Cover
Title Page
Acknowledgments
Introduction
Methodology
About the Author
Part 1: The History
1. 1 The Right Drug, the Right Patient, the Right Time
  1. The Origins of Precision Medicine
  2. Technology Toolkit in Place: Transition to Meaning in the Clinic
  3. References
2. 2 Decision‐Making Machines
  1. References
3. 3 Precision Medicine around the World
  1. France
  2. United Kingdom
  3. Germany
  4. References
Part 2: The Present
1. 4 Our Reality Today
  1. Breast Cancer
  2. Metastatic Melanoma
  3. References
2. 5 Toward the Day We Just Call It “Medicine”
  1. Access to Preventative Care
  2. Access to In Vitro Diagnostics (IVD)
  3. Access to Imaging Diagnostics
  4. Access to Treatments
  5. Conclusion
  6. References
3. 6 Precision Medicine around the World
  1. References
4. 7 Shifting Rules
  1. Drug Regulation in the United States
  2. Targeted Therapy Approval Process and Challenges
  3. Diagnostics Approval Process and Challenges
  4. Improving the Regulatory Pathway in Precision Medicine
  5. Drug and Diagnostic Coverage
  6. Coding and Payment
  7. Health Economic Studies
  8. References
5. 8 Precision Medicine around the World
  1. Brazil
  2. Mexico
  3. Argentina
  4. South America: Beyond
  5. References
6. 9 Patients as the Poorest Princesses
  1. References
7. 10 Informatics under the Hood
  1. Let’s Start with What “It” Is
  2. References
8. 11 Precision Medicine around the World
  1. References
Part 3: The Future
1. 12 A Personalized Stomach
  1. Current Microbiome‐Targeted Treatments
  2. The Future of Precision Medicine and the Microbiome
  3. Transplantation of Defined Bacterial Communities
  4. Next‐Generation Probiotics
  5. Secreted Factor/Metabolites and Other Drug Candidates
  6. System‐Level Approaches
  7. Opportunities and Ongoing Challenges
  8. References
2. 13 Consumer Is King
  1. Accuracy of Consumer‐Based Precision Medicine Products
  2. Clinical Utility of Consumer‐Based Precision Medicine Products
  3. References
3. 14 Precision Medicine around the World
  1. Kingdom of Saudi Arabia (KSA)
  2. Qatar
  3. United Arab Emirates (UAE)
  4. Conclusion
  5. References
4. 15 Sci‐Fi Potential
  1. References
5. 16 Precision Medicine around the World
  1. References
6. 17 A New Hope
  1. Immuno‐oncology
  2. References
Afterword
Index
End User License Agreement

