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Chapman & Hall/CRC
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Shein-Chung Chow, Duke University School of Medicine, USA
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Real-World Evidence
in a Patient-Centric
Digital Era
Edited by
Kelly H. Zou
Lobna A. Salem
Amrit Ray
iv
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v
Contents
Preface: Real World Evidence and Digital Innovation to Combat
Noncommunicable Diseases................................................................................vii
List of Contributors...............................................................................................xiii
About the Editors................................................................................................... xv
Disclaimer.............................................................................................................xvii
1. Real-World Evidence Generation.................................................................. 1
Joseph S. Imperato, Joseph P. Cook, Diana Morgenstern, Kim Gilchrist,
Tarek A. Hassan, Jorge Saenz, and Danute Ducinskiene
2. Applications of RWE for Regulatory Uses................................................. 27
Eleanor E. Panico, Corinne S. Pillai, Ewa Filipowska, and Kelly H. Zou
3. Patient Data Privacy, Protected Health Information, and Ethics of
Real-World Evidence...................................................................................... 51
Corinne S. Pillai, Eleanor E. Panico, Kelly H. Zou, and
Ewa Filipowska
4. Real-World Data, Big Data, and Artificial Intelligence: Recent
Development and Emerging Trends in the European Union................. 73
Kelly H. Zou
5. Patient Centricity and Precision Medicine................................................ 83
Diana Morgenstern, Mina B. Riad, Claudia Zavala, and Amrit Ray
6. Health Information Technology................................................................... 95
Joseph P. Cook, Gabriel Jipa, Claudia Zavata, and Lobna A. Salem
7. Digital Health Technologies and Innovations........................................ 137
Kelly H. Zou, Mina B. Riad, Shaantanu Donde, Joan van der Horn, and
Tarek A. Hassan
8. Economic Analysis and Outcome Assessment........................................ 153
Jean-Pascal Roussy and Kelly H. Zou
9. Partnerships and Collaborations............................................................... 165
Salman Rizvi and Urooj A. Siddiqui
v
vi
vi Contents
10. Global Perspective: China Big Data Collaboration to
Improve Patient Care.................................................................................. 173
Zhi Xia Xie, Jim Z. Li, Yvonne Huang, Olive Jin,
Wei Yu, and Kelly H. Zou
11. The Future of Patient-Centric Data-Driven Healthcare....................... 181
Kelly H. Zou, Lobna A. Salem, and Amrit Ray
Index...................................................................................................................... 187
vii
Preface
Real World Evidence and Digital Innovation
to Combat Noncommunicable Diseases
Kelly H. Zou,1 Lobna A. Salem,1 Joseph P. Cook,1
Anurita Majumdar,2 and Amrit Ray3
1
Viatris, 2GlaxoSmithKline, 3Principled Impact, LLC
Why do Real-World Evidence and Digital Technologies Matter?
The Food & Drug Administration (FDA) defines Real-World Data (RWD) as
“the data relating to patient health status and/or the delivery of healthcare rou-
tinely collected from a variety of sources” (FDA, 2022a). Healthcare facilities
routinely collect medical and patient data and electronically record them when
patients use their facilities. Such recording continues even after patients leave
the healthcare facility. The gathering of these data provides the healthcare com-
munity with a significant amount of useful medical and patient information.
Real-world evidence (RWE) “is the clinical evidence regarding the usage
and potential benefits or risks of a medical product derived from analysis of
RWD” (FDA, 2022a). As the name suggests, RWE provides scientific and clin-
ically relevant real-world information to improve medical care for patients
globally (FDA, 2018).
Digital technologies support access to quality healthcare in a number
of ways and for separable purposes. They include electronic healthcare
(“eHealth”), which covers a range of electronic technologies applied to
healthcare and relates principally to the application of computers. Mobile
health (“mHealth”) relates to the subset of eHealth that uses mobile technolo-
gies to share information over the radio waves. Artificial intelligence combines
systems that mimic human intelligence and robust datasets to propel healthcare
with new insights across early diagnosis, prevention, and treatment.
