Current Topics in Nonclinical Drug Development

Pritam S. Sahota, Global ToxPath LLC, Kennewick, Washington, USA, has extensive experience in toxicologic pathology and drug development within 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 pathology degrees (MSc and PhD) from Punjab Agricultural University, India. He is a diplomate of the American Board of Toxicology. After receiving his PhD in 1976, he started working as a toxicologic pathologist at Dawson Research Corporation (DRC), Orlando, Florida, a contract research organization involved 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 of pathology as well as toxicology at DRC. While working briefly for Dynamac Corporation, Research Triangle Park, North Carolina (1986–1987), he conducted retrospective scientific audits of 23 NTP carcinogenicity studies and participated in discussions with the representatives of NTP, FDA, and EPA to review the results of scientific audits of over 200 NTP carcinogenicity studies. In 1987, he joined Ciba-Geigy Pharmaceuticals in New Jersey as Head/Manager of pathologists in preclinical safety and was also responsible for establishing pathology peer review, quality control, and scheduling systems. He continued to work primarily in this position with increasing responsibilities at Ciba-Geigy and then Novartis Pharmaceuticals (after Ciba-Sandoz merger in 1997) to become director and eventually Executive Director and Head of pathology. During this time, he also served as an international project team representative for a number of successfully marketed CNS, immunosuppression, diabetes, and cardiovascular drugs, including Diovan, which eventually became one of the 15 all-time, best-selling prescription drugs. He also held an adjunct academic appointment of Assistant Professor at the University of Medicine and Dentistry, New Jersey, for 8 years. He successfully led several global preclinical safety initiatives at Novartis, including patient centricity, review of best practices in cardiotoxicity and ocular toxicity, as well as evaluation of rodent carcinogenicity potential based on noncarcinogenicity data to minimize future delays in regulatory submissions. Since retirement from Novartis Pharmaceuticals in 2012, Dr Sahota has been the President of Global ToxPath LLC located in 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 (Second Edition, 2018); (3) The Illustrated Dictionary of Toxicologic Pathology and Safety Science (First Edition, 2019); (4) CT-NCDD: Volume 1 (due to be published 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 International LLC. He studied biochemistry at the University of Hull, UK, graduating with a BSc in 1970 and a PhD in 1974. He had postdoctoral fellowships at the Universities of Basel, Switzerland, and Mainz, Germany. His postdoctoral research centered upon formation and inactivation of reactive metabolites and the enzymes involved in the metabolism of foreign compounds. In 1979, he joined the Investigative Toxicology group (known as Cell Biology) in the Toxicology Department of Ciba-Geigy, Basel, Switzerland, and remained with the company, later Novartis, until 2014. In these 35 years, he held various management positions in Europe and the United States with responsibility for Investigative Toxicology; Drug Metabolism; Drug Metabolism and Toxicology; Preclinical Safety Europe; Drug Metabolism and Pharmacokinetics; Toxicology/Pathology United States; Preclinical Safety United States; and Global Preclinical Safety. In these positions, he contributed to the registration of more than 45 marketed drug products and the preparation of several hundred investigational new drugs (INDs). He has 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 to integrate data from the different preclinical disciplines to enable translation to determine the clinical relevance of the findings. He is very familiar with global drug registration requirements and working on global projects. He has authored more than 80 scientific publications, has lectured in toxicology at the University of Basel for more than 30 years, and is a past president of the European Society of Biochemical Pharmacology and the Swiss Society of Toxicology. He was a member of the PhRMA/IQ Preclinical Leadership (DruSafe) Committee for 16 years, a member of the advisory board of the PSTC Biomarker consortium, and a member of the expert working group for revision of the ICH S2 guidance on genotoxicity testing 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 drug development. Dr. Wojcinski received his undergraduate degree (BSc) in Zoology from the University of Toronto and his DVM and DVSc (Pathology) degrees from the Ontario Veterinary College, University of Guelph. He is a board-certified diplomate of the American Board of Toxicology and a diplomate of the American College of Veterinary Pathologists. He is also recognized as a specialist in Veterinary Pathology by the Canadian Veterinary Medical Association. Dr Wojcinski gained experience in drug development and toxicologic pathology during his 22-year tenure with Parke-Davis/ Warner-Lambert and Pfizer Global Research and Development and then 31/2 years with Fulcrum Pharma Developments, Inc. In 2011, he founded Drug Development Pathology Services, LLC in Ann Arbor, Michigan, and subsequently grew the organization into Drug Development Preclinical Services, LLC to provide toxicology, pathology, and drug metabolism and pharmacokinetic services. Dr Wojcinski has extensive experience as a study director, study pathologist, and review pathologist for numerous acute and repeated dose toxicity studies, including carcinogenicity studies. Throughout his career, he has managed successful cross-functional drug development teams in CNS, metabolic diseases, and dermatology therapeutic areas. As therapeutic area leader for Dermatology at Pfizer, Dr Wojcinski was responsible for development and implementation of the safety and risk management strategies for, what was then, a new therapeutic area. He has also been directly involved in the preparation of pre-IND documents, nonclinical safety assessments for IND/IMPD/NDA/MAA, investigator’s brochures, and labeling (USPI, SmPC) negotiations in CNS, anti-infective, and dermatology therapeutic areas. Dr Wojcinski has had numerous interactions with regulatory agencies in the United States, Europe, Canada, and Australia for compounds at various stages of development. He has also provided pathology consultation and histopathology peer review on several projects in various therapeutic areas, including respiratory infections, dermatitis, ophthalmic disease, anticancer, and hypolipidemics, and served on Pathology Working Groups. Dr Wojcinski is a full member of numerous professional societies including the American College of Veterinary Pathologists, Society of Toxicologic Pathologists, Society of Toxicology, American College of Toxicology, American Veterinary Medical Association, Canadian Veterinary Medical Association, Canadian Association of Veterinary Pathologists, Regulatory Affairs Professionals Society, and Roundtable of Toxicology Consultants. He has served as president of the Dermal Toxicity Specialty Section of the Society of Toxicology, an associate editor for the Society of Toxicologic Pathology, editor of The Scope for the Society of Toxicologic Pathology, and chair of the Society of Toxicologic Pathology Recruitment Subcommittee. Dr Wojcinski has lectured at the Ontario Veterinary College and the University of Maryland and authored/coauthored numerous scientific reports, manuscripts, and book chapters. Recently, he was coeditor for The Illustrated Dictionary of Toxicologic Pathology & Safety Science (First Edition, published in 2019) and is currently contributing editor for Road to Greatness (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).