List of Illustrations

Chapter 01
1. Figure 1.1 The CFTR defect in cystic fibrosis.
2. Figure 1.2 Kalydeco’s mechanism of action. The drug acts to open up the protein gate that regulates the movement of chloride ions between the outside and the inside of the cell.
3. Figure 1.3 Molecular diagnostics examine the molecules in the cell, that is, the DNA, RNA, or proteins, and their role in human biology and disease.
4. Figure 1.4 The history of DNA.
5. Figure 1.5 The double‐helix structure of DNA. The molecule consists of four bases—adenine (A), guanine (G), cytosine (C), and thymine (T) and a sugar‐phosphate backbone. Adenine always binds to thymine (A–T) and guanine always binds to cytosine (C–G).
6. Figure 1.6 From DNA to protein. Single‐stranded mRNA is created when DNA is replicated. The mRNA is then translated to protein on the ribosome, where tRNA reads the three‐letter code (or codon) in the mRNA, with each codon coding for a different amino acid in the protein being built.
7. Figure 1.7 The polymerase chain reaction (PCR) process. PCR amplifies DNA by repeating cycles that each duplicates the base sequence in a specific section of the DNA strand [18].
8. Figure 1.8 Herceptin’s mechanism of action. Herceptin is a drug that binds to a cell surface protein called HER2, which is overexpressed in certain cancers. By blocking its downstream actions, Herceptin prevents HER2, causing cancer survival and growth.
9. Figure 1.9 The diagnostics continuum.
10. Figure 1.10 The evolution of lung adenocarcinoma, showing the explosion in the number of molecular targets for therapeutic intervention [36].
Chapter 02
1. Figure 2.1 Changed chromosomes 9 and 22 [2].
2. Figure 2.2 ABL and BCR gene combination [3].
3. Figure 2.3 Abnormal white blood cell counts in a leukemia patient [6].
4. Figure 2.4 Comparison of chemotherapeutic drugs [7].
Chapter 03
1. Figure 3.1 European demographic facts.
2. Figure 3.2 Distribution of INCa platforms in France [1].
3. Figure 3.3 Deaths per 100,000 population from malignant neoplasms from 2004 to 2011 (the last year for which data is available from the OECD for all EU5 countries) [10].
Chapter 04
1. Figure 4.1 The different possible outcomes of ER, PR, and HER2 tests.
2. Figure 4.2 Definitions of different stages of breast cancer.
3. Figure 4.3 Six different treatment options for breast cancer patients.
4. Figure 4.4 Simplified breast cancer patient journey today and in the future [23].
5. Figure 4.5 The various drugs available to treat metastatic melanoma.
Chapter 05
1. Figure 5.1 The four hurdles to precision care access.
Chapter 06
1. Figure 6.1 Japan’s demographic facts.
2. Figure 6.2 Comparison of birth rates in Australia, Brazil, Canada, the European Union, Japan, and the United States [5].
Chapter 07
1. Figure 7.1 FDA drug approval process.
2. Figure 7.2 Proportion of cancer medicines reimbursed (example countries).
Chapter 08
1. Figure 8.1 Latin America’s demographic facts.
Chapter 09
1. Figure 9.1 The three categories of supportive care services.
Chapter 10
1. Figure 10.1 Big data stakeholders in the global healthcare ecosystem [1].
2. Figure 10.2 Basic steps in analyzing big data.
3. Figure 10.3 Global collaboration efforts in big data and bioinformatics [1].
Chapter 11
1. Figure 11.1 India demographic facts.
2. Figure 11.2 Comparison of cost of baseline cancer treatment between India and the United States [5].
3. Figure 11.3 Relative prevalence of smokeless tobacco use and alcohol consumption [5].
Chapter 12
1. Figure 12.1 Examples of microbe species that live within the human body.
2. Figure 12.2 Decrease in gut microbiome diversity caused by antibiotic use [13].
3. Figure 12.3 Volume of PubMed articles versus Google searches containing term “microbiome” [27]. *Relative Google search volumes with 2015 set at 100%.
4. Figure 12.4 How DNA, RNA, proteins, and metabolites influence cellular processes [35].
Chapter 13
1. Figure 13.1 Major trends in health and wellness.
2. Figure 13.2 Wellness solutions for the connected consumer.
3. Figure 13.3 Framework for analyzing connected health devices.
Chapter 14
1. Figure 14.1 Middle East’s demographic facts [1].
Chapter 15
1. Figure 15.1 Example of a zinc finger motif method of binding DNA [2, 3].
2. Figure 15.2 CAR gene ion.
3. Figure 15.3 In vitro fertilization [24, 25].
Chapter 16
1. Figure 16.1 China demographic facts.
Chapter 17
1. Figure 17.1 Therapeutic targets in immuno‐oncology [2].
2. Figure 17.2 Clinical programs in immuno‐oncology.
3. Figure 17.3 Therapeutic pipeline in oncology [3].
4. Figure 17.4 Market highlights in immuno‐oncology.
5. Figure 17.5 Precision medicine stakeholder map in 2017.

This edition first published 2017
© 2017 John Wiley & Sons, Inc.