Randomized controlled trials (RCTs) often do not address the complex
intersection of many diseases and comorbid conditions, which are patient cen-
tric and require us to find alternate ways of getting evidence to support such
need gaps.
vii
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viii Preface
NonCommunicable Diseases around the World
Noncommunicable diseases (NCDs) are the leading cause of death around
the world. The devastation of a “silent killer” has increasingly become a crit-
ical global health burden. Despite the overwhelming burden of NCDs, RCTs
address disease entities and not NCDs holistically (KFF, 2019).
The problem of NCDs cannot be overstated, according to the World
Health Organization (WHO). NCDs account for 71% (41 million) of global
deaths each year, nearly 44% of which are attributable to cardiovascular
disease (CVD), including stroke and ischemic heart disease; 22% to cancer;
9% to chronic respiratory disease; and 4% to diabetes (Noncommunicable
Diseases, WHO). Around 30% of these deaths are premature, occurring
before the age of 70 years, and it is documented that every two seconds one
person between the ages of 35–75 would die prematurely from NCDs. CVD
is often categorized as a disease of wealthy, industrialized societies. Yet with
increased urbanization and changing lifestyles over the years, over 75%
of CVD-related global deaths occur in low-and middle-income countries
(LMIC), while in high-income countries (HICs), cancer is particularly preva-
lent. Europe, for example, with one-eighth of the world population, has
one-quarter of all cancer cases. Three-hundred million people have chronic
respiratory diseases worldwide, and this number is increasing. Likewise,
the number of people with diabetes has increased nearly fourfold since 1980.
With the coronavirus disease of 2019 (COVID) pandemic disproportionately
impacting people living with NCDs, many patients suffered NCD-related
comorbidities blurring the lines between what are known widely as com-
municable versus noncommunicable diseases. The pandemic has added to
the complexity of the public health challenge and the difficulty in providing
an effective solution to the growing NCDs burden. Hence, understanding
NCDs with the objective of effective control should be a key consideration in
the healthcare agendas of governments, multilateral organizations, and the
private sector (WHO, 2022; KFF, 2019; Pan American Health Organization
[PAHO], 2022).
A sobering reality of NCDs is not only their mortality burden but also
their major contribution to morbidity and disability. To make things more
complicated, NCDs associated with the greatest morbidity and disability
burden differ from those responsible for the greatest risk of mortality. For
example, mental illness and chronic pain are recognized as key drivers of
NCD-related morbidity and disability with a heavy economic burden but are
not considered major contributors to mortality.
The overall economic burden of NCDs continues to increase and it has
been estimated that a cumulative US $47 trillion in economic output will
be lost to NCDs between 2010 and 2030 (The US Government and Global
Non-Communicable Disease Efforts). In the United States (US) alone, the
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Preface ix
costs of managing chronic diseases are projected to total US $4.2 trillion
yearly by 2023. To understand how to combat the burden of NCDs, there
needs to be a thorough understanding of the underlying causes of NCDs.
Two major factors contribute to the burden of NCDs, namely disease-related
and healthcare system-related factors. Disease-related factors include envir-
onmental and behavioral risk factors, some of which are modifiable, such
as tobacco use and unhealthy diet, while others are non-modifiable, such as
CVD that is more common in men than women.
For healthcare system-related factors, the lack of patient awareness and
empowerment, along with limited access to well-trained primary care
physicians to manage NCDs, leads to an overall gap in the integration/
coordination of care across the patient journey. Despite the technology revo-
lution seen in many other sectors, technology in healthcare has not been
leveraged to provide adequate solutions to the challenges posed by NCDs.
Gaps in leveraging big data are revealing signs of the struggles to take advan-
tage of what technology and diverse data sources (drug registries, healthcare
data) can offer. Analyses of these data sources with the patient with chronic
diseases at their center has the ability to generate meaningful learnings that
could contribute significantly to address the data gap in NCDs’ burden.
Real-World Evidence in NonCommunicable Diseases
Given the negative impact of NCDs on patients’ and their families’ lives, we
recommend the use of data-driven methods (e.g., RWE) for understanding
global healthcare policymaking with a view to address the burden and
impact of NCDs broadly. We believe that RCTs tend to focus on less diverse
patient populations to compare therapies, which leaves gaps in the evidence
(FDA, 2022b). Hence, we recommend the use of RWE to complement the evi-
dence, which would help in obtaining timely data for actionable insights and
enabling informed decision making for NCD policies. There are also ways to
consider external control arms and synthetic control arms (FDA, 2019).
