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A Practical
Guide to Drug
Development
in Academia
Daria Mochly-Rosen
KevinGrimes Editors
The SPARK Approach
SecondEdition
A Practical Guide to Drug Development
in Academia
Daria Mochly-Rosen • Kevin Grimes
Editors
A Practical Guide to Drug
Development in Academia
The SPARK Approach
Second Edition
Editors
Daria Mochly-Rosen
Department of Chemical and
Systems Biology
Stanford University School of Medicine
Stanford, CA, US
Kevin Grimes
Department of Chemical and
Systems Biology
Stanford University School of Medicine
Stanford, CA, US
ISBN 978-3-031-34726-9 ISBN 978-3-031-34724-5 (eBook)
https://doi.org/10.1007/978-3-031-34724-5
© The Editor(s) (if applicable) and The Author(s), under exclusive license to Springer Nature
Switzerland AG 2017, 2023, Corrected Publication 2024
This work is subject to copyright. All rights are solely and exclusively licensed by the Publisher, whether
the whole or part of the material is concerned, specically the rights of translation, reprinting, reuse of
illustrations, recitation, broadcasting, reproduction on microlms or in any other physical way, and
transmission or information storage and retrieval, electronic adaptation, computer software, or by similar
or dissimilar methodology now known or hereafter developed.
The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication
does not imply, even in the absence of a specic statement, that such names are exempt from the relevant
protective laws and regulations and therefore free for general use.
The publisher, the authors, and the editors are safe to assume that the advice and information in this book
are believed to be true and accurate at the date of publication. Neither the publisher nor the authors or the
editors give a warranty, expressed or implied, with respect to the material contained herein or for any
errors or omissions that may have been made. The publisher remains neutral with regard to jurisdictional
claims in published maps and institutional afliations.
Editorial Contact: Charlotte Nunes
This Springer imprint is published by the registered company Springer Nature Switzerland AG
The registered company address is: Gewerbestrasse 11, 6330 Cham, Switzerland
Paper in this product is recyclable.
We dedicate this book to our SPARKees—
Stanford faculty, postgraduate fellows, and
students who have stepped beyond the
connes of traditional academia to embrace
the challenges of drug discovery and
development. We are inspired by your efforts
to translate your discoveries into new
treatments that will benet patients, and we
have learned a great deal from each of you.
vii
Preface
Our intention in writing and updating this volume, A Practical Guide to Drug
Development in Academia: The SPARK Approach, was not to generate a compre-
hensive “how to” book; this topic cannot be taught in 282 pages. Rather, this volume
addresses requests from our own SPARKees as well as from other academic institu-
tions that have established or are planning to establish their own translational
research programs. This book provides only a few pages on each topic that are part
of the long process of drug development. The book is intended for novices who
embark on this amazing path of translating basic research or clinical ndings into
new therapeutics or diagnostics to benet patients. Ideally, you will read this book
before you begin your translational effort, so that you will understand the path
ahead—starting with the end in mind; planning what the nal product will be (“tar-
get product prole” in industry lingo); and then creating a path back to where the
project is today—doing it the industry way, with our own academic twist. This book
should also be useful for students and postdoctoral fellows who plan to begin their
career in the biopharmaceutical industry or who hope that their academic career will
be translational in nature.
SPARK at Stanford is now in its 17th year. The program evolved slowly. We have
found a certain formula that works well for our academic inventors and we hope that
it will work for you as well. This book was written mainly by our SPARK mentors—
the true engine behind the success of the program. It is not a complete guide to what
needs to be done, but provides a general overview of the important topics in the
development process.
Drug development is an applied science with a concrete goal in mind. It is also
highly challenging, and academia can greatly help in this effort; not only through
our inventions, but also by rethinking the drug and diagnostic development process,
so that success rates will be higher and approval of the interventions will be faster.
Successful implementation of a translational research program requires securing
experts in multiple disciplines (chemistry, biology, pharmacology, toxicology,
medicine, regulatory science, statistics, and many more). Therefore, in addition to
covering some key issues in each topic, we peppered the chapters with lessons that
surprised us along our journey through biotechnology entrepreneurship. With these,
we hope to demonstrate how drug development is not necessarily intuitive. You will
nd these in boxed text throughout the chapters.
viii
After working on my own translational research projects and mentoring over six
dozen other academic projects, I can summarize the following key lessons that I
have learned.
1. Check your ego at the door—drug discovery is not about any one person; it is a
true team effort, requiring experts in multiple disciplines. The weakest link is
standing between you and a total failure.
2. Consult, consult, consult—there is always someone who knows much more than
you about what is needed (preferably more than one person). Find these
individuals and get their advice.
3. Always continue to apply your own judgment, as even experienced advisors can
be wrong.
As the editors of this volume, Kevin Grimes and I hope that you will nd it useful
in your endeavor.
And now—let’s SPARK.
Stanford, CA, US DariaMochly-Rosen
KevinGrimes
Preface
ix
Acknowledgements
We wish to express our sincere gratitude to Dr. Adriana A.Garcia for her tireless
efforts to bring this volume to completion and Mary Romeo for careful editing of
the text. Thanks also to our many contributing authors, who have generously shared
their expertise and knowledge to help advance the cause of academic drug discovery.