Edition History
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Library of Congress Cataloging‐in‐Publication Data

Names: Pothier, Kristin Ciriello, 1974– author.
Title: Personalizing Precision Medicine: A Global Voyage from Vision to Reality / Kristin Ciriello Pothier.
Description: Hoboken, NJ : John Wiley & Sons, Inc., 2017. | Includes bibliographical references and index. |
Identifiers: LCCN 2017020345 (print) | LCCN 2017021066 (ebook) | ISBN 9781118792179 (pdf) | ISBN 9781118792124 (epub) | ISBN 9781118792117 (pbk.)
Subjects: | MESH: Precision Medicine–trends
Classification: LCC R733 (ebook) | LCC R733 (print) | NLM WB 300 | DDC 610–dc23
LC record available at https://lccn.loc.gov/2017020345

Cover Design and Image: Courtesy of Diana Saville.

Acknowledgments

This book would not have been completed without the support of my loving family—Bryan, Olivia, and Luke—and our parents and dear friends and the support of Ernst & Young LLP. I would like to give special thanks to my Personalizing Precision Medicine life sciences lead editorial team in the firm’s Parthenon‐EY practice, led by Mahala Burn, Brian Quinn, Joe Zaccaria, Jessica Lin, and Jay Canarick. Additional thanks goes to our team of Parthenon‐EY consultants who contributed to the research in the book, including Alasdair Milton, Jay Buckingham, Jessica Bernheim, Alex Chen, Glenn Engler, Will Janover, Ankit Goel, Eric Haskel, Ryan Juntado, Hayley Kriman, Harish Kumar, Chen Liu, Melissa Maggart, Armelle Sérose, Hanu Tyagi, Eleonora Brero, Shushant Malhotra, Derek Matus, Amy McLaughlin, Will Poss, Melanie Gaynes, Chris Bravo, Gillian O’Connell, Jeremy Rubel, Hamza Sheikh, Mark Sorrentino, Yuan Wang, Maxine Winston, Gary Yin, Ike Zhang, and Scott Palmer. Also, thanks for the support of my Ernst & Young leadership teams worldwide, my quality, legal, graphics, and marketing teams; my cover illustrator Diana Saville; and external copy editor and oldest, most honest friend, Kristin Walker Overman. Also incredible thanks to my publisher Wiley and its team led by Jonathan Rose for having the patience to wait for the completion of this book. And finally, thanks to my friends, family, and trusted colleagues affected by cancer, who generously devoted their time and support to help me make this book a reality.

Introduction

It was the spotted lung scan day.

My old friend Heather¹ said this to me, matter of fact, over pizzas one evening as she described one of many pivotal moments in the last 2 years of her life with cancer.

Her statement, on a day memorialized in her mind by a diagnostic test, is a small window into the life of a cancer patient. Her life pre‐cancer was busy, successful. She managed her own design business and ran hard and spirited, traits we were all envious of in college and that stuck with her. There was no time for anything other than her business, her husband, and her zest for life. A nagging, mild tender breast that just didn’t go away prompted her to go to the doctor more out of annoyance than anything else. She was slated to meet her husband abroad at the end of the week for a European vacation; this was 1 appointment out of 20 she needed to check off her list. She hadn’t even had a routine mammogram because she had barely reached her 40s and hadn’t gotten around to it yet. That European trip never came.

Heather watched curiously as the administrator of her mammogram went from calm to concerned to alarmed. The administrator called her boss. Her boss’s face also did not hide the alarm. Heather was scheduled for a biopsy immediately.

The days after the diagnosis were filled with research and calls to any friends that could help, from a medical point of view and from a support point of view. Thankfully, Heather’s support system also included a childhood friend who was a cancer researcher at one of the top institutions in the United States and could get her to the right physicians in her own city.

And then the treatment began.