Contents

PREFACE VII

ACKNOWLEDGMENTS IX

EDITORS XI

CONTRIBUTORS XV

1 Bioinformatics/Impact of Computational Biology

for Molecular Safety Assessment during Drug

Development 1

JULIANE PERNER, MEGUMI ONISHI-SEEBACHER,

ALBERTO DEL RIO ESPINOLA, ELAINE TRITTO, PHILIPPE COUTTET,

RÉMI TERRANOVA, AND JONATHAN MOGGS

2 Integrating Toxicogenomics Data into Risk

Assessment 23

ARUN R. PANDIRI, WARREN CASEY, AND SCOTT S. AUERBACH

3 New Approaches in Development

of Medical Devices 53

SHANNON M. WALLACE, PEGGY A. LALOR,

AND KATHLEEN A. FUNK

4 Recent Advances in the Development

of Novel Biomarkers of Toxicity 81

DOMINIQUE BREES, DANA WALKER, DAVID LEDIEU,

DAVID BROTT MICHAEL MERZ, AND JACQUELINE TARRANT

5 Preclinical Evaluation and Translational

Development of Cell and Gene Therapies 121

SHON GREEN, TIMOTHY K. MACLACHLAN, JENNIFER L.

MARLOWE, AND PRASHANT NAMBIAR

6 Value of Juvenile Toxicity Studies 185

PAUL BALDRICK

7 Photosafety Testing of Drugs 223

ANTHONY M. LYNCH AND DANIEL BAUER

8 Combination Safety Assessment During Drug

Development 275

JOANNE BIRKEBAK, SHERRY L. RALSTON,

AND LEIGH ANN BURNS-NAAS

INDEX 307