Special thanks to Dr. Phil Pizzo, the previous Dean of Stanford University School
of Medicine, who endorsed the SPARK program from the start, and to our current
Dean, Dr. Lloyd Minor, for his continued and unwavering support. Lastly, we owe
a tremendous debt of gratitude to our SPARK advisors, whose generous and loyal
support has been instrumental in SPARK’s success. —DM-R & KVG
xi
Contents
1 Getting Started . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
Daria Mochly-Rosen, Kevin Grimes, Robert Lum,
and Rebecca Begley
1.1 Advancing New Treatments from Academia to Biopharma . . . . . . 2
1.2 Overview of Drug Discovery and Development . . . . . . . . . . . . . . . 9
1.3 Assessing Clinical Need . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16
1.4 Target Product Prole . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20
1.5 Project Management and Project Planning . . . . . . . . . . . . . . . . . . . 25
Key Terms and Abbreviations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32
2 Therapeutics and Diagnostics Discovery . . . . . . . . . . . . . . . . . . . . . . . . 33
Daria Mochly-Rosen, Kevin Grimes, Rami N. Hannoush,
Bruce Koch, Gretchen Ehrenkaufer, Daniel A. Erlanson, Julie Saiki,
Jennifer L. Wilson, Shelley Force Aldred, Adriana A. Garcia,
Jin Billy Li, Rosa Bacchetta, Maria Grazia Roncarolo,
Alma-Martina Cepika, Harry Greenberg, Steven N. Goodman,
and Michael A. Kohn
2.1 Finding and Validating Drug Targets . . . . . . . . . . . . . . . . . . . . . . . 35
2.2 Repurposing Drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37
2.3 Developing Assays for High-Throughput Screening . . . . . . . . . . . 42
2.4 Medicinal Chemistry and Lead Optimization . . . . . . . . . . . . . . . . . 47
2.5 Natural Products . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 54
2.6 Approaching Machine Learning in Drug Development . . . . . . . . . 56
2.7 Therapeutic Antibody Discovery . . . . . . . . . . . . . . . . . . . . . . . . . . 62
2.8 siRNA, Gene Editing, and RNA Editing . . . . . . . . . . . . . . . . . . . . 67
2.9 Cell and Gene Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 75
2.10 Vaccine Development . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 82
2.11 Diagnostic Biomarkers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 86
Key Terms and Abbreviations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 92
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 97
xii
3 On the Way to the Clinic . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 101
Daria Mochly-Rosen, Kevin Grimes, C. Glenn Begley, Dirk Mendel,
Werner Rubas, Emily Egeler, Collen Masimirembwa,
Terrence F. Blaschke, and Michael Taylor
3.1 When to Begin Animal Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . 102
3.2 Robustness of Preclinical Studies . . . . . . . . . . . . . . . . . . . . . . . . . . 105
3.3 In Vivo Pharmacology: Multiple Roles in Drug Discovery . . . . . . . 110
3.4 Pharmacokinetics and ADME . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 117
3.5 Pharmacogenomics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 123
3.6 Route of Administration and Drug Formulation . . . . . . . . . . . . . . . 129
3.7 Preclinical Safety Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 133
Key Terms and Abbreviations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 137
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 141
4 Preparing for the Clinic . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 143
Daria Mochly-Rosen, Kevin Grimes, Carol D. Karp, Robert Lum,
Mark Backer, Lyn Frumkin, and Ted McCluskey
4.1 Regulatory Considerations in Product Development . . . . . . . . . . . 144
4.2 Manufacturing and Quality Control . . . . . . . . . . . . . . . . . . . . . . . . 150
4.3 Technical Development and Manufacturing of Biological
Products . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 154
4.4 Clinical Trial Design . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 164
4.5 Phase 3 Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 176
Key Terms and Abbreviations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 179
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 182
5 Technology Transfer and Commercialization . . . . . . . . . . . . . . . . . . . . 185
Daria Mochly-Rosen, Kevin Grimes, Judy Mohr, Karin Immergluck,
Emily Egeler, Jennifer Swanton Brown, Nicholas Gaich,
Eugenio L. de Hostos, Grace Hancock, Mary Wang, Robert
F. Booth, Julie Papanek Grant, Leon Chen, Nina Kjellson,
Haim Zaltzman, J. Jekkie Kim, John Walker, Alan Mendelson,
Peter Boyd, and Christopher M. Reilly
5.1 Intellectual Property . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 187
5.2 Working with the University Technology Transfer Ofce . . . . . . . 190
5.3 Navigating Conicts of Interest . . . . . . . . . . . . . . . . . . . . . . . . . . . 195
5.4 Working with the University Compliance Ofce . . . . . . . . . . . . . . 198
5.5 Not-for-Prot Drug Development . . . . . . . . . . . . . . . . . . . . . . . . . . 202
5.6 Personal Lessons from a Reluctant Entrepreneur . . . . . . . . . . . . . . 207
5.7 Selecting the Market for Your Drug . . . . . . . . . . . . . . . . . . . . . . . . 209
5.8 Commercial Assessments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 215
5.9 Making a Compelling Pitch to Potential Investors . . . . . . . . . . . . . 219
5.10 Venture Capital Funding . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 225
5.11 Legal Aspects of a Startup Biotechnology Company . . . . . . . . . . . 229
5.12 Plan, Organize, Motivate, and Control . . . . . . . . . . . . . . . . . . . . . . 232
Key Terms and Abbreviations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 240
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 240
Contents