred investigational new drugs (INDs). Hehas vast experience in the areas of drug metabolism and disposition, toxicology/pathology, genetic toxicology, pharmacokinetics/toxicokinetics,and all aspects of investigative toxicology. He is well grounded in biochemistry,cell biology, molecular biology, and pharmacology with the ability tointegrate data from the different preclinical disciplines to enable translationto determine the clinical relevance of the findings. He is very familiar withglobal drug registration requirements and working on global projects.He has authored more than 80 scientific publications, has lecturedin toxicology at the University of Basel for more than 30 years, and is apast president of the European Society of Biochemical Pharmacologyand the Swiss Society of Toxicology. He was a member of the PhRMA/IQPreclinical Leadership (DruSafe) Committee for 16 years, a member of theadvisory board of the PSTC Biomarker consortium, and a member of theexpert working group for revision of the ICH S2 guidance on genotoxicitytesting and the PhRMA expert group on genotoxic impurities.Zbigniew W. Wojcinski is president of Toxicology & Pathology Consulting,LLC, in Ann Arbor, Michigan, and has over 30 years of experience in drugdevelopment. Dr. Wojcinski received his undergraduate degree (BSc) inZoology from the University of Toronto and his DVM and DVSc (Pathology)degrees from the Ontario Veterinary College, University of Guelph. He is aboard-certified diplomate of the American Board of Toxicology and a diplomateof the American College of Veterinary Pathologists. He is also recognizedas a specialist in Veterinary Pathology by the Canadian VeterinaryMedical Association. Dr Wojcinski gained experience in drug developmentand toxicologic pathology during his 22-year tenure with Parke-Davis\Warner-Lambert and Pfizer Global Research and Development and then 31/2years with Fulcrum Pharma Developments, Inc. In 2011, he founded DrugDevelopment Pathology Services, LLC in Ann Arbor, Michigan, and subsequentlygrew the organization into Drug Development Preclinical Services,LLC to provide toxicology, pathology, and drug metabolism and pharmacokineticservices. Dr Wojcinski has extensive experience as a study director,study pathologist, and review pathologist for numerous acute and repeateddose toxicity studies, including carcinogenicity studies. Throughout hiscareer, he has managed successful cross-functional drug developmentteams in CNS, metabolic diseases, and dermatology therapeutic areas. Astherapeutic area leader for Dermatology at Pfizer, Dr Wojcinski was responsiblefor development and implementation of the safety and risk managementstrategies for, what was then, a new therapeutic area. He has alsobeen directly involved in the preparation of pre-IND documents, nonclinicalsafety assessments for IND/IMPD/NDA/MAA, investigator’s brochures,and labeling (USPI, SmPC) negotiations in CNS, anti-infective, and dermatologytherapeutic areas. Dr Wojcinski has had numerous interactions withregulatory agencies in the United States, Europe, Canada, and Australia forcompounds at various stages of development. He has also provided pathologyconsultation and histopathology peer review on several projects in varioustherapeutic areas, including respiratory infections, dermatitis, ophthalmicdisease, anticancer, and hypolipidemics, and served on Pathology WorkingGroups. Dr Wojcinski is a full member of numerous professional societiesincluding the American College of Veterinary Pathologists, Societyof Toxicologic Pathologists, Society of Toxicology, American College ofToxicology, American Veterinary Medical Association, Canadian VeterinaryMedical Association, Canadian Association of Veterinary Pathologists,Regulatory Affairs Professionals Society, and Roundtable of ToxicologyConsultants. He has served as president of the Dermal Toxicity SpecialtySection of the Society of Toxicology, an associate editor for the Society ofToxicologic Pathology, editor of The Scope for the Society of ToxicologicPathology, and chair of the Society of Toxicologic Pathology RecruitmentSubcommittee. Dr Wojcinski has lectured at the Ontario Veterinary Collegeand the University of Maryland and authored/coauthored numerous scientificreports, manuscripts, and book chapters. Recently, he was coeditorfor The Illustrated Dictionary of Toxicologic Pathology & Safety Science (FirstEdition, published in 2019) and is currently contributing editor for Road toGreatness (due to be published in 2020); coeditor for Toxicologic Pathology:A Primer (due to be published in 2021); and coeditor for Toxicologic Pathology:An Atlas (due to be published in 2022).

• ContentsPREFACE VIIACKNOWLEDGMENTS IXEDITORS XICONTRIBUTORS XV1 Bioinformatics/Impact of Computational Biologyfor Molecular Safety Assessment during DrugDevelopment 1JULIANE PERNER, MEGUMI ONISHI-SEEBACHER,ALBERTO DEL RIO ESPINOLA, ELAINE TRITTO, PHILIPPE COUTTET,RÉMI TERRANOVA, AND JONATHAN MOGGS2 Integrating Toxicogenomics Data into RiskAssessment 23ARUN R. PANDIRI, WARREN CASEY, AND SCOTT S. AUERBACH3 New Approaches in Developmentof Medical Devices 53SHANNON M. WALLACE, PEGGY A. LALOR,AND KATHLEEN A. FUNK4 Recent Advances in the Developmentof Novel Biomarkers of Toxicity 81DOMINIQUE BREES, DANA WALKER, DAVID LEDIEU,DAVID BROTT MICHAEL MERZ, AND JACQUELINE TARRANT5 Preclinical Evaluation and TranslationalDevelopment of Cell and Gene Therapies 121SHON GREEN, TIMOTHY K. MACLACHLAN, JENNIFER L.MARLOWE, AND PRASHANT NAMBIAR6 Value of Juvenile Toxicity Studies 185PAUL BALDRICK7 Photosafety Testing of Drugs 223ANTHONY M. LYNCH AND DANIEL BAUER8 Combination Safety Assessment During DrugDevelopment 275JOANNE BIRKEBAK, SHERRY L. RALSTON,AND LEIGH ANN BURNS-NAASINDEX 307