Current Topics in Nonclinical Drug Development Volume 1

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

Biography

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).