There are multiple ways that RWE can help address the NCD crisis,
including in relation to prevention, epidemiology, diagnosis, risk-
assessment, patient journey analysis, treatment choices, and prognosis.
Using evidence generated from multiple sources in the real world and
from multiple markets, we can map patient journeys to better understand
adherence to therapies and to measure outcomes. In NCDs, in particular, it
is common for patients to have multiple comorbid conditions and diseases
that overlap. Therefore, quantitative and qualitative information can help
evaluate patients’ diagnoses, therapies, and prognoses holistically and
comprehensively. Furthermore, a beyond NCD-only approach can also be
x
x Preface
considered with approaches that seek to address social determinants of
health, integrated care models, and innovative technologies such as tele-
medicine to improve patient outcomes and access to medicines.
Social Determinants of Health
Global evidence suggests that social determinants of health account for a
major part of the distribution of disability and mortality from NCDs (Healthy
People 2030, U.S. Department of Health and Human Services). Currently,
NCDs still cannot be effectively addressed without addressing the social
inequalities that impact NCDs and their risk factors.
The prevention of NCDs requires intersectoral partnerships and
collaborations to effectively address the conditions that give rise to NCDs,
and to implement policies that support people to minimize their exposure
to modifiable risks. Indeed, the WHO Commission on Social Determinants
of Health calls for integrated action across all sectors.
To address the issues of social inequalities in health and its impact on the
mortality and morbidity of NCDs, a coordinated approach through robust,
adequately resourced, and empowered partnerships and frameworks for
NCD prevention and control that strongly engage other relevant sectors is
essential to improve awareness, screening, diagnosis, access to medications,
and control in NCDs in the LMICs. It is vital that health systems in LMICs
ensure equitable access to preventative, acute, and chronic care to support
health equity and health rights.
Dynamics of Evolving Information for Value-Based Care
RWE offers a wealth of information to improve population health by iden-
tifying additional risks, costs, and benefits. RWE has long been used in the
post-marketing safety monitoring of new medicines, as even though clin-
ical trials provide important information on a drug’s efficacy and safety, it is
“impossible to have complete information” at the time of a new medicine’s
approval (FDA, 2022b; 2022c). In the same way, evidence about a medicine’s
reimbursement value to patients will expand and evolve over its market life
and support changes to private and public reimbursement strategies using
the best available evidence (Solle et al., 2020). Finally, technologies related to
the gathering and analyzing of data continue to evolve as well, making avail-
able new types of evidence.
Adaptive licensing, in some forms, recognizes the lack of complete infor-
mation and even embraces it. In such processes, evidence requirements and
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Preface xi
access are balanced over time to allow sensible access while further evi-
dence is developed that might allow for the license to be supplemented to
extend access (Eichler, 2012). Learning is undertaken, recognizing there is
some residual uncertainty, and further phases of data generation and ana-
lysis facilitate further learning. Supplemental indications and adjustments
to existing indications are intended to be iterated over time. “FDA will work
with its stakeholders to understand how RWE can best be used to increase the
efficiency of clinical research and answer questions that may not have been
answered in the trials that led to the drug approval, for example how a drug
works in populations that weren’t studied prior to approval” (FDA, 2018).
What is the role of a pharmaceutical company in
patient-centric care as an amplifier for the voices of
caregivers and other healthcare stakeholders?
Different teams within the pharmaceutical industry harness RWE to work
with internal and external partners, and to amplify the voices of multiple
healthcare stakeholders. For example, for medical affairs, RWE can help
enable partnerships with agencies making authorization decisions, help pro-
vide academic and physician associations with new evidence to develop
treatment guidelines and recommendations, and provide enriched con-
tent for medical education. For regulatory affairs, RWE can help prioritize
product registration processes, support regulatory authorities’ data queries,
and provide insights for label expansion. Moreover, for commercial, RWE
can provide information to support pricing and reimbursement decisions by
payors, support business strategies and business development plans, enable
commercial and due diligence assessments, make growth plans for informed
decision-making, and deliver insights for market access.