Her days, which before were measured in her meetings with clients to restore their historic homes, her long dinners with her husband, and her energetic throes into SoulCycle, were now measured differently. Days measured in test results, in exhaustion from the drug regimens, in pain from the surgeries, and in desperate hope for the next day highlighted in her support systems surrounding her. She did everything right. Her physicians personalized her treatment for her with drugs that would work on her specific cancer. The cancer looked like it was gone. And then, a follow‐up scan suggested a suspected relapse and potential spread of the cancer to the lung. Her lungs looked, well, “spotted.” And it started all over again.

Indeed, as much as this experience was personal to Heather, we are only starting to personalize cancer treatment in the truest sense. “I did certain things to ‘hack’ my experience specifically for me … both medically and psychologically. But I understand it is difficult for doctors to do this with thousands of patients,” Heather said. The ability to tailor a drug regimen to a specific genetic code that is truly personalized to that specific DNA double helix has been a dream of researchers, physicians, and patients alike. Advances in precision medicine, specifically around the genome and the helices embedded, are making this dream a reality.

Patients struggle with “chemo,” drugs that indiscriminately kill both cells in their tumors and normal cells like their hair follicles, the lining of their throats and stomachs, and their sperm and eggs in their reproductive systems. According to Christopher Cutie, a urologist by training and the current chief medical officer of the innovative bladder cancer company Taris, “With any therapy that hasn’t been tested for a lifetime of a patient, there is risk of what the body may do. The body craves homeostasis. When we expose it to insult, even if correcting one part of the body, it may manifest itself differently in another part.”

Today, biomarkers directly connected to drugs or to crucial outcomes in the human body allow physicians to identify drugs that are most likely to help a patient, and those drugs can be used to target cancerous cells only, which reduces the side effects that the patient experiences. 28% of all drugs approved by the FDA today have biomarker information, with more in the pipeline to come. But while new advances in precision medicine hold so much promise, many challenges must be overcome before precision medicine can truly transform healthcare. For example, former President Obama’s Precision Medicine Initiative aims to collect genetic and metabolomic profiles, medical records, and other health information for at least one million people, and the wealth of data will help researchers advance their understanding of diseases. “Wearables,” which are devices like watches or chest monitors worn on a person, will also aid in the collection of tremendous amounts of health data. However, fundamental questions must first be addressed, such as how to store these sensitive data, how to share the data, and how to use these data to create value for patients.

Furthermore, access to healthcare remains a global challenge. Targeted therapies are among the most sought‐after and most expensive therapies in the world, and market access and payment issues must be solved to ensure that precision medicine benefits all patients, not just a select few. Here in the United States, we have built some of the most prestigious cancer centers in the world, and the likes of the University of Texas MD Anderson Cancer Center, Memorial Sloan Kettering Cancer Center, Massachusetts General Hospital, and Mayo Clinic provide some of our best demonstrated examples of precision medicine from vision to reality. But not all regions of the world, or even regions of the United States, have complete access to these types of institutions although they each continue to enhance and broaden their reach, and I admittedly spend more time in this book analyzing the global challenges we are facing when access is not yet achieved.

The power of precision medicine also opens the door to controversy given that the most advanced techniques can be used to do far more than cure disease. Many fear that new technology will enable the creation of designer babies or the elimination of diversity. While many scientists have discussed limitations on this type of human engineering, biomedical research is global, and there is no single authority that can limit how technologies are used.

This book explores the advances that have been made in precision medicine and discusses the global implications for companies, payers, researchers, physicians, and patients who are translating precision medicine from vision to reality. The research and one‐on‐one discussions with pioneers in precision medicine, day‐to‐day caregivers, and patients and their supporters worldwide provide firsthand experience into the reality behind the hype and demonstrate the raw emotion in building an entirely new discipline that not only brings so much good to our patients in need but also introduces many challenges. We have truly hit a new frontier, and the goal here is to bring clarity to the progress we have made, to begin a discussion of the complexities and challenges we face, and to inspire hope in the future we are building by personalizing precision medicine.

Personalizing Precision Medicine

A Global Voyage from Vision to Reality

Acknowledgments

Introduction

Note

Methodology

About the Author

Part 1
The History