About the Book
This book on RWE and digital innovation provides an overview of concepts,
methodologies, and examples to generate patient-centric insights. Specifically,
it exemplifies NCDs as the leading cause of death and disability worldwide.
It examines an array of topics such as bioethics, ethics, regulations, and com-
pliance in big data. It highlights emerging and current trends and guidelines
for best practices. It illustrates methods through examples and use- case
studies to demonstrate impact. Finally, it provides guidance on data and
digital applications for analytics.
xii
xii Preface
References
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TF, Hirsch G. Adaptive licensing: taking the next step in the evolution of drug
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xii
Contributors
Joseph P. Cook Corinne Pillai
Shaantanu Donde Amrit Ray
Danute Ducinskiene Mina Riad
Ewa Filipowska Salman Rizvi
Kim Gilchrist Jean-Pascal Roussy
Tarek A. Hassan Jorge Enrique Saenz
Yvonne Huang Lobna A. Salem
Joseph S. Imperato, Urooj Siddiqui
Jim Z. Li Joan van der Horn
Olive Jin Zhi Xia Xie
Gabriel Jipa Wei Yu
Anurita Majumdar Claudia Zavala
Diana Morgenstern Kelly H. Zou
Eleanor Panico
xiii
xiv
xv
About the Editors
Kelly H. Zou, Ph.D., PStat® is Head of Global Medical Analytics and
Real World Evidence, Viatris. She is an elected Fellow of the American
Statistical Association and an Accredited Professional Statistician. Previously,
at Pfizer Inc, she was Vice President and Head of Medical Analytics &
Insights; Senior Director of Real-World Evidence; Group Lead of Methods
& Algorithms and Analytic Science Lead; and Senior Director of Statistics.
She was Associate Professor of Radiology at Harvard Medical School, as
well as Director of Biostatistics at its affiliated teaching hospitals. She was
Associate Director of Rates at Barclays Capital. Dr. Zou is the Vice Chair
of the Methods and Data Council of AcademyHealth and Methodologies
Working Group, Digital Medicine Society. She has published exten-
sively on both clinical and methodological topics and 160 peer-reviewed
publications. She has served on the editorial board of Significance, Statistics
in Medicine, Academic Radiology, and Radiology. She was the theme editor
of “Mathematical and Statistical Methods for Diagnoses and Therapies”
in “Philosophical Transactions of the Royal Society A.” She has authored
Statistical Evaluation of Diagnostic Performance: Topics in ROC Analysis,
Patient-Reported Outcomes: Measurement, Implementation and Interpretation,
and Statistical Topics in Health Economics and Outcomes Research published
by Chapman and Hall/CRC, Taylor & Francis. She also authored a book
chapter in Leadership and Women in Statistics.
Lobna A. Salem, MD, MBA is the Regional Chief Medical Officer for
North, Europe, Japan, Australia & New Zealand at Viatris. Previously, she
was Chief Medical Officer, Developed Markets, Upjohn, a Division of Pfizer
Inc. Lobna has more than 25 years of experience of global experience in the
biopharmaceutical industry across various leadership positions that spanned
global, regional and local roles in various parts of the world including both
high-, middle-, and low-income countries. In addition to her broad med-
ical affairs experience Dr. Salem has held different cross- functional experi-
ence in clinical development, regulatory as well as commercial roles in the
pharmaceutical industry. Before joining industry Lobna was a physician in
the National cancer institute in Egypt. Dr Salem is a key advocate and expert
in strategies to combat NCD (Non communicable disease) across the globe
and has been forging strong partnerships with different stakeholders to drive
solutions in this highly unmet public health need. As an expert in the med-
ical affairs field Lobna has been working across industry to evolve the role
of medical affairs in the pharma industry to be the strong voice that bridges
industry and healthcare ecosystem. Lobna has been recognized for driving
innovation across Research and Development in Legacy Upjohn, a Division
of Pfizer Inc. Dr Salem is a Clinical Pathologist/ Hematologist by training;
